UNIVERSITY OF CALGARY. Development and Testing of Cardiovascular Quality Indicators for Rheumatoid Arthritis. Claire Ellen Hawkins Barber A THESIS

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1 UNIVERSITY OF CALGARY Development and Testing of Cardiovascular Quality Indicators for Rheumatoid Arthritis by Claire Ellen Hawkins Barber A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN COMMUNITY HEALTH SCIENCES CALGARY, ALBERTA November, 2015 Claire Ellen Hawkins Barber 2015

2 Abstract Rheumatoid arthritis (RA) is an autoimmune inflammatory arthritis with a 50% increased risk of cardiovascular disease (CVD) related deaths. Traditional CVD risk factors including smoking, hypertension and diabetes may be under-identified and/or undertreated in RA, indicating a gap in care. Quality indicators (QIs) are an important tool for quality improvement and are lacking in this area. The objectives of this dissertation were to: (1) identify existing recommendations pertaining to screening and management of CVD risk in RA; (2) to develop a set of CVD QIs for RA based on the best practices; and (3) to test the QIs in clinical practice. A systematic review of existing CVD QIs and guidelines was conducted (Study 1). All CVD recommendations from high quality guidelines and relevant quality measures were abstracted and best practices in RA were identified. In Study 2, a panel of cardiologists and rheumatologists developed a set of CVD QIs for RA based on best the practices identified. The QIs were presented to an international panel of experts through a novel online modified Delphi process where they were rated and discussed over 3 rounds. In the final study, performance on the CVD QIs was evaluated in 170 early and biologic treated RA patients. Based on the process described above, 11 CVD QIs for RA were developed and were rated as highly relevant and valid by our international panel of experts. This was the first time the online platform was used for QI development and it demonstrated many advantages. Performance on the QIs from our cohort suggests under screening and inconsistent management of CVD risk factors. Also evident, was that our patients had a high burden of obesity, hypertension and smoking, suggesting this is a clinically ii

3 meaningful gap in care. The primary area for future improvement was noted for QIs relating to communication of CVD risk and coordination of care between rheumatology and primary care. Therefore, future efforts should focus on improving coordination of CVD care as well as improving efficiency of QI measurement and reporting for timely and effective improvements in CVD care. iii

4 Preface Two of the three manuscripts in this thesis have been published and the third has been submitted for publication. The first author conducted the analyses, and wrote the manuscripts with guidance from her supervisors, thesis committee and co-authors. All authors met international authorship criteria. Permission was received for reproduction of the manuscripts in this thesis from the publishers and all co-authors. 1. Barber CE, Smith A, Esdaile JM, Barnabe C, Martin LO, Faris P, Hazlewood G, Noormohamed R, Alvarez N, Mancini GB, Lacaille D, Keeling S, Aviña-Zubieta JA, Marshall DA. Best Practices for Cardiovascular Disease Prevention in Rheumatoid Arthritis: A Systematic Review of Guideline Recommendations and Quality Indicators. Arthritis Care Res (Hoboken) 2015; 67(2): Barber CE, Marshall DA, Alvarez N, Mancini GB, Lacaille D, Keeling S, Aviña- Zubieta JA, Khodyakov D, Barnabe C, Faris P, Smith A, Noormohamed R, Hazlewood G, Martin LO, Esdaile JM. Development of Cardiovascular Quality Indicators (QIs) for Rheumatoid Arthritis: Results from an International Expert Panel Using a Novel Online Process. The Journal of Rheumatology 2015; 42(9): Please note, the version in this dissertation is a pre-copy editing, author-produced manuscript. The definitive, publisher-authenticated version is available online at jrheum.org. 3. Barber CE, Esdaile JM, Martin LO, Faris P, Barnabe C, Guo S, Lopatia E, Marshall, DA. Gaps in Addressing Cardiovascular Risk in Rheumatoid Arthritis: Assessing iv

5 Performance Using Cardiovascular Quality Indicators. A version of this manuscript has been submitted to Arthritis Care Res. v

6 Acknowledgements This work has been supported by three educational scholarships/fellowships: a Vanier Canada Graduate Scholarship, an Alberta Innovates Health Solutions (AIHS) Health Research Fellowship, and a UCB Canada- Canadian Rheumatology Association (CRA) -The Arthritis Society (TAS) - Post Graduate Rheumatology Research Fellowship. A Canadian Institutes of Health Research (CIHR) Planning Grant has also supported the second phase of this work. The Arthritis J.E. Child Chair in Rheumatology Research has provided support throughout the project. I would like to acknowledge the exceptional mentorship of my supervisors Drs. Deborah Marshall and John Esdaile without whom this would not be possible. I am also very grateful to the guidance and invaluable input from the members of my supervisory committee including Drs. Barnabe, Faris and Martin. I have also received a tremendous amount of support from my friend and fellow PhD Candidate Dr. Hazlewood. I would also like to thank the members of the division of rheumatology and our rheumatoid arthritis patients at the University of Calgary for their contributions to the Alberta Biologics Pharmacosurveillance Program (ABioPharm) and the Early Rheumatoid Arthritis (ERA) cohort. Tanja Harrison was also instrumental in assisting with access to both of these databases. In particular I would like to thank my Division Head, Dr. Mosher, for mentoring me since medical school and encouraging me to come to Calgary to pursue a career as a clinician scientist in rheumatology. vi

7 Dedication ~To the love of my life- Michael vii

8 Table of Contents Abstract... ii Preface... iv Acknowledgements... vi Dedication... vii Table of Contents... viii List of Tables... xii List of Figures and Illustrations... xiii List of Abbreviations and Nomenclature... xiv CHAPTER ONE: INTRODUCTION Overview Cardiovascular Disease in Inflammatory Conditions Epidemiology of Cardiovascular Disease in Rheumatoid Arthritis Mortality Gap in Rheumatoid Arthritis Cardiovascular Mortality in Rheumatoid Arthritis Risk of Incident Cardiovascular Events Rates of Silent Myocardial Infarctions and Sudden Cardiac Death in Rheumatoid Arthritis Timing of Cardiovascular Events in Patients with Rheumatoid Arthritis Risk of Subclinical Atherosclerosis Postulated Pathophysiology of Cardiovascular Disease in Rheumatoid Arthritis Traditional Risk Factors in Rheumatoid Arthritis Hypertension Dyslipidemia Diabetes Physical Activity Treatment of Rheumatoid Arthritis and Risk of Cardiovascular disease Corticosteroid Usage Non-Steroidal Anti-Inflammatory Drugs Disease Modifying Anti-Rheumatic Drugs (DMARDs) Biologic Agents Cardiovascular Risk Estimation in Rheumatoid Arthritis Summary of Gaps in Cardiovascular Care in Rheumatoid Arthritis Quality Indicators Quality Indicators in Rheumatic Diseases Methodological Approaches to Development and Testing of Quality Indicators Study Objectives Dissertation Outline...36 CHAPTER TWO: BEST PRACTICES FOR CARDIOVASCULAR DISEASE PREVENTION IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF GUIDELINE RECOMMENDATIONS AND QUALITY INDICATORS...40 viii

9 2.1 Abstract Introduction Materials and Methods Data Sources and Inclusion Criteria Guideline Quality Assessment Recommendation and Indicator Abstraction Results Audience, Population, Methods and Quality of the Included RA Guidelines Assessment of CVD Risk: Recommendations from RA Guidelines Lowering Disease Activity as a Means of Preventing CVD Risk in RA Other Recommendations for Lowering CVD Risk in RA: Lipids, Hypertension, Smoking, Diet, Exercise, Aspirin & Drug Safety Secondary Prevention and Other Cardiovascular Complications Multidisciplinary Care QIs Relevant to CVD Prevention in RA CVD Recommendations and Indicators from General Population Guidelines and Indicators Discussion...54 CHAPTER THREE: DEVELOPMENT OF CARDIOVASCULAR QUALITY INDICATORS FOR RHEUMATOID ARTHRITIS: RESULTS FROM AN INTERNATIONAL PANEL USING A NOVEL ONLINE PROCESS Abstract Introduction Materials and Methods Phase 1: A Systematic Review of Existing Guidelines and Indicators and Development of Background Reports Phase 2: Expert Consensus Meeting to Finalize Scope, Wording and Specifications of Candidate Indicators Phase 3: Online Modified-Delphi Panel with International Experts to Finalize the Candidate Indicators Using a Modified RAND/UCLA Appropriateness Methodology Online Panel Composition and Recruitment Panel Rating of Relevance, Validity, Feasibility, and Likelihood of Use of the QIs Analysis of panellist responses Results ExpertLens Panel Participant Characteristics and Participation Rates Cardiovascular Disease Quality Indicators Discussion...78 CHAPTER FOUR: GAPS IN ADDRESSING CARDIOVASCULAR RISK IN RHEUMATOID ARTHRITIS: ASSESSING PERFORMANCE USING CARDIOVASCULAR QUALITY INDICATORS Abstract Introduction...91 ix

10 4.3 Patients and Methods Patient Population Inclusion Criteria Data Sources and Abstraction Sample Size Calculations Clinical Variables Cardiac Risk Assessment Analysis Ethics Approval Results Baseline Characteristics Cardiovascular Risk Profile Quality Indicator Reporting Inter-rater Reliability of QIs Discussion CHAPTER FIVE: DISCUSSION Cardiovascular Care in Rheumatoid Arthritis: A Quality Gap Summary of Dissertation Work and Updates in the Field Measurement of Cardiovascular Quality in RA: A Broader Context Strengths, Limitations & Lessons Future Directions: How Do We Close The Gap Tools to Implement QIs in Clinical Practice Electronic Medical Records as a Quality Tool Audit Tools Registries For Quality Improvement: RISE Strategies to Correct Performance Deficits Pay for Performance Plan-Do-Study-Act Knowledge Translation Local Changes to Cardiovascular Screening in Rheumatology Conclusions REFERENCES APPENDIX A: APPENDIX MATERIALS FROM STUDY A.1. Methods of Included Rheumatoid Arthritis Guidelines A.2. RA QI Characteristics A.3. AGREE II Domain Scores: Quality of Included Rheumatoid Arthritis Guidelines A.4. Abstracted Recommendations on Lipids, Hypertension, Smoking, Exercise, Diet and Weight Control, Aspirin Use, and Medication Safety A.5. Medline Search Strategy A.6. Grey Literature Search Strategy APPENDIX B: APPENDIX MATERIALS FROM STUDY x

11 B.1. Example of the ExpertLens Platform Demonstrating Panellists Display of an Indicator B.2. Quality Indicator Specifications B.2.1. Quality Indicator #1: Communication of Increased Cardiovascular Risk in Rheumatoid Arthritis B.2.2. Quality Indicator #2: Cardiovascular Risk Assessment B.2.3. Quality Indicator #3: Smoking Status and Cessation Counselling B.2.4. Quality Indicator #4: Screening for Hypertension B.2.5. Quality Indicator #5: Communication to Primary Care Physician About a Documented High Blood Pressure B.2.6. Quality Indicator #6: Measurement of a Lipid Profile B.2.7. Quality Indicator #7: Screening for Diabetes B.2.8. Quality Indicator #8: Exercise B.2.9. Quality Indicator #9: BMI Screening and Lifestyle Counselling B Quality Indicator #10: Minimizing Corticosteroid Usage B Quality Indicator #11: Communication About Risks/Benefits of Anti- Inflammatories in Patients at High Risk of Cardiovascular Events APPENDIX C: MATERIALS FROM STUDY C.1. Chart Abstraction Form for Retrospective Review of Quality Indicators APPENDIX D: TOOLS FOR CARDIOVASCULAR QUALITY IMPROVEMENT D.1. Prospective Cardiovascular Disease Screening Tool D.2. Simplified Cardiovascular Disease Quality Indicator Audit Tool APPENDIX E: CO-AUTHOR & PUBLISHER PERMISSIONS xi

12 List of Tables Table 1.1 Comparison of cardiovascular risk assessment calculators Table 1.2 Example of a quality indicator Table 1.3 Examples of different types of quality indicators: process, structure, and outcome Table 2.1 Topics abstracted from rheumatoid arthritis guidelines and quality indicators relevant to cardiovascular care in rheumatoid arthritis Table 2.2 Rheumatoid arthritis-specific cardiovascular disease recommendations from guidelines Table 2.3 Rheumatoid arthritis quality indicators relevant to cardiovascular disease prevention Table 2.4 General population cardiovascular guidelines recommendations addressing the risk in persons with rheumatoid arthritis Table 3.1 Description of criterion used to select quality indicators Table 3.2 Self-reported ExpertLens participant characteristics Table 3.3 Final validity, feasibility and relevance ratings from the ExpertLens panel on the 11 cardiovascular quality indicators Table 3.4 Final set of eleven cardiovascular disease quality indicators for rheumatoid arthritis patients Table 4.1 Baseline clinical characteristics for patients in the biologics and early rheumatoid arthritis (ERA) cohorts included in the quality indicator review Table 4.2 Cardiovascular risk profile & treatment Table 4.3 Adherence to 11 cardiovascular quality indicators in 2 cohorts* Table 4.4 Assessment of inter-rater reliability for each cardiovascular quality indicator in 48 randomly selected charts xii

13 List of Figures and Illustrations Figure 2.1 Study selections Figure 3.1 Methods for developing the quality indicator set for cardiovascular care in rheumatoid arthritis xiii

14 List of Abbreviations and Nomenclature Abbreviation AACE ABioPharm ACE ACR AGES AGREE AHA Anti-CCP ARB ASA ASCVD BMI BP BSR CAC CBC CCS CD CI COMORA CORRONA COX CRP CRA CVD DAS28 DMARD EAS ERA ESC ESR EULAR EUMUSC FP FRS HAQ HDL HR IL IPRAS IPR IQR Definition American Association of Clinical Endocrinologists Alberta Biologic Pharmacosurveillance Program Angiotensin Converting Enzyme American College of Rheumatology Advanced Glycation End Products Appraisal of Guidelines Research and Evaluation American Heart Association Anti-Cyclic Citrullinated Peptide Angiotensin II Receptor Blocker American Stroke Association Atherosclerotic Cardiovascular Disease Body Mass Index Blood Pressure British Society of Rheumatology Coronary Artery Calcium Complete Blood Count Canadian Cardiovascular Society Cluster of Differentiation Confidence Interval Comorbidities in Rheumatoid Arthritis Consortium of Rheumatology Researchers of North America Cyclooxygenase C-Reactive Protein Canadian Rheumatology Association Cardiovascular Disease Disease Activity Score-28 Disease Modifying Anti-rheumatic Drug European Atherosclerosis Society Early Rheumatoid Arthritis European Society of Cardiology Erythrocyte Sedimentation Rate European League Against Rheumatism European Musculoskeletal Conditions Surveillance and Information Network Family Practitioner Framingham Risk Score Health Assessment Questionnaire High Density Lipoprotein Hazard Ratio Interleukin Interpercentile Range Adjusted for Symmetry Interpercentile Range Interquartile Range xiv

15 IRR LDL MeSH MI NICE NR NSAIDs NYHA OR PDSA QIs QRISK-2 RA RACGP RCT RF RISE RR RRS SD SCORE SER SIGN SLE SMR TC TNF-α UCLA UK Incidence Rate Ratio Low Density Lipoprotein Medical Subject Heading Myocardial Infarction National Institute for Health and Care Excellence Not Reported Non-Steroidal Anti-Inflammatories New York Heart Association Odds Ratio Plan-Do-Study-Act Quality Indicators QRISK-2 Rheumatoid Arthritis Royal Australian College of General Practitioners Randomized Controlled Trial Rheumatoid Factor Rheumatology Informatics System for Effectiveness Relative Risk Reynolds s Risk Score Standard Deviation Systematic Coronary Risk Evaluation Spanish Society of Rheumatology Scottish Intercollegiate Guidelines Network Systemic Lupus Erythematosus Standardized Mortality Ratio Total Cholesterol Tumour Necrosis Factor Alpha University of California, Los Angeles United Kingdom xv

16 Chapter One: Introduction 1

17 1.1 Overview In this introductory chapter, the risk of cardiovascular disease (CVD) in inflammatory conditions is reviewed in section 1.2. The following sections ( ), focus in detail on the epidemiology, pathophysiology, and risk assessment of CVD in rheumatoid arthritis (RA). This information provides a necessary background to understanding the importance and rationale for this dissertation. As the overall aim of the work is to describe the development and testing of the first set of cardiovascular quality indicators (QIs) for RA, section 1.5 provides a review of QIs in rheumatology and an introduction to the methodology for QI development and testing. Finally, the objectives of the dissertation are provided in section 1.6 and an outline of the dissertation is provided in section Cardiovascular Disease in Inflammatory Conditions While this dissertation focuses on RA, it should be noted that a number of inflammatory conditions might also carry an increased risk of CVD. However, the burden of CVD in many other inflammatory conditions has often been less well described than in RA, as discussed below. For example, Jamintski et al. (1) conducted a systematic review of CVD morbidity and mortality in patients with psoriatic arthritis but were unable to metaanalyze the data given differences in study design and clinical endpoints. They found four studies including 4810 patients and reported that psoriatic arthritis appeared to be associated with an increased risk of CVD morbidity (1). The study also highlighted elevated rates of hypertension, diabetes and dyslipidemia (1). There have been two recent systematic reviews on the relationship between CVD and the inflammatory skin condition, psoriasis (2, 3). One of these studies also chose not 2

18 to meta-analyze the data due to heterogeneity, but also concluded that there appeared to be relationship between CVD and psoriasis but the magnitude of risk was not reported (2). The second study meta-analyzed seven studies and found a relative risk, RR, of 1.2 (95% confidence interval, CI, 1.1, 1.3) for a combined endpoint of myocardial infarction (MI) or stroke (3). The risk of CVD in another type of inflammatory arthritis, ankylosing spondylitis, has been investigated in a meta-analysis of three longitudinal studies (2266 patients and controls) and this work demonstrates a possible increased risk of MI for patients with ankylosing spondylitis, however, this did not meet statistical significance (RR 1.88, 95% CI 0.83, 4.28) (4). Systemic lupus erythematosus (SLE) is an autoimmune condition affecting many organ systems. While RA affects approximately 1% of the population, lupus is less common, approximately 1 case per 1000 population and therefore there are fewer epidemiologic studies addressing CVD risk (5). Nevertheless, a bimodal mortality has been described in SLE due to high disease activity early after diagnosis, whereas the later peak is attributed to increased CVD risk (6). It has also long been documented that patients with lupus have a substantially increased CVD event rate of between 2 to >10 fold higher than seen in the general population (as reviewed by Symmons et al. (5)). More recently, evidence is emerging that patients with inflammatory bowel disease may be at increased risk of CVD (7). A systematic review of 6 studies has demonstrated a 19% increase in ischemic heart disease in patients with inflammatory bowel disease (odds ratio, OR, 1.19, 95% CI 1.08, 1.31) (8). 3

19 Of all of the inflammatory conditions, the increased risk of CVD has been probably best studied in RA as reviewed in the following section. 1.3 Epidemiology of Cardiovascular Disease in Rheumatoid Arthritis RA is the most common form of inflammatory arthritis affecting between % of the population (9-13). It is a leading cause of work disability (14) and is associated with increased mortality (15-17). In addition to the effects on the joints, patients with RA have a substantially increased burden for CVD, including MI and stroke (5) Mortality Gap in Rheumatoid Arthritis In 1999, Gabriel et al. (15) examined the trends in survival in patients with RA over four decades in Rochester, Minnesota and concluded that the rates of survival for RA patients had not changed despite the improvements in longevity seen in the general population over the same period of time. More recently, in the same population, Gonzalez et al. (17) has again demonstrated a mortality gap in RA that has remained constant between 1965 and 2005 (2.4 for female and 2.5 for male RA patients per 100 personyears compared to 0.2 for female and 0.3 for male members of the general population per 100 person-years). These findings have led to the concept of a widening mortality gap in RA, whereby the improvements in mortality rates due to advances in health in the general population have not been demonstrated in RA to date (17). Similar observations of a widened mortality gap in RA have been made in other RA populations in more recent cohorts (18-23). It is estimated that this mortality gap translates into a reduced life expectancy in RA compared to the general population of between years (24). 4

20 Cardiovascular Mortality in Rheumatoid Arthritis Much of the mortality gap in RA has been attributed to an increased risk of cardiovascular death (5). This has been clearly demonstrated over the last 20 years and is best summarized in a meta-analysis by Aviña-Zubieta et al. (25) of 24 observational studies capturing 111,759 patients and 22,927 cardiovascular events which found a 50% increased risk of cardiovascular death in RA patients (meta-standardized mortality ratio 1 (SMR) of 1.50, 95% CI 1.39, 1.61). In this study, increased mortality rates in RA were observed for both stroke and ischemic heart disease (meta-smr for stroke of 1.52, 95% CI 1.40, 1.67 and meta-smr for ischemic heart disease of 1.59, 95% CI 1.46, 1.73) (25). The relative risk of cardiovascular mortality was also similar between women and men (meta-smr 1.58, 95% CI 1.35, 1.84 versus meta-smr 1.45, 95% CI 1.11, 1.90 respectively) (25). Symmons et al. (5) has noted that while the relative risk of CVD mortality in patients with RA is higher in women and in younger patients, the patients with the highest risk are men and older patients with RA Risk of Incident Cardiovascular Events The elevated risk of incident cardiovascular events in RA patients is also clearly documented by another highly cited meta-analysis by Aviña-Zubieta et al. (26). In this study, the risk of incident cardiovascular events was evaluated in 16 studies in 41,490 patients with RA. RA patients had a 48% higher risk of incident CVD compared to the general population (pooled RR, 1.48, 95% CI 1.36, 1.62). When examined separately, 1 A meta-standardized mortality ratio (meta-smr). A standardized mortality ratio reports the following ratio: the number of observed deaths in a population to the number of expected deaths in the reference population. Meta-SMR summarizes the results from more than one study. 5

21 patients with RA had a 68% increased risk of MI (95% CI 1.40, 2.03) and a 41% increased risk of stroke, (95% CI 1.14, 1.74). As with their study on cardiovascular mortality (25), there was no substantial effect seen on their results when stratified by sex (26). Many have likened the increased risk of CVD observed in RA to the risk of CVD in diabetes (24, 27, 28). Indeed, RA is often considered a diabetes equivalent and some advocate for managing CVD risk in RA as aggressively as in diabetics, with more stringent target levels for blood pressure control, lipid treatment and even preventive therapy with aspirin (27, 28). Although the concept that RA carries equivalent CVD risk to diabetes is still controversial, it is supported by a prospective cohort study by Peters et al. (29) from the Netherlands, which examined 353 outpatients with RA and compared them to 1852 controls from the general population, of whom 155 had type II diabetes. Both cohorts were followed over 3 years and the incidence of CVD in patients with RA was more than double that in the general population (9% versus 4.3%). After age and sex adjustment the hazard ratio (HR) for CVD in RA patients was similar to that of diabetics (HR 2.16 in RA patients, 95% CI 1.28, 3.63 versus HR 2.04 in patients with diabetes, 95% CI 1.12, 3.67). One criticism of the Peters study was that the RA cohort and the general population control cohort were from disparate time periods and also that the study was underpowered (30). In order to address these issues, a Danish National population-based study examined the rate of MIs in patients with incident RA compared to those with incident diabetes and found that RA and diabetes confer a similar risk of MI 6

22 (incidence rate ratio, IRR 2, for RA of 1.7, 95% CI 1.5, 1.9 and for diabetes 1.7, 95% CI 1.6, 1.8, p=0.64) (30) Rates of Silent Myocardial Infarctions and Sudden Cardiac Death in Rheumatoid Arthritis In a second similarity with diabetes, a few studies have reported elevated rates of clinically silent MI and an increased risk of sudden cardiac death in RA. In a Rochester, Minnesota, Maradit-Kremers et al. (31) examined the rates of unrecognized or silent MIs defined according to recognized guidelines (i.e., presence of characteristic electrocardiogram findings in a patient with no previous history of MI) in an RA incidence cohort compared to age and sex-matched controls. Importantly, this study demonstrates that the risk of unrecognized or silent MI was over 5 times more prevalent in RA patients before their diagnosis of RA compared to the non-ra controls (OR 5.5, 95% CI 1.22, 24.81) and an elevated risk persisted over time. Conversely, the rates of angina were lower both before the diagnosis of RA and following diagnosis (31). The results of an Australian study on re-perfusion therapy in RA patients support the notion that RA patients are more likely to have clinically silent MIs (32), which may explain in part worse outcomes and higher rates of death observed in this population. This retrospective study revealed that RA patients were significantly less likely to receive re-perfusion therapy (including thrombolysis or percutaneous coronary intervention) compared to controls (16% versus 37%, respectively; OR, 0.27; 95% CI 0.10, 0.64) (32). A delay in presentation was the most common reason for failure to provide acute 2 The incidence rate ratio (IRR) is a ratio describing the rate at which new cases occur during a time period in those exposed versus unexposed to a condition (e.g., RA or diabetes as the exposure). 7

23 reperfusion. Almost 40% of RA patients did not experience chest pain compared to 22% of controls (OR 0.5, 05% CI 0.3, 0.9), likely contributing to the delay in presentation (32). The disparity in intervention rates with re-perfusion therapy following acute MI in RA patients was also confirmed in a larger Australian population-based study (32). Rates of sudden cardiac death may also be elevated in RA. In the RA cohort described above from Rochester, the cumulative incidence of sudden cardiac death at 30 years was 6.7% in the RA cohort compared to 3.8% in the control population (after adjusting for competing causes, p=0.052) (31). This corresponded to more than a doubling of the risk of sudden cardiac death in the RA population (HR 2.36, 95% 1.30, 4.27) (31). The high rates of CVD events and high risk of silent ischemia and sudden cardiac death seen in RA mean it is critical to develop strategies for identification of cardiac risk factors and for risk prevention in RA Timing of Cardiovascular Events in Patients with Rheumatoid Arthritis The timing of CVD events in RA is important in establishing the potential etiology of CVD risk in RA, understanding the impact of potential risk factors on the risk of CVD events as well as determining the best timing for intervention to mitigate CVD risk. Unfortunately, the timing of CVD events in RA and their relation to disease duration is a matter of controversy as reviewed below. In both of the meta-analyses reviewed above by Aviña-Zubieta et al. (25, 26), the risk of cardiovascular death or incident cardiac disease appeared higher in prevalent cohorts than inception cohorts, which suggests that the duration of disease may impact the risk of events. The authors postulate that a latent period may be present between the 8

24 RA diagnosis and when the increased risk of cardiovascular death is observed (25). This hypothesis is supported by other studies including a population-based RA cohort study from the Netherlands, where excess mortality rates in RA were observed after 10 years of follow-up and were predominantly due to CVD (18). In contrast, a few studies have suggested that the risk of cardiovascular events may begin shortly after the diagnosis of RA or even predate the diagnosis. In the population-based study from Rochester, by Maradit-Kremers et al. (31) described above, there was a statistically significant increased risk of cardiovascular events in the 2-years prior to the diagnosis of RA (using the 1987 American College of Rheumatology, ACR, criteria) compared to a non-ra control population (8 events versus 0, p<0.001). A population-based health survey in Norway of 786 patients with RA also found that incident RA but not osteoarthritis was associated with a previous history of CVD (33). In this study for each unit increase in Framingham risk score (FRS) there was a 6% greater chance of developing RA (OR 1.06, 95% CI 1.05, 1.08, P <0.001) (33). In contrast, a Swedish RA cohort did not find an increase in MIs prior to the diagnosis of RA (34); however, they did find a trend to an increase in events in the first year following RA diagnosis compared to population controls (RR for MI of 1.4, 95% CI 0.9, 2.1) (35). This topic has recently been reviewed by Kerola et al. (36). This paper highlights that understanding the timing of CVD events in RA may help us elucidate some of the underlying causes and illustrates two competing theories. In the first, risk factors for CVD accumulate over time leading to increased risk. Such risk factors may include the prolonged use of high-risk medications such as glucocorticoids and non-steroidal antiinflammatory drugs (NSAIDs) or represent the prolonged effects of inflammation from 9

25 RA on the vascular endothelium (36). The second theory is that CVD and RA may share some common risk factors such as smoking, diet or even genetic predisposition (36). It is likely that there is some contribution from both theories. Also highlighted in the review by Kerola et al. (36) is a reminder that changing definitions for the classification of RA may also contribute to some of the differences seen when describing the timing of CVD events in relation to the diagnosis of RA as the 2010 ACR criteria (37) classify patients with earlier disease compared to the 1987 ACR criteria (38) Risk of Subclinical Atherosclerosis Not only is there evidence of clinical CVD risk in RA, there is also evidence of subclinical disease including evidence of premature atherosclerosis and increased arterial stiffness (39-42). There are a variety of validated modalities for investigating subclinical atherosclerosis including ultrasound or high resolution computed tomography investigation of plaque, intimal-medial distance as a measure of arterial wall hypertrophy and flow-mediated dilatation as a marker of imbalance between vasodilatory and vasoconstricting mediators. Given the rates of silent ischemia and sudden cardiac death discussed above, these modes of investigating subclinical disease may be relevant to understanding potential strategies for better cardiovascular risk stratification in RA, which is reviewed further in the discussion of this dissertation (Chapter 5) Postulated Pathophysiology of Cardiovascular Disease in Rheumatoid Arthritis Atherosclerosis is an inflammatory condition (43). It is believed that the additive systemic inflammation from a condition such as RA, may impact risk of premature 10

26 atherosclerosis, plaque instability, rupture and hence cardiovascular events as parallel mechanisms may drive joint inflammation and cardiovascular disease in RA (44, 45). This section summarizes the classic steps of atherogenesis, which have been recently reviewed by Skeoch and Bruce (45) and highlights the role RA may play: 1. Endothelial activation is the earliest stage of atherosclerosis. During this stage cellular adhesion molecules are increased and help facilitate passage of inflammatory cells and lipid molecules into the sub-epithelium. A variety of traditional risk factors have been associated with endothelial activation, including smoking and hypertension (45). RA is also associated with increased endothelial activation as evidenced by small studies that demonstrate elevations in endothelial markers (46, 47). Cytokines which are important to the pathogenesis of RA and atherosclerosis, including Tumor Necrosis Factor-alpha (TNF-α), and interleukins (ILs) including IL-6 and IL-1β, likely play an important role as mediators of endothelial activation and dysfunction (45, 48). 2. Plaque development: once the inflammatory cells (e.g., monocytes) and lipid molecules have entered the sub-endothelial layer, they become involved in the initiation of plaque development. The low-density lipoproteins (LDL) become oxidized and the monocytes differentiate into macrophages, which become foam cells after taking up the oxidized LDL (45). Here too, pro-inflammatory cytokines including TNF-α play a role by stimulating superoxide molecule formation by endothelial cells and monocytes which leads to the formation of oxidized LDL (48). Advanced glycation end products (AGEs) develop through glycation and oxidation of lipids and proteins in the presence of increased oxidative stress (48). 11

27 AGEs act as a ligand for their receptor, which is expressed on the cell surface of many cells including neutrophils, and macrophages (48). The engagement of AGEs to their ligand activates intracellular signaling processes, which up-regulate and maintain endothelial activation and ongoing inflammation (48). Indeed the presence of AGEs has been investigated as a marker of CVD in RA (49). The inflammatory signaling mediated through these processes contributes to smooth muscle proliferation leading to narrowing of the intimal-medial layer and plaque formation (45). 3. Amplification of the inflammatory response and neovascularization: Additional inflammatory cells are recruited to plaque and in a positive feedback loop enhances further uptake of oxidized LDL and contributes to further foam cell development (45). Neovascularization occurs with plaque growth; however, the new vessels are prone to bleeding causing intra-plaque hemorrhage, which further contributes to inflammatory responses (45). 4. Plaque destabilization and rupture: Over time plaques mature and complex plaques can rupture. When this occurs, pro-thrombotic particles are released into the lumen of the vessel leading to thrombosis and occlusion of the vessel. It is hypothesized that thinning of the fibrous cap of plaques may be caused by inflammatory cells via secretion of enzymes called matrix metalloproteinases, which are also implicated in RA pathogenesis (45). 1.4 Traditional Risk Factors in Rheumatoid Arthritis The role of traditional risk factors for CVD including smoking, hypertension and dyslipidemia has been extensively examined in RA. The following section reviews 12

28 the epidemiology of traditional risk factors in RA and their relationship to the cardiovascular risk in RA. Traditional risk factors are prime targets for risk reduction strategies and this section also describes existing evidence from a number of studies that suggests under-screening and treatment of these traditional risk factors in RA Smoking Cigarette smoking is a major modifiable cardiovascular risk factor in the general population (50). Smoking is also associated with increased risk for RA (51-53) and current smokers may have more severe RA disease activity compared to former or never smokers (54). A history of smoking is also more prevalent in patients with RA than the general population, as revealed in a meta-analysis of four case control studies (three incident RA cohorts (31, 53, 55) and one prevalent RA cohort (56), OR 1.56, 95% CI 1.35, 1.80) (57). Absolute smoking rates in RA patients vary by RA population as shown in the recent international Comorbidities in RA (COMORA) study (58). In this study, 13.2% of the 4586 RA patients in 17 participating countries were current smokers, but this varied by country and was as low as 0.9% in Morocco and as high as 48% in Austria (58). A small prospective study of subclinical atherosclerotic plaque development in 35 patients compared to matched controls demonstrates that smoking may be one of three important risk factors for the development of new plaque, along with age and duration of corticosteroid use, after controlling for other RA disease factors (i.e., markers of inflammation, disease duration, functional class and other RA treatments) (59). 13

29 A recent meta-analysis also evaluated the relationship between smoking and cardiovascular events in RA (60). Based on four relevant studies, there was a 50% increased risk of cardiovascular morbidity (including MI, angina, heart failure, stroke and peripheral arterial disease) in smokers compared to non-smoking RA patients (RR 1.50, 95% CI 1.15, 1.84) (60). Cardiovascular primary prevention guidelines universally recommend screening for smoking and offering smoking cessation strategies (61-63). However, there has been little study of the uptake of promotion of smoking cessation in rheumatology settings including on the rates of screening for smoking status. In one study evaluating cardiovascular screening practices of rheumatologists compared to primary care physicians for patients with RA, rheumatologists identified risk factors including smoking, far less frequently than their primary care provider counterparts (64), suggesting a possible gap in care Hypertension Although the prevalence of hypertension may be similar in RA populations compared to the general population (57, 65), hypertension is nonetheless a very common comorbidity in patients with RA. In the COMORA study (58) 40.4% of patients had hypertension (95% CI 0.39, 0.42) (58). However, hypertension may be under-diagnosed and undertreated in the RA outpatient rheumatology setting. This is evidenced by two recent studies that conducted formal, prospective and targeted assessments for CVD risk factors in RA patients and found that between 9 to 18% of RA patients were hypertensive and had no previous diagnosis of hypertension indicating a gap in diagnosis and treatment for this risk factor (58, 66). 14

30 There is an important and well defined relationship between hypertension and increased risk of cardiovascular events in the general population (67). Not surprisingly, hypertension is also a risk factor for cardiovascular events in RA. In a meta-analysis of eight studies, the relative risk of MI was 84% higher in hypertensive than in nonhypertensive RA patients (95% CI 1.38, 2.46) (60) Dyslipidemia Dyslipidemia is another strong modifiable CVD risk factor (68) and measurement of a fasting lipid profile is part of most formal cardiovascular risk assessments (Table 1.1). However, the relationship between lipid levels and CVD in RA is not a straightforward association of hyperlipidemia leading to CVD. In an observation that appears contradictory to the clearly higher risk for CVD in RA, lipid levels may be lower in patients with RA compared to the general population (31, 69). This phenomenon has been called the lipid paradox (44). However, despite lower lipid levels, there is often evidence of an unfavourable atherogenic index (ratio of total cholesterol/high-density lipoprotein, TC/HDL) in RA patients, where cardio-protective levels of HDL are low in relation to TC levels and this lead to an unfavourable index (70). Furthermore, there is evidence of a shift to an inflammatory form of HDL that contributes to LDL oxidation and foam cell formation described above, which may also contribute to the elevated risk despite the lower total levels of cholesterol (44). Unsurprisingly, a meta-analysis of three studies did not find that the prevalence of hypercholesterolemia varied between RA patients and controls (OR 0.84, 95% CI 0.67, 1.04) (57), although, the rates of unfavourable atherogenic indices were not examined. 15

31 There is evidence that hypercholesterolemia, when it does occur in RA, is associated with a 73% increased incidence of cardiovascular morbidity (including MI, angina, stroke and peripheral vascular disease, RR % CI 1.03, 2.44), as assessed in a meta-analysis of six studies (60). This may be an important observation, as the recent international COMORA study (58) found approximately one-third of RA patients had hypercholesterolemia (32%, 95% CI 0.30, 0.33). Furthermore, like many of the cardiovascular risk factors described above, dyslipidemia may also be under-diagnosed (58, 66) and under-treated (71) in patients with RA. Even in RA patients with additional risk factors such as diabetes or previous pre-existing CVD, there is evidence of underscreening for dyslipidemia. This has been demonstrated in 16,893 Medicare beneficiaries in the United States with RA who had major risk factors for CVD (72). Only 63% of RA patients with indications for lipid screening were tested and the rates were significantly lower than observed in the general population (72) Diabetes As mentioned above, diabetics have a much greater risk of CVD compared to the general population and diabetes is considered a coronary heart disease equivalent in that the risk of CVD events is of similar magnitude to patients with a prior CVD event having a recurrent event (73). Diabetes may in fact be more common in patients with RA (57, 65, 74). This is best illustrated in the results of a meta-analysis of seven studies demonstrating an OR of 1.74 (95% CI 1.22, 2.50) for diabetes in RA compared to general population or osteoarthritis controls (57). In the COMORA study (58) 14% of RA patients had diabetes (range 6 to 21%, no 95% CI reported). Furthermore, the risk of CVD in patients who have both RA and diabetes appears to be additive (30). The latter 16

32 was shown in a population-based study from the Netherlands where the risk of MI was examined in patients with RA, diabetes, or RA and diabetes and compared to general population (30). In total 556 patients had both RA and diabetes and the IRR for MI in this group was 2.6 (95% CI 1.7, 3.9) (30), which was roughly equal to the additive IRRs for MI in the patients who only had one comorbidity (diabetes or RA) Obesity Obesity is prevalent in patients with RA (75). Obesity may even be a risk factor for the development of RA (76) and in early RA, obesity has been associated with RA persistency (77). Obesity is also associated with poor RA patient outcomes (78). Patients with obesity and RA also have an increased number of traditional cardiac risk factors such as insulin resistance, diabetes and hypertension (79-81). In a second paradox observed in RA (82), it is well documented that low body mass index (BMI) is associated not only with higher all cause mortality in RA (81, 83), but also higher cardiovascular mortality (84, 85). The greatest mortality risk may be for patients with a low BMI who were previously obese (83). This may be due to rheumatoid cachexia; a wasting state related to prolonged, uncontrolled inflammation (85). Other hypothesized contributors include poor functional status, poor nutrition and/or underlying malignancy (83). Recently however, there have been increasing reports that obesity in RA not only contributes to CVD risk factors such as hypertension, but that it is also independently associated with CVD including angina, MI and need for coronary revascularization (79, 81). This was recently summarized in a meta-analysis of four studies that demonstrated 17

33 obesity was associated with a 16% increase in the incidence of cardiovascular events in RA patients (95% CI 1.03, 1.29) (60) Physical Activity Low physical activity levels are closely linked to obesity and other cardiovascular risk factors in the general population and patients with RA have been shown to have lower physical activity levels (86). Physical activity is safe in patients with RA and improves function with no evidence of joint damage (87). Aerobic activity is also associated with reduction of cardiac risk factors, improved cardiorespiratory fitness and endothelial function in patients with RA (88, 89). There are very few studies that have examined the relationship between physical activity in RA and risk of CVD disease and the recent meta-analysis of two of these studies has not shown a clear benefit to date on CVD event rates (RR 1.00, 95% CI 0.71, 1.29) (60) Treatment of Rheumatoid Arthritis and Risk of Cardiovascular disease Once a diagnosis of RA is established, then treatment is offered. The following section discusses the cardiovascular impact of treatments for RA including: corticosteroids and NSAIDs (which are used primarily for symptomatic relief), Disease Modifying Anti-rheumatic Drugs (DMARDs) such as methotrexate (which is the cornerstone of treatment in RA) and biologic therapies (which are used when traditional DMARD therapies have failed) (90). 18

34 Corticosteroid Usage Corticosteroid use in RA is associated with metabolic derangements including decreased insulin sensitivity (91) and increased cholesterol (92). Corticosteroid use is also associated with increased cardiovascular events in patients with RA (93-96). In a study of 779 patients with RA, a dose-dependent effect of corticosteroid exposure on death from CVD was observed (HR of 1.08 per mg of prednisone per day, 95% CI 1.05, 1.12) that was independent of other risk factors even after investigations for confounding by indication were conducted (95). Further evidence to support the cardiovascular risk associated with corticosteroids was shown in a population-based study of 8384 RA cases, where current steroid use was associated with a 68% increased risk of MI and increasing dose and higher cumulative dose of steroids were associated with increased risk (93). Minimization of corticosteroid use should be considered a key facet of CVD prevention in RA, as there is no known safe dose of steroids Non-Steroidal Anti-Inflammatory Drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used as adjunctive therapy in patients with RA to treat residual joint pain. There are two main categories of NSAIDs, ones that selectively block cyclooxygenase-2 (COX-2) and ones that block COX-1 and/or COX-2 (97). In 2004, rofecoxib, a COX-2, inhibitor was withdrawn from the market due to concerns about increased CVD event rates (97, 98). Since that time there has been controversy as to whether other NSAIDs also carry increased CVD risk. A meta-analysis of studies of four randomized controlled trials (RCTs) on celecoxib, also a COX-2 inhibitor, has also shown elevated MI event rates 19

35 (OR 2.26, 95% CI 1.0, 5.1), but other CVD events and composite event rates were not increased (99). A larger meta-analysis of patient-level data from celecoxib RCTs confirmed an increase rate of adverse CVD events and found that risk was dependent on dose and baseline CVD risk factors (100). Other research has focused on comparing CVD event rates between agents to determine if COX-2 inhibitors carry a higher risk. The Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program evaluated pooled data from three trials in patients with osteoarthritis or RA evaluating etoricoxib (a COX-2 inhibitor) or diclofenac (a traditional NSAID ) (101). The trial was designed as a non-inferiority trial to determine if CVD event rates were similar with use of these agents, which had different mechanisms of action. The HR for thrombotic CVD was similar between the two groups (HR of 0.95, 95% CI 0.81, 1.11); however, no placebo group was included (101). A large prospective trial: The Standard of care versus Celecoxib Outcome Trial (SCOT), is ongoing with the objective to compare the CVD safety of celecoxib to other traditional NSAIDs in patients with osteoarthritis or RA in Europe (102). In contrast, a large network meta-analysis of 31 trials and more than 115,000 patient-years of follow-up suggested that there was little evidence demonstrating the cardiovascular safety of any of the investigated anti-inflammatory medications, although some appeared to have higher risks than others (103). A recent meta-analysis examined the risk of medications, including NSAIDs, on cardiovascular event rates in patients with RA, psoriasis and psoriatic arthritis (104). In RA, NSAIDs increased the risk of a composite CVD endpoint (including MI, heart failure, stroke and/or major cardiac events, RR 1.18, 95% CI 1.01, 1.38; p=0.004). The 20

36 authors note this was predominantly driven by COX-2 inhibitors, rather than other nonselective NSAIDs, although the number of studies was limited and included rofecoxib, which been withdrawn from the market (104). In RA patients with pre-existing CVD morbidity there is even less information as to the safety of NSAID medications as evidenced by a Cochrane review that did not find any studies to include (105) Disease Modifying Anti-Rheumatic Drugs (DMARDs) DMARDs including methotrexate, hydroxychloroquine, sulfasalazine and leflunomide are recommended first-line treatments for RA alone or in combination (90, 106). There is evidence that DMARDs may be cardio-protective. The best evidence for a cardio-protective effect exists for methotrexate ( ). This is summarized in a metaanalysis of 10 studies, nine of which were in RA populations, which demonstrated a 21% lower risk for CVD in patients treated with methotrexate (95% CI 0.71, 0.87) (109). The mechanism of CVD protection with methotrexate is likely complex, but limited evidence suggests improvement in lipid profiles and improved macrophage cholesterol handling with reduced foam cell formation may play a role (110). Currently, a large randomized controlled trial is ongoing in the United States to investigate the use of low-dose methotrexate in preventing cardiovascular events in patients with type 2 diabetes who have pre-existing CVD (111). Limited and conflicting information is available on the effect of leflunomide on CVD risk. Evidence that it may be associated with an increased CVD risk arises from a Greek cohort of 325 patients with RA of whom 14 developed CVD at a median of 10 years of follow-up. Leflunomide was independently associated with risk of CVD (HR per year of leflunomide treatment 1.02, 95% CI 1.00, 1.05), although the HR was lower than 21

37 other identified risk factors including baseline history of hypertension, age, and elevated C-reactive protein (CRP) as measured after one year (112). Interestingly, hypertension, a known side effect of leflunomide (113), was not associated with leflunomide use in this study (112). A potential detrimental effect of leflunomide on CVD event rates in RA is also suggested by a population-based study which found increased CVD events in patients treated with cytotoxic agents of which leflunomide was one of three evaluated together (others included azathioprine or cyclosporine) (96). Conversely, a few studies have shown a protective effect of leflunomide, similar to that seen with other DMARDs (114, 115). There is less evidence in RA for the cardio-protective effects of hydroxychloroquine and sulfasalazine. Sulfasalazine use has been shown to be protective in a few studies (107, 114). Conversely, although hydroxychloroquine use has been associated with improved lipid profiles in RA (116, 117), there is no evidence that it reduces CVD risk when used as monotherapy in RA (107). Although, there is evidence in other autoimmune disorders such as systemic lupus that hydroxychloroquine is protective against vascular events (118) Biologic Agents In patients who fail traditional DMARD treatments, biologic agents are targeted therapies, which are used as alternative or adjunctive agents in the treatment of RA. There are a number of different classes of biologic agents that differ in their therapeutic targets including agents that block cytokines or their receptors e.g., TNF-α (adalimumab, certolizumab, etanercept, golimumab, and infliximab), IL-6 (tocilizumab), and IL-1 (anakinra). Abatacept works by blocking CD28 interaction between antigen presenting 22

38 cells and T cells, and rituximab is an anti-cd20 monoclonal antibody that depletes B- cells. The impact of anti-tnf-α agents on CVD was reviewed in a systematic review of 16 studies including 13 cohort studies and 3 RCTs (119). The authors found a reduction in CVD endpoints in all cohort studies reviewed. However, in a meta-analysis of the three RCTs there was no statistically significant decreased risk of CVD endpoints with anti- TNF-α use compared to traditional DMARDs (pooled RR 0.85, 95% CI 0.28, 2.59). The author s postulate this may be due to a healthy user effect whereby the individuals in anti-tnf-α RCTs were likely healthier and more likely to receive aggressive RA and CVD management with lower baseline CVD risk compared to patients included in cohort studies leading to this result. Another limitation to the study is that the RCTs included were likely underpowered and did not have adequate follow-up to detect CVD events (119). Since this publication, additional population-based RA cohorts have supported the finding that anti-tnf-α agents lower CVD risk in RA (120, 121); however, not to the same levels of risk seen in the general population (121). The mechanism by which anti-tnf-α agents reduce CVD risk may include: decreasing systemic inflammation leading to improvements in disease activity, and increased exercise capacity. Decreased inflammation may also improve the metabolic disturbances caused by active RA including the atherogenic lipid profile (110, 122), HDL levels (123) and reduced insulin resistance (124). Anti-TNF-α may also reduce endothelial activation (125) and evidence of subclinical atherosclerosis (126). Genetic studies have suggested that IL-6 plays a role in the development of CVD and IL-6 receptor blockade has been proposed as a potential therapeutic target for CVD 23

39 risk reduction (127). In RA, treatment with tocilizumab (anti-il6) has been shown to cause elevation in lipids to a greater degree than seen with other RA treatments such as anti-tnf-α agents (128), although like anti-tnf agents, a more favourable HDL profile is seen following treatment (129). The overall safety profile of tocilizumab with regard to cardiovascular events appears similar to the control populations used in data from randomized trials (130). However, some authors note that further longitudinal CVD data are needed to ascertain the long-term impacts of this treatment. For example, a recent retrospective evaluation of 3986 RA patients treated with tocilizumab examined the predictors of major CVD endpoints and found that patients with older age, a prior history of CVD, higher disease activity at baseline, and a higher TC: HDL cholesterol ratio were more likely to have CVD events over follow-up (131). As reviewed by Choy et al. (44) and confirmed with updated literature searching for this chapter, there is very little data about the impact of other biologic agents including rituximab and abatacept (44). Although small studies have demonstrated improvements in atherogenic profile in patients treated with rituximab (132, 133), as well as improvements in markers of subclinical disease including decreased pulse wave velocity at 12 months (134) and improved flow mediated dilation following treatment (132, 135, 136) Cardiovascular Risk Estimation in Rheumatoid Arthritis Cardiovascular risk scores are used to help estimate cardiac risk and guide treatment decisions especially around statin use for lipid lowering effect. There are many cardiovascular risk scores available (see examples of commonly used risk scores in Table 1.1); however, only one, the QRISK-2 score, adjusts for RA as an independent risk factor 24

40 (137), while the Reynolds s Risk Score (RRS) (138, 139) adjusts for inflammation as it incorporates a CRP. In Canada, current guidelines advocate for use of the FRS (62), while the Systemic Coronary Evaluation score (SCORE) method is most commonly used in Europe (140, 141). In the United States a new risk calculator, the Atherosclerotic Cardiovascular Disease (ASCVD) calculator, has recently been adopted by the American Cardiology Society and has supplanted the FRS (142). As only one CVD risk score adjusts for RA (QRISK-2) and this score has limited applications outside the United Kingdom where it was validated, there has been frequent critique that general population cardiovascular risk scores underestimate risk in RA. Evidence for risk underestimation using CVD risk scores comes from two sources: longitudinal epidemiologic studies (143) and imaging studies demonstrating high-risk vascular lesions in individuals with low risk estimations based on accepted risk calculators (144, 145). In an example of an epidemiologic study demonstrating discordance between CVD risk score and observed CVD events, the Rochester Epidemiology Project followed 525 RA patients for a mean of 8.4 years. The FRS was calculated at baseline and compared to observed rates of CVD over follow-up. The FRS underestimated risk in women with RA by 102% and in men by 65% (143). The study also examined the RRS (138, 139), which incorporates a CRP and found that it too underestimated CVD risk in women with RA (143). Similar findings have been reported in a larger cohort of RA patients from the Netherlands (the Nijmegen Inception Cohort) where 1050 patients with RA without preexisting CVD were evaluated over 9957 patients-years of analysis and 149 developed a 25

41 CV event (146). The FRS, RRS, SCORE and QRISK-2 were evaluated in this cohort for their predictive ability. All of the risk scores have good discriminative ability as measured by the c-statistic (146). The c-statistic is a measure of predictive accuracy of logistic regression models where a c-statistic of 0.5 indicates the model predicts no better than chance and 1 is perfect discriminatory ability (147). This finding indicated that all models were good at discriminating between patients with and without CVD events (cstatistic ). However, when the calibration of the models was evaluated by comparing the observed to predicted events at different deciles of risk, the risk scores underestimated (FRS, SCORE, RRS) or overestimated (QRISK-2) CVD risk. This was seen predominantly in the lower two-thirds of the risk strata. There is also evidence that existing cardiac risk scores do not accurately predict surrogate markers of CVD. In a recent study three risk scores including the FRS, RRS and the new ASCVD risk estimator were compared against a surrogate marker of CVD, the coronary artery calcification or CAC score (144). The new ASCVD risk estimator increased correct classification into the high-risk group by 10% compared to FRS; however, this difference was not statistically significant, although the authors note the sample was small (n=98) and it is possible this could be clinically significant. Overall, the authors concluded that even with the new risk calculator, 59% of the patients with high CAC scores were assigned a low-risk category by the risk estimator (144), again indicating suboptimal performance of general population risk estimators in RA. A similar study demonstrated that that a quarter of women with RA and a low SCORE risk had evidence of subclinical atherosclerotic disease by ultrasound evaluation of plaque (145). 26

42 Two principle approaches thus far have been used to mitigate the issues in performance of CVD risk scores in RA: inclusion of RA-specific risk factors into existing risk models (148), or a multiplication factor applied to a risk score to account for the estimated increased risk seen in RA (149). Unfortunately, these strategies have also largely led to sub-optimal risk estimation as described below. In a second study from the Nijmegen cohort, the SCORE algorithm for CVD risk estimation was compared to an adapted SCORE algorithm adjusting for RA risk factors (148). The adapted SCORE algorithm included the following additional coefficients for predictors of CVD including TC: HDL ratio, BMI, diabetes at baseline, hypertension at baseline, and high baseline DAS28. The adapted SCORE performed similar to the original with respect to discrimination. Calibration of the adapted SCORE algorithm was examined and there was no substantial useful reclassification using the adapted algorithm (148). Recently researchers from the Consortium of Rheumatology Researchers of North American (CORRONA) developed a new CVD risk algorithm for patients with RA (150). The new algorithm includes the following RA-specific variables: a measure of disease activity (the Clinical Disease Activity Index), disability (Health Assessment Questionnaire, HAQ), daily prednisone use, and disease duration in addition to traditional risk factors (age, sex, diabetes, hypertension, hyperlipidemia and tobacco use). The authors report that the new risk algorithm demonstrated a 10-17% improved risk stratification over models containing only traditional risk factors (depending on the number of risk categories examined) when predicted and observed CVD events were compared (150). Although, this study is encouraging, the authors did not have access to 27

43 exact lipid or blood pressure values and included the risk factors dichotomously instead. Furthermore, their follow-up was limited to a median of 2.2 years and prediction models were developed for event rates over 10 years. Additionally, they were not able to compare the new algorithm to existing scores such as the FRS that included lipid and blood pressure levels. These factors potentially limit the predictive ability of their algorithm. The application of a multiplication factor is a second strategy that has been reported to adjust for RA risk in CVD risk algorithms. The principle example of this is the EULAR recommendations (149), which suggest a multiplication factor of 1.5 to be applied to CVD risk algorithms (usually the SCORE algorithm) when the following clinical factors are present: disease activity >10 years, seropositivity or presence of extraarticular manifestations. A Spanish cohort of 200 consecutive RA patients was examined for CVD risk using the SCORE algorithm both unadjusted and adjusted for RA as per the guidelines. Although the multiplication factor applied to 59% of patients, the modified score resulted in an increased threshold infrequently and the authors concluded the impact of this modified score to be low (151). Clearly CVD risk estimation is complex and current models of risk estimation may be inadequate to completely predict disease in RA. At a minimum general population guidelines and risk estimators should be followed while recognizing their limitations until appropriate risk adjustments are established for RA CVD risk prediction (i.e., in Canada according to current guidelines this would the FRS (62)) Summary of Gaps in Cardiovascular Care in Rheumatoid Arthritis In the preceding introductory section we have reviewed the epidemiology of CVD and risk factors for CVD in RA. As described, there is evidence of a high burden of CVD 28

44 risk factors in patients with RA and it is clear that many traditional risk factors play a role in CVD risk in this population. Unfortunately, epidemiologic studies continue to report under-screening for CVD risk factors and suboptimal CVD management in RA and this represents a gap in care. In RA, as reviewed above, the identified gaps are in screening and/or management of CVD risk factors including: smoking (64), obesity (64), hypertension (58, 66), and dyslipidemia (58, 66). QIs are tools that can help measure and monitor gaps in care. The aim of the present dissertation is to develop a set of CVD QIs as a tool to improve CVD risk identification and management to assist in better defining the care gap so that it can be closed. In the next section of this introductory chapter, quality in healthcare and gaps in care are further defined and QI development and use is reviewed. 1.5 Quality Indicators Measuring quality in health care is a concept that has been gaining momentum for the last few decades. The concept has been driven largely by publications demonstrating significant deficits in the quality of health care in the United States (152, 153) and the United Kingdom (154). The movement for investigating and improving quality of care is driven by various stakeholders, including third-party payers, the federal government, patient advocacy groups and physician groups, and as such, measuring quality in health care has many potential endpoints that need to be considered depending on the measure and target audience including: research, quality improvement and accountability (155). Quality in healthcare has been classically defined into six domains (152) and care gaps may occur in any domain. A gap in care occurs when there is a failure of the health system to translate knowledge to practice leading to a diminished quality of care (152). 29

45 This is usually reflected in gaps in adherence to best practices as defined by clinical guidelines. A list of the six domains of quality in healthcare is described below (152). High quality health care should be: 1. Safe: Care provided to patients should be safe (potential harms are minimized). 2. Effective: Care provided to patients should be based on scientific evidence. 3. Patient-Centered: Care provided to patients should be responsive to patient preferences and needs and congruent with patient values. 4. Timely: Care provided should be timely and avoid harmful delays in service delivery. 5. Efficient: Care provided should avoid waste of resources and be costeffective. 6. Equitable: Care provided should not vary due to socio-demographic factors (e.g., income, gender, age, race) or geography. While clinical guideline recommendations offer direction about best practices in specific clinical situations, they are not designed to be measurable and are of limited use in measuring improvements in care quality. QIs are tools for measuring and monitoring quality of care and are often derived from guidelines. They are statements describing a structure, process or outcome of care (156) and are frequently worded using an IF, THEN statement (157) (see example below in Table 1.2). QIs often capture minimal standards of care and are designed to be measurable. QIs can also be designed to be aspirational (as 30

46 opposed to a minimum standard of care) to foster improvements in clinical practice. Table 1.3 provides an example for each type of indicator from using RA as an example. Performance measures can be derived from QI statements by specifying a numerator and denominator and reporting performance on the measure as a percentage over a specific reporting period (157). Thus, performance measures are imminently testable and can be used as a tool to highlight areas in need of quality improvement Quality Indicators in Rheumatic Diseases In rheumatology, the ACR has taken a leading role in advocating for defining, measuring and improving quality of care for rheumatic diseases (155). In 2011 a working group from the ACR developed a White Paper outlining their position in the quality movement and defining a framework for study in this area (155). Although many definitions of quality and quality measurement exist (155, 158), the ACR defines quality measurement as a means to improve long-term outcomes and safety and enhance access to appropriate treatment (155). There are many domains of quality; however, in rheumatology the most important and frequently targeted domains are process measures (e.g., access to care, frequent reassessment of disease activity, appropriate treatment strategies and monitoring) and outcome measures (e.g., attaining remission, improving and maintaining function thereby preventing disability, reducing morbidity and mortality) (155). Performance outcome measures are less common in rheumatology as appropriate and acceptable risk adjustment strategies have yet to be defined to ensure that physician performance is fairly measured and reported. Appropriate risk adjustment for performance measures is especially important if the measures are used for accountability purposes. 31

47 In rheumatology to date, QIs have been developed for osteoarthritis ( ), RA ( ), gout (168) and systemic lupus erythematosus (169). A recent systematic review found only four sets of RA QIs and they were rated as sub-optimal, largely because patient input was lacking (161). Currently, the ACR is in the process of developing QIs for the treatment and monitoring of RA; however, developing QIs for the screening and management of cardiovascular disease in RA is not part of their current mandate (personal communication, Quality Measures Subcommittee, ACR, 2014). This represents a significant gap as CVD represents the leading cause of morbidity and mortality in this patient population Methodological Approaches to Development and Testing of Quality Indicators Variations in development of QIs are described and may occur at the conceptual level, at a methodological level or both. Stelfox and Straus (170) describe two conceptual approaches to QI development: a deductive approach, whereby the concept of an indicator is first developed based on scientific evidence and expert opinion, and an inductive approach which uses data to drive indicator development. Sometimes a hybrid approach is used where feasibility of measurement in existing data sources is a critical aspect of QI development and only indicators demonstrating important unwarranted variations in care are fully specified (170). In rheumatology, a deductive approach has traditionally been used (157). However, in the United States, increasingly the availability of data is driving QI development. Currently proposed measures require electronic specification (also known as E-specification) in order to extract measures successfully for measurement using electronic medical records and it is likely a hybrid approach will predominate as better data sources become available to a majority of physicians. 32

48 Methodologically, QIs must be developed with three key characteristics in mind, which have been variably summarized by different sources (155, 157, ): importance (as it relates to public impact and clinical relevance), scientific soundness and feasibility of measurement. To ensure QIs are scientifically sound, they are typically developed based on clinical practice guidelines (158) and/or based on a research synthesis (170). Once a candidate set of QIs has been suggested based on guidelines, best practices and/or high-level evidence, typically experts are asked to weigh in on the perceived characteristics including the importance, scientific soundness (validity), feasibility using a consensus procedure. One of the most commonly used consensus procedures for quality measure development is the RAND/University of California, Los Angeles (RAND/UCLA) Appropriateness Method (174). This method has been commonly used in rheumatology QI development with some modification (157) and will be described in detail here as it pertains to the methodology employed in this dissertation. The original RAND/UCLA methodology was developed as a tool to help combat unwarranted practice variation in medical and surgical procedures (174). This methodology is a hybrid of Delphi (175), which is a set of structured rounds of expert rating on questionnaires followed by statistical feedback, and another consensus technique called the Nominal Group Technique (176), the latter is a structured brainstorming interaction. The original description of the RAND/UCLA Appropriateness Methodology is as follows: a literature review and synthesis of evidence are used to develop a list of indications for medical and surgical procedures. A group of experts (typically nine) rates the appropriateness of the procedures in different clinical scenarios on a Likert scale of 1-33

49 9 as appropriate (9), uncertain (5) or inappropriate (1) (174). Following initial voting, an in-person meeting is held to review the ratings from the group and discuss any areas of disagreement. A final vote is conducted independently and each indication is classified accordingly as appropriate, uncertain or inappropriate. A modification of the original RAND/UCLA Appropriateness Method has typically been used in rheumatology and other areas for QI development (167, 169, 177). In the most commonly reported modification, instead of a list of medical or surgical procedures, a list of candidate indicators are provided to the panel of experts and instead of rating appropriateness, experts are asked to rate the validity and feasibility of the candidate indicators (167, 169, 177). A critique of the above method for QI development is that frequently patients (161) and other non-expert (e.g., non research-based) healthcare providers are not involved in QI development. One method of overcoming this is to use a more inclusive methodology of QI development. For this dissertation, a platform called ExpertLens (RAND Corporation) was used for the first time in QI development. This novel approach was supported by the RAND Corporation and funding from the Canadian Institutes of Health Research. The platform allowed a large international, multi-disciplinary panel input on the candidate QIs. ExpertLens is an online platform that builds upon the RAND/UCLA Appropriateness Method described above but uses an online platform for participant interaction (178, 179). Round 1 and Round 3 voting occurs online and instead of an in-person discussion round in-between, there is a moderated, online asynchronous discussion (178, 179). 34

50 Finally, a crucial step in the development of QIs is testing their feasibility, and reliability (171, 180). This is done by examining whether performance on the QIs can be measured feasibly by the available sources and that if chart review is needed that there is acceptable inter-rater reliability (180). Over time, additional attributes of QIs can be evaluated including sensitivity to change (whether the QIs can measure the impacts of improvement strategies), predictive validity (whether or not improvements in QI predict better patient outcomes) and acceptability (whether the findings captured by the QI are acceptable to the provider and the system) (173). 1.6 Study Objectives The study objectives of this dissertation are threefold: 1. To systematically summarize the literature on cardiovascular risk screening and management QIs and guidelines for RA and to identify best practices for CVD care in RA (Study 1). 2. To derive the first comprehensive set of QIs for cardiovascular screening and management in RA care using a state-of-the-art method for deriving QIs from guidelines and employing a panel of international experts and patients (Study 2). 3. To test the QIs in the context of routine clinical practice over a broad-spectrum of disease severity and duration in patients with RA to determine their feasibility, and reliability and to report on current levels of QI performance (Study 3). 35

51 1.7 Dissertation Outline To achieve this goal, three studies are reported here in subsequent chapters. Study 1 (Chapter 2) is a published systematic review of QIs and guidelines for RA and cardiovascular disease, which identifies existing recommendations for screening and management of cardiovascular risk in RA (181). This study informed the development of the first cardiovascular QIs for RA (Study 2, Chapter 3) (182). In Study 3 (Chapter 4) the QIs were tested in routine clinical practice in the University of Calgary Rheumatology Clinics in two cohorts representing a spectrum of RA disease: an early RA cohort and a biologics cohort. Chapter 5 discusses the implications of this work including potential limitations, plan for future work and application of the QIs and introduces some physician-developed tools for QI improvement including an audit tool and prospective CVD screening tool. 36

52 Table 1.1 Comparison of cardiovascular risk assessment calculators Risk calculator Country of validation Age Gender Total Cholesterol HD Diabetes Systolic Blood Pressure Hypertension treatment Race Smoking Status CRP Family History of CVD Chronic kidney disease Atrial fibrillation Rheumatoid Arthritis BMI Cholesterol/HDL ratio Postal code FRS United States RRS United States QRISK 2 United Kingdom ASCVD Risk Estimator United States SCORE Europe Atherosclerotic Cardiovascular Disease (ASCVD); Body Mass Index (BMI); C-reactive protein (CRP); Cardiovascular Disease (CVD); Framingham Risk Score (FRS), High-Density Lipoprotein (HDL); Reynolds Risk Score (RRS), QRISK-2 (is not an abbreviation), Systematic Coronary Risk Evaluation (SCORE) 37

53 Table 1.2 Example of a quality indicator Quality Indicator IF a patient has a myocardial infarction, THEN they should be prescribed aspirin therapy. Numerator All the patients with a myocardial infarction who have been prescribed aspirin. Denominator Period of Assessment Performance Measurement All the patients with a myocardial infarction. One-year measurement period. The percentage of patients with a myocardial infarction who were prescribed aspirin therapy during the measurement year. 38

54 Table 1.3 Examples of different types of quality indicators: process, structure, and outcome Type of quality indicator Process Structure Outcome Example of a quality indicator IF a patient has RA, THEN they should have a disease activity measured at least once over the proceeding 12 months IF a rheumatology clinic is seeing patients with RA, THEN an electronic medical record should be available to record and trend disease activity so this can be used as a tool to help target a low disease activity state IF a patient has newly diagnosed RA, THEN they should be in a low-disease activity state or remission within 12 months of diagnosis Corresponding performance measure Percentage of RA patients with a disease activity measured at least once over the last 12 months Percentage of RA clinics with an electronic medical record that is available to record and trend disease activity measures Percentage of patients with newly diagnosed RA in a low-disease activity state or remission within 12 months of diagnosis 39

55 Chapter Two: Best Practices for Cardiovascular Disease Prevention in Rheumatoid Arthritis: A Systematic Review of Guideline Recommendations and Quality Indicators 40

56 2.1 Abstract Objective: Cardiovascular disease (CVD) is a leading cause of mortality in rheumatoid arthritis (RA). This study systematically reviewed and appraised guidelines and quality indicators (QIs) pertaining to CVD risk management in patients with RA. Methods: Four electronic medical databases (MEDLINE, EMBASE, CINHAL and Web of Science) and the grey literature were searched using terms and keywords pertaining to: guidelines, QIs, RA and CVD (RA and general population literature searched). Abstracts were screened for inclusion and rated using the Appraisal of Guidelines for Research & Evaluation II instrument independently by two of three reviewers. Results: 16,064 abstracts were screened and 808 underwent full text review. A total of 17 guidelines and three QI sets published between were included. A number of consistent themes emerged including the increased CV risk faced by RA patients and the need to address modifiable risk factors on a regular basis. The role of the multidisciplinary team in risk optimization was also highlighted. Ten guidelines provided recommendations for CVD prevention in patients with RA. Unfortunately most recommendations lacked the specificity required to determine adherence to the recommendation. Only four RA-specific CVD QIs were identified [(1) general comorbidity screening, (2) formal CVD risk estimation, (3) exercise, and (4) minimizing steroid use]. Conclusions: Regular screening for CVD risk factors is an important part of care in patients with RA. Unfortunately, existing RA-specific CVD QIs do not adequately 41

57 address risk factor management, and existing guideline recommendations lack specificity for measurement and use in quality improvement initiatives. 42

58 2.2 Introduction Cardiovascular disease (CVD) is a leading cause of death in patients with rheumatoid arthritis (RA) and the risk of CVD in RA is comparable to the CVD risk incurred by diabetes (30). Systematic reviews of RA cohorts suggest that patients have a 50% increased risk of death due to myocardial infarction (MI) and stroke compared to the general population (25) as well as a 48% increased risk of incident MI (26). The reasons for increased cardiovascular risk in RA patients are complex and postulated to be related to chronic inflammation, inadequate management of modifiable risk factors and potentially medications including corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) (82, 85, 93). Numerous prior studies have suggested that a significant number of RA patients have unidentified or undertreated modifiable risk factors such as hypertension and dyslipidemia (58, 64, 66, 71, 183, 184). Furthermore, there appears to be controversy as to which practitioners (e.g., primary care practitioners, nurses, or specialists) should address cardiovascular comorbidities and how (85). Finding methods to enhance a patient-centered model for screening and prevention of CVD in patients with RA is important to the realization of optimal patient care and risk factor modification in this population. Guidelines and Quality Indicators (QIs) are tools that can aid in improving the quality of care provided. Guidelines are primarily used as a means of disseminating information to practitioners about best practices; however, adherence to recommendations is often not measurable and evidence suggests that guidelines do little to change clinical practice (185, 186). QIs are often systematically developed from guidelines (158) and are statements about optimal processes, structures or outcomes of care that can be operationalized into measures, which specify a numerator, denominator 43

59 and appropriate exclusions. Therefore, adherence to QIs can be measured and used for benchmarking and quality improvement. Furthermore, adherence to process QIs in rheumatology has recently been shown to be associated with improved patient outcomes (187). Given the noted gap in cardiovascular screening and care in this high-risk population, the objective of the present study was to systematically review the literature to identify and appraise all cardiovascular prevention guideline recommendations and QIs pertaining to RA patients to determine the current best practices for cardiovascular care in patients with RA. 2.3 Materials and Methods Data Sources and Inclusion Criteria Four electronic databases (MEDLINE, EMBASE, CINAHL and Web of Science) were searched between January 1st, 2003 and April 7 th, 2013 using both Medical Subject Heading (MeSH) terms and keywords pertaining to four major themes combined with the following Boolean operators: ( cardiovascular disease OR rheumatoid arthritis ) AND ( guidelines OR quality indicators ). An extensive review of the grey literature was also done (database and Grey Literature search strategy shown in Appendix A5 & A6). All articles were screened for inclusion by 2 of 3 reviewers (CEB, AS, and RN). Guidelines and QIs were eligible for inclusion if the following criteria were met: English language, QIs and guidelines developed and currently endorsed by a major medical or allied health professional society. In the case of QIs from the United States, measures needed to be endorsed by the National Quality Forum (a non-profit public organization that reviews and endorses standardized healthcare performance measures) or 44

60 a professional society. Additionally, QIs presented as checklists without any accompanying methodology as to how they were developed were excluded. Guidelines or QIs had to be directly relevant to primary prevention of CVD in RA patients. Although publications from the last 10 years were searched, guidelines and QIs published prior to 2008 were subsequently excluded because they were felt to no longer be sufficiently current given the rapidity of changes in recommendations in this field (shown in Figure 2.1) Guideline Quality Assessment The Appraisal of Guidelines for Research and Evaluation (AGREE) version II is a framework for appraising the quality of guidelines and can also be applied as a methodological strategy for guideline development (188). The tool is comprised of 23 items in 6 domains and an overall assessment of quality of the guideline ( recommend, recommend with modifications or do not recommend the guideline for use in practice ). The quality of all guidelines was rated independently using the AGREE II (188) tool by 2 of 3 reviewers (CEB, AS, or RN); where major disagreements in the overall assessment, agreement was reached by consensus between two reviewers. Only those with a rating of recommend or recommend with modifications were included Recommendation and Indicator Abstraction A spreadsheet was generated and recommendations relevant to RA cardiovascular care from included guidelines and QIs were abstracted. Categories for guideline recommendation and QI data abstraction were determined a priori and included the following themes: cardiovascular risk calculation (use of specific standardized tools to 45

61 calculate CVD risk e.g., Framingham risk calculator (189)), general risk factor screening (if guidelines or QIs recommended screening for more than one risk factor in a single recommendation or recommended risk factor screening without further specification they were captured in this category), hypertension screening and targets, lipid screening and targets, exercise, diet and weight management (abstracted separately but, due to significant overlap, diet and weight management are presented as a combined theme), diabetes screening, smoking, and medication use (aspirin, corticosteroids, NSAIDs (including COX-2 selective inhibitors), biologic and non-biologic disease modifying antirheumatic drugs (DMARDs)). Recommendations around coordination of comorbidity care were also abstracted in an other category. The level of evidence and the grade of the recommendation were recorded as reported in the guidelines when available. If a recommendation encompassed more than one category it was placed in the most general category (usually general risk factor screening). Recommendations that encompassed these themes (e.g., such as glucocorticoid or NSAIDs use) but did not link the recommendation to reducing cardiovascular risk in RA were not abstracted (e.g., minimizing NSAIDs use to decrease gastrointestinal bleeding risk). 2.4 Results A total of 16,064 unique abstracts were reviewed and 808 manuscripts were subjected to a full text review. A total of 10 RA guidelines (106, 149, ) and three RA QI sets (four indicators) (162, 165, 198) met inclusion criteria (Figure 2.1). Only seven general population guidelines discussed CV risk in RA (62, 63, 140, ) and none of the general population QIs specified RA patients in the numerator or denominator (Figure 2.1). Of the included RA guidelines, only one was dedicated entirely 46

62 to CV risk reduction in RA patients [The European League Against Rheumatism, EULAR guidelines (149)] and a further nine addressed CV prevention in addition to other RA treatment recommendations (106, ). Of the excluded RA guidelines, 27 made no recommendation about cardiovascular preventive care, eight were published before 2008, and a further 11 did not meet AGREE II criteria (188) Audience, Population, Methods and Quality of the Included RA Guidelines The primary audience for the RA guidelines was healthcare professionals caring for patients with RA, primarily rheumatologists (Appendix A1). One guideline was specific to primary care physicians (195). Two guidelines covered early RA (194, 195), although different definitions were used (Appendix A1). One guideline specified RA after the first two years of diagnosis (192) and an additional two guidelines included additional patient populations: ankylosing spondylitis and other inflammatory arthritides (149); and patients with rheumatologic conditions on low dose glucocorticoids (197). The methods for RA guideline development varied (Appendix A1). For example, the composition of the guideline development groups varied and different methods were used for rating the level of evidence (Appendix A1). The American College of Rheumatology (ACR) guidelines used the RAND/UCLA appropriateness method (203) for developing the guidelines (106), whereas many other guidelines reported using a consensus conference with unspecified methodology for achieving consensus (Appendix A1). Only two guidelines used AGREE II (190, 192) for document preparation. Although all included guidelines met AGREE II (188) criteria (either recommend or recommend with modification), the domain scores were highly variable (median domain scores varied 47

63 between 31.25% to 93.05%) with particularly low scores noted in the Applicability domain (median 31.25%, range 2.1%-91.7%) (Appendix A3) Assessment of CVD Risk: Recommendations from RA Guidelines Assessment of CV risk factors was recommended in five RA guidelines (149, , 195). Only the EULAR guidelines (149) and The British Society of Rheumatology (BSR) guidelines (192) recommended the use of a cardiovascular risk score. The remainder made more general recommendations about cardiovascular risk screening (Tables 2.1 & 2.2). The EULAR guidelines (149) were the only guidelines to suggest a formal adjustment of the cardiovascular risk score to account for presence of RA (Table 2.1). The BSR (192) guidelines recommend screening and management of cardiovascular risk factors and presented a table with thresholds for treatment depending on risk score based on the Joint British Societies CVD risk prediction charts. The remainder of the RA guidelines suggested assessment and treatment of CVD risk factors such as hypertension, obesity and smoking but did not specify the use of a formal cardiovascular risk assessment using a validated risk calculator to assist in stratifying patient risk (Tables 2.1 & 2.2). The level of evidence supporting these recommendations varied considerably (Table 2.2). Definitions for the level of evidence used by each guideline are shown in Appendix A Lowering Disease Activity as a Means of Preventing CVD Risk in RA All included guidelines covering general treatment recommendations for RA (106, ) recommend an early and targeted approach to therapy to control disease activity and reduce functional disability with the goal of improving RA outcomes. Only 48

64 the EULAR guidelines formally recommend control of disease activity as a potential means of reducing CVD risk in RA (149). Two additional guidelines discuss this concept but did not make formal recommendations (191, 192) (Table 2.2). Three guidelines suggested that some medications used to treat RA might reduce the risk of CVD events without specific recommendations being made. The Australian (195), Spanish Society of Rheumatology (Sociedad Española de Rheumatología, SER) (191) and BSR (192) guidelines discussed the potential for methotrexate to reduce cardiovascular risk. The SER guidelines (191) also discussed the potential for plaquenil to have a beneficial effect on lipid lowering and that anti-tnf agents may be associated with reduced CV events Other Recommendations for Lowering CVD Risk in RA: Lipids, Hypertension, Smoking, Diet, Exercise, Aspirin & Drug Safety The abstracted recommendations for specific strategies to reduce CVD risk in patients with RA related to smoking, diet, exercise, and drug safety are shown in Appendix A4. Lipid screening and monitoring for hypertension were included as part of a CVD risk assessment in a number of guidelines (Appendix A4). Very few specific treatment recommendations for dyslipidemia or hypertension were made. The EULAR (149) and SER (191) guidelines recommend that treatment of dyslipidemias should be carried out according to national guidelines and that statins are the preferred treatment agent. A single guideline (191) made an ungraded recommendation around lipid monitoring for patients on tocilizumab therapy. There was only an ungraded recommendation suggesting strict control of blood pressure while on leflunomide with no specification of frequency of monitoring, 49

65 thresholds for anti-hypertensive treatment or when to discontinue it (191) (Appendix A4). For treatment of hypertension, the EULAR guideline suggested that angiotensin converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor blockers (ARBs) are the preferred anti-hypertensive agents (149). Only three RA guidelines made specific recommendations with regards to smoking cessation (149, 191, 195). Three guidelines made recommendations about exercise in the context of improving aerobic capacity and/or reducing CVD risk (191, 193, 195); however, the accompanying evidence was limited and related to only short term outcomes such as improved aerobic or functional capacity and not long-term reductions in CVD events. Dietary recommendations were made in two guidelines (193, 195). The National Institute for Care and Clinical Excellence (NICE) guidelines (193) suggested that patients should be encouraged to follow the principles of a Mediterranean diet as it may impact CVD risk; however, evidence for this type of diet lowering CVD risk in RA patients specifically was not presented. The Australian guidelines (195) suggested dietary control in the context of weight management and recommended a diet with a focus on fruit, vegetables and whole grains and low in fat; but, again no evidence was cited and the dietary recommendations were ungraded. Although a number of guidelines provided recommendations on glucocorticoid use (191, ) very few discussed the potential CVD implications. The BSR guidelines (192) discuss that glucocorticoids may worsen CVD risk profile by impacting blood pressure, potentiating dyslipidemia or impairing glucose tolerance but also cited a single study showing some improvement in lipid profiles in RA patients on glucocorticoids and, ultimately, no clear recommendation was made. The SER guidelines 50

66 (191) also acknowledge the effects of glucocorticoids on blood pressure and recommend strict control of blood pressure in patients on glucocorticoids in an ungraded recommendation. Only the EULAR guidelines (149) recommend using the lowest possible dose of glucocorticoids. EULAR also published a set of consensus-based recommendations on monitoring for complications of low-dose glucocorticoid therapy ( 7.5 mg/day prednisone equivalent) and suggest monitoring for diabetes, hypertension and body weight as part of routine care for patients on low-dose glucocorticoids (197). None of the guidelines make recommendations about the use of aspirin for primary prophylaxis for CVD risk in RA. The BSR (192), NICE (193) and Australian (195) guidelines recommend against the co-prescription of aspirin and NSAIDs so as to minimize gastrointestinal bleeding and/or interference of anti-platelet effects of aspirin. Five guidelines (149, ) made recommendations about the use of NSAIDs and COX-2 selective agents and discussed the potential for increased cardiovascular risk with these agents. Concepts discussed in the recommendations included: (1) caution when considering these agents in patients with known CVD or at high risk of cardiovascular events and (2) using the lowest possible dose of NSAID for the shortest period of time and (3) avoiding NSAID combinations (Appendix A4) Secondary Prevention and Other Cardiovascular Complications Although not a primary focus of this review, recommendations and QIs around other aspects of CVD care including secondary prevention were also abstracted. Secondary prevention of CVD was largely not addressed by the RA guidelines. The BSR guidelines (190) suggest the use of ACE inhibitors in RA patients with heart failure and the control of blood pressure with ACE inhibitors and thiazide diuretics in RA patients who have had CVD events (both ungraded recommendations). These guidelines also 51

67 discuss that RA patients may be less likely to receive secondary prophylaxis with antiplatelet agents following a CVD event, which may contribute to higher mortality; however, no specific recommendations were made. The SER guideline encourages the use of aspirin in RA patients who have had a CVD event in an ungraded recommendation (191). Four guidelines discussed the cardiovascular safety of anti-tnf agents (106, 190, 191, 196). All recommended avoiding their use in patients with New York Heart Association (NYHA) class III or IV heart failure. The BSR 2010 (190) guidelines also reviewed the evidence for myocardial infarction and other cardiovascular events in relation to anti-tnf use but no formal recommendations were made. The SER guidelines address other cardiovascular complications of RA including pericarditis, myocarditis and their treatment and were the only guidelines to do so (191) Multidisciplinary Care Multidisciplinary care of patients with RA is discussed in a number of guidelines (191, 193, 194), although only the Australian (195) and BSR (192) guidelines discuss the importance of multidisciplinary care in the context of comorbidity management. The BSR (192) guidelines recommend that an annual review of comorbidities, disease activity, and medications is best undertaken in the context of a multidisciplinary approach. The authors further suggests that CVD screening is often more appropriate and conveniently done by a general practitioner whereas arthritis disease activity measurement and associated RA care is best provided by rheumatologist or other rheumatology allied health professional. 52

68 2.4.7 QIs Relevant to CVD Prevention in RA A total of three relevant RA QI sets were found including the European Musculoskeletal Conditions Surveillance and Information Network (EUMUSC) (162), NICE (198) and the ACR (165). From these sets a total of four indicators was abstracted in the following themes: cardiovascular risk assessment, glucocorticoid use, and exercise (Table 2.3). Methodology used to develop the QIs is described in Appendix A2. The EUMUSC (162) indicators suggested an annual review of comorbidities although the published specifications of the indicator did not outline which specific comorbidities should be evaluated. The NICE indicator measures the percentage of RA patients with RA with a CVD risk assessment using a validated risk calculator (198) CVD Recommendations and Indicators from General Population Guidelines and Indicators A total of 104 guidelines covering recommendations for primary prevention of CVD in the general population were reviewed and 30 met AGREE II criteria (188) (Figure 2.1). Only seven general population guidelines (62, 63, 140, ) (23.3%) recognized RA as a condition that increased cardiovascular risk (Table 2.4). None of the guidelines recommended specific treatment thresholds for RA but earlier screening was often recommended (Table 2.4). Six sets of general population indicators were found for CVD primary prevention; however, none of the indicators specified RA as a condition with excess cardiovascular risk and all were excluded on this basis. 53

69 2.5 Discussion This work represents the first systematic review of guidelines and QIs for cardiovascular care and prevention of CVD in patients with RA. While only one identified guideline was entirely dedicated to CVD prevention (149), an additional nine guidelines covered varied aspects of cardiovascular care in RA (106, ). Of the identified general population guidelines, seven (62, 63, 140, ) identified patients with RA as having increased cardiovascular risk but made very few RA-specific recommendations. Only four QIs measured processes of care potentially relevant to decreasing CVD risk in this population but the measures did not cover the recognized breadth of CVD preventive care in RA. Unfortunately this body of work highlights a number of limitations to the current recommendations and indicators addressing cardiovascular screening and care for patients with RA. First, the methods used to derive the guidelines and indicators are varied. This was particularly evident when comparing similar recommendations from different societies, as levels of supportive evidence were often variable. Second, there is a lack of high-level evidence to support many of the RA-specific recommendations. This is most evident in exercise and dietary recommendations where, even if a recommendation had Level 1 evidence from meta-analysis or multiple randomized trials, this often did not pertain to cardiovascular endpoints. Surprisingly, even smoking cessation recommendations were associated with a low level of evidence. This is inconsistent with general population studies or recommendations (204). Although no routinely applied quality rating assessment exist for QIs, there are some generally accepted criterion that QIs should satisfy (170, 205): there should be evidence that the indicator serves to measure an important gap in quality of care and that 54

70 there is adequate scientific validity to support the indicator. The indicators should also be feasible to measure, reliable and precisely defined and specified and be useful to quality improvement efforts. Although the four indicators found may measure important gaps in care and have adequate scientific validity to support their use, only the NICE indicator (198) (Table 2.3) was defined precisely enough to be potentially useful in quality improvement efforts. There were a number of areas where recommendations on screening for CVD risk factors were lacking. For example, although tocilizumab is noted to cause dyslipidemia in randomized controlled trials (128), our review found no clear guidance on how frequently lipids should be assessed, although the product monograph does provide a suggested frequency of lipid monitoring (206). Additionally, leflunomide is known to cause hypertension (113) but there was no clear guidance on how to monitor for this complication in the reviewed guidelines. Finally, specific recommended thresholds for treatment of modifiable risk factors (e.g., lipid levels) are lacking; it was unclear whether thresholds should be lower in patients with RA than the general population. Only two guidelines recommended using risk calculators to assess CVD risk (149, 192); and the EULAR guidelines (149) were the only ones that adjusted cardiovascular risk calculation to account for RA. After the completion of this systematic review the Joint British Societies published the third iteration of their recommendations and also recommended the use of a risk calculator that incorporated RA (QRISK Lifetime) (207). One NICE QI (198) addressed CV risk assessment using a calculator that adjusted for RA but the recommended calculator [QRISK (137)] is United Kingdom (UK)-specific and is not endorsed in guidelines 55

71 outside of the UK. In addition, the indicator was geared towards general practitioners in the UK and is not necessarily applicable in other settings. A strength of this review is that it encompassed both RA and general population guidelines and indicators. A number of consistent themes from these two bodies of literature emerged including the increased cardiovascular risk faced by RA patients and the need to address modifiable risk factors on a regular basis. Given that the risk of CVD occurs earlier than in the general population, screening for risk factors should commence earlier; however, the frequency of assessment and when this should commence is inconsistently specified. A second important theme that emerged from this review was that of the role of the multidisciplinary care team in comorbidity care. As has been noted by other authors, there is a perception that completing a formal cardiovascular risk assessment in addition to RA disease activity assessment can be a time-consuming endeavour (66). Involving other healthcare professionals including primary care practitioners and allied health professionals in comorbidity management appears key to high quality care and ideally CVD risk assessment should be a shared responsibility. Screening and treating risk factors however can be challenging especially if the primary care practitioner and rheumatologist do not practice in the same medical home. Communication between primary care, specialists, multidisciplinary teams and the patient is a critical issue in preventive care strategies and ensuring continuity of comorbidity care between primary and secondary care should be a focus for quality improvement initiatives. Capturing these concepts in quality measures can be challenging and not surprisingly no QIs specifying communication of CVD risk or screening practices were found. Given the relatively low 56

72 prevalence of RA in general population, the Australian guidelines (195) highlight that additional tools for general practitioners are needed to facilitate screening and treatment of modifiable risk factors and we propose that carefully designed guideline recommendations or quality measures could be designed to enhance comorbidity care and communication of such care between primary and secondary practitioners. This review suggests that there is a gap in high quality guidelines and quality measures for RA CVD care due to the aforementioned limitations. QIs are often derived from high quality guideline recommendations, which may explain the paucity of specific RA comorbidity measures addressing CVD risk in this population. It can however be argued that even in the absence of comprehensive CVD screening guidelines derived from high quality evidence in RA populations, there exists a multitude of general population guidelines and indicators that could be applied to patients with RA with some modifications. Future research efforts should also be aimed at determining how to best ascertain CVD risk in RA and determining optimal thresholds for lipid-lowering and other therapies. Research should focus on what processes/models of care best enable continuity and communication of comorbidity care amongst providers such that results of CVD screening can be acted on in a timely and effective manner. In conclusion, although limitations to current RA guidelines for CVD preventive care exist, there are clear gaps in clinical care that could be quantified and addressed by carefully designed QIs. Such QIs would need to draw on CVD prevention concepts highlighted in the reviewed guidelines but would need to be bolstered by general population recommendations and harmonized with existing QIs for the general population. 57

73 58

74 Figure 2.1 Study selections Abbreviations in Figure 2.1: AGREE II: Appraisal of Guidelines, Research and Evaluation CV: Cardiovascular, refers to general population guidelines and quality indicators about cardiovascular disease CVD: Cardiovascular disease RA: Rheumatoid arthritis, refers to rheumatoid arthritis guidelines and quality indicators QI: Quality Indicator 59

75 Table 2.1 Topics abstracted from rheumatoid arthritis guidelines and quality indicators relevant to cardiovascular care in rheumatoid arthritis Guideline or QI sets Recommendations (n)* Total Relevant to CV care Topics of Abstracted Recommendations Related to Cardiovascular Disease (CVD) Risk Calculation RA Guidelines ACR (106) BSR (192) BSR (190) EULAR (149) EULAR (197) NICE (193) RACGP (195) GPP:71 GPP:11 SIGN (194) GPP:18 GPP:3 SER 2011 > NR: 5 (191) SER (196) Quality Indicator Sets ACR 2008 (165) EUMUSC 2013 (162) NICE 2012 (198) General risk assessment Lipids Hypertension Smoking Exercise Diet and Weight Management Aspirin Anti-TNF safety NSAID safety Steroid safety Other 60

76 *Total recommendations abstracted refer to the total number of recommendations in the guideline or number of quality indicators in the set. Only major recommendations or good practice points (GPPs) are noted in this count where applicable additional ungraded statements or information from algorithms or tables were abstracted and this is noted in footnotes. Relevant to CV care refers to the total number of recommendations relevant to cardiovascular prevention in RA care that were abstracted from the guideline. Topics covered by the graded and ungraded recommendations/good practice points (GPPs) are indicated by a checkmark ( ). Abbreviations: American College of Rheumatology (ACR), British Society of Rheumatology (BSR), Cardiovascular (CV), European Musculoskeletal Surveillance and Information Network (EUMUSC), European League Against Rheumatism (EULAR), Good Practice Points (GPP, ungraded recommendations); National Institute for Health and Care Excellence (NICE), Not Rated (NR), Royal Australian College of General Practitioners (RACGP), Spanish Society of Rheumatology (SER), Scottish Intercollegiate Guidelines Network (SIGN). 1 There were 4 topics and recommendations in text and algorithms were not numbered therefore harder to enumerate. 2 In addition to the 2 graded recommendations, an additional 5 ungraded Key Interventions or relevant statements were abstracted. 3 There are 3 recommendations on monitoring of glucocorticoids in clinical trials (not abstracted as not relevant) and Table 1 and Table 2 of the guidelines describes recommended monitoring frequency in clinical trials and practice for 20 & 22 adverse events respectively, 8 of which have recommendations for monitoring in daily practice. 4 There are 12 Graded recommendations but 15 statements (some recommendations have more than one part and these were counted separately). 5 Number of recommendations difficult to enumerate as not numbered. 6 Two of these measures are endorsed by ACR but not part of Physician Consortium for Performance Improvement approved measurement set. 7 Total number of RA specific indicators in the 2013/14 General Medical Services contract Quality and Outcomes Framework. 61

77 Table 2.2 Rheumatoid arthritis-specific cardiovascular disease recommendations from guidelines Guideline Recommendation Level and/or Grade of Evidence as Reported in Guideline* Cardiovascular Risk Assessment (Formal Risk Assessment) BSR 2009 (192) EULAR 2010 (149) EULAR 2010 (149) Patients should be screened and managed for cardiovascular disease. Table 4 in the manuscript suggests treatment thresholds based on cardiovascular risk thresholds, BP, and lipid levels based on the Joint British Societies CVD risk prediction charts. CV risk assessment using national guidelines is recommended for all patients with RA... Risk assessments should be repeated when antirheumatic treatment has been changed. Risk score models should be adapted for patients with RA by introducing a 1.5 multiplication factor. This multiplication factor should be used when the patient with RA meets two of the following three criteria: -Disease duration of more than 10 years -RF or anti-ccp positivity -Presence of certain extra-articular manifestations. Level of evidence 2, Grade of recommendation A Level of evidence 3-4; Strength of recommendation C Level of evidence 3-4, Strength of recommendation C Cardiovascular Risk Assessment (General Review of Cardiovascular Risk Factors and General Treatment advice) BSR 2009 (192) BSR 2009 (192) BSR 2009 (192) An annual review is recommended, incorporating disease assessment, damage, functional outcomes, patient goals and evaluation of comorbidity. Description of the annual review: Assess and screen for comorbidity including cardiovascular risk factors. Lifestyle interventions to reduce CVD risk are recommended for all patients and include smoking cessation, weight reduction where they are overweight and appropriate dietary modification. Patients should moderate their alcohol consumption and the importance of maintaining aerobic fitness should be emphasized. Manage cardiovascular risk factors in patients with RA: measure blood pressure (BP), measure fasting lipids and glucose, check weight and Body Mass Index (BMI), encourage exercise, smoking cessation advice, remember that patients with high inflammatory Level of evidence 3, Grade of recommendation C NR NR 62

78 SER 2011 (191) NICE 2009 (193) markers carry an increased risk of cardiovascular disease. "Cardiovascular complications: Individual risk factors for cardiovascular (CV) complications should be identified and treated: age, male sex, highly active arthritis, smoking, arterial hypertension, hypercholesterolemia, and history of CV episode." "Offer people with RA an annual review to: check for the development of comorbidities, such as hypertension, ischemic heart disease Level of evidence1b, Grade of recommendation A NR RACGP 2009 (195) Patients with RA should be assessed and treated for cardiovascular risk factors such as smoking, obesity, physical inactivity, hypercholesterolemia, hypertension and diabetes." Grade B RACGP 2009 (195) RACGP 2009 "Cardiovascular risk factors should be assessed at least three times per year." Lifestyle advice should be given to all RA patients to encourage smoking cessation, dietary modification, weight control and exercise." NR ( Good practice point ) NR ( Good practice point ) (195) Description of the definitions for the level of evidence and Grade or Strength of the recommendation from each guideline presented in Appendix A. Abbreviations: American College of Rheumatology (ACR), British Society of Rheumatology (BSR), Cardiovascular (CV), European League Against Rheumatism (EULAR), National Institute for Health and Care Excellence (NICE), Not Rated (NR), Royal Australian College of General Practitioners (RACGP) 63

79 Table 2.3 Rheumatoid arthritis quality indicators relevant to cardiovascular disease prevention Quality Indicator Set ACR 2008 (165) EUMUSC 2013 (162) EUMUSC 2013 (162) Quality Indicator Percentage of patients 18 years and older with a diagnosis of rheumatoid arthritis (RA) who have been assessed for glucocorticoid use and, for those on prolonged doses of prednisone > 10 mg daily (or equivalent) with improvement or no change in disease activity, documentation of glucocorticoid management plan within 12 months * If a patient is diagnosed with RA then review of comorbidities, adverse events and risk factors related to pharmacological therapy should be performed at least annually. If a patient is newly diagnosed with RA then a referral to a relevant health professional for instruction on an individualized exercise program including advice for physical activity, range of motion-, muscle strengthening- and aerobic exercises should be provided within 3 months. NICE (198) The percentage of patients with rheumatoid arthritis aged years who have had a cardiovascular risk assessment using a CVD risk assessment tool adjusted for RA in the preceding 15 months Note the risk assessment tool adjusted for RA refers to the QRISK tool but "this indicator may be updated with new tools which adjust for RA. Abbreviations: American College of Rheumatology (ACR), European Musculoskeletal Surveillance and Information Network (EUMUSC), National Center for Clinical Excellence (NICE). *Although this quality indicator document does not directly reference cardiovascular prevention as a rationale for the indicator, it references an earlier set of indicators that highlight the role of glucocorticoids in cardiovascular disease in rheumatoid arthritis patients (163). 64

80 Table 2.4 General population cardiovascular guidelines recommendations addressing the risk in persons with rheumatoid arthritis Guideline Recommendation Level of evidence AACE 2012 (201) CCS 2010 (62) ESC 2012 (140) ESC/EAS 2011 (63) AHA/ASA 2011 (200) AHA 2011 (202) Malaysian Dyslipidemi a Guidelines (199) "Identify risk factors... which enables the physician to personalize therapy for dyslipidemia according to each patient s risk level and thereby maximize treatment effectiveness." These guidelines discuss inflammatory disorders including RA as having an increased risk of CVD but make no specific recommendations as to different screening or treatment in these individuals. "Adults with the following risk factors should also be screened at any age: rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis..." "Modification of traditional risk factors through lifestyle changes, including dietary modification, smoking cessation, and increased daily exercise, and appropriate drug prescription may be of particular importance in reducing risk in individuals with psoriasis or rheumatoid arthritis." "Lipid profiling is recommended in subjects with chronic inflammatory disease" "Patients with chronic inflammatory disease such as RA or SLE should be considered at increased risk for stroke." Mentions RA as increasing CVD risk in women but no specific interventions, even lists RA as a major risk factor in Table 2 "Classification of CVD risk in women" Other risk factors not included in the general risk profile that should be taken into account in evaluating risk include: -Chronic autoimmune inflammatory disorders such as systemic lupus erythematosus and rheumatoid arthritis These individuals are at high risk of developing CVD. They should be screen for traditional risk factors and treated appropriately. Grade A, Level 1 (but no level of evidence reported for adaptations related to patients with RA) NR NR Class I, Level C Class I; Level of Evidence B Abbreviations: American Association of Clinical Endocrinologists (AACE) ; American Heart Association (AHA); American Stroke Association (ASA); Canadian Cardiovascular Society (CCS); European Society of Cardiology (ESC); European Atherosclerosis Society (EAS), Not Rated (NR) NR NR 65

81 Chapter Three: Development of Cardiovascular Quality Indicators for Rheumatoid Arthritis: Results from an International Panel Using a Novel Online Process 66

82 3.1 Abstract Objective: Patients with rheumatoid arthritis (RA) have a high risk of premature cardiovascular disease (CVD). We developed CVD quality indicators (QIs) for screening and use in rheumatology clinics. Methods: A systematic review of the literature on CVD risk reduction in RA and the general population was conducted. Based on the best practices identified from this review, a draft set of 12 candidate QIs were presented to a Canadian panel of rheumatologists and cardiologists (n=6) from three academic centers to achieve consensus on the QI specifications. The resulting 11 QIs were then evaluated by an online modified-delphi panel of multidisciplinary health professionals and patients (n = 43) to determine their relevance, validity and feasibility in three rounds of online voting and threaded discussion using a modified RAND/UCLA Appropriateness Methodology. Results: Response rates for the online panel were 86%. All 11 QIs were rated as highly relevant, valid and feasible (median rating 7 on a 1-9 scale) with no significant disagreement. The final QI set addresses the following themes: communication to primary care about increased CV risk in RA, CV risk assessment, defining smoking status and providing cessation counselling, screening and addressing hypertension, dyslipidemia and diabetes, exercise recommendations, body mass index screening and lifestyle counselling, minimizing corticosteroid use and communicating to patients at high risk of CVD about the risks/benefits of non-steroidal anti-inflammatory drugs. Conclusion: Eleven QIs for CVD care in RA patients have been developed and are rated 67

83 as highly relevant, valid and feasible by an international multidisciplinary panel. 68

84 3.2 Introduction Patients with RA have approximately a 50% higher mortality rate if they have a cardiovascular event when compared to the general population (25). Although chronic inflammation probably contributes to premature atherosclerosis and endothelial dysfunction (208), improvements in treatment for RA have not consistently translated into reduced cardiovascular disease (CVD) events (18, 209). Some authors have recently proposed there may be a trend towards a widening mortality gap in RA due to CVD, as survival rates from CV events have improved in the general population but have remained stagnant in RA populations (17, 18). Despite general recognition that patients with RA are at increased risk of CVD events, there is ample evidence that even well established CVD risk factors such as hypertension and dyslipidemia are not identified and managed consistently in RA populations (58, 64, 66, 71, 183, 184, ). One strategy to reduce CVD risk in RA is therefore to better identify and manage modifiable risk factors such as smoking, hypertension, obesity and dyslipidemia. Quality Indicators (QIs) are statements about optimum process or outcomes of care that can be further developed into performance measures. Performance measures have a specified numerator, denominator and exclusion criteria. They can be used for measuring the percent adherence to the process or the proportion of patients achieving the desired outcome and are critical for quality improvement initiatives (171). QIs are often based on guidelines from national or international professional societies but have a greater specificity than the recommendations from which they are derived (158, 171). They can represent either an optimum or minimum standard of care depending on the intended use of the measure (quality improvement versus accountability 69

85 e.g., in the form of pay for performance or use for accreditation). Although a variety of methodologies exist for developing QIs (158), a key feature of indicator development is the use of high grade evidence combined with expert opinion. Current QIs for RA focus primarily on the treatment of joint inflammation and the monitoring of drug side effects (161, 163, 167). To date, they have not completely addressed the most important cause of mortality in this population: cardiovascular disease. The objective of this study was to develop a set of QIs to address cardiovascular risk factor management in patients with RA for the purposes of quality improvement and research. The intended audience for the proposed indicators is healthcare professionals caring for patients with RA, primarily rheumatologists and other rheumatology providers (e.g., rheumatology nurses, clinical nurse specialists or nurse practitioners). In addition, the indicators are highly relevant to cardiologists, internists and primary care practitioners responsible for the medical management of patients with RA. 3.3 Materials and Methods The approach used to develop the CVD QIs is shown in Figure 3.1. The development of the CVD QIs for RA involved three phases: 1) a systematic review to define the existing best practices for CVD preventive care in RA and drafting of the candidate indicators, 2) an in-person expert panel meeting with 6 experts to achieve consensus regarding the scope, wording and specifications of the candidate measures and 3) an international online modified-delphi panel [n=43] employing a novel RANDdeveloped platform to finalize the indicators, rate the relevance, validity, and feasibility to RA care, while also obtaining feedback about whether the measures would be used in clinical practice. 70

86 3.3.1 Phase 1: A Systematic Review of Existing Guidelines and Indicators and Development of Background Reports Quality measures are often developed from existing guideline recommendations (158). Therefore in phase 1, a systematic review of existing guidelines and quality indicators in both the general population and RA literature was conducted and relevant manuscripts from the last five years ( ) were included. The detailed methods and results of the systematic review are published elsewhere (181). The results of the systematic review were used to identify best practices for cardiovascular care in patients with RA and to inform the development of candidate QIs. The QIs were worded in a standard format (IF-THEN-BECAUSE) to identify the clinical situation of interest (IF), the recommendation (THEN) and the evidence and rationale for the QI (BECAUSE). A clear numerator, denominator and exclusion criteria were also identified for each QI to ensure accurate measurement of the indicator upon application in a routine clinical practice setting (173). A report describing each candidate QI and its specifications as well as the supporting guidelines and reported level of evidence were generated for subsequent stages Phase 2: Expert Consensus Meeting to Finalize Scope, Wording and Specifications of Candidate Indicators The candidate indicators and associated reports were presented to a select group of cardiologists and rheumatologists from three academic centers in Canada (NA, GBJM, DL, SK, JAA-Z, JME). These individuals represented a convenience sample of clinicians and researchers with an expertise in CVD in RA and/or quality improvement. The 71

87 specifications and wording of the indicators were refined in an in-person meeting and consensus was achieved through an iterative process. These experts were not part of the online modified-delphi panel in Phase Phase 3: Online Modified-Delphi Panel with International Experts to Finalize the Candidate Indicators Using a Modified RAND/UCLA Appropriateness Methodology The candidate indicators were then presented to an online international panel using an innovative, iterative, online, previously evaluated platform called ExpertLens (178, 179), which has been previously used to elicit expert opinion on a range of healthcare topics, including the identification of definitional features of Continuous Quality Improvement (214) and of aspirational research goals for preventing suicide (215). Nonetheless, this is the first time the platform has been used for QI development. ExpertLens is an iterative online system used to obtain and analyze opinions from medium to large groups of people combining a number of approaches including the Delphi, Nominal Group and Crowdsourcing techniques (179). With the online platform a larger number of panellists can be included than in typical RAND/UCLA appropriateness panels, enabling diverse geographical representation, and the findings have been shown to be reproducible among different groups (178). The online panel is therefore more cost and time efficient than typical large international consensus meetings. Additional benefits of the system are the use of unique identifiers, which can avoid dominance of the group by a small number of vocal individuals (179) Online Panel Composition and Recruitment A diverse group of 43 expert stakeholders from North America and Europe were invited to participate including cardiologists, rheumatologists and primary care 72

88 physicians from both academic and non-academic practices. Pharmacists, nurses, clinician scientists, and patients were also represented. Although many participants were recruited based on their prior publications in the area of CVD in RA, effort was also made to include clinicians in community practices and other types of participants including patients. These individuals were identified through a variety of means including National Societies (e.g., Canadian Rheumatology Association, Allied Health Professions Association), patient advocacy groups (e.g., Arthritis Patient Advisory Board of the Arthritis Research Center of Canada) as well as snowball recruitment. Participants were recruited via an invitation and agreed to participate prior to the panel start date. Participants did not receive financial incentives for participation. The University of Calgary Conjoint Health Research Ethics Board [ethics identification REB ] approved the project and the RAND Human Subjects Protection Committee determined this study to be exempt from review Panel Rating of Relevance, Validity, Feasibility, and Likelihood of Use of the QIs Between November 4 th and December 3 rd 2013, participants took part in a three round ExpertLens process. In Round 1, participants rated QIs on four criteria (see Table 3.1 for description of criteria). In Round 2, they reviewed the automatically-generated distribution of group s responses to each question that included: (1) a bar chart showing the frequency of each response category for the group, (2) a group median, (3) interquartile range and (4) participant s own response to that question (see Appendix B1). Participants also were encouraged to participate in an online, asynchronous, anonymous discussion, which was moderated by CEHB to ensure they remained on-topic and 73

89 constructive. Finally, in Round 3, participants were requested to revise their Round 1 responses based on group feedback and discussion and share their study experiences by answering a brief series of satisfaction questions. Each round was open for 7 to 14 days, depending on participation rates. Periodic reminders to participate were sent via to maximize participation. Participants were asked to rate candidate QIs on the following four rating criteria during Round 1 and again in Round 3. The first two criteria have been used previously to assess validity and feasibility (169, 177), the third and fourth criteria were formulated during Phase 2 with the expert panellists to assess relevance and likelihood of use. All criteria were Likert-type 1-9 scales with labeled end points. Detailed definitions of each criterion are shown in Table Analysis of panellist responses To be included in the final set, indicators had to be rated as highly valid and feasible (median validity and feasibility scores 7), with no disagreement among participants. Disagreement was calculated using a formula that examines the distribution of the ratings according to the RAND/UCLA Appropriateness Method handbook (174). Disagreement exists when the Interpercentile Range (IPR) (difference between the 30 th and 70 th percentiles) is larger than the Interpercentile Range Adjusted for Symmetry (IPRAS), which was calculated using the following formulae: IPRAS=2.35+[Asymmetry Index (AI)*1.5](derivation of the formulae shown in the RAND/UCLA Appropriateness Method handbook (174)). 74

90 3.4 Results The results of the systematic review of existing guidelines and QIs are presented elsewhere (181). Briefly, recommendations and indicators were abstracted from both RA and general population guidelines that were relevant to primary CVD prevention (e.g., CVD risk assessment, lipid, diabetes and hypertension screening, exercise, smoking and lifestyle counselling). Based on the systematic review results, a set of 12 candidate indicators was drafted and presented to the Phase 2 small expert working group of two cardiologists and four rheumatologists at an in-person meeting (Phase 2, Figure 3.1). The 12 drafted indicators encompassed the following topics: communication of the importance of CVD care in RA to the primary care provider, CVD risk assessment, smoking status and counselling for cessation, screening for hypertension, communicating to a primary care provider about an elevated blood pressure, blood pressure control, measurement of a fasting lipid profile, dietary counselling, exercise counselling, corticosteroid tapering to lowest dose, and avoidance of NSAIDs in patients at high risk of CVD events. The expert panel in Phase 2 made recommendations as to the wording of the indicators and the specifications. Major expert panel recommendations included the following: Outcome measures (or interim outcome measures) such as blood pressure targets should not be included in the QI set because such measures were not felt to be in the rheumatologist s scope of practice. Although maintaining a low disease activity state or remission was felt to be important in reducing CVD risk in patients with RA, general treatment of RA and 75

91 measurement of disease activity was not felt to be within the scope of these QIs because of the focus on QIs that specially address CVD. Many of the QIs were designed to measure communication between the rheumatologist and other care providers to encourage a cohesive approach to monitoring and caring for CVD risk and to recognize that CVD risk management is a responsibility that is shared between all physicians who care for a patient with RA but is not necessarily the primary responsibility of the rheumatologists. Frequency of conducting a formal CVD risk assessment was discussed and minimum intervals were proposed in accordance with guideline recommendations. The timing of other measures where there was no guideline for the frequency of measurement was based on the panel s consensus. Stand alone QIs that recommended only measuring a risk factor without a specific action (e.g., measuring a lipid profile or ascertaining smoking status) were discouraged as it was felt that this may lead to clinical inertia (e.g., measuring more lipid profiles but not calculating CVD risk or appropriately treating if indicated). A QI on screening for diabetes was recommended and added to the set. The QI on dietary counseling was not felt to be within the purview of a rheumatologist and measuring body mass index (BMI) was recommended instead. A revised set of 11 QIs was selected for presentation to the ExpertLens panellists. 76

92 3.4.1 ExpertLens Panel Participant Characteristics and Participation Rates There were 43 individuals who were invited to participate in the online ExpertLens panel, of which 37 (86.0%) participated. The self-reported characteristics of the ExpertLens participants are shown in Table 3.2. Twenty-eight completed all three rounds (65%). There were four participants who completed Round 1, but not Round 3, and five who completed Round 3, but not Round 1. During Round 2 (online discussion board), there were 24 discussion threads and 113 discussion comments. As this demographic information was asked during Round 1, a maximum of 32 respondents answered these questions. In a sensitivity analysis, we analyzed the responses from all participants who completed Round 3 and also on those who completed both Round 1 and 3; there were no significant differences (in Table 3.3 we report the results from individuals who participated in both rounds) Cardiovascular Disease Quality Indicators After Round 2, a few minor changes to the QIs were made based on feedback from earlier rounds and presented to the panel in Round 3. For example, for QI 4 (Screening for hypertension), the specifications of the measure originally suggested at a minimum measuring the blood pressure once per year; however, panellists expressed during Round 2 discussions that this was not frequent enough (especially since many rheumatologic medications impact blood pressure) and the measure was modified to better reflect guideline recommendations which suggest more frequent screening. In Round 3, all eleven CVD QIs were rated as highly relevant, valid, and feasible by the panellists without significant disagreement (Table 3.3). Participants also agreed 77

93 that they were likely to advocate for the QIs to be used in local quality improvement initiatives. The final indicator statements are shown in Table 3.4, and the full specifications, including descriptions of the numerator, denominator and relevant exclusions, are shown in Appendix B Discussion The proposed set of 11 CVD QIs for RA has been agreed upon as highly relevant, valid and feasible for measurement and quality improvement initiatives in RA by a large international, multidisciplinary panel of healthcare professionals and patients. The recommended QIs comprehensively cover many aspects of CVD preventive care in RA and are evidence-based and aligned with current high-quality guidelines based on our systematic review (181). Where RA guidelines were lacking in evidence to support these measures, it was decided that as a minimum, general population guidelines should be followed and these were used to support and help define the QIs. The 11 QIs define processes important to CVD preventive care in RA. Riskadjusted outcome or interim outcome measures (e.g., lipid or blood pressure targets) were not felt to be within the scope of this project as it was determined that screening for CVD risk factors and primary prevention should be a shared responsibility and not solely the responsibility of the rheumatologist. Importantly, in the United States, the National Quality Strategy recognizes care coordination as an important gap in quality measurement (216). The set of CVD QIs are unique as they emphasize communication between providers in caring for patients with RA, which we hope will improve coordination of comorbidity care for patients with RA. 78

94 Our work represents the first time ExpertLens has been used for QI development and shows that the online platform had a number of advantages. Typical RAND/UCLA appropriateness panels used for QI development frequently have a limited number of participants (often 9), which limits the diversity among participants and may prevent inclusion of informed patients as included participants are often experts (174). By using the online platform, we were able to get broader representation from a diverse group of international participants. Unfortunately, not all recruited participants ended up providing their expert opinion. This may have been for a variety of reasons. Some participants may not have been available during panel times or decided not to participate. Others may not have received ExpertLens invitation s, which could have been re-routed to the spam folders of their inbox by their provider. Nonetheless, our overall participation rate of 86% was excellent and compared favourably with participation rates in other ExpertLens (178) and online Delphi panels with fewer rounds (217). An advantage of the online platform was the ability to anonymously obtain responses and discussion threads on topics from participants, which avoided dominance of the discussion by a subset of participants. Some participants commented, however, that they would have liked more time to discuss the QIs or would have benefited from a conference call to review certain aspects of the measures. However, by Round 3, general consensus was achieved, and it is unknown if further discussion in person or online would have altered the measures significantly. To mitigate the potential disadvantages of holding a QI development panel entirely online alluded to above, we first had a small meeting of experts to review the QI specifications and wording. Based on the recommendations of this group, QIs, which 79

95 only measured clinician documentation of a risk factor, e.g., smoking status, or lipid profile, were discouraged as it was felt they would be unlikely to lead to quality improvement if clinicians were not prompted to do something if a risk factor was identified. Therefore, some of the proposed measures included more than one measurement concept (e.g., documenting smoking status AND recommending smoking cessation). This potentially made voting challenging for some of the online participants who may have agreed with one part of the QI, but not another and consequently may have led to lower ratings for some of the presented QIs. As the measures are for quality improvement and not accountability, we feel that it is reasonable that a measurement concept be coupled with an action concept to avoid clinical inertia, while recognizing that it increases the complexity of executing and practically assessing the measure. An additional strength of this work is the diversity of individuals who participated from around the world. Nonetheless, it should be noted that recruitment of individuals from community practice (especially rural practice), as well as certain physician types (e.g., general internists and primary care practitioners) was challenging because these individuals were harder to identify and recruit. Consequently these groups were underrepresented. As shown in the literature (218), it is possible that panels with a different composition could have voted differently on the proposed indicators. In this case, it is possible that feasibility ratings for some of the indicators may have been lower if the panel composition had included more rheumatologists in community practice. We encourage pilot testing of the indicators and selection of the most appropriate measures depending on the clinical setting. 80

96 We plan to further validate the QIs in rheumatology practice. This further work will involve evaluation of the feasibility of measuring the indicators in different practice settings, measurement of inter-rater reliability, assessing whether a gap in care exists and determining how best to implement improvements (172, 173). In conclusion, patients with RA have a significantly higher rate of death due to CVD than the general population. Ensuring high quality CVD preventive care for patients with RA is one method of potentially mitigating this risk and is in keeping with current RA and general population guidelines. In this study, we proposed a comprehensive set of 11 CVD QIs for patients with RA for the purposes of quality improvement and research. Our work represents the first time ExpertLens has been used for QI development and shows that the online platform had a number of advantages and is a useful tool for QI development. 81

97 Systematic review of existing guidelines and quality indicators 12 Candidate quality indicators identified Face-to-face meeting of experts in cardiology and rheumatology to finalize wording and specifications of the quality indicators 11 Candidate quality indicators specified ExpertLens panel voting on validity, feasibility and relevance of the quality indicators Panel rated all 11 indicators as valid, feasible and relevant Figure 3.1 Methods for developing the quality indicator set for cardiovascular care in rheumatoid arthritis 82

98 Criterion Relevance Table 3.1 Description of criterion used to select quality indicators Question Please rate the relevance of the above indicator (1=not relevant, 9=relevant). In doing so, consider whether: The aspect of care covered by the above quality indicator is relevant to high quality care for patients with rheumatoid arthritis. Validity Feasibility Please rate the validity of the above indicator (1=not valid, 9=valid). In doing so, consider whether: There is adequate scientific evidence or professional consensus to support the indicator. There are identifiable health benefits to patients who receive care specified by the indicator. A physician with significantly higher rates of adherence to the indicator would be considered a higher quality provider, in your experience. The majority of factors that determine adherence to the factor are under the control of the physician. Please rate the feasibility of the above indicator (1=not feasible, 9=feasible). In doing so, consider whether: The information necessary to determine adherence to the quality indicator described above is possible to find in an average medical record. Failure to document such information itself is a marker of poor quality of care. The estimate of adherence to the indicator based on medical record data is likely to be reliable and unbiased. Use Considering the above quality indicator, please rate how likely (1=not likely, 9=likely) you would be to use or encourage the use of the measure for internal quality improvement in your practice/center. 83

99 Table 3.2 Self-reported ExpertLens participant characteristics Participant characteristics * N (%) Professional Background Physicians Allied health professionals Patients Methodologists/researchers Physician and methodologist/researcher** Country Canada United States of America Europe Other No response Other characteristics 26 (81.3%) 2 (6.3%) 2 (6.3%) 1 (3.1%) 1 (3.1%) 14 (43.8%) 6 (18.8%) 9 (28.1%) 1 (3.1%) 2 (6.3%) Urban 31 (96.9%) Prior Quality Indicator Work 12 (37.5%) Prior Guideline Work 16 (50%) Health Professional Characteristics (includes physicians and allied health professionals) Health Professional Specialty Rheumatology Cardiology Primary care Other Years in practice < >21 No response Practice Setting Community Academic: clinical/teaching Academic: research No response 16 (55.2%) 8 (27.6%) 3 (10.3%) 2 (6.9%) 3 (10.3%) 5 (17.2%) 10 (34.5%) 10 (34.5%) 1 (3.4%) 3 (10.3%) 18 (62.1%) 6 (20.7%) 2 (6.9%) *Note only a maximum of 32 participants responded to the demographic questions and all percentages calculated based on this maximum response rate for this section. ** Background was mutually exclusive with no original option for methodologist/researcher, however one participant listed themselves as a researcher and clinician, which was added here. As shown in practice setting there are potentially six individuals who may better fit this category. 84

100 Table 3.3 Final validity, feasibility and relevance ratings from the ExpertLens panel on the 11 cardiovascular quality indicators Quality Indicator Validity Feasibility Relevance Use of QI for local improvement 1. Communication of increased CVD risk in RA 2. CVD risk assessment 3. Smoking status and cessation counselling 4. Screening for hypertension 5. Communication to PCP about a documented high BP 6. Measurement of a lipid profile 8.0 (4-9) 88.9% 8.0 (5-9) 85.7% 9.0 (6-9) 96.4% 9.0 (5-9) 96.4% 9.0 (7-9) 100% 7.5 (4-9) 82.1% 7. Screening for 8.0 (4-9) diabetes 89.3% 8. Exercise 8.0 (6-9) 96.4% 9. BMI screening 8.0 (4-9) and lifestyle 89.3% counselling 10. Minimizing corticosteroid usage 11. Communication about risks/benefits of antiinflammatories in patients at high risk of CV events 9.0 (5-9) 92.9% 8.0 (4-9) 85.2% Median Rating (Min-Max) % Agreement (Rating>=7) 8.0 (5-9) 85.7% 7.0 (3-9) 67.9% 8.5 (6-9) 92.9% 9.0 (7-9) 100% 9.0 (7-9) 100% 8.0 (4-9) 89.3% 8.0 (4-9) 82.1% 8.0 (5-9) 85.7% 8.0 (4-9) 78.6% 8.0 (4-9) 85.7% 7.0 (3-9) 78.6% 8.0 (5-9) 92.9% 7.0 (3-9) 88.9% 8.5 (6-9) 100% 9.0 (7-9) 96.4% 9.0 (7-9) 100% 8.0 (4-9) 85.7% 8.0 (4-9) 92.9% 8.0 (5-9) 89.3% 8.0 (4-9) 92.9% 8.0 (4-9) 92.9% 7.0 (3-9) 85.7% 8.0 (1-9) 82.1% 7.5 (3-9) 67.9% 9.0 (5-9) 92.9% 9.0 (7-9) 100% 9.0 (4-9) 92.6% 8.0 (3-9) 82.1% 8.0 (3-9) 85.2% 8.0 (3-9) 77.8% 7.0 (3-9) 85.7% 8.5 (1-9) 85.7% 7.0 (1-9) 75.0% Disagreement * in any of the domains (Y/N) The results presented are those obtained from the 28 participants who completed both Round 1 & Round 3 of voting. Possible range of scores is 1-9. Disagreement measured using the Interpercentile Range greater than the Interpercentile range adjusted for symmetry (IPR>IPRAS) (174). Disagreement exists when the Interpercentile Range (IPR) (difference between the 30 th and 70 th percentiles) is larger than the Interpercentile Range Adjusted for Symmetry (IPRAS), which was calculated using the following formulae: IPRAS=2.35+[Asymmetry Index (AI)*1.5] Abbreviations: Cardiovascular Disease (CVD), Body Mass Index (BMI), Blood Pressure (BP), Primary Care Physician (PCP), Rheumatoid Arthritis (RA) N N N N N N N N N N N 85

101 Table 3.4 Final set of eleven cardiovascular disease quality indicators for rheumatoid arthritis patients 1. Communication of increased CV risk in RA: IF a patient has rheumatoid arthritis, THEN the treating rheumatologist should communicate to the primary care physician, at least once within the last 2 years that patients with RA have an increased cardiovascular risk. 2. CV risk assessment: A) IF a patient has rheumatoid arthritis THEN a formal cardiovascular risk assessment according to national guidelines should be done at least once in the first two years after evaluation by a rheumatologist AND B) if low risk it should be repeated once every 5 years; OR C) if initial assessment suggests intermediate or high-risk, THEN treatment of risk factors according to national guidelines should be recommended. 3. Smoking status and cessation counselling: A) IF a patient has rheumatoid arthritis THEN their smoking and tobacco use status should be documented at least once in the last year AND B) if they are current smokers or tobacco users they should be counselled to stop smoking. 4. Screening for hypertension: IF a patient has rheumatoid arthritis THEN their blood pressure should be measured and documented in the medical record at 80% of clinic visits. 5. Communication to PCP about a documented high blood pressure: IF a patient has rheumatoid arthritis AND has a blood pressure measured during a rheumatology clinic visit that is elevated (systolic blood pressure 140 and/or diastolic blood pressure 90) THEN the rheumatologist should recommend that it be repeated and treatment initiated or adjusted if indicated. 6. Measurement of a lipid profile: IF a patient has rheumatoid arthritis THEN a lipid profile should be done at least once in the first two years after evaluation by a rheumatologist AND A) if low risk according to cardiovascular risk scores, the lipid profile should be repeated once every 5 years; OR B) if cardiovascular risk assessment suggests intermediate or high-risk, then treatment according to national guidelines should be recommended. 7. Screening for diabetes: IF a patient has rheumatoid arthritis THEN diabetes should be screened for as part of a cardiovascular risk assessment at least once within the first 2 years of evaluation by a rheumatologist and A) once every 5 years in low risk patients or B) yearly in intermediate or high-risk patients AND if screening is abnormal, this information should be communicated to the primary care provider for appropriate followup and management if indicated. 8. Exercise: IF a patient has rheumatoid arthritis THEN physical activity goals should be discussed with their rheumatologist at least once yearly. 86

102 9. BMI Screening and Lifestyle Counselling: A) IF a patient has rheumatoid arthritis THEN their body mass index (BMI) should be documented at least once every year AND B) if they are overweight or obese according to national guidelines they should be counselled to modify their lifestyle. 10. Minimizing corticosteroid usage: IF a patient with rheumatoid arthritis is on oral corticosteroids THEN there should be evidence of intent to taper off the corticosteroids or reduce to the lowest possible dose. 11. Communication about risks/benefits of anti-inflammatories in patients at high risk of CV events: IF a patient has rheumatoid arthritis AND has established cardiovascular disease OR is at intermediate or high cardiovascular risk AND is on a non-steroidal anti-inflammatory drug (NSAID or Cox-2 inhibitor) THEN a discussion about the potential cardiovascular risks should occur and be documented. 87

103 Chapter Four: Gaps in addressing cardiovascular risk in rheumatoid arthritis: assessing performance using cardiovascular quality indicators 88

104 4.1 Abstract Objective: Cardiovascular disease (CVD) is a major comorbidity for patients with rheumatoid arthritis (RA). We sought to determine performance on 11 recently developed CVD Quality Indicators (QIs) for RA in routine clinical practice. Methods: Medical charts for RA patients (early disease or biologic-treated) followed at one centre were retrospectively reviewed. A systematic assessment of adherence to 11 QIs over a two-year period was completed. Performance on the QIs is reported as a percentage pass rate. Results: 170 charts were reviewed (107 early disease and 63 biologic-treated). The most frequent CVD risk factors present at diagnosis (early disease) and biologic start (biologictreated) included hypertension (26%), obesity (25%), smoking (21%) and dyslipidemia (15%). Performance on the CVD QIs was highly variable. Areas of low performance (<10% pass rates) included documentation of a formal CVD risk assessment, communication to the primary care provider that patients with RA are at increased risk of CVD, body mass index documentation and counselling if overweight, communication to a primary care provider about an elevated blood pressure, and discussion of risks and benefits of anti-inflammatories in patients at CVD risk. Rates of diabetes screening and lipid screening were 67 and 69% respectively. The area of highest performance was observed for documentation of intent to taper corticosteroid (98-100% for year 1 and 2 respectively). Conclusion: Gaps in CVD risk management were found and highlight the need for 89

105 quality improvements. Key targets for improvement include coordination of CVD care between rheumatology and primary care and communication of increased CVD risk in RA. 90

106 4.2 Introduction Cardiovascular disease (CVD), including myocardial infarction (MI) and stroke, is more common in patients with rheumatoid arthritis (RA) compared to the general population, with an estimated increased risk of 48% for incident CVD (26). The reasons for this increased risk are complex, ultimately reflecting the consequences of the inflammatory process predisposing to endothelial dysfunction (46, 47, 49, 219, 220) and premature atherosclerosis (82, 145, 221). Despite improvements in the treatment of the inflammatory burden in RA, there continues to be evidence of a widened mortality gap (23). One potential contributor is the under-identification and under-treatment of traditional CVD risk factors frequent in RA patients, including smoking, hypertension, obesity and dyslipidemia (58, 64, 66, 183), treatment for which results in improved CVD outcomes in the general population. To guide an improvement in the quality of CVD care delivered to patients with RA we developed a set of 11 CVD quality indicators (QI) to assess risk factor screening and management (182). The QIs were developed following a systematic review of guidelines and existing QIs (181) and a subsequent multi-step process involving an online modified Delphi panel of international experts who rated the validity, expected feasibility, relevance and importance of the proposed QIs (182). Full descriptions of the QIs, including the inclusion and exclusion criteria for each QI, are published elsewhere (182). In this study we report on the adherence to the CVD QIs for two cohorts of RA patients followed at the University of Calgary Rheumatology Clinics: an early RA (ERA) cohort and a biologics-treated RA cohort. The objective of the study was to determine the 91

107 performance on the QIs over a two-year measurement period, while concurrently assessing the feasibility of capturing the QIs from subspecialty medical records. 4.3 Patients and Methods Patient Population Two established patient cohorts were used in the study to represent a spectrum of both disease and treatment. i) ERA cohort: The cohort was established in 2004 to accept patients with arthritis of recent onset (<12 weeks) (222, 223). ERA patients were selected from this cohort (see inclusion criteria below). Standardized data are collected at baseline including demographic information (age, gender, ethnicity, duration of symptoms and comorbidities) and medication history. Disease activity, medications and functional status are recorded at each clinic visit. Patients are typically followed for one year in this clinic and then discharged to the regular rheumatology clinic for follow-up. Follow-up intervals and treatment of patients are at the discretion of the treating rheumatologist (n=7). ii) The Alberta Biologics Pharmacosurveillance Program (ABioPharm - Calgary). This provincial registry was initiated in 2000 to evaluate the efficacy, safety and costeffectiveness of biologic therapies for patients with RA (224, 225). Patients are assessed at baseline initiation or switching of a biologic, 3 months after new therapy initiation, and then yearly or more frequently if required. Data elements collected are the same as for the ERA cohort. For this study, only data for Calgary patients (n=10 rheumatologists) with a new therapy initiated during the study period were reviewed. 92

108 4.3.2 Inclusion Criteria Charts were randomly selected using a computer-generated random sample of half of the patients from each physician in each of the two cohorts and included if the patient met 2010 criteria for RA (37), had no pre-existing diagnosis of CVD including prior MI, stroke, or peripheral vascular disease, and were enrolled in one of the cohorts between January 1 st 2010 and August 1 st This start date was selected as it was approximately 3 months after the online publication of a set of international recommendations for CVD risk management for patients with RA (149), bringing heightened attention to the need for management of this comorbidity Data Sources and Abstraction Medical charts of patients enrolled in either cohort were randomly selected for retrospective review. This included both rheumatologists paper charts and electronic medical records. It did not include review of primary care or other consultant specialist charts. Three reviewers with medical training abstracted the data independently (one rheumatologist, one cardiologist and one medical student). Standardized data abstraction forms were developed to capture the data elements listed in the next section (shown in Appendix C1) Sample Size Calculations As routine CVD screening is not currently a mandate for either of these clinics, a worst-case scenario of 50% +/- 10% adherence to the QIs was assumed when conducting sample-size calculations. Sample size adjustments were also made to account for physician practice variation using an inter-class correlation coefficient of 0.05 (226) as 93

109 well as the population sizes of eligible patients in the two cohorts (217 in ERA and 148 in the biologics cohort). Based on these calculations a minimum of 59 biologic charts and 98 ERA would need to be included. To ensure that performance rates were estimated with the desired precision some additional charts were included. Further estimation of confidence intervals was not done for QI pass rates as our sample size ensures a precision of +/- 10% or narrower Clinical Variables Comorbidities including hypertension, diabetes and dyslipidemia were deemed present at baseline if there was a documented history in the medical record or the patient was on treatment for the condition. Obesity was defined as a body mass index (BMI) 30 kg/m 2 and overweight as a BMI kg/m 2. Hypertension was defined as 140/90 mmhg and patients with a lower recommended threshold due to diabetes or chronic kidney disease were excluded from the denominator of hypertension QIs, as other published guidelines and/or quality measures better applied to these populations. Medications were captured from case record forms and chart review at each clinic visit. Where there was disagreement between the case record forms and the chart review, the data in the medical chart was used Cardiac Risk Assessment A Stata module (Framingham) (227) was used to calculate a baseline 10-year Framingham risk score (FRS) (189) in eligible patients (ages of years and not on a statin at baseline). The FRS was chosen as it is recommended by the Canadian Cardiovascular Society Guidelines (62). Lipid values closest to the baseline visit were 94

110 used in FRS calculation within a window up to 6-months prior to the baseline visit or one-year post visit, which is more stringent than previous retrospective applications of the score (143). Patients for whom a 10-year FRS score could be calculated were classified into the following levels of risk: <10% (low risk), 10 to 19% (intermediate risk), 20% (high risk) (62). Disease activity was calculated using the Disease Activity Score-28 ESR (DAS- 28) (228, 229) and patients were classified according to disease activity score: remission ( 2.6), low disease activity ( ), moderate disease activity ( ) and high disease activity (>5.1). The Health Assessment Questionnaire (HAQ) measured baseline functional status (230) Analysis Descriptive statistics for the combined patient population and each cohort were used to summarize baseline clinical features and cardiovascular comorbidities using proportions and means and their standard deviation (SD) or medians (interquartile range, IQR), depending on the normality of the data. N denotes the number of total observations available in the Tables where the numbers were less than the expected total cohort size because of missing values. Chi-square or Fisher s exact test and t-tests or Wilcoxon-Mann-Whitney tests as appropriate for the data were used to investigate baseline characteristics for patients where a FRS could be computed compared to those in whom it could not. Adherence to each QI was reported as a percentage and calculated based on the predefined criteria for the numerator, denominator and for exclusion (182) (case record 95

111 form shown in Appendix C1). Patients were not eligible for inclusion in the denominator of measures reported at year two if one or more of the following conditions were met. The patient: i) was lost to follow-up; ii) died; iii) was followed less than two years based on their baseline date of study entry; iv) had a CVD event during the course of follow-up. Inter-rater reliability of extraction of data was assessed on 48 randomly selected charts reviewed in duplicate. The percent agreement and Cohen s Kappa (231) were calculated for each QI. Kappa scores were interpreted according to suggested guidelines (232): almost perfect agreement ( ), substantial agreement ( ), moderate agreement ( ), fair agreement ( ), slight agreement ( ). Stata IC version 13.1 (StataCorp, College Station, Texas) was used for all analyses (233) Ethics Approval The University of Calgary Health Research Ethics Board approved this project (REB ). 4.4 Results Baseline Characteristics Demographic and clinical characteristics of the included patients are shown in Table 4.1. There were 170 patients included in total (63 in the biologics cohort and 107 in the ERA cohort) with a mean age of 55 years and 70% were female. The median total available follow-up between the baseline date and last clinic visit within the two-year window of evaluation was 607 days and the median number of visits was 6. When compared to other ERA and biologic cohorts the baseline demographic information were similar (234, 235). 96

112 As expected, the RA patients from the biologics cohort had higher disease activity, worse functional status, more erosions, nodular disease and extra-articular manifestations of RA compared to the ERA cohort (see Table 4.1). Baseline treatments are shown in Table 4.1, 38% were on a non-steroidal anti-inflammatory drugs (NSAIDs), while 22% received oral prednisone. Over the course of follow-up the disease activity declined to a mean DAS28 of 2.3 ± 1.2 and 76% were in clinical remission. A total of 7 patients were lost to follow-up, 2 patients could not be assessed for two-year outcomes based on their baseline date of entry in to the cohorts and 2 patients had cardiovascular events documented in the medical record. For these reasons, 11 patients in total were not included in the denominators of year 2 QI reporting or in QIs where measurement occurred over a 2-year period Cardiovascular Risk Profile The cardiovascular risk profile of patients is shown in Table 4.2. A quarter of patients had a history of hypertension (26%), and 90% these patients were on treatment. A further 14% had elevated blood pressures ( 140/90) at their first visit but had no preexisting documented history of hypertension. A quarter of patients were also obese (25%). Eleven patients had diabetes (7%) and 26 (15%) had dyslipidemia. Twenty percent of patients were current smokers and a third were ex-smokers. Based on available information a baseline FRS could be calculated for 44% of eligible patients (n=59). Where a FRS could be calculated, 34% were at intermediate or high risk of CVD events. We examined the clinical characteristics between patients for whom there was enough available information to calculate a FRS compared to eligible patients who did not have enough information to calculate an FRS and there were no statistically significant 97

113 differences when comparing age, sex, number of visits and baseline cardiovascular comorbidities Quality Indicator Reporting The results of the QI reporting are shown in Table 4.3. The lowest performance rates were on documentation of a formal CV risk assessment (QI #2), which was not present on any of the charts during the period of review. Low performance rates (2%) were also observed for communication to the primary care practitioner that RA is associated with an increased risk of CVD disease (QI #1). High performance rates (94%) were noted with baseline documentation of smoking status (QI #3a); however by year two, re-documentation of smoking status in known smokers was lower (42%). Documentation of smoking cessation advice to current smokers (QI #3b) was low in both measurement years (17% and 24% in year 1 and year 2, respectively). QI#4 assesses whether a blood pressure has been measured at 80% or more of clinic visits during each measurement period. For this QI, performance rates for year 1 and 2 were 58 and 66%, respectively. However, when an elevated blood pressure was recorded, recommendations for addressing this were rarely sent back to the primary care provider (5% and 7% in year 1 and 2, respectively, QI #5). Lipid (QI #6) and glucose screening (QI #7) were measured over the two-year period of follow-up in 69% and 67% of charts, respectively. However, QI #7b, which captured whether there has been yearly measurement of a fasting glucose or a hemoglobin A1C in individuals with risk factors for diabetes, was slightly lower (48% in year 1 and 54% in year 2). 98

114 Yearly discussion of physical activity recommendations (QI #8) had poor performance in year 1 (33%) that declined in year 2 (15%). Similarly BMI screening rates were low (QI #9a, 4-6%). Although the rates of calculation of BMIs were low, height and weight were available on the majority of patients and were used to estimate the denominator for QI #9b, which captures lifestyle counselling to overweight and obese patients. Performance on this part of the indicator was also low (5-9%). Finally, with regards to the two treatment QIs, performance on QI #10 (minimizing corticosteroid usage) was high (98-100% depending on the measurement year). In contrast, communication regarding risks of NSAIDs in patients at intermediate or high risk of CVD events was low, although the denominator was small as many patients were excluded as the level of risk was uncertain or they were not clearly on NSAIDs during the year of measurement. While the mandate of this study was not to compare the QI performance rates between cohorts, the majority of performance rates were similar between them with two exceptions. The rate of blood pressure screening was significantly lower in year 1 in the biologics cohort compared to the ERA cohort (33% versus 72%, p<0.001) and the rates of exercise counselling were higher in the ERA cohort in year 1 compared to the biologics cohort (41% versus 19%, P=0.003) Inter-rater Reliability of QIs Inter-rater reliability was calculated using Cohen s Kappa for each QI in 48 charts (Table 4.4). Overall there was moderate to perfect agreement in 11 out of 13 measures where a Kappa score could be calculated (85%) with some variation in scores by year noted. Because of the known properties of Kappa, whereby QIs with a high or low performance can be accompanied by a high agreement but a low Kappa score (236), two 99

115 Kappa scores were misleading (QI #1 Communication of increased CV risk in RA and QI #2b, If initial risk assessment suggests intermediate or high-risk, THEN treatment of risk factors according to national guidelines should be recommended, Table 4.4). 4.5 Discussion Our study systematically addresses performance on recently developed CVD QIs for RA (182). The performance review highlights a number of potential gaps in cardiovascular screening and care in RA patients. Consistent with reports from other cohorts, including the recently published Comorbidities in RA (COMORA) study (58), our patients have a high burden of cardiovascular risk factors including high rates of hypertension (26%), obesity (25%) and smoking (20%), and would benefit from improvements in screening and management of CVD risk. There is substantial debate in the rheumatology community about the role rheumatologists should play in evaluating and treating CVD risk factors (237). Proponents of the rheumatologists taking a role in management of CVD risk cite deficits in primary care screening management of CVD risk factors in RA (64, 72, 210, 211). Indeed prospective and systematic evaluation of RA patients in a number of studies has uncovered previously unidentified and untreated risk factors including hypertension, dyslipidemia and hyperglycemia (58, 66). Conversely, primary care physicians are expert in CVD screening in the general population and some argue that screening should occur in primary care. Although to accomplish better primary care screening for CVD risk in RA, primary care education and improved coordination of care with the rheumatologist are likely necessary to achieve optimal processes and outcomes (195, 237). 100

116 Unfortunately, a major critique of systematic assessment for CVD risk factors is that it can be time consuming (66). The CVD QIs evaluated in this study were developed and worded to enhance CVD care in RA without placing the entire burden of care on the rheumatologist (182). For example, many of the QIs are framed in such a way that captures whether another physician, e.g., the primary care provider, was reminded to monitor the patients cardiovascular risk factors which shares the burden of care and removes it somewhat from the rheumatologist, who may be less familiar with CVD treatment guidelines. Unfortunately, many of the communication QIs had poor adherence. QI #5 (which captures communication to a primary care provider about a documented high blood pressure) is one example. Also, CVD preventive care such as smoking cessation advice, exercise review and lifestyle counselling may be happening in clinic, but is poorly documented. Failure to document such discussions is an opportunity for quality improvement not only in CVD risk screening but also in coordination of care between the rheumatology team and primary care. Although the main objective of the study was not to compare the performance of the QIs between the cohorts, two areas were noted where there were significant differences between them. Performance on QI #4 (Blood pressure measurement) was higher in the ERA cohort compared to the biologics cohort and this may reflect differences in who was collecting baseline clinic in the cohort charts (i.e., there were more nursing assessments in the baseline biologic assessments and it is possible that routine blood pressure estimation was done less frequently for these visits than a typical rheumatologist visit). Exercise (QI #8) was more frequently discussed in the ERA cohort 101

117 in year 1 and this likely reflected the practice of referring new patients for a physiotherapy assessment and exercise counselling in this cohort. Our study demonstrated that although cardiovascular risk estimation was not documented in this study (QI #2a), 69% of the time there was a lipid profile done within 2 years of baseline (QI #6) and often there was available information for calculation a risk score, which is substantially higher than in other reports (183). Also of note for QI #9A, although BMI was actually calculated on very few charts, both height and weight were captured on all charts at baseline but this did not meet criteria for the QI numerator. Failure to document BMI and CVD risk assessments may be lost opportunities for identification of risk and further work will need to be done to examine barriers to risk estimation and CVD screening in the rheumatology clinic. Alternatively, an evaluation of primary care practices of CVD risk estimation and treatment in RA could be done to better understand this suspected gap in care as our study did not have access to primary care records and it is unclear to what degree risk assessment and treatment is occurring at this level in our region. Limitations of our study and application of our approach for other centres are recognized. Firstly, although the QIs could be measured using information extracted from patient charts, it should be highlighted that the process was time consuming and resource intensive, and may not be a practical approach in routine practice. Secondly, although 85% of all QIs had moderate to perfect agreement based on Kappa score, not all QIs met this threshold. We do not believe this substantially impacted our final results as our results are based on a gold standard review, where any disagreements between 102

118 reviewers were evaluated and verified in the chart to obtain the most accurate data capture. During our assessment of inter-rater reliability, we noted three types of potential challenges with applying the QIs and we have identified potential solutions below: 1. Issues with correctly determining eligibility for a QI: Accurate calculation of dates is required to ascertain whether a patient was eligible for a QI performance rate assessment. Errors may also have occurred where criteria for inclusion into denominators were more complex. An example of this would be QI #11, were performance was based on two or more factors, i.e., where patients in the denominator had to be on NSAIDs, AND had to have intermediate or high risk for CVD during the required time period of evaluation. Electronic capture of the QIs with automatic calculation and checking of dates as well as eligibility criteria would be the best method of rectifying this problem. 2. Difficulty interpreting QI wording to ascertain inclusion in the numerator: this was most problematic for QI #8 (Exercise: IF a patient has rheumatoid arthritis THEN physical activity goals should be discussed with their rheumatologist at least once yearly). Although specific criteria for meeting this were listed in the case record form, there were different interpretations of eligibility for this QI. We suggest a modification to the inclusion criteria for the QI, which requires healthcare provider documentation that the patient is meeting defined exercise targets according to guidelines. In Canada (238), this would be documentation that the patient was meeting a target of 150 minutes of moderate-intensity activity per week in bouts of 10 minutes or more, in the absence of contraindications. 103

119 3. Complexity of chart review due to multiple sources of data: Some pieces of information, e.g., smoking status for the biologic patients, were more reliably captured in the study chart than the clinical chart. This led to poor inter-rater reliability in some cases depending on the thoroughness and/or interpretation of data for review in these multiple sources. This may also have been an issue with QI #11 (Communication about risks/benefits of anti-inflammatories in patients at high risk of CV events) as it was sometimes unclear if the patient was on an NSAID. Again, a single data source (e.g., perhaps an electronic medical record with better medication capture) would be helpful in documenting adherence to many of the QIs. A final limitation of our study is that we were not able to assess the QIs over a longer period of time. In the original specification of many of the QIs the interval for evaluation for low-risk patients was up to 5 years. Unfortunately there was not enough follow-up time on our patients from the time when CV guidelines were first recommended (149). In summary, this study demonstrates that even in a highly controlled setting where standardized data collection is completed for reporting on clinical cohorts, there is room for improvement in CVD screening and care in RA. Gaps in CVD risk management were found and highlight the need for quality improvements. Key targets for improvement include coordination of CVD care between rheumatology and primary care and communication of increased CVD risk in RA. 104

120 Table 4.1 Baseline clinical characteristics for patients in the biologics and early rheumatoid arthritis (ERA) cohorts included in the quality indicator review Overall (N=170*) Biologics (n=63*) ERA (n=107*) Mean age (SD) 54.6 (13.6) Range 22 to (15.1) Range 25 to (12.4) Range 22 to 89 Female Sex 119 (70%) 51 (81.0%) 68 (63.6%) Ethnicity 82 (48.3%) Caucasian 69 (40.6%) not stated Duration of disease since diagnosis in years at baseline visit Duration between symptom onset and diagnosis Duration of follow-up** See biologics as N/A for ERA Median 6.1 months (IQR 3.3, 12.2) (n=159) Median 607 days (IQR 482, 678) 42 (66.7%) Caucasian 13 (20.6%) not stated Median 5.5 years (IQR 2, 15) (N=62) Median 6.7 months (IQR 3, 21.8 months) (n=52) Median 616 days (IQR 524, 685) 40 (37.4%) Caucasian 56 (52.3%) not stated N/A Median 6.1 months (IQR 3.5, 11.6 months) (n=107) Median 606 (IQR 472, 674) Rheumatoid 125 (73.5%) 45 (71.4%) 80 (74.8%) factor positive Anti-CCP 139 (81.8%) (N=166) 47 (74.6%) (N=61) 92 (86.0%) (N=105) positive Nodules 20 (11.8%) 14 (22.2%) 6 (5.6%) Erosions on 59 (34.7%) (N=165) 40 (63.5%) (N=62) 19 (17.8%) (N=103) baseline radiographs Extra-articular 11 (6.5%) 8 (12.7%) 3 (2.8%) RA manifestations*** Mean Baseline 1.35 (0.7) (N=165) 1.7 (0.6) (N=63) 1.13 (0.7) (N=102) HAQ score (SD) Mean Baseline 5.46 (1.37) (N=156) 5.76 (1.04) (N=59) 5.28 (1.51) (N=97) DAS28 (SD) Moderate Disease 49 (31.4%) 17 (28.8%) 32 (33.0%) Activity (DAS28 >3.2 to 5.1) High Disease Activity (DAS28 >5.1) 97 (62.2 %) 42 (71.2%) 55 (56.7%) 105

121 Baseline RA treatment (at end of the first visit) Overall (N=170*) Biologics (n=63*) ERA (n=107*) Any baseline 153 (90%) 53 (84%) 100 (93%) DMARD Plaquenil 94 (55.3%) 21 (33.3%) 73 (68.2%) Methotrexate 124 (72.9%) 37 (58.7%) 87 (81.3%) Leflunomide 10 (5.9%) 10 (15.9%) 0 Sulfasalazine 12 (7.1%) 8 (12.7%) 4 (12.7%) Combination 80 (47.1%) 18 (28.6%) 62 (57.9%) DMARD therapy (any combination) Methotrexate + 66 (38.8%) 8 (12.7%) 58 (54.2%) Plaquenil Biologics 62 (36.5%) 62 (98.4%) 0 NSAID (other 64 (37.7%) 30 (47.6%) 34 (31.8%) than ASA at first visit) Prednisone 37 (21.8%) 21 (33.3%) 16 (15%) Intra-muscular 62 (36.5%) 7 (11.1%) 55 (51.4%) glucocorticoids Intra-articular glucocorticoids 12 (7.1%) 3 (4.8%) 9 (8.4%) Number of follow-ups over study & Disease activity at end of follow-up Mean number of Mean 6.1 (1.9) Mean 5.9 (1.8) Mean 6.3 (2.0) follow-up visits over 2 year (SD) DAS-28 at end of 2.3 (1.2) (N=108) 2.9 (1.3) (N=38) 2.1 (1.1) (N=70) follow-up (SD) Remission or 82 (75.9%) 23 (60.5%) 59 (84.3%) Low Disease Activity (DAS 3.2) CVD events over the course of follow-up 2 patients (two MIs, one aneurysm repair) 0 2 (two MIs, one aneurysm repair) * The numbers of patients included is as described at the top of the table, unless otherwise specified. **Duration of follow-up between baseline visit and last follow-up date within 2 years (in ERA clinic this is calculated from date of diagnosis of RA and in Biologics from biologics clinic date where a switch or new start to a biologic was made) ***Other Extra-articular manifestations included the following: interstitial lung disease, pleural disease, RA vasculitis (rheumatoid nodules not counted here) Abbreviations: cardiovascular disease (CVD), Disease activity score-28 (DAS-28), Disease Modifying Antirheumatic Drug (DMARD), Health Assessment Questionnaire (HAQ), interquartile range (IQR), Rheumatoid Arthritis (RA) 106

122 Table 4.2 Cardiovascular risk profile & treatment Overall (N=170) Biologics (n=63) ERA (n=107) Hypertension 44 (25.9%) 23 (36.5%) 21 (19.6%) Blood pressure 23 (13.5%) 4 (6.4 %) 19 (17.8%) 140/90 at first visit and no prior diagnosis of hypertension Diabetes 11 (6.5%) 4 (6.3%) 7 (6.5%) Dyslipidemia* 26 (15.3%) 10 (15.9%) 16 (15.0%) Obesity (BMI 30) 43 (25.3%) 14 (22.2%) 29 (27.1%) Mean BMI (SD) 27.3 (4.9) 26.7 (5.1) 27.5 (4.9) Family history of Cardiovascular disease 4 (2.4%) 58 (34.1%) missing information 1 (1.6%) 41 (65.0%) missing information 3 (2.8%) 17 (15.9%) missing information Current smoker 35 (20.6%) 8 (12.7%) 27 (25.2%) Ex-smoker 56 (32.9%) 26 (41.3%) 30 (28.0%) Non-smoker 69 (40.6%) 25 (39.7%) 44 (41.1%) Missing smoking data *Baseline Framingham Risk score (FRS) (N=59 FRS calculated) 10 (5.9%) 4 (6.4%) 6 (5.6%) (N=8 FRS calculated) (N=51 FRS calculated) FRS low 39 (66%) 6 (75%) 33 (65%) FRS intermediate 13 (22%) 2 (25%) 11 (22%) FRS high 7 (11%) 0 (0%) 7 (14%) FRS could not be 75 (56%) (N= 134 eligible for FRS) 39 (83%) (N=47 eligible for FRS) 36 (41.4%) (N=87 eligible for FRS) Baseline Cardiovascular Risk Factor Treatment (at end of first visit) Aspirin 19 (11.2%) 9 (14.3%) 10 (9.4%) Statin** 19 (11.3%) (N=168) 7 (11.3%) (N=62) 12 (11.3%) (N=12) Anti-hypertensive agents (any) 40 (23.5%) 21 (33.3%) 19 (17.8%) * Baseline Framingham Risk Score was calculated with baseline variables at first visit using lipid values from up to 6months prior to first visit and 1 year after. ** 2 patients had major missing and/or conflicting information in the chart and statin use and dyslipidemia history could not be determined Abbreviations: Body Mass Index (BMI), Framingham Risk Score (FRS) 107

123 Table 4.3 Adherence to 11 cardiovascular quality indicators in 2 cohorts* Quality Indicator Total Biologics ERA 1. Communication of increased CV risk in RA: IF a patient has rheumatoid arthritis, THEN the treating rheumatologist should communicate to the primary care physician, at least once within the last 2 years that patients with RA have an increased cardiovascular risk. 2. CV risk assessment: a. IF a patient has rheumatoid arthritis THEN a formal cardiovascular risk assessment according to national guidelines should be done at least once in the first two years after evaluation by a rheumatologist 2b. If initial assessment suggests intermediate or high-risk, THEN treatment of risk factors according to national guidelines should be recommended. 3a.Smoking status and cessation counselling: IF a patient has rheumatoid arthritis THEN their smoking and tobacco use status should be documented at least once in the last year 3b. IF they are current smokers or tobacco users they should be counselled to stop smoking. 4. Screening for hypertension: IF a patient has rheumatoid arthritis THEN their blood pressure should be measured and 3/158 (1.9%) 0/62 (0%) 3/96 (3%) 0/150 (0%) 0/58 (0%) 0/92 (0%) There were no patients with a risk assessment, therefore both the numerator and denominator for this QI was 0. Y1 Y2 Y1 Y2 Y1 Y2 16/38** 59/63 5/10** 101/107 (42%) (94%) (50%) (94%) 160/170 (94%) 6/35 (17%) 98/170 (58%) 4/17 (24%) 105/159 (66%) 3/8 (38%) 21/63 (33%) 1/4 (25%) 45/62 (73%) 3/27 (11%) 77/107 (72%) 11/28** (39%) 3/13 (23%) 60/97 (62%) 108

124 documented in the medical record at 80% of clinic visits. 5. Communication to PCP about a documented high blood pressure: IF a patient has rheumatoid arthritis AND has a blood pressure measured during a rheumatology clinic visit that is elevated (systolic blood pressure 140mmHg and/or diastolic blood pressure 90mmHg) THEN the rheumatologist should recommend that it be repeated and treatment initiated or adjusted if indicated. 6. Measurement of a lipid profile: IF a patient has rheumatoid arthritis THEN a lipid profile should be done at least once in the first two years after evaluation by a rheumatologist 7. Screening for diabetes: IF a patient has rheumatoid arthritis THEN diabetes should be screened for as part of a cardiovascular risk assessment at least once within the first 2 years of evaluation by a rheumatologist. *** 7b. Yearly in intermediate or high-risk patients. 8. Exercise: IF a patient has rheumatoid arthritis THEN physical activity goals should be discussed with their rheumatologist at least once yearly. 5/76 (7%) 3/59 (5%) 3/24 (4%) 1/19 (5%) 2/52 (4%) 2/40 (5%) 110/159 (69%) 37/62 (59%) 73/97 (75%) 100/149 (67%) 34/58 (59%) 66/91 (73%) Y1 Y2 Y1 Y2 Y1 Y2 72/132 (54%) 57/119 (48%) 21/50 (42%) 20/44 (45%) 51/82 (62%) 37/75 (49%) 55/168 24/158 12/63 12/62 43/105 12/96 (33%) (15%) (19%) (19%) (41%) (13%) 109

125 9. BMI Screening and Lifestyle Counselling: a. IF a patient has rheumatoid arthritis THEN their body mass index (BMI) should be documented at least once every year. 9b. If they are overweight or obese according to national guidelines they should be counselled to modify their lifestyle. 10. Minimizing corticosteroid usage: IF a patient with rheumatoid arthritis is on oral corticosteroids THEN there should be evidence of intent to taper off the corticosteroids or reduce to the lowest possible dose. 11. Communication about risks/benefits of antiinflammatories in patients at high risk of CV events: IF a patient has rheumatoid arthritis AND has established cardiovascular disease OR is at intermediate or high cardiovascular risk AND is on a non-steroidal antiinflammatory drug (NSAID or Cox-2 inhibitor) THEN a discussion about the potential cardiovascular risks should 11/170 (6%) 10/111 (9%) 56/57 (98%) 2/23 (9%) 6/159 (4%) 5/103 (5%) 28/28 (100%) 0/17 (0%) 6/63 (10%) 1/40 (3%) 25/26 (96%) 0/4 (0%) 6/62 (10%) 2/39 (5%) 18/18 (100%) 0/6 (0%) 5/107 (5%) 9/71 (13%) 31/31 (100%) 2/19 (11%) 0/97 (0%) 3/64 (5%) 10/10 (100%) 0/11 (0%) occur and be documented. *Note: QIs are reported either over a one or a two-year measurement basis (as indicated in the table). The denominators vary for each indicator as shown depending on the eligibility criteria for each denominator criteria as published in (182) and rationale for exclusion from the denominators is available upon request. Overall, there 11 patients who were not eligible for inclusion in any of the denominator for indicators in year 2 due to lack of follow-up or new incident cardiovascular disease after year 1. **Note the denominator for this indicator in Y2 does not include patients who were documented to be non-smokers in Y1. 110

126 *** The final part of this indicator AND if screening is abnormal, this information should be communicated to the primary care provider for appropriate follow-up and management if indicated (was not reported on due to very small sample sizes in the denominator). Abbreviations: Body Mass Index (BMI), Cardiovascular (CV), Early Rheumatoid Arthritis (ERA), Non-steroidal anti-inflammatory (NSAID), primary care physician (PCP), Year (Y) 111

127 Table 4.4 Assessment of inter-rater reliability for each cardiovascular quality indicator in 48 randomly selected charts Quality Indicator Kappa Percent agreement Interpretation (N=48) 1. Communication of increased CV risk in RA 0* 47 (98%) Falsely low due to low performance on the indicator 2. CV risk assessment (100%) Perfect agreement 2b. If intermediate or high risk according to guidelines THEN recommended that treatment of RF be initiated. 3. Smoking status and cessation counselling 0* 41 (85%) Falsely low due to low performance on the indicator Y1 Y2 Y1 Y (65%) 39(81%) Fair agreement Y1 and moderate agreement Y2 3b. If smoker counselled to quit smoking (96%) 44 (92%) Almost perfect agreement Y1 and moderate agreement Y2 4. Screening for hypertension (96%) 38 (79%) Almost perfect agreement Y1 and moderate agreement Y2 5. Communication to PCP about a (85%) 41 (85%) Substantial agreement documented high blood pressure 6. Measurement of a lipid profile /48 (96%) Almost perfect agreement 7. Screening for diabetes: /48 (92%) Almost perfect agreement 7b. Yearly screening for diabetes in patients at intermediate or high risk Y1 Y2 Y1 Y (83%) 38 (79%) Substantial agreement 112

128 Quality Indicator Kappa Percent agreement (N=48) Interpretation 8. Exercise (77%) 37 (77%) Moderate agreement Y1 and Fair agreement Y2 9. BMI Screening and Lifestyle Counselling (98%) 44 (92%) Almost perfect agreement Y1 and substantial agreement Y2 9b. If they are overweight or obese (85%) 42 (88%) Substantial agreement according to national guidelines they should be counselled to modify their lifestyle. 10. Minimizing corticosteroid usage (90%) 40 (83%) Substantial agreement Y1 and 11. Communication about risks/benefits of anti-inflammatories in patients at high risk of CV events moderate agreement Y (88%) 45 (94%) Moderate agreement Y1 and substantial agreement Y2 The inter-rater reliability for 2 of 3 chart-reviewers was reported for each QI by calculating a Kappa score. The interpretation of the score is as follows: Below 0.0 poor; Slight agreement; Fair agreement; Moderate agreement; Substantial Agreement and Almost Perfect agreement between reviewers. * Note: due the way Kappa scores are calculated, these indicators have a high agreement but a low Kappa score and are falsely

129 Chapter Five: Discussion 114

130 5.1 Cardiovascular Care in Rheumatoid Arthritis: A Quality Gap Cardiovascular disease is a leading cause of premature death in patients with rheumatoid arthritis. As reviewed in Chapter 1, the reasons for this are likely complex and involve the interplay between traditional cardiac risk factors such as smoking, hypertension, diabetes and obesity as well as non-traditional risk factors, including inflammation. Despite improved treatment for RA that has evolved over the last 20 years, there remains a mortality gap and CVD is the major contributor to this gap. Many studies have demonstrated under-identification and under-treatment of traditional risk factors in RA and this care gap may contribute to the increased CVD risk observed in RA. Unfortunately, there are no large randomized trials of specific treatment of CVD risk factors in RA to address the mitigation of CVD risk; however, there are many guidelines for risk reduction in RA based on other sources of data including extrapolation from the general population guidelines, other types of epidemiologic studies in RA, and expert opinion as summarized in Chapter 2. Guidelines are unfortunately often of limited value in effecting clinical change (185, 186). Also, by their nature, guidelines are often not measurable as the recommendations lack descriptions of a specific numerator and denominator for reporting adherence or performance on the recommendation. Measurement of clinical practice is key to understanding important unwarranted variations in practice and QIs are key tools for quality improvement. This dissertation describes the development of the first comprehensive set of CVD QIs in RA for quality improvement and research purposes. 115

131 5.2 Summary of Dissertation Work and Updates in the Field The first step in QI development was to establish the evidence base for the candidate QIs. As QIs are designed to measure best practices, a systematic review of existing guidelines and QIs for CVD care in RA was conducted to determine best practices for CVD care in RA. There were 10 RA guidelines and three RA QI sets with four indicators that met inclusion criteria and an additional seven guidelines from the general population that addressed RA as a risk factor for CVD. From this review it was determined that there was only one existing CVD QI that was likely measurable. This measure was published by NICE in the UK (198) and was directed at primary care providers. Thus, a gap in quality measures in RA for CVD screening and care was identified. Since the publication of the systematic review there have been a few new cardiovascular guidelines and QIs that warrant mention. In 2014 the American Heart Association and the American College of Cardiology published a new set of guidelines on the assessment of cardiovascular risk (142). As described in Chapter 1, there were major changes in this guideline and a new risk calculator (ASCVD risk estimator) was recommended, and this risk calculator supplants the FRS in the United States (142). The primary reason for the change was that the FRS score was not felt to be representative of the American population as it was derived in a predominantly Caucasian population. The new ASCVD risk score was developed to predict risk of CVD endpoints including cardiovascular death, nonfatal MI or strokes based on data from cohorts that included African-Americans. While the guideline development group did consider additional risk markers including a CRP, the risk of inflammatory conditions such as RA was not 116

132 addressed in these guidelines and to date there has been only limited review of the performance of this risk estimator in RA populations (144). Despite the international reverberations from the recent American cardiovascular guideline publication, to date there has been no shift in Canadian recommendations. The Canadian Cardiovascular Society has issued a statement (239) that continues to endorse the 2013 version of the Canadian dyslipidemia guidelines including the use of the FRS; although, the society recommends ongoing evaluation of both sets of CVD risk algorithms. In contrast, new guidelines published by the Joint British Societies (207) do recognize the increased CVD risk associated with RA and recommend using a risk estimator that incorporates RA as a risk factor (JBS3 Risk Calculator which is based on QRISK-Lifetime score (240)). This risk calculator has to date only been validated in the UK and further validation of its predictive ability in the context of other RA populations is warranted. In the second study (Chapter 3), a set of 11 CVD QIs was developed using a multi-step process and state-of-the-art methods with an international panel of experts, clinicians and patients. The QIs are based on existing guideline recommendations established in Study 1 (Chapter 2) and address screening and care for CVD risk factors. Topics addressed include communication of increased CVD risk to the primary care provider, smoking status and cessation counselling, screening for hypertension, measurement of lipid profile and estimation of CVD risk, exercise counselling, BMI screening and lifestyle counselling, minimizing corticosteroid usage and communication about risks and benefits of anti-inflammatories in patients at higher risk of CVD events. 117

133 The indicators were rated as highly relevant and valid (>= 7 out of 9) by the QI international panel. To our knowledge this is the only comprehensive set of CVD QIs for RA. This study also represents the first time the online platform ExpertLens (RAND Corporation) was used for QI development. In close collaboration with RAND experts, we adapted the established RAND Appropriateness Methodology (174) for use on the ExpertLens platform. This platform offered a number of advantages for QI development, including the ability to consider the views of a larger number of panellists from around the world, as well the ability to include patient representatives and other types of healthcare providers. In the third study (Chapter 4), the QIs were tested in two cohorts of RA patients representing a spectrum of RA disease duration and treatment including an early RA cohort and a biologics cohort. This study demonstrated that our patients have a high burden of CVD risk factors including hypertension, smoking and obesity. When compared to another international study of comorbidities in RA (COMORA) (58) our patients had a higher frequency of current smokers (20.6% versus 13.2% in the COMORA study) and were more likely to have a history of being overweight or obese (63.5% versus 50.7% in the COMORA study). Despite our high rates of observed risk factors, there was evidence of sub-optimal adherence to the CVD QIs indicating a gap in care. The area identified for quality improvement was in QIs involving communication of increased risk or risk factor counselling and in the coordination of care between providers. Finally, two tools were proposed as examples of how the QIs could be used in clinical practice. The first is a paper-based tool designed to enhance CVD QI 118

134 performance in the clinic. This tool incorporates detailed directions on CVD screening and captures adherence to the CVD QIs using checklists and spaces to record CVD variables and can be filled out by nurses or physicians in the rheumatology clinic. The second is a chart audit tool and represents a simplified checklist capturing the CVD QIs that can be tallied by physicians looking to retrospectively evaluate their performance. Both tools were reviewed by a group of 3 practicing rheumatologists and are presented in Appendix D. 5.3 Measurement of Cardiovascular Quality in RA: A Broader Context As discussed in Study 2 (Chapter 3), four quality measures addressing CVD risk in RA were identified in the literature (181). The following section reviews how these existing measures have been applied in practice and compares them to the current measurement set. Two indicators from the EUMUSC group (162) were identified that addressed CVD care in RA: one addressed comorbidity screening, but the types of co-morbidities were non-specifically defined in the measure specifications. A second indicator addressed exercise and suggested referral to a relevant health professional for an individualized exercise program (162). A search of the literature and the organization s website did not yield any reports on the indicator testing. However, the group has developed a related set of patient-centred standards for RA (241) that also states that patients with RA should be fully assessed for comorbidity, including CVD risk factors, and that these assessments should occur annually and that patients should be advised to exercise appropriately. The EUMUSC group has also embarked on the first step of implementation of the measures: understanding the barriers to implementation. In this regard they have published the 119

135 results of a European survey, which review the perceived facilitators to implementation of the project and 11 were defined (242). The facilitators include: accessibility of the recommendations, agreement with the recommendations, shared cultural values around the recommendations as well as shared personal attitudes toward the recommendations, personal motivations for change, supports from organizations (patient, professional etc.), environmental factors (facilities, equipment), time and economic resources and the belief that the recommendations will be used (outcome expectancy). The group anticipates reporting measures on their website within three years (emusc.net). The present CVD measurement set is more comprehensive than the EUMUSC measures. As highlighted previously, the EUMUSC measures (especially the comorbidity measure), are not clearly defined and may be harder to measure and report on than the present CVD measurement set. Nevertheless, it is important to note that comorbidity care and exercise quality metrics resonate in different healthcare contexts and this likely strengthens the argument for our present measurement set. In future it will be interesting to examine how EUMUSC implements and reports on the measures within all of the different European countries involved as it may provide some insights on how to manage quality improvement efforts for arthritis care in the Canadian context, given our differing provincial healthcare systems. The ACR QI on the topic of glucocorticoid management (165) that was included in the systematic review from Study 2 was not included in the newly developed ACR set of four QIs (243). However, it is included in a new registry called RISE (Rheumatology Informatics System for Effectiveness (244)) (see below for description), and is used in the Centers for Medicare and Medicaid Services Physician Quality Reporting System. 120

136 While system performance on some of the ACR QIs has been published ( ), published performance rates on the glucocorticoid measure could not be readily found. This may again highlight that the measure was not as easily captured from data sources and/or did not describe an important enough variation in care to be publishable. Finally, the indicator found in the literature that appeared to be best defined for measurement and embedded in a framework for quality reporting and pay-forperformance in the UK addressed whether patients with RA had a CV risk assessment (198); however, no published literature on performance of this measure or the impact on patient outcomes was found. This review of these existing measures highlights some issues in the interface between research and quality improvement. While it is possible the measures are in use and improving practice, it is hard to tell, as there do not appear to be published performance reports on many of these measures (either on websites or in scholarly published articles). This does not mean they are not in use, but the results may not be publicly available. Additionally, there was no reporting on testing of the measures for feasibility prior to implementation. Again, depending on the QIs and the organization, this may not be publicly available information. We therefore believe the present dissertation imparts important lessons in development and testing of QIs that is not readily available in the published literature on this topic. A strategy for knowledge translation for the present project is discussed below and may address some of the concerns with the existing QIs sets and their implementation/reporting. 121

137 5.4 Strengths, Limitations & Lessons This dissertation work includes the first systematic review of guidelines and QIs to define best practices for CVD care in RA. On this basis we have developed the first comprehensive set of CVD QIs for RA care. This study was also the first time the ExpertLens platform had been used for QI development and this platform has subsequently been used for the development of performance measures for inflammatory arthritis care in Canada (248) and a set of key performance indicators for OA and RA centralized intake in Alberta (249). Analysis of participant feedback from all three studies suggests a high level of participant acceptability with this process for measure development (250). A major strength of this study is the use of a systematic approach for QI measure development followed by testing the QIs in clinical practice to ensure measurement feasibility and to identify any important gaps in care. While the QIs were measurable, given the complex nature of charts in our center, a lesson from this work was that the process was time consuming and resource intensive. A few of the QIs had sub-optimal performance on inter-rater reliability. One example was QI #8 Exercise, because the criteria for meeting this measure were interpreted differently by the reviewers. To rectify this, we suggest increasing the specificity of the inclusion criteria for the QI by requiring documentation that the patient meets defined exercise targets. Also, to reduce errors in ascertaining eligibility for measurement, we recommend incorporating CVD measurement and reporting into an electronic medical record for use in continuous improvement. An additional complexity of the proposed QIs is that some cover more than one specific performance measure. For example, QI #2 states IF a patient has RA THEN a 122

138 formal cardiovascular risk assessment according to national guidelines should be done at least once in the first two years after evaluation by a rheumatologist AND B) if low risk it should be repeated once every 5 years; OR C) if initial assessment suggests intermediate or high-risk, THEN treatment of risk factors according to national guidelines should be recommended. This can then be reported as three performance measures: 1) percentage of patients with a formal CVD risk assessment according to guidelines, 2) percentage of low-risk patients who had this repeated once every 5 years and 3) percentage of patients deemed at high risk where treatment of risk factors according to guidelines was recommended. While this added to the complexity of the measures, our QI development team felt it was appropriate to include a measure of action if a patient had a risk assessment that was deemed intermediate or high risk in order to prevent clinical inertia and to ensure the measures were effective at improving important changes in clinical practice. The additional benefit of this structure for QI reporting is that physicians do not get penalized twice for a failure to screen for a CVD risk factor. One exception to this is the hypertension QIs (QI # 4 and 5), which describe screening and management separately as these were considered easy targets for QI improvement. An important lesson from the exercise of measuring these types of complex QIs, is that they should be automated in an electronic record (i.e., prompting reminders to physicians to complete and offering reports as to QI performance) as in the current clinic model they are unlikely to get captured or acted upon. Possible strategies for implementation of the measures are further described below (Section 5.5). The clinics in which these measures were tested were in a single academic center at two hospital sites. The physicians in these clinics were paid by an academic alternative 123

139 funding plan (not fee for service) and some of the data collected was collected systematically for the RA cohorts. These factors likely affect the generalizability of our findings, as performance on the QIs would likely be lower in a fee for service environment with less systematic collection of data and a higher volume of patients seen per day. A limitation of the QIs is that they are based on guideline recommendations that were not based on large randomized trials in RA patients. At present there are very few such trials in RA (24). At a minimum, however, it was determined that QIs could be proposed if there were guidelines in RA and/or the general population that were relevant even if these recommendations were supported by evidence from cohort studies and/or expert opinion. The approach for combining evidence with expert opinion for areas where an existing evidence base may be weaker has been included in a proposed framework for measure development by Stelfox and Straus (170). Their framework for QI development that is similar to the methodology we describe in this dissertation: research synthesis/environmental scan, identification of potential QIs, QI consensus methodology to define QIs that are then used in setting benchmarks and testing in practice (170). Such QIs should still target important areas for quality improvement, be precisely defined, valid and reliable (170). It could be argued that CVD QIs from the general population could be applied to RA patients; however, our QI development team felt that specific wording of QIs in RA was necessary to ensure the full burden of CVD risk factor treatment was not applied to the rheumatologist. For example, to meet QI#1 (Cardiovascular risk assessment), the rheumatologist had to conduct a cardiovascular risk assessment using a tool such as the 124

140 FRS; however, if they document that this has been done by another physician, then they are excluded from the measure. The reasons for this are that: a) a CVD risk assessment can take up to 15 minutes (66) of clinical time; and b) there may not be time and/or resources to accomplish this during typical rheumatology appointments. Furthermore rheumatologists may not be trained and/or feel comfortable screening for and managing CVD risk factors. Therefore, at a minimum, many of the QIs are worded such that a communication back to the primary care provider to address the risk could be an acceptable means of meeting the indicator. We feel the measures can be used to enhance coordination of care and communication, which is another key learning from this work. Another potential critique of the QIs is the incorporation of a formal CVD risk assessment in QI #2 as not only can this be time consuming, but as discussed in Chapter 1, formal risk scores do not adequately predict risk in patients with RA, especially in the lower deciles of risk (143, 144, 146, 148, 251). However, current general population guidelines (62, 140, 142, 207) recommend use of CVD risk scores to help guide treatment. Until a validated, RA specific CVD risk score is developed; at a minimum, RA patients should receive equivalent care to the general population. Therefore, we would argue that if a patient is determined to be at high risk according to a general population derived CVD risk score, then treatment should be offered in accordance with general population guidelines. Furthermore, the QI is worded such that it is preferred to use a risk score that includes RA as a risk factor if one is available for use in the population to which it is being applied. Nevertheless, we emphasize that risk may be underestimated in RA by most existing scores. It is possible that in future, the use of adjunctive predictive modalities, including imaging with ultrasound or other techniques to evaluate subclinical 125

141 atherosclerosis may be recommended routinely to help with risk estimation; however, this is not currently standard of care as there are only a limited number of studies, generally of small size, that evaluate the predictive value of these modalities in RA (252). A final point of discussion of this work is that some rheumatologists feel that CVD risk screening is not their job. We would like to emphasize that many of the medications used in rheumatology impact CV risk and therefore screening for side effects from these medications is important and indeed a shared responsibility with other care providers. For example, as described in Chapter 1, leflunomide is strongly associated with hypertension and some drugs including tocilizumab may increase lipid profiles (and sometimes to unfavourable levels that could incur CV risk). Corticosteroids can also cause weight gain, hypertension, metabolic derangements and increase CVD risk. NSAIDs are associated with hypertension and a higher risk of CVD events. Therefore, we feel that the targets for improvement suggested by the CVD QIs are both very reasonable and within the purview of rheumatologists scope of practice. Our international panel of experts and patients share this view. 5.5 Future Directions: How Do We Close The Gap The present study has focused on the development and retrospective testing of the CVD QIs in patient charts. It is likely, that to effect changes in clinical practice two things need to occur: 1) the QIs need to be embedded into clinical practice through the use of tools for measurement and reporting and 2) where deficits are identified based on measurement and reporting on the QIs, strategies to improve care are developed to translate this knowledge into clinical practice. In this section, we describe some implementation and knowledge translation strategies to help achieve these two goals. It is 126

142 important to recognize that different strategies may be employed in different centers based on stakeholder preferences and resources available Tools to Implement QIs in Clinical Practice In the following sections a number of tools are described for QI implementation into clinical practice Electronic Medical Records as a Quality Tool Electronic medical records (EMRs) are increasingly being used as a tool for continuous quality improvement to evaluate practice patterns in real time to find areas for improvement (253). EMRs can facilitate practice audits and a variety of tools can be set up to encourage best practices where applicable. For example, a physician dashboard is a tool that tracks EMR data and displays performance measures over time graphically (254). EMRs may also have templates that prompt the collection of specific types of data (e.g., CV risk factors) or embed flags to remind users of when tests need to be done (e.g., measurement of lipid levels). Unfortunately, in our center, the current EMR used in the university-based rheumatology practices is not amenable for use in quality improvement cycles as data extraction for audits of practice is extremely cumbersome. Consequently, a longitudinal program of data collection, called Rheum4U, is in development for use in quality improvement, clinical care and research. A major objective of this program is that QIs can be captured in a systematic fashion and fed back for continuous quality improvement. In future work, inclusion of the CVD QIs will be piloted in Rheum4U. 127

143 Audit Tools Other potential uses for the CVD QIs include the development of an audit tool for physician use. Currently in Canada, physicians are required to participate in the Royal College s Maintenance of Certification Program (255), which requires reporting on the following activities during five-year reporting cycles: group learning, self-learning and assessment. In the assessment session, physicians are granted three credits per hour for chart audit and feedback. Therefore, one potential use for the QIs is the development of a chart audit tool to facilitate individual physician chart audits. An example of such a tool has been developed and reviewed with a group of three practicing rheumatologists and is presented in Appendix D2. The tool incorporates a simplified version of the CVD QIs in a spreadsheet for tracking QI adherence over a one-year measurement period. We suggest that between consecutive patients could be evaluated to determine if there are areas in need of quality improvement (for further tool instructions see Appendix D2) Registries For Quality Improvement: RISE The ultimate goal of most QIs is to positively impact not only physician and health system performance but also to improve patient outcomes. Although this concept seems intuitive, there is little research to date in rheumatology that adherence to existing QIs improves outcomes although evidence is emerging for some measure sets (187). The reason for this is likely related to availability and quality of data sources to capture QI adherence and patient outcomes. In the United States, the ACR has recently launched a clinical data registry called the Rheumatology Informatics System for Effectiveness (RISE) (244), and it is likely that better tracking of quality measures and patient outcomes will lead to more research in this area. 128

144 5.5.2 Strategies to Correct Performance Deficits Pay for Performance The proposed CVD QIs are not suggested at the present time for use in pay for performance in Canada; however, it should be noted that incentive programs might be effective in driving improvements in care. In the UK, the implementation of pay for performance in primary care in 2004 effected a positive change in the management of patients with diabetes, with higher rates of treatment provided to patients following institution of the program (256). Similarly, in patients with chronic kidney disease in the UK, blood pressure control has improved since the institution of pay for performance, as has use of anti-hypertensive therapies (257). In the United States, a small randomized trial of a pay for performance incentive in the United States in 42 participating clinics revealed some improvements in a number of CVD care processes and outcomes (258) Plan-Do-Study-Act Alternative strategies for changing practice need to be considered in the absence of a major change health policy such as the institution of a program like pay for performance. Effecting change in clinical practice can be complex and a variety of frameworks have been described. One of the most common is the Plan-Do-Study-Act (PDSA) cycle (259). In this framework, a team approach is used to set the goals of change and to test them in a cyclical fashion by continuously evaluating the impact of changes made. Having measurable goals is critical in determining success and QIs can be used in this process. However, timely feedback is clearly important in this process and conducting chart reviews can be time consuming and costly. One potential means of 129

145 reducing chart reviews is to develop a prospective tool for use in clinics with the goal of improving adherence to CVD QIs. A paper version of a candidate tool has been reviewed by a group of three rheumatologists and is available in Appendix D. Nonetheless; information would ideally be captured online to maximize accuracy, efficiency and timeliness of feedback on quality of care as described above Knowledge Translation A variety of frameworks for translating knowledge into practice exist (260, 261). The most commonly used is that by Graham et al. (262). The QI set developed could be considered a product of a knowledge translation framework, as it is a tool to improve adherence to evidence-based practices. Yet, a strategy for further knowledge translation to improve uptake of the QIs and to better translate documented deficits in care is needed. A complete description of such a strategy is beyond the scope of the present dissertation, as the implementation of such a strategy would likely vary by jurisdiction and even by clinic depending on resources and stakeholders involved. However, general pieces that would be considered in a knowledge translation strategy are outlined in this section based on an adapted knowledge translation framework (263, 264). Importantly the steps outlined are iterative and circular (e.g., may move back and forth amongst steps in a continuous fashion). Knowledge Funnel 3 : The QI set represents a knowledge tool/product that is derived from the first two steps in the framework (see footnote). 3 The knowledge funnel depicts three stages of knowledge creation and products in healthcare through: knowledge inquiry, knowledge synthesis, and knowledge tools/products (264). 130

146 Step 1: Identification of the problem or gap. In our center this has been done in Study 3 where gaps in performance were identified. Step 2: The knowledge has to be adapted to the local context. For example the stakeholders in different centers may vary and the implementation and/or interpretation of QI performance may depend on the local context. E.g., in some centers a nurse-led approach may be appropriate for implementing CVD screening, while in other contexts a pharmacist or a family physician may be a key stakeholder for measure implementation. Step 3: Barriers to knowledge use need to be identified and addressed. Barriers to QI implementation, reporting and quality improvement should be identified and may involve clinic structure, processes or buy-in from healthcare professionals, managers or patients. Step 4: Select, tailor, and implement interventions. This step will depend on the first two steps but could involve an approach for indicator measurement and monitoring that involves local nurse champions. Step 5: Monitor knowledge use. In this step, ongoing QIs reporting is used to monitor the effects of interventions. Step 6: Evaluate outcomes. This may be in the form of physician report cards on performance. More importantly, in future, greater uptake of the measures should actually lead to better patient outcomes including higher satisfaction with care, improved CVD risk factor management and better cardiovascular outcomes. 131

147 Step 7: Sustained knowledge use. Systems to sustain quality measurement, reporting and translation of reporting into quality improvement need to be developed locally to ensure continued use and action of knowledge gained through these processes Local Changes to Cardiovascular Screening in Rheumatology While a formal knowledge translation project has not been undertaken in our center, some changes have occurred as a result of this work. There is a new clinic data form that captures smoking status at each clinic visit. Also, in a nurse-led clinic at one of the rheumatology sites, FRS is now routinely calculated on patients. While these changes are positive and likely benefit patient care, there remain critical gaps in how the information that is necessary for quality reporting is captured in paper or electronic records. Currently, data on pertinent clinical variables that are relevant to quality metrics are not easily available for feedback to clinicians as aggregate data for performance reports. Capturing this information would require conducting a timeconsuming chart review. This means it will remain difficult to determine if there are ongoing deficits in CVD risk factors identification or management after changes in practice processes. This is not only a problem for measurement of the CVD QIs, but also for other potentially relevant quality metrics relating to RA patient treatment and outcomes. As described above, a separate platform is being developed for the tracking and trending of key metrics for quality in rheumatology in our division. Engagement with stakeholders including patients, rheumatologists, allied health professionals and primary care physicians will be necessary to determine how to best improve CVD care in RA in our center. 132

148 5.6 Conclusions Eleven QIs for CVD screening and care have been developed and tested through a rigorous, multistep process. Application of the indicators in two cohorts of RA patients has identified gaps in care and areas for quality improvement. This work represents significant progress not only in the area of CVD screening and management in RA but also in quality measure development. The use of the ExpertLens platform (RAND Corporation) was shown to be a highly feasible and acceptable means for developing measures and has subsequently been used in other projects including the recent development of system-level performance measures for inflammatory arthritis (248). In future, we hope that routine collection of the CVD QIs using an electronic platform will allow for continuous quality improvement in processes of care and ultimately help improve the clinical outcomes for patients with RA. 133

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168 APPENDIX A: APPENDIX MATERIALS FROM STUDY 1 153

169 A.1. Methods of Included Rheumatoid Arthritis Guidelines Guideline ACR 2012 (106) BSR 2009 (192) RA management after first 2 years Audience & Population covered by recommendations Audience: Primarily rheumatologists Population: All RA patients Audience: Health professionals in primary and secondary care, health care commissioners and patients with RA Population: RA 2 years after diagnosis Methods Two expert panels: Core Expert Panel responsible for selection of topics, systematic literature review, evidence synthesis and development of clinical scenarios. Task force panel tasked with rating scenarios sing RAND/UCLA Appropriateness method, Strength of evidence assigned, Derivation of recommendations, ACR peer review *Literature review, evidence graded and document prepared according to AGREE II criteria. Unclear how recommendations developed. Evidence rating/ Grading/ Strength of Recommendation Strength of Recommendation: A Data were derived from multiple RCTs B Data were derived from a single randomized trial or nonrandomized studies C Data were derived from consensus opinion of experts, case studies, or standards of care **Unclear Inclusion of Patient s View Yes Yes 154

170 Guideline BSR 2010 anti-tnf Safety (190) Audience & Population covered by recommendations Audience: Healthcare professionals involved in assessing patients for anti-tnf therapies and monitoring for efficacy and toxicity Population: All RA patients on anti-tnf therapies Methods *Literature review Evidence graded according to the Royal College of Physicians of London. Document prepared according to AGREE II criteria. Unclear how recommendations developed. Evidence rating/ Grading/ Strength of Recommendation Level of evidence & Grade of Recommendation: [Ia,A] Meta-analysis of RCTs [Ib, A] At lease one RCT [IIa,B] At least one well designed, controlled study but without randomization [IIb, B] At least one well designed, quasi-experimental study; [III, B] At least one well designed, non-experimental descriptive study (e.g., comparative studies, correlation studies, case studies); [IV, C] Expert committee reports, opinions and/or experience of respected authorities. This grading indicates that directly applicable clinical studies of good quality are absent [Consensus of Working Party, D] Recommended good practice based on the clinical experience of the Guideline Development Group Inclusion of Patient s View Yes 155

171 Guideline EULAR 2010 (149) CVD Audience & Population covered by recommendations Audience: Primarily rheumatologists, also other physicians caring for RA patients Population: All RA patients (also covers AS and PsA) Methods EULAR methods used: Multidisciplinary panel, Systematic review Consensus conference Evidence rating/ Grading/ Strength of Recommendation Level of evidence 1A From meta-analysis of RCTs 1B From at least 1 RCT 2A From at least 1 controlled study (not randomized) 2B From at least 1 quasiexperimental study 3 From descriptive studies 4 From expert opinion Inclusion of Patient s View No Strength of recommendation A Category 1 evidence B Category 2 evidence or extrapolated recommendations from Category 1 evidence C Category 3 evidence or extrapolated recommendations from Category 1 or 2 D Category 4 evidence or extrapolated recommendations from Category 2 or 3 156

172 Guideline EULAR 2010 Glucocorticoid guidelines (197) Audience & Population covered by recommendations Presumed primarily rheumatologists Population: Patients on low dose GCs ( 7.5mg/d prednisone equivalent) in clinical practice and trials Methods *Literature Review, Consensus conference Evidence rating/ Grading/ Strength of Recommendation Level of evidence: Not reported Strength of recommendation: Not reported Inclusion of Patient s View Yes NICE 2009 (193) Audience: All healthcare professionals People with RA and their carers Patient support groups Commissioning organizations Service providers Population: All RA patients NICE methods used: Systematic review Draft recommendations drawn up by the GDG Public and stakeholder consultation Levels of evidence 1++ High quality metaanalyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1+ Well conducted metaanalyses, systematic reviews, or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2++ High quality systematic reviews of CC or Cohort studies. High quality CC or cohort studies with a very low risk of confounding or bias and a high probability the relationship is causal Yes 157

173 2+ Well conducted CC or cohort studies with a low risk of confounding or bias and a moderate probability the relationship is causal 2- CC or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g., case reports or series 4 Expert opinion, formal consensus Strength of recommendation not reported Note: This guideline also describes levels of evidence for diagnostic studies separately (not reported here). 158

174 Guideline RACGP 2009 (195) Audience & Population covered by recommendations Audience: PCPs and patients Also relevant to Multidisciplinary team: physiotherapist, nurses, OTs, Sports Medicine, Podiatrist, Dietician, Pharmacists, Community Health Workers Population: Early RA ( 2 years) Methods Identification and appraisal of existing guidelines for use as primary reference, Systematic literature review, GDG developed evidence statements from which each graded recommendation and algorithm is based, Peer review and public consultation Evidence rating/ Grading/ Strength of Recommendation Grade of Recommendation: A Excellent evidence- body of evidence can be trusted to guide practice B Good evidence- body of evidence can be trusted to guide practice in most situations C Some evidence- body of evidence provides some support for recommendation(s) but care should be taken in its application D Weak evidence- body of evidence is weak and recommendation must be applied with caution Inclusion of Patient s View Yes Note: Body of evidence assessment matrix which describes the volume of evidence, consistency, clinical impact, generalizability and applicability of the studies in the Grade categories not reported here 159

175 Guideline SIGN 2011 (194) Audience & Population covered by recommendations Audience: Rheumatologists, PCPs, Rheumatology nurse specialists, Physiotherapists, OTs, Dieticians, Podiatrists, Pharmacists Population: Early RA ( 5 years) Methods SIGN methods used: Systematic review, Draft recommendations, National open meeting to discuss, External peer review Evidence rating/ Grading/ Strength of Recommendation Levels of evidence 1++ High quality metaanalyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1+ Well conducted metaanalyses, systematic reviews, or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2++ High quality systematic reviews of CC or Cohort studies. High quality CC or cohort studies with a very low risk of confounding and a high probability the relationship is causal 2+ Well conducted CC or cohort studies with a low risk of confounding or bias and a moderate probability the relationship is causal 2- CC or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal Inclusion of Patient s View Yes 160

176 3 Non-analytic studies, e.g., case reports or series 4 Expert opinion Grades of recommendation A At least one study rated as 1++ and directly related to the target population OR A body of evidence rated as 1+ directly applicable to the target population and demonstrating consistency of results B A body of evidence including 2++ studies OR extrapolated studies rated as 1++ or 1+ C A body of evidence including studies rated as 2+ OR extrapolated evidence from 2++ studies D Evidence level 3 or 4 or extrapolated from studies rated as

177 Guideline SER 2010 (196) SER 2011 (191) Audience & Population covered by recommendations Audience: Rheumatologists and those involved in the treatment of RA Population: RA patients on biologics Audience: Advance practice nurse, nurses, OTs, PTs, physician assistants, physicians, psychologists, social workers Population: All RA patients Methods Systematic literature review Consensus achieved by a panel of experts through meetings using a nominal group technique followed by Delphi survey Systematic literature review and meta-analysis Meeting with GDG Drafting of chapters and provisional recommendations Meeting with GDG to make modifications and editing Evidence rating/ Grading/ Strength of Recommendation Level of evidence: Used Oxford Centre for Evidence-Based Medicine (not reported here, available at Levels of evidence: Used Oxford Centre for Evidence-Based Medicine (not reported here, available at Grades of Recommendation: A Based on results of consistent level 1 studies. B Based on the results of consistent level 2 or 3 studies or on extrapolations from level 1 studies. C Based on the results of level 4 studies or on extrapolations from level 2 or 3 studies. D Based on the results of level 5 studies or on troublingly inconsistent or inconclusive evidence. Inclusion of Patient s View No No 162

178 Abbreviations: American College of Rheumatology (ACR), Appraisal of Guidelines for Research and Evaluation (AGREE II), Ankylosing Spondylitis (AS), British Society of Rheumatology (BSR), Case Control (CC), Guideline Development Group (GDG), European League Against Rheumatism (EULAR), National Institute for Health and Care Excellence (NICE), Occupational Therapist (OT), Physical Therapists (PT), Primary Care Practitioners (PCPs), Psoriatic arthritis (PsA), Rheumatoid Arthritis (RA), Randomized Controlled Trials (RCTs); Royal Australian College of General Practitioners (RACGP) ; Spanish Society of Rheumatology (SER) * Unclear if systematic literature review based on description ** Link to grading presented in guideline no longer functional. Presumed similar to other BSR criteria described below. Author contacted twice to clarify in September 2013 and February 2014 with no response. 163

179 A.2. RA QI Characteristics QI ACR (PCPI measures only) (165) Audience, Care Setting & Population Audience: Use by physicians and other eligible health professionals Care Setting: Ambulatory at individual clinician level Population: All RA patients 18 years and older Methods Measures based on evidencebased recommendations from the ACR and the BSR; Measures harmonized with existing measures; Consensus procedure; Measures specified for multiple different data sources Intended use of the Measure Individual quality improvement Data registries CME programs Board certification programs Accountability Inclusion of Patient s View NS EUMUSC (162) Audience: NS, presumed rheumatologist Care Setting: NS, presumed ambulatory Population: All RA patients Systematic Literature Review of existing healthcare quality indicators for RA; International panel participated in Delphi process by and ranked topics; Audit in 6 countries to establish final version of QIs To perform proper bench marking processes with the goal to equalize and improve the care (among different centers). Yes NICE (198) Audience: Primary care Care Setting: Ambulatory, primary care Population: Topic decided at a QOF stakeholder workshop; Indicator based on NICE RA guideline, other RA guidelines and policy documents considered; QI selected is part of QOF which is a voluntary incentive scheme for GP practices in the UK, Results published annually Yes 164

180 Confirmed RA Formal testing of clarity, reliability, acceptability, feasibility and implementation; Cost impact assessed; Health Economic report on indicator; Abbreviations: American College of Rheumatology (ACR), British Society of Rheumatology (BSR); European Musculoskeletal Surveillance Network (EUMUSC), National Institute for Health and Clinical Excellence (NICE); Not Specified (NS); Physician Consortium for Performance Improvement (PCPI); Quality Outcomes Framework (QOF); United Kingdom (UK) 165

181 A.3. AGREE II Domain Scores: Quality of Included Rheumatoid Arthritis Guidelines Guideline Scope and Purpose Stakeholder Involvement AGREE II Domains and Scores Rigour of Development Clarity of Presentation Applicability Editorial Independence Overall Rating ACR 2012 (106) 97.2% 69.4% 88.5% 88.9% 22.9% 87.5% R BSR 2009 (192) RA management after first 2 years 97.2% 50.0% 67.7% 88.9% 91.7% 66.7% R BSR 2010 anti-tnf Safety (190) EULAR 2010: CVD (149) EULAR 2010 Glucocorticoid guidelines (197) 97.2% 88.9% 67.7% 86.1% 43.8% 87.5% 83.3% 47.2% 59.4% 72.2% 20.8% 79.2% 77.8% 63.9% 72.9% 52.8% 37.5% 79.2% R R* R* NICE 2009 (193) 100% 100% 94.8% 97.2% 91.7% 79.2% R RACGP 2009 (195) 88.9% 100% 91.7% 91.7% 25.0% 41.7% R SIGN 2011 (194) 100% 83.3% 88.5% 83.3% 62.5% 75.0% R SER 2010 (196) 66.7% 41.7% 56.3% 58.3% 12.5% 70.8% R* 166

182 AGREE II Domains and Scores Guideline Scope and Purpose Stakeholder Involvement Rigour of Development Clarity of Presentation Applicability Editorial Independence Overall Rating SER 2011 (191) 83.33% 52.8% 78.1% 77.8% 2.1% 50.0% R* Median domain score of all reviewed RA guidelines (range) 93.1% ( %) 66.7% ( %) 75.5% ( %) 84.7% ( %) Abbreviation: Appraisal of Guidelines for Research and Evaluation (AGREE II); R: Recommend; R*: Recommend with modification 31.3% ( ) 77.1% ( %) NA 167

183 A.4. Abstracted Recommendations on Lipids, Hypertension, Smoking, Exercise, Diet and Weight Control, Aspirin Use, and Medication Safety Guideline Recommendation Level of Evidence; Grade or Strength of recommendation Lipid Screening and Treatment EULAR 2010 (149) TC/HDL cholesterol ratio should be used when the SCORE model is used LOE 3; Strength C EULAR 2010 (149) Intervention should be carried out according to national guidelines (Note: LOE 3; Strength C pertains to lipid and antihypertensive therapies and targets) EULAR 2010 (149) Statins, ACE inhibitors and/or AT-II blockers are preferred treatment options LOE 2a-3; Strength C- D SER 2011 (191) Hyperlipidemias should be treated in accordance with general recommendations, NR not forgetting the possible positive influence of the statins on the inflammatory process in RA. Hypertension EULAR 2010 CVD (149) EULAR 2010 CVD (149) SER 2011(191) Smoking "Statins, ACE inhibitors and/or AT-II blockers are preferred treatment options" LOE 2a-3; Strength C- D Intervention should be carried out according to national guidelines" LOE 3; Strength C Strict control and monitoring of arterial pressure, especially in patients treated with drugs that can elevate blood pressure (NSAIDs, steroids, leflunomide), is important. EULAR 2010 CVD Recommend smoking cessation LOE 3; Strength C (149) SER 2011 (191) Discontinuation of all tobacco use is indicated in RA patients LOE 5, Grade D RACGP 2009 (195) Smoking cessation should be highly recommended NR NR 168

184 Guideline Recommendation LOE;Grade/Strength Exercise Recommendations SER 2011 (191) Therapeutic exercise: From the time of diagnosis, a program of aerobic physical exercise is recommended. It should initially be supervised to adapt to the individual's level of physical preparation and the specific joint and extra-articular circumstances stemming from the disease and comorbidities. LOE 1a, Grade A (but discussion does not discuss CVD endpoints) NICE 2009 (193) People with RA should have access to specialist physiotherapy, with periodic review to: - improve general fitness and encourage regular exercise RACGP 2009 (195) General practitioners should encourage patients with RA to engage in regular dynamic physical activity compatible with their general abilities in order to maintain strength and physical functioning. Diet and Weight Control NICE 2009 (193) "Inform people with RA who wish to experiment with their diet that there is no strong evidence that their arthritis will benefit. However, they could be encouraged to follow the principles of a Mediterranean diet (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on vegetable and plant oils)." RACGP 2009 (195) General practitioners should encourage dietary modification and weight control for all RA patients. RACGP 2009 (195) The diet recommended for arthritis is similar to that for good health generally, with special emphasis on cardiovascular risk prevention. This includes: eating plenty of fruit, vegetables and whole grain cereal foods; eating foods rich in fish oil (omega-3); eating a diet low in fat; maintaining a healthy body weight; limiting alcohol intake; eating only a moderate amount of sugars and foods containing added sugars, and choosing low salt foods and using salt sparingly. RACGP 2009 (195) Healthy diet and regular exercise are important in long term weight control. LOE 1++/1+ for RA improved muscle strength and walking endurance, not CVD endpoints. Strength of recommendation NR Grade C LOE 1+ for weight loss (overall strength of recommendation not reported) Grade B NR NR 169

185 Guideline Recommendation LOE;Grade/Strength Aspirin SER 2011 (191) Corticosteroid Use Unless there are contraindications, platelet inhibitors should be used prophylactically in RA patients who have suffered a previous CV event. EULAR 2010 (149) Corticosteroids: use the lowest dose possible. EULAR 2010 (197) Recommendation From Table 1: Monitoring of blood pressure is advised while on low-dose corticosteroids (defined in the recommendations as 7.5 mg of prednisone or equivalent per day). Frequency of monitoring for this is listed in Table 2 "Standard Care" in daily practice EULAR 2010 (197) Recommendation From Table 1: Monitoring for Ischemic CVD/atherosclerosis is advised while on low-dose corticosteroids (defined in the recommendations as 7.5 mg of prednisone or equivalent per day). In Table 2, method for monitoring is listed as "Questioning" as part of "Standard care" in daily practice EULAR 2010 (197) Recommendation From Table 1: Monitoring for diabetes/glucose tolerance is advised while on low-dose corticosteroids (defined in the recommendations as 7.5 mg of prednisone or equivalent per day). Frequency of monitoring for this is listed in Table 2: it is recommended to do a fasting blood glucose at start of treatment with prednisone and as "Standard care" in daily practice EULAR 2010 (197) Recommendation From Table 1: Monitoring for body weight and fat re-distribution is advised while on low-dose corticosteroids (defined in the recommendations as 7.5 mg of prednisone or equivalent per day). Frequency of monitoring for this is listed in Table 2: it is recommended to measure height and weight as part of "Standard Care" in daily practice NR LOE 3; Strength C NR NR NR NR 170

186 Guideline Recommendation LOE;Grade/Strength Non-Steroidal Anti-inflammatory (NSAID) Safety BSR 2009 (192) "Current guidance advises caution in the use of both NSAIDs and coxibs in those NR with cardiovascular risk and gastrointestinal risk factors and avoidance in those with established ischemic heart disease. While the alternative use of analgesics, intra-articular or intramuscular steroid injections and better use of DMARDs or biologic therapy to control synovitis should be considered a preferable strategy to relying on long-term use of NSAIDs or coxibs, there may be individuals who have residual pain and functional impairment and who opt for anti-inflammatory drugs despite the risks. Documented discussion of these risks in copy correspondence is recommended to avoid any confusion." BSR 2009 (192) The co-prescription of ibuprofen and aspirin should be avoided NR EULAR 2010 (149) The role of coxibs and most NSAIDs in CV risk is not well established and needs further investigation. Hence, we should be very cautious about prescribing them, especially for patients with a documented CV disease of in the presence of CV risk factors NICE 2009 (193) "Oral NSAIDs/COX-2 inhibitors should be used at the lowest effective dose for the shortest possible period of time" NICE 2009 (193) "All oral NSAIDs/COX-2 inhibitors have analgesic effects of a similar magnitude but vary in their potential gastrointestinal, liver and cardio-renal toxicity; therefore, when choosing the agent and dose, healthcare professionals should take into account individual patient risk factors, including age. When prescribing these drugs, consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors." NICE 2009 (193) If a person with RA needs to take low-dose aspirin, healthcare professionals should consider other analgesics before substituting or adding an NSAID or COX-2 inhibitor (with a PPI) if pain relief is ineffective or insufficient." RACGP 2009 (195) Avoid NSAIDs and COX-2 inhibitors in patients taking anticoagulants or corticosteroids" LOE 2a-3; Strength C LOE for withdrawals and adverse events 1+/1++ LOE for withdrawals and adverse events 1+/1++ LOE for withdrawals and adverse events 1+/1++ NR 171

187 Guideline Recommendation LOE;Grade/Strength Non-Steroidal Anti-inflammatory (NSAID) Safety Continued RACGP 2009 (195) "Paracetamol is the analgesic of choice in the presence of pregnancy, peptic ulcer disease, or significant cardiac, renal, and other comorbidities. RACGP 2009 (195) General practitioners should apply caution when using traditional NSAIDs and COX-2 inhibitors. Choice of NSAIDs or COX-2 inhibitors should be based on consideration of the patient s specific needs, baseline risk profile and concomitant medication. The potential benefits need to be measured in relation to potential harms. Caution is particularly required in those at risk, such as the elderly or patients who have gastrointestinal, renal or cardiovascular comorbidities. RACGP 2009 (195) NSAIDs and COX-2 inhibitors should be used for the shortest possible duration. Commentary: Studies suggest that the risk of cardiovascular and gastrointestinal tract events is associated with the dose and duration of NSAID use. RACGP 2009 (195) Long term use of NSAIDs should be at the lowest effective dose. RACGP 2009 (195) Blood pressure and renal function should be monitored, particularly in older people and others at risk. RACGP 2009 (195) "Only one NSAID or COX-2 inhibitor should be prescribed at a time. NR Grade A SIGN 2011 (194) "The lowest NSAID dose compatible with symptom relief should be prescribed." Grade B SIGN 2011 (194) "NSAID dose should be reduced and if possible withdrawn when a good response Grade B to DMARDs is achieved." SIGN 2011 (194) "NSAIDs least likely to cause GI and/or cardiovascular effects should be NR prescribed." SIGN 2011 (194) "Long term NSAID use should be reviewed periodically." NR SIGN 2011 (194) "Only one NSAID should be prescribed at a time" (See associated commentary described above) NR NR NR NR NR 172

188 Guideline Recommendation LOE;Grade/Strength Other Recommendations BSR 2009 (192) Systemic inflammation may promote atherosclerotic CVD in RA. It is important to treat RA to try and minimize disease activity and inflammatory disease burden. EULAR 2010 (149) RA should be regarded as a condition associated with higher risk for CV disease The increased risk appears to be due to both an increased prevalence of traditional risk factors and the inflammatory burden. EULAR 2010 (149) Adequate control of disease activity is necessary to lower the CV risk. SER 2011 (191) RA Comorbidity: The rheumatologist is responsible for controlling the inflammatory process and should monitor RA-associated comorbidity with the support of the primary care physician and with recourse to other specialists when need. RACGP 2009 (195) "General practitioners should be involved in monitoring disease progression, response to treatment, and comorbidities in conjunction with the treating rheumatologist and other members of the multidisciplinary team. RACGP 2009 (195) General practitioners should encourage and support a management approach that is based on individual patient need and involvement of a multidisciplinary team of health professionals" RACGP 2009 (195) If initiating DMARD therapy, GPs should use methotrexate as the first choice, particularly when the disease is judged to be moderate to severe or when there is a high risk of erosive disease. Associated commentary: In addition to the disease modifying effect in relation to joints, there is also evidence that treatment with MTX can reverse the cardiovascular risk associated with active RA. NR LOE 2B-3; Strength B LOE 2B-3; Strength B LOE 5, Grade D Grade B Grade B Grade A Abbreviations: Angiotensin Converting Enzyme (ACE), American College of Rheumatology (ACR), Angiotensin II (AT-II), British Society of Rheumatology (BSR), Cardiovascular (CV), Cyclooxygenase II inhibitor (COX-2 or coxibs), Disease modifying antirheumatic drugs (DMARDs), European League Against Rheumatism (EULAR), High Density Lipoprotein (HDL), National Institute for Health and Care Excellence (NICE), Methotrexate (MTX), Not Rated (NR), Non-steroidal Anti-inflammatories (NSAIDs), Proton-pump Inhibitor (PPI), Royal Australian College of General Practitioners (RACGP), Spanish Society of Rheumatology (SER), Total Cholesterol (TC) 173

189 A.5. Medline Search Strategy 1. exp arthritis, rheumatoid/ 2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheuma$ or reumat$ or revmarthrit$) adj3 (arthrit$ or arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw. 3. inflammatory arthritis.tw. 4. or/ practice guideline/ or clinical pathway/ or consensus development/ or good clinical practice/ or nursing care plan/ or nursing protocol/ 6. guideline$.tw. 7. clinical protocol/ 8. consensus.tw. 9. recommendation$.tw. 10. clinical pathway$.tw. 11. nursing protocol$.tw. 12. good clinical practice$.tw. 13. nursing care plan$.tw. 14. directive$.tw. 15. (standard* adj3 (care or practice* or protocol*)).tw. 16. or/ exp Quality Indicators, Health Care/ 18. exp Quality Assurance, Health Care/st [Standards] 19. exp "Quality of Health Care"/st [Standards] 20. Quality Assurance.tw. 21. Quality of Health Care.tw. 22. Quality improvement.tw. 23. quality indicator$.tw. 24. quality criterion$.tw. 25. quality measure$.tw. 26. performance indicator$.tw. 27. performance measure$.tw. 28. outcome indicator$.tw. 29. audit.tw. 30. process assessment$.tw. 31. structure indicator$.tw. 32. quality parameter$.tw. 33. process parameter$.tw. 34. structure parameter$.tw. 35. outcome parameter$.tw. 36. performance parameter$.tw. 37. quality assurance.tw. 38. quality improvement.tw. 39. clinical indicator$.tw. 40. quality assessment$.tw. 174

190 41. or/ cardiovascular disease/pc 43. cardiovascular disease/th 44. Cardiology/st 45. Hypertension/pc 46. Blood Pressure Determination/st 47. Cholesterol/st 48. Lipids/st 49. or/ (prevent$ adj5 (coronar$ adj3 (event$ or disease$))).tw. 51. (prevent$ adj5 (myocardi$ adj3 (infarct$ or ischaemi$ or ischemi$))).tw. 52. (prevent$ adj5 (cardiovascular adj2 (disease$ or event$))).tw. 53. blood pressure.tw. 54. hypertensi$.tw. 55. $lipid$.tw. 56. $cholesterol$.tw. 57. or/ primary prevention/st and or 51 or 52 or 49 or or and and or limit 64 to animals not limit 66 to yr="2003 -Current" 175

191 A.6. Grey Literature Search Strategy Canadian Sources The Alberta College of Family Physicians: Tools for Practice Alberta Health and Wellness. Alberta Health Technologies Decision Alberta Medical Association British Columbia Ministry of Health Services Bone and Joint Canada Canadian Agency for Drugs and Technologies in Health. Projects in progress (CADTH) Canadian Agency for Drugs and Technologies in Health. Advanced Search Canadian Cardiovascular Society Canadian College of Family Physicians Canadian Diabetes Association Canadian Endocrine Society CMA Infobase Canadian Institute for Health Information (CIHI) Canadian Rheumatology Association Canadian Society of Atherosclerosis Thrombosis and Vascular Biology Canadian Standards Association Canadian Task Force on Preventive Care e.aspx -completed-reviews.html view/ ced and =view&id=137&itemid= nal-health-andsafety/icat/ohs/&bklist=icat,4,shop,publications, ohs 176

192 Health Quality Council of Alberta Health Quality Council Saskatchewan Health Quality Ontario Hypertension Canada The Institut national d excellence en santé et en services sociaux (INESSS). Institute for Clinical Evaluative Sciences (ICES). Institute for Health Economics Manitoba Centre for Health Policy McGill University Health Centre NLCAHR : Newfoundland and Labrador Centre for Applied Health Research. Ottawa Hospital Research Institute (OHRI) Program for the assessment of technology in Health (Canada) Public Health Agency of Canada Therapeutics Initiative: Evidenced-Based Drug Therapy UBC Thrombosis Canada University of Ottawa, school of rehabilitation science American Sources Aetna Inc. Clinical Policy Bulletins Agency for Healthcare Research and Quality: technology assessments org_id= Presentations/Publications/Reports.aspx n/search_results.php html 177

193 Agency for Healthcare Research and Quality: Evidence-based Practice Centers evidence reports and technology assessments Agency for Healthcare Research and Quality: Effective health care reports American Association of Endocrinology American College of Cardiology American College of Rheumatology American Diabetes Association American Heart Association American Medical Association American Medical Association, PCPI approved quality measures American Society of Hypertension Blue Cross and Blue Shield Association Bone and Joint Initiative USA California Technology Assessment Forum Centers for Disease Control (CDC) Prevention Guidelines Centers for Medicare and Medicaid Services Institute for Clinical and Economic Review (ICER) Institute of Medicine The Joint Commission -based-reports/hypergap3tp.html arch-for-guides-reviews-and-reports/ Guidelines/Rheumatoid_Arthritis_(Members Only)/ x mentsguidelines/bytopic/topicsa- C/ACCAHA-Joint- Guidelines_UCM_321694_Article.jsp Hypertension/Hypertension-Guidelines.aspx id.html review.org/index.php/table/completed- Appraisals/ Safety.aspx 178

194 Kidney Disease Improving Global Outcomes (KIDGO) National Guideline Clearinghouse National Heart Lung and Blood Institute National Quality Forum National Quality Measures Clearinghouse (Agency for Health Care Research) Primary care practice guidelines Quality Net RAND U.S. Preventive Task Force U.S. Department of Veterans Affairs Research & Development. U.S. Department of Health and Human Services (through AHRQ web link) Washington State Health Care Authority es/index.php c/pguidelines/index-primarycare =Page&pagename=QnetPublic%2FPage%2FQn ethomepage&cid= ecommendations.htm p European Sources AQUA institute (GERMAN) Institute for Applied Quality Improvement and Research in Health Care GmbH Bandolier (UK) Belgian Society of Rheumatology British Cardiovascular Society British Hypertension Society British Society of Rheumatology asp?pageid=

195 Czech Society for Rheumatology Clinical Evidence BMJ College voor zorgverzekeringen (CVZ). Health Care Insurance Board (Netherlands) Committee for Evaluation and Diffusion of Innovative Technologies (CEDIT) France Danish Rheumatism Society De Gezondheidsraad (GR). Health Council of the Netherlands (DIMDI) German Institute of Medical Documentation and Information Dutch Society of rheumatology eguidelines.co.uk Estonia Rheumatology Society eumusc.net European League Against Rheumatism (EULAR) European Society of Cardiology European Society of Hypertension EuroScan Secretariat Finnish Office for Health Technology Assessment (FinOHTA). Finnish Society of Rheumatology French National Authority for Health # DEFANCHOR_ m ypertension.aspx sation/units/technologies_and_practices_assess ment page=12 istedisciplines ens+arbejde/the+danish+rheumatism+associatio n rtal=si_ &typesf=guidelines 180

196 GAIN (Guidelines and Audit implementation Network) Ireland German society of Rheumatology Haute Autorité de santé/ French National Authority for Health. (HAS) Healthcare Improvement Scotland (SIGN) Health Information and Quality Authority (Ireland) Health Technology Assessment Agency (Spain)Agencia de Evaluación de Tecnologias Sanitarias, Instituto de Salud Carlos III. Hungarian Society of rheumatology Institute of Technology assessment (Austrian) IQ Scientific Institute for Quality Healthcare (Netherlands) Irish Health Repository Irish Society of Rheumatology Italian Society of Rheumatology Kenniscentrum voor de Gezondheidszorg / Le Centre d'expertise des soins de santé. Belgian Health Care Knowledge Centre (KCE) National Health Service for Wales. ATTRACT National Institute for Health and Clinical Excellence (NICE) National Institute of Health Research. Horizon Scanning Centre (NHSC). Outputs by Specialty NETSCC, HTA [formerly NCCHTA]. NIHR Health Technology Assessment Programme vateloginhas.jsp?redirect=http%3a%2f%2f sp%3fportal%3dsi_ %26amp%3bid% 3Dsd_ /welcome_to_healthcare_improvem.aspx (note link from CADTH did not work, I think this is the right one) =358538&type= lters=type:biblio%20ss_biblio_secondary_title: "KCE%20Reports"&retain-filters=

197 Norwegian Knowledge Centre for the Health Services (Norway) Norwegian Rheumatology Society Portuguese Society of Rheumatology Primary Care Rheumatology (PCR) UK SIGN under guidelines Spanish Society for Rheumatology (GUIPCAR, SER) Sundhedsstyrelsen. Danish Centre for Evaluation and Health Technology Assessment (DACEHTA). Denmark Swedish Council on Technology Assessment in Health Care Swiss Federal Office of Public Health. Swiss Network for Health Technology Assessment (SNHTA) Swiss Rheumatology Association World Health Organization Regional Office for Europe International Sources Academy of Medicine of Malaysia Argentinian rheumatology association Australian Rheumatology Association Bolivian Society of Rheumatology Brazilian Society of Rheumatology Chilean Society of Rheumatology B8y/Konsensusbaserte+prosesser+i+arbeidet+ med+kvalitetsindikatorer.+en+praktisk+veilede r+for+avdeling+for+kvalitetsm%c3%a5ling+ og+pasientsikkerhet cms ex.html e=...p%3fconfig%5broot_dir%5d%3d%5c% 5C%5C%27%20%20%2F%2Fcontact.php id=

198 China Rheumatology Association Cuba society rheumatology The Endocrine Society Ecuador Society of Rheumatology Heart Foundation New Zealand Hong Kong Society of Rheumatology Guidelines International Network (GIN) Indian Rheumatology Association International League Against Rheumatism (ILAR) INAHTA Secretariat Japan College of Rheumatology Korean Rheumatology Association Malaysian Rheumatology Association Mexican Rheumatology Association National Health and Medical Research Council (Australia) National Heart Foundation of Australia National Vascular disease prevention alliance (Australia) New Zealand Guidelines Group (NZGG) NSW Therapeutic Advisory Group (Australia) resources/health-professionals/cardiovascularrisk-management p?pagetype=1&submit=go for-professionals/clinical- Information/Pages/hypertension.aspx com_content&view=article&id=47&itemid= ews/indicators-individual.html 183

199 Pan-American League of Association for Rheumatology (PANLAR) Peruvian Society of Rheumatology Philippine Rheumatology Association Royal Australian College of General Practitioners Salvadorian Association of rheumatology Syrian Rheumatology Association University of Queensland Clinical Practice Library Uruguayan Society of Rheumatology WHO/ISH Hypertension World Health Organization Regional Office for Europe ml arthritis/ Asociaciones_M_dicas/Asociaci_n_Salvadore_ a_de_reumatolog_a_-_a.s.r._165.html delines/hypertension/en/ 184

200 APPENDIX B: APPENDIX MATERIALS FROM STUDY 2 185

201 B.1. Example of the ExpertLens Platform Demonstrating Panellists Display of an Indicator This screenshot demonstrates what a panellist views during Round 2 and Round 3: a bar chart showing the frequency of each response category, a group median (vertical line), interquartile range (shaded area around the median). Note: color adapted for publication in black and white. 186

202 B.2. Quality Indicator Specifications B.2.1. Quality Indicator #1: Communication of Increased Cardiovascular Risk in Rheumatoid Arthritis Quality Indicator: IF a patient has rheumatoid arthritis (RA), THEN the treating rheumatologist should communicate to the primary care physician (PCP), at least once within the last 2 years that patients with RA have an increased cardiovascular risk. Numerator Adult patients (18 years and older) with a diagnosis of RA whose rheumatologist has communicated* to the PCP that RA is associated with increased cardiovascular risk at least once within the last 2 years. Denominator Denominator Exclusions *Communication of increased cardiovascular risk includes but is not limited to: - Documenting in the letter back to the PCP that patients with RA have an increased risk of cardiovascular disease. - Documenting in the letter back to the PCP or in the medical chart that the patient was notified about the increased cardiovascular risk associated with RA and told to follow-up with the PCP. - Completion of a formal cardiovascular risk assessment with communication to the patient or the PCP can also contribute to the numerator but is not necessary for fulfillment of this measure. Note: It should be noted that some patients with RA have a higher cardiovascular risk than others. RA patients with the following features have an increased cardiovascular risk: Seropositive disease (RF or anti-ccp positivity) Disease duration 10 years Presence of extra-articular manifestations However, the PCP should be alerted to the potential of increased cardiovascular risk in all patients to reinforce change in modifiable risk factors in RA patients. Adult patients with RA (18 years and older) who have been seen by a rheumatologist at least twice over a period of two years. Documentation of a reason for not communicating an increased cardiovascular risk associated with RA: - Palliative patients - Patient is already under the care of a cardiologist or internist for established cardiovascular disease or cardiovascular risk reduction and already receiving appropriate treatment and screening - No PCP caring for the patient 187

203 Period of Assessment At any point over the course of available follow-up provided the rheumatologist has seen the patient at least twice during a two-year period. 188

204 B.2.2. Quality Indicator #2: Cardiovascular Risk Assessment Quality Indicator: A) IF a patient has rheumatoid arthritis (RA) THEN a formal cardiovascular (CV) risk assessment according to national guidelines should be done at least once in the first two years after evaluation by a rheumatologist AND B) if low risk it should be repeated once every 5 years; OR C) if initial assessment suggests intermediate or high-risk, THEN treatment of risk factors according to national guidelines should be recommended. Numerator A) Adult patients (30 years and older)* with a diagnosis of RA who have documentation in their medical record of a formal CV risk** assessment done once within the first two years after evaluation by a rheumatologist using a validated cardiovascular risk score according to national guidelines. **Examples include but are not limited to: Framingham Risk Score, SCORE, QRISK, Reynolds Risk Score. Use of a CV risk assessment tool that adjusts for the presence of RA is suggested but not necessary for fulfillment of this indicator. AND B) If low risk according to initial risk assessment then risk scores are repeated once every 5 years OR C) If intermediate or high risk THEN it is recommended*** that treatment of risk factors be initiated according to national guidelines. ** The cardiovascular risk scores described above are each validated for a defined lower age limit: if using QRISK lower age limit is 25; if using Framingham 10-year risk prediction lower age limit is 30; if using SCORE method lower age limit is 40 etc. Evaluation for modifiable risk factors should occur in younger ages as described in other indicators; however, given limited validity of risk calculators in younger age groups (18-29 years) they are not included in this indicator. ***Appropriate means of conveying this recommendation include but are not limited to: - Documentation in a letter to the primary care physician (PCP or other healthcare provider) that the patient is at intermediate or high CV risk and that treatment of risk factors should be initiated as indicated according to national guidelines. - Documenting that this information was given to the patient and they were told to follow-up with their PCP (or other healthcare provider) to discuss modification of risk factors. - Documentation that the rheumatologist made treatment adjustments, initiated therapy or made recommendations to address modifiable risk factors. 189

205 Denominator Denominator Exclusions Period of Assessment Note: This quality indicator can be reported as 3 quality measures: - A) Percentage of patients with RA with a documented cardiovascular risk assessment within 2 years of evaluation by a rheumatologist. - B) Percentage of patients with RA with a low risk baseline cardiovascular risk score who have a risk assessment repeated at least once every 5 years. - C) Percentage of patients with RA with an intermediate or high risk baseline cardiovascular risk score AND who have documentation in their medical record that treatment of risk factors was recommended. A) All adult patients with RA (30 years and older) seen at least twice over a 2 year measurement period B) For low risk: number of patients (30 years and older) seen at least twice over a 5 year measurement period C) For intermediate or high risk: number of patients (30 years and older) seen at least twice over a 2 year measurement period Documentation of a reason for not recommending CV risk assessment including: - Palliative patients - Documented patient refusal of CV risk assessment - Those already under the care of a cardiologist or internist for known cardiovascular disease (e.g., previous stroke, peripheral vascular disease or ischemic heart disease) and already receiving appropriate screening and treatment of modifiable risk factors - If another treating physician or care provider has conducted a screening CV risk assessment according to national guidelines, and this is clearly documented in the medical record, then this obviates the need for the rheumatologist to repeat the risk assessment and these cases would contribute to the denominator exclusions. A) Low-risk: 5 year measurement period B) Intermediate or high risk: 2 year measurement period 190

206 B.2.3. Quality Indicator #3: Smoking Status and Cessation Counselling Quality Indicator: A) IF a patient has rheumatoid arthritis (RA) THEN their smoking and tobacco use status should be documented at least once in the last year AND B) if they are current smokers or tobacco users they should be counselled to stop smoking. Numerator A) Adult patients (18 years and older) with RA who had their smoking and tobacco use status documented one or more times in the medical record in the last year AND B) if they were current smokers or tobacco users they were counselled* to stop smoking or using tobacco. *Counselling includes but is not limited to: - Documenting that the patient was counseled to stop smoking - Patient was prescribed a medication to assist with smoking cessation - Letter from rheumatologist has requested that the primary care provider discuss smoking cessation with the patient - Patient was provided with written smoking cessation information - Patient was referred (or provided a self-referral number) to a smoking cessation intervention Note this indicator provides two quality measures: A) Percentage of RA patients who have their smoking status documented at least once during the measurement period. B) Percentage of RA patients who are current tobacco users who are counseled to stop smoking. Denominator A) Patients 18 years and older with a diagnosis of RA seen at least once during the measurement period. B) Patients 18 years and older with a diagnosis of RA seen at least once during the measurement period who are current smokers. Denominator Documented life-long non-smoker Exclusions Period of 1 year measurement period Assessment 191

207 B.2.4. Quality Indicator #4: Screening for Hypertension Quality Indicator: IF a patient has rheumatoid arthritis THEN their blood pressure should be measured and documented in the medical record at 80% of clinic visits. Numerator Adult patients with RA (18 years and older) who have had a blood pressure measured at 80% of clinic visits per year and documented in their medical record. Note: documentation that the blood pressure was normal but not reporting the value is insufficient for inclusion in the numerator Denominator All patients 18 years and older with a diagnosis of RA at the start of the measurement period. Denominator Exclusions - Documented physician reason why blood pressure can t be measured - Documented patient refusal Period of Assessment - Palliative patient 1 year measurement period 192

208 B.2.5. Quality Indicator #5: Communication to Primary Care Physician About a Documented High Blood Pressure Quality Indicator: IF a patient has rheumatoid arthritis AND has a blood pressure measured during a rheumatology clinic visit that is elevated (systolic blood pressure 140 and/or diastolic blood pressure 90) THEN the rheumatologist should recommend that it be repeated and treatment initiated or adjusted if indicated Numerator Adult patients with RA (18 years and older) who have had a blood pressure measured during a rheumatology clinic visit that is elevated (systolic blood pressure 140 and/or diastolic blood pressure 90) AND the rheumatologist has recommended that the blood pressure be repeated and antihypertensive treatment initiated or adjusted if indicated. Appropriate means of conveying this information include but are not limited to: 1. Having the patient repeat the blood pressure measurement at home and following up with their PCP (or other healthcare provider) if elevated for appropriate treatment if indicated. 2. Ordering or advising the PCP (or other healthcare provider) to order 24-hr ambulatory blood pressure monitoring for the patient and follow-up with their PCP (or other healthcare provider) if elevated for appropriate treatment if indicated. 3. Documentation in a letter to the PCP (or other healthcare provider) the need to repeat the blood pressure and initiate or adjust antihypertensive treatment if indicated. 4. Documenting this information was given to the patient and they were told to follow-up with their PCP (or other healthcare provider) to repeat the blood pressure and get treatment if indicated. 5. Documentation that the rheumatologist made an antihypertensive treatment adjustment or initiated anti-hypertensive therapy. Denominator Note: lower target thresholds may be indicated for patients with diabetes and chronic kidney disease but are not captured within this indicator. More urgent or aggressive approaches may be warranted in more severe hypertensive stages; however, it is out of the scope of the present quality indicator to create specific measures for each hypertensive stage. All adult patients with RA (18 years and older) with a diagnosis of rheumatoid arthritis and an elevated blood pressure measurement 193

209 Denominator Exclusions Period of Assessment defined as a systolic blood pressure 140 and/or diastolic blood pressure Patients with concomitant diabetes or chronic kidney disease where a lower threshold target threshold may be more appropriate - Documented blood pressure target that is above the 140/90 threshold for medical reasons (e.g., very elderly frail individual with severe postural hypotension). - Palliative patient 1 year measurement period 194

210 B.2.6. Quality Indicator #6: Measurement of a Lipid Profile Quality Indicator: IF a patient has rheumatoid arthritis (RA) THEN a lipid profile should be done at least once in the first two years after evaluation by a rheumatologist AND A) if low risk according to cardiovascular risk scores, the lipid profile should be repeated once every 5 years; OR B) if cardiovascular risk assessment suggests intermediate or high-risk, then treatment according to national guidelines should be recommended. Numerator Adult patients (18 years and older) with a diagnosis of rheumatoid arthritis (RA) who have documentation in their medical record of a lipid profile assessment done once within the first two years after evaluation by a rheumatologist. AND A) A) If low risk according to initial risk assessment*, then lipid profile is repeated once every 5 years. OR B) If intermediate or high risk according to initial risk assessment*, then recommendation that patients be treated according to national guidelines. Appropriate means of conveying this information include but are not limited to: 1. Documentation in a letter to the primary healthcare provider (PCP or other healthcare provider) the need to start or adjust lipid-lowering treatment if indicated. 2. Documenting this information was given to the patient and they were told to follow-up with their PCP (or other healthcare provider) to discuss their abnormal lipid profile. 3. Documentation that the rheumatologist made treatment adjustments or initiated lipid-lowering therapy. *Examples include but are not limited to: Framingham Risk Score, SCORE, QRISK, or Reynolds Risk Score. Use of a CV risk assessment tool that adjusts for the presence of RA is suggested but not necessary for fulfillment of this indicator. Note: testing for Apolipoprotein B (ApoB) instead of routine lipid screening may also be counted in the numerator, but is not necessary for fulfillment of this indicator. Note: Lipid profiles do not need to be repeated if done within the specified time frame by another physician. Note: More frequent lipid measurement and cardiovascular risk assessment may be warranted following major treatment changes (e.g., addition of corticosteroids, addition of tocilizumab etc.). 195

211 Note: Patient might still be eligible for therapy according to national guidelines if LDL-C very high (e.g., >5mmol/L in Canadian guidelines) Denominator Denominator Exclusions Period of Assessment A) For low risk: number of patients (18 years and older) seen at least twice over a 5 year measurement period B) For intermediate or high risk: number of patients (18 years and older) seen at least twice over a 2 year measurement period - Documented physician reason for not performing the test - Documented patient refusal - Palliative patient A) Low-risk: 5 year measurement period B) Intermediate or high risk: 2 year measurement period 196

212 B.2.7. Quality Indicator #7: Screening for Diabetes Quality Indicator: IF a patient has RA THEN diabetes should be screened for as part of a cardiovascular (CV) risk assessment at least once within the first 2 years of evaluation by a rheumatologist and A) once every 5 years in low risk patients or B) yearly in intermediate or high-risk patients AND if screening is abnormal, this information should be communicated to the primary care provider (PCP) for appropriate follow-up and management if indicated. Numerator Patients 18 years of age and older with a diagnosis of RA who have had a fasting glucose AND/OR a Hemoglobin A1C to screen for diabetes at least once within 2 years of first seeing a rheumatologist. AND A) Every 5 years in low risk patients as part of a cardiovascular risk assessment OR B) Yearly in patients at intermediate or high risk* for diabetes Note: *Patients at High or Intermediate Risk for diabetes include patients with the following risk factors: - Family history of type 2 diabetes in a first degree relative - History of metabolic syndrome - Obesity or overweight (body mass index 25 kg/m2) - Steroid use - History of gestational diabetes or a macrosomic infant - History of impaired fasting glucose - History of hypertension (blood pressure 140/90 mmhg) - Member of a high risk population (e.g., aboriginal, Asian, Hispanic, South Asian, African, Pacific Islanders) - High risk based on validated diabetes risk calculators - High or intermediate cardiovascular risk based on cardiovascular risk calculators (Framingham, SCORE etc.) Low risk patients refer to patients without risk factors for diabetes on history or physical exam and that are also at low risk for cardiovascular disease based on a formal cardiovascular risk assessment and not taking steroids. Note: More frequent or specialized testing (for example the homeostasis model assessment (HOMA) estimated Insulin Resistance) may be indicated in some high-risk groups including patients on corticosteroids but is not within the scope of this quality indicator. Denominator A) For low risk: Number of patients (18 years and older) seen at least twice over a 5 year measurement period B) For intermediate or high risk: Number of patients (18 years and older) seen at least twice over a 2 year measurement period Denominator - Diabetes already diagnosed and managed by an appropriate 197

213 Exclusions Period of Assessment care provider according to national guidelines. - Palliative patient - Documented patient refusal to be screened - Documented other physician reason why screening not appropriate - Fasting glucose or hemoglobin A1C do not need to be repeated if done within the specified time frame if ordered by another physician A) Low-risk: 5 year measurement period B) Intermediate or high risk: 2 year measurement period 198

214 B.2.8. Quality Indicator #8: Exercise Quality Indicator: IF a patient has rheumatoid arthritis THEN physical activity goals should be discussed with their rheumatologist at least once yearly. Numerator Adult patients with rheumatoid arthritis (18 years of age and older) who have discussed* physical activity goals with their rheumatologist at least once within the last year. *Discussion may include but is not limited to: - Directing patients to a physiotherapist for physical activity assessment and recommendations - Directing patients to an appropriate community or hospital physical activity program - Directing patients to information about National physical activity guidelines - Documented discussion in chart about increasing physical activity Note: Discussion about physical activity goals and exercise is an important part of comprehensive rheumatology care and should occur as part of every patient encounter. A once yearly evaluation as part of a holistic assessment is considered a minimum. Denominator Adult patients with RA (18 years and older) who have been seen by a rheumatologist at least once over the last year. Denominator Documented reason why physical activity is not recommended: Exclusions palliative patient, patient documented refusal, wheelchair bound patient, Period of Assessment other significant comorbidity preventing an increase in physical activity 1 year measurement period 199

215 B.2.9. Quality Indicator #9: BMI Screening and Lifestyle Counselling Quality Indicator: A) IF a patient has rheumatoid arthritis (RA) THEN their body mass index (BMI) should be documented at least once every year AND B) if they are overweight or obese according to national guidelines they should be counselled to modify their lifestyle. Numerator A) Adult patients (18 years of age and older) with a diagnosis of RA who had their BMI calculated at least once every year AND B) If overweight or obese according to national guidelines were counselled* to modify their lifestyle. Denominator Denominator Exclusions Period of Assessment *Examples of counselling include but are not limited to: - Referral to a registered dietician (or documented recommendation to general practitioner to do so) - Following national food guide - Following an endorsed heart health healthy diet (e.g., Mediterranean diet, DASH diet) - Diet discussed and brochure provided - Weight reduction - Moderating caloric intake - Increasing physical activity - Told to follow-up with primary care practitioner or other allied health professional to seek weight loss advice. Note: If waist circumference, body fat percentages, or other clear documentation that the patient is overweight or obese are used instead of BMI, these cases can be included in the numerator. This quality indicator provides two quality measures: A) Percentage of adult patients with RA who had their BMI calculated at least once within the last year. B) Percentage of adult patients with RA who were overweight or obese who were counseled to modify their lifestyle. A) Adult patients with RA (18 years and older) who have been seen by a rheumatologist at least once in the last year. B) Adult patients with RA (18 years and older) who have been seen by a rheumatologist at least once in the last year and who are overweight or obese according to national guidelines. - Physician documented exclusion including patient refusal to discuss, patient already followed by a dietician or other care provider for weight loss. - Palliative patient 2 year measurement period 200

216 B Quality Indicator #10: Minimizing Corticosteroid Usage Quality Indicator: IF a patient with rheumatoid arthritis (RA) is on oral corticosteroids THEN there should be evidence of intent to taper off the corticosteroids or reduce to the lowest possible dose Numerator Adult patients (18 years and older) with a diagnosis of RA who are on oral corticosteroids and who have a documented written plan to taper off corticosteroids or decrease to the lowest possible dose. Evidence of intent to taper steroids includes: - A written plan in the chart or letter back to the primary care provider (PCP) detailing the plan for the corticosteroid taper - A copy of a corticosteroid taper calendar in the chart or documentation that one was given to the patient - Mention of initiating a taper (without further specification detailed) - Evidence that dose of corticosteroids was reduced or stopped over the 1 year measurement period based on pharmacy data Denominator Number of patients 18 years of age and older with a diagnosis of RA who are on corticosteroids at any dose during the measurement period. Denominator Exclusions Period of Assessment - Documented contraindication to tapering prednisone (e.g., existing or presumed adrenal insufficiency either primary or secondary) - Corticosteroid was prescribed for another indication (e.g., malignancy, other inflammatory condition or extra-articular feature requiring steroid treatment, end-stage COPD) - Patient refusal to taper - Other documented physician reason why taper is inappropriate (e.g., presence of other significant comorbidities precluding other treatments, palliative patient for symptom control) 1 year measurement period 201

217 B Quality Indicator #11: Communication About Risks/Benefits of Anti- Inflammatories in Patients at High Risk of Cardiovascular Events Quality Indicator: IF a patient has rheumatoid arthritis (RA) AND has established cardiovascular disease OR is at intermediate or high cardiovascular risk AND is on a non-steroidal anti-inflammatory drug (NSAID or Cox-2 inhibitor) THEN a discussion about the potential cardiovascular risks should occur and be documented Numerator Adult patients (18 years of age and older) with RA and known cardiovascular disease (or at intermediate or high risk for cardiovascular disease) who are prescribed anti-inflammatories including non-steroidal anti-inflammatory (NSAID) or Cox-2 inhibitors (COXIBS) and have a documented* discussion about the risks and benefits of using antiinflammatory drug in their medical record. *Documentation of the discussion of risks and benefits can include but is not limited to: - Documentation that a discussion of risks and benefits of NSAID and COXIB use occurred - Documentation that written information detailing the risks and benefits was provided to the patient - Documentation that cardiovascular risks were minimized by using an anti-inflammatory with a known lower or neutral cardiac risk profile - Documentation that the patient was informed of the risks and it was their preference to continue or start an anti-inflammatory for symptom relief - Documentation that risks and benefits were considered but no other treatment options were viable for management of patient symptoms (other RA treatments maximized and other pain medications contraindicated for other reasons) Denominator Patients 18 years of age and older with a diagnosis of rheumatoid arthritis (RA) and known cardiovascular disease (or high risk for cardiovascular disease). Includes patients with but not limited to: Past history of myocardial infarction or ischemic heart disease Past history of Stroke History of peripheral vascular disease Intermediate or High risk based on a validated cardiovascular risk score* *Examples of cardiovascular risk assessment tools include but are not limited to: Framingham Risk Score, SCORE, QRISK, Reynolds Risk Score. Denominator None identified Exclusions Period of 1 year measurement period 202

218 Assessment 203

219 APPENDIX C: MATERIALS FROM STUDY 3 204

220 C.1. Chart Abstraction Form for Retrospective Review of Quality Indicators Baseline information initials of reviewer Clinic ERA Site RRDTC SHC Biologics U of C Biological sex Female Male Birth Year and Month (Y/M) Ethnicity (patient identified) If parent Not stated Caucasian South Asian Black Other Specify: ethnicity only identified First Nations Hispanic and more than one, select Asian other and specify Date of diagnosis of RA (If unclear use date of 1 st rheumatologist contact where diagnosis clearly documented) Date of Baseline visit (if ERA will be same as First ERA visit if Biologics will be first visit date) (Y/M/D) (Y/M/D) Date of symptom onset Taken from: Case record form Referral letter Clinic letter Last clinic visit date after 2 years of follow-up Criteria for RA (2010 ACR-EULAR Classification Criteria for RA) Target population: Patients must have 1. At least 1 joint with synovitis 2. With synovitis not better explained by another disease (Y/M) (Y/M/D) Definitions for Classification Algorithm Large joints refers to shoulders, elbows, hips, knees and ankles Small joints refers to MCPs, PIPs, 2-5MTPs, thumb IPs, wrists Joint involvement refers to any tender or swollen joint on exam For serologic tests negative is ULN, low-positive are higher than ULN but 3 times the ULN, high-positive are >3 times the ULN Joints not included in count: DIPs, CMC. 1 st MTP A. Joint involvement Patient Score 1 large joint large joints small joints +/- large joint involvement small joints +/- large joint involvement 3 > 10 joints (at least 1 small joint) 5 B. Serology (at least 1 test result is needed for classification) Negative RF AND negative anti-ccp 0 Low-positive RF OR low-positive anti-ccp 2 High-positive RF OR high-positive anti-ccp 3 C. Acute-phase reactants (at least 1 test result needed for classification) Normal CRP and normal ESR 0 Abnormal CRP or abnormal ESR 1 D. Duration of disease <6 weeks 0 6 weeks 1 205

221 Total score ( 6/10 meets criteria for RA) Add totals from A-D Meets criteria for RA Yes No -- Comorbidities at baseline (from specialist s letter, case record form or referral letter) Established Cardiovascular Disease at Baseline (at first eligible study visit, mark all that apply) Myocardial infarction Angina Otherwise unspecified acute coronary syndrome Heart Failure Stroke Transient ischemic attack (TIA) Peripheral vascular disease Other: *Note if patient has established CVD (any of the above) then the CVD QIs do not apply. Items below do not disqualify from CVD QI assessment: Atrial Fibrillation Other arrhythmia No Cardiovascular disease of any kind (qualifies for CVD QI assessment) Not reported/too much missing information to determine if there is a history of CVD (generally will accept if no mention in chart at baseline then no baseline history of CVD unless there are concerns about significant inconsistencies in chart as judged by both reviewers) Hypertension at Baseline (at first eligible study visit) Hypertension (on antihypertensive therapy or by medical history documented in record or by documented hypertension BP 140/90mmHg on at least 3 occasions) Hypertension (BP 140/90mmHg) at first visit but no prior history (not on antihypertensive therapy or by medical history) No history of hypertension (acceptable if no mention in medical history, BP not elevated and not on medication at baseline) Not reported/too much missing information (i.e., no documented blood pressures, medical history, medications) Diabetes at Baseline (at first eligible study visit) Diabetes Type I Type II (on oral hypoglycaemic or insulin or by medical history documented in record) No history of diabetes (acceptable if no labs done and not on diabetic medication, does not apply if HgbA1C >=6.5% and/or fasting glucose >=7.0mmol/L within 6 months prior to clinic visit) Not reported/too much missing information to determine if there is a history of diabetes (i.e., no medication information) Dyslipidemia at Baseline (at first eligible study visit) Established dyslipidemia (on lipid lowering therapy or by medical record) No history of dyslipidemia (acceptable if no labs done and not on lipid lowering 206

222 therapy, does not apply if lipid levels available within 6 months prior to clinic visit done and grossly abnormal) Not reported/too much missing information to determine if there is a history of dyslipidemia (i.e., no medication information, no past medical history) Obesity at Baseline (at first eligible study visit) Obesity (By medical record, BMI >=30) BMI= No history of obesity (normal BMI and no mention of obesity or need for weight loss in the chart) Not reported/too much missing information to determine if there is a history of obesity (no reported BMI or weight or waist circumference) Family history of first degree relative with premature CVD (M<55, F<65) Yes No (clearly documented no family history of CVD) Not reported/too much missing information to determine if there is a history of CVD Smoking status Current smoker Ex-smoker Non-smoker Not reported/too much missing information to determine smoking status Pulmonary Interstitial lung disease COPD Asthma Other No pulmonary disease Not reported/too much missing information to determine (no past history documented) Gastrointestinal Gastro-oesophageal reflux disease or gastric ulcers (documented on history) Inflammatory bowel disease Other: No GI disease Not reported/too much missing information to determine (no past history documented) Chronic kidney disease Chronic kidney disease not on dialysis (documented on medical history) OR GFR <60 ml/min/1.73m 2 for 3 months Dialysis Other: No chronic kidney disease Not reported/too much missing information to determine (i.e. no labs) Other medical problems 207

223 Baseline medications at start of data collection DMARDS Hydroxycholorquine(Plaquenil) Chloroquine (Aralen) Methotrexate (Rheumatrex) Leflunomide (Arava) Gold shots (myochrysine, solganol) Salazopyrin (Sulfasalazine) Other On no DMARDs at baseline visit but DMARDs started at this visit Major concern about missing information in the chart can t determine if on DMARDs or not based on chart review (no medical information) Clearly on NO DMARD and none started at this visit NSAIDS Acetylsalicylic acid (ASA, aspirin, entrophen, EC-ASA) Celecoxib (Celebrex) Diclofenac (Voltaren, D Voltaren-rapide) Diclofenac-misoprostol (Arthrotec) Diflusinal (Dolobid) Etodolac (Lodine, lodine-xl, DUltadol) Fenoprofen (Nalfon) Fluriprofen (Ansaid, DFroben, DFroben-SR) Ibuprofen (Motrin, Advil, Rufen, Nuprin) Indomethacin (Indocin, Indocin-SR, Indocid, Indocid-SR) Ketoprofen (Orudis, orudis KT, acrton, Oruvail, DRhodis) Ketrorolac (Toradol) Meclofenamate (Meclomen) Mefenamic acid (Ponstel, ponstan) Meloxicam (Mobic, DMobicox) Nambutone (Relafen) Naproxen (Aleve, Anaprox, Naprosyn, EC-Naprosyn, Naprelan, Vimovo) Oxaprozin (Daypro) Piroxicam(Feldene) Salsalate (Disalcid, Salflex, Amigesic) Sulindac (clinoril) Tenoxicam(DMobiflex) Tiaprofenic Acid (DSurgam, DAlbertTiafen) Tenoxicam (Tolmetin) Other Dose at baseline visit Dose at baseline visit 208

224 On no NSAIDs at baseline visit but an NSAID started at this visit Can t determine if on NSAIDs or not based on chart review Clearly on NO NSAIDs and none started at this visit Biologic agent Adalumimab (Humira) Etanercept (Enbrel) Golimumab (Simponi) Certolizumab (Cimzia) Infliximab (Remicade) Rituximab (Rituxan) Tocilizumab (Actemra) Abatacept (Orencia) On no Biologic at baseline visit but a biologic started at this visit Can t determine if on biologics or not based on chart review Clearly on NO Biologic agent and none started at this visit Lipid lowering agents Statins Rosuvastatin (Crestor, prefix-rosuvastatin) Atorvastatin (Lipitor, prefix-atorvastatin) Simvastatin (Zocor, prefix-simvastatin) Lovastatin (Mevacor, prefix-lovastatin) Pravastatin (Pravachol, prefix-pravastatin) Fluvastatin (Lescol, Lescol XL, Teva-fluvastatin) Dose at baseline visit Bile acid sequestrants Cholestyramine (Novo-cholamine, Olestyr, Questran) Colestipol (colestid) Colesevelam (Lodalis) Fibrates Gemfibrozil (Lopid, prefix-gemfibrozil) Fenofibrate (Apo-Feno-Micro, prefix-febofibrate, Lipidil supra, Lipidil Micro, Fenofibrate micro, PRO-feno-Super) Bezafibrate (Benzalip SR) Niacin and derivatives Nicotinic acid Cholesterol absorption inhibitors Ezetimibe (Ezetrol) Other: 209

225 On no Lipid lowering agent at baseline visit but a lipid lowering agent recommended at this visit On no Lipid lowering agent at baseline visit but a lipid lowering agent started at this visit Can t determine if on lipid lowering agents or not based on chart review Clearly on NO Lipid lowering agent and none started at this visit Antihypertensive agents Thiazide-type diuretics Hydrochlorothiazide (apo-hydro, prefix-hydrochlorothiazide, novohydrazide, Nu-Hydro) Chlorthalidone (apo-chlorthalidone) ACE inhibitors/arbs Benzapril (lotensin) Captopril (Capoten) Cilzapril (Inhibace) Enalapril (Vasotec) Fosinopril (Monopril) Lisinopril (Prinivil, Zestril) Moexipril (Univasc) Perindopril (Aceon) Quinapril (Acupril) Ramipril (Altace) Trandolapril (Mavik) Losartan (Cozaar) Irbesartan (Avapro) Telmisartan (Micardis, Twynsta) Candesartan (Atacand) Azilsartan (Edarbi) Olmesartan (Benicar) Valsartan (Diovan) Calcium channel blockers Amlodipine (Norvasc, Twynsta) Diltiazem (Cardizem, Tiazac) Felodipine (Plendil) Flunarizine Nifedipine (Procardia) Nimodipine (Nimotop) Verapamil (Calan, Verelan, Covera-HS) Beta blockers Acebutolol (Sectral, prefix-acebutolol) 210

226 Atenolol (Tenormin, prefix-atenolol) Bisoprolol (Zebeta, prefix- Bisoprolol) Carvedilol (Coreg, prefix- Carvedilol) Esmolol (Brevibloc, prefix- Esmolol) Labetalol (Lopressor, Toprol XL, prefix-labetalol) Metoprolol (Normodyne, Trandate, prefix- Metoprolol ) Nadolol (Corgard, prefix- Nadolol) Nebivolol (Nebivolol, prefix- Nebivolol) Pindolol (Visken, prefix- Pindolol) Propranolol (Inderal, Inderal LA, Innopran XL, prefix- Propranolol ) Sotalol (Betapace, prefix-sotalol) Timolol (Blocadren, prefix- Timolol) Other: On no anti-hypertensive agent at baseline visit but a antihypertensive agent recommended at this visit On no antihypertensive agent at baseline visit but a antihypertensive agent started at this visit Major concern about missing information in the chart can t determine if on antihypertensive agents or not based on chart review (e.g., no medication history taken) Clearly on NO antihypertensive agent and none started at this visit Glucocorticoids Oral prednisone IM steroids Intra-articular steroids On no glucocorticoids at baseline visit but a glucocorticoid started at this visit Major concern about missing information in the chart can t determine if on glucocorticoids or not based on chart review (e.g., no medication history taken) Clearly on NO glucocorticoid agent and none started at this visit Other relevant medications 211

227 RA characteristics of poor prognosis at baseline RF positive (acceptable if done any time prior to Yes No Not done first visit or within 6 months of 1 st subsequent visit) Anti-CCP positive (acceptable if done any time Yes No Not done prior to first visit or within 6 months of 1 st subsequent visit) Rheumatoid Nodules (at baseline visit) Yes No (acceptable if no mention of nodules and clearly documented physical exam) Not documented (no clear physical exam documented) Erosions on baseline x-rays (at diagnosis of RA or within 3 months if ERA or within 1 year of Yes No Not done baseline visit if biologic) Other extra-articular RA manifestation (lung, cardiac etc.) Yes No Not done if no medical past history documented Specify: Disability HAQ score at baseline Dressing and Grooming Without ANY difficulty = 0; With MUCH difficulty =2 With SOME difficulty = 1; UNABLE to do =3 Take the highest score within a category Adjusted score to a minimum of 2 if need aid, if original score already 2 or higher then leave it the same. Arising Eating Walking Hygiene Reach Original Score: Need aid? Yes No Adjusted score: Original Score: Need aid? Yes No Adjusted score: Original Score: Need aid? Yes No Adjusted score: Original Score: Need aid? Yes No Adjusted score: Original Score: Need aid? Yes No Adjusted score: Original Score: Need aid? Yes No Adjusted score: 212

228 Grip Activities Pain score baseline (out of 10) Original Score: Need aid? Yes No Adjusted score: Original Score: Need aid? Yes No Adjusted score: Number of clinic visits over 2-year period of follow-up 213

229 Disease activity, functional assessment and medication changes at baseline and each clinic visit over 2-years of follow-up Date Tender Swollen Physician Patient ESR CRP BP Changes to RA Changes to CVD QI notes YYYY- Joint Joint Global Global Medication (DMARD, Medication (antihypertensive, lipid communication, smoking (i.e., risk assessment/ MMM- Count Count Biologic, Corticosteroids, DD (28) (28) NSAIDS) lowering, ASA, other) status/ cessation, BP counselling, lipid panel, fasting glucose, haemoglobin A1C, exercise, BMI, corticosteroid, NSAID) 214

230 Was there enough information to calculate a Framingham risk score at a clinic visit at least once within 2 years? (Note: Lipid level, fasting glucose/hga1c within 6 month before or 1 month after clinic visit acceptable) Baseline Visit date (Y/M/D) Date of lipid level (Y/M/D) Follow up Visit date (Y/M/D) Date of lipid level (Y/M/D) No lipid panel done over course of follow up Total cholesterol HDL Systolic BP Diastolic BP (vascular age) BP treated? Diabetes Smoker Family Hx of premature CVD Total cholesterol HDL Systolic BP Diastolic BP (vascular age) BP treated? Diabetes Smoker Family Hx of premature CVD Total cholesterol level mmol/l HDL Level mmol/l Systolic BP Diastolic BP BP treated (Y/N) Diabetes (Y/N) Smoker (Y/N) Family Hx (Y/N) Could a FRS be calculated (Y/N) If Yes: Calculated FRS Calculated Vascular age Was this done in clinic (Y/N) Total cholesterol level mmol/l HDL Level mmol/l Systolic BP Diastolic BP BP treated (Y/N) Diabetes (Y/N) Smoker (Y/N) Family Hx (Y/N) Could a FRS be calculated (Y/N) If Yes: Calculated FRS Calculated Vascular age Was this done in clinic (Y/N) 215

231 Quality Indicators for Cardiovascular Care in RA Instructions: See accompanying document entitled Final set of 11 QIs Prior to testing for further inclusion/exclusion descriptions QI# 1 Communication of Increased Cardiovascular risk in RA Numerator Rheumatologist has communicated* to the PCP that RA is associated with increased cardiovascular risk at least once within the last 2 years. Denominator Adult patients with RA (18 years and older) who have seen their rheumatologist at least twice over a period of two years. Exclusions Chart meets criteria Yes/No Observation Date Y/M/D Comments Palliative patient Patient is already under the care of a cardiologist or internist for established CVD or CV risk reduction and already receiving appropriate treatment and screening, No PCP caring for the patient Other, specify *Communication of increased cardiovascular risk includes but is not limited to: - Documenting in the letter back to the PCP that patients with RA have an increased risk of cardiovascular disease. - Documenting in the letter back to the PCP or in the medical chart that the patient was notified about the increased cardiovascular risk associated with RA and told to follow-up with the PCP. - Completion of a formal cardiovascular risk assessment with communication to the patient or the PCP can also contribute to the numerator but is not necessary for fulfillment of this measure. 216

232 QI# 2 Cardiovascular risk assessment (Part 1) N/A, age <30 Numerator Adult patients (30 years and older) with a diagnosis of RA who have documentation in their medical record of a formal CV risk assessment done once within the first two years after evaluation by a rheumatologist using a validated cardiovascular risk score according to national guidelines. Denominator Adult patients with RA (30 years and older) seen at least twice over a 2-year measurement period. Exclusions Palliative patients Documented patient refusal of CV risk assessment, Already under the care of a cardiologist or internist for known CVD and already receiving appropriate screening and treatment of modifiable risk factors. If another treating physician or care provider has conducted a screening CV risk assessment according to national guidelines, and this is clearly documented in the medical record If another treating physician has already started patient on statin and anti-hypertensive and patient is at target Other, specify Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Part 2 Cardiovascular risk assessment (Intermediate or High risk patients only) Numerator If intermediate or high risk according to CVD risk assessment THEN it is recommended*** that treatment of risk factors be initiated according to national guidelines Denominator Patient (30 years and older) seen at least twice over a 2 year measurement period with a documented CVD risk assessment demonstrating they are at high or intermediate CVD risk. Exclusion Same as above Chart Meets criteria Yes/No Date of Observation Y/M/D Comments ***Appropriate means of conveying this recommendation include but are not limited to: - Documentation in a letter to the primary care physician or other healthcare provider that the patient is at intermediate or high CV risk and that treatment of risk factors should be initiated as indicated according to national guidelines. - Documenting that this information was given to the patient and they were told to follow-up with their PCP or other healthcare provider to discuss modification of risk factors. 217

233 QI# 3 Smoking Status and Cessation Counselling (measuring smoking status) Part 1 Numerator Comments Adult patients (18 years and older) with RA who had their smoking and tobacco use status documented one or more times in the medical record in the last year. Denominator Patients 18 years and older with a diagnosis of RA seen at least once during the measurement period. Exclusions Chart Meets criteria Yes/No Date of Observation Y/M/D Y1 Y2 Y1 Y2 Y1 Y2 Documented life-long non-smoker For year 2, documented ex-smoker Other, specify QI# 3 Part 2 Smoking Status and Cessation Counselling (smoking cessation recommended) Numerator Current smokers or tobacco users who were counselled* to stop smoking or using tobacco. Denominator Patients 18 years and older with a diagnosis of RA seen at least once during the measurement period who are current smokers. Exclusions Documented life-long non-smoker. Ex-smoker (clearly documented) Other, specify Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Y1 Y2 Y1 Y2 Y1 Y2 * Counselling includes but is not limited to: Documenting that the patient was counseled to stop smoking Patient was prescribed a medication to assist with smoking cessation Letter from rheumatologist has requested that the primary care provider discuss smoking cessation with the patient Patient was provided with written smoking cessation information Patient was referred (or provided a self-referral number) to a smoking cessation intervention 218

234 QI# 4: Screening for hypertension YEAR 1 Numerator Was blood pressure measured during the clinic visit? Was BP measured at 80% of clinic visits Yes No (documented on follow-up chart) Denominator Patients 18 years and older with a diagnosis of RA seen at least once during the measurement period Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Exclusions Documented physician reason why blood pressure can t be measured, Documented patient refusal Palliative patient Other specify QI# 4: Screening for hypertension YEAR 2 Was blood pressure measured during the clinic visit? Was BP measured at 80% of clinic visits Yes No (documented on follow-up chart) Denominator Patients 18 years and older with a diagnosis of RA seen at least once during the measurement period Exclusions Documented physician reason why blood pressure can t be measured, Documented patient refusal Palliative patient Other specify 219

235 QI# 5: Communication to PCP About a Documented High Blood Pressure (BP) Numerator Patients with RA who have had a BP measured during a rheumatology clinic visit that is elevated (systolic BP 140mmHg and/or diastolic BP 90mmHg) AND the rheumatologist has recommended that the BP be repeated and antihypertensive treatment initiated or adjusted if indicated. (See documentation of dates on p9) Denominator Adult patient (18 years and older) with a diagnosis of rheumatoid arthritis AND an elevated blood pressure measurement defined as a systolic blood pressure 140 and/or diastolic blood pressure 90. (See documentation on previous page) Exclusions Chart Meets criteria Yes/No Patients with concomitant diabetes or chronic kidney disease where a lower threshold target threshold may be more appropriate. Documented BP target that is above the 140/90mmHg threshold for medical reasons (e.g., very elderly frail individual with severe postural hypotension). Palliative patient Other specify List the number of clinic visits where indicator was not met Year 1 Number of clinic visits indicator not met Year 1Total number of clinic visits with a BP done Year 2 Number of clinic visits indicator not met Year 2 Total number of clinic visits with a BP done Date of Observation Y/M/D Comments Y1 Y2 Y1 Y2 Y1 Y2 220

236 QI# 6 Measurement of a lipid profile (Part 1) Numerator Adult patients (18 years and older) with a diagnosis of rheumatoid arthritis (RA) who have documentation in their medical record of a lipid profile assessment done once within the first two years after evaluation by a rheumatologist. (Lipid panels done up to 6 months prior to the baseline visit can be counted) Denominator Adult patients with RA (18 years and older) seen at least twice over a 2-year measurement period. Exclusions Documented physician reason for not performing the test. Documented patient refusal. Palliative patient Other specify Chart Meets criteria Yes/No Date of Observation Y/M/D Comments **Appropriate means of conveying this information include but are not limited to: 1. Documentation in a letter to the primary healthcare provider (PCP or other healthcare provider) the need to start or adjust lipid-lowering treatment if indicated. 2. Documenting this information was given to the patient and they were told to follow-up with their PCP (or other healthcare provider) to discuss their abnormal lipid profile. 3. Documentation that the rheumatologist made treatment adjustments or initiated lipid-lowering therapy. 221

237 QI# 7: Screening for Diabetes Part 1 Numerator Chart Meets criteria Yes/No Patients 18 years of age and older with a diagnosis of RA who have had a fasting glucose AND/OR a Haemoglobin A1C to screen for diabetes at least once within 2 years of first seeing a rheumatologist. (Measurements done up to 6 months prior to the baseline visit can be counted) Denominator Adult patients with RA (18 years and older) seen at least twice over a 2-year measurement period. Exclusions Diabetes already diagnosed and managed by an appropriate care provider according to national guidelines. Palliative patient. Documented patient refusal to be screened. Documented other physician reason why screening not appropriate. Other specify QI# 7: Screening for Diabetes (Intermediate/high risk) Part 2 Numerator Yearly in patients at intermediate or high risk* for diabetes Denominator Adult patient with RA (30 years and older) seen at least twice over a 2 year measurement period who are documented to be at intermediate or high diabetic risk Exclusion Same as above Chart Meets criteria Yes/No Date of Observation Y/M/D Date of Observation Y/M/D Comments Comments Y1 Y2 Y1 Y2 Y1 Y2 *Patients at High or Intermediate Risk for diabetes include patients with the following risk factors: - Family history of type 2 diabetes in a first degree relative - History of metabolic syndrome - Obesity or overweight (body mass index 25 kg/m2) - Steroid use - History of gestational diabetes or a macrosomic infant - History of impaired fasting glucose (>=6.1mmol/L), or HbA1C >= 6.0% - History of hypertension (blood pressure 140/90 mmhg) - Member of a high risk population (e.g., aboriginal, Asian, Hispanic, South Asian, African, Pacific Islanders) - High risk based on validated diabetes risk calculators or High or intermediate cardiovascular risk based on cardiovascular risk calculators (Framingham, SCORE etc.) 222

238 QI #8: Exercise Numerator Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Y1 Y2 Y1 Y2 Y1 Y2 Adult patients with rheumatoid arthritis (18 years of age and older) who has discussed* physical activity goals with their rheumatologist at least once within the last year Denominator Adult patients with RA (18 years and older) who has been seen by a rheumatologist at least once over the last year. Exclusions Documented reason why physical activity is not recommended: palliative patient, patient documented refusal, wheelchair bound patient, other significant comorbidity preventing an increase in physical activity Other specify Discussion may include but is not limited to: - Directing patients to a physiotherapist for physical activity assessment and recommendations - Directing patients to an appropriate community or hospital physical activity program - Directing patients to information about National physical activity guidelines - Documented discussion in chart about increasing physical activity 223

239 QI# 9: BMI Screening and Lifestyle Counselling (BMI) Numerator Adult patients (18 years of age and older) with a diagnosis of RA who had their BMI calculated at least once every year. Note: *If waist circumference, body fat percentages, or other clear documentation that the patient is overweight or obese are used instead of BMI, these cases can be included in the numerator. Denominator Adult patients with RA (18 years and older) who have been seen by a rheumatologist at least once in the last year. Exclusions Chart Meets criteria Yes/No Physician documented exclusion including patient refusal to discuss, Patient already followed by a dietician or other care provider for weight loss. Palliative patient. Other specify QI# 9: BMI Screening and Lifestyle Counselling (Counselling) N/A, BMI <25 Numerator If overweight or obese according to national guidelines (BMI >=25 kg/m 2 ) were counselled* to modify their lifestyle. Denominator Adult patient with RA (18 years and older) who has been seen by a rheumatologist at least once in the last year and who is overweight or obese according to national guidelines. Exclusions Same as above Date of Observation Y/M/D *Examples of counselling include but are not limited to: - Referral to a registered dietician (or documented recommendation to general practitioner to do so) - Following national food guide - Following an endorsed heart health healthy diet (e.g., Mediterranean diet, DASH diet) - Diet discussed and brochure provided - Weight reduction - Moderating caloric intake - Increasing physical activity - Told to follow-up with primary care practitioner or other allied health professional to seek weight loss advice Comments Y1 Y2 Y1 Y2 Y1 Y2 Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Y1 Y2 Y1 Y2 Y1 Y2 224

240 QI# 10: Minimizing Corticosteroid Usage Not applicable (not on a corticosteroid) Numerator Adult patient (18 years and older) with a diagnosis of RA who are on oral corticosteroids and who have a documented written plan to taper off corticosteroids or decrease to the lowest possible dose. Denominator Patients 18 years of age and older with a diagnosis of RA who are on corticosteroids at any dose during the measurement period. Exclusions Documented contraindication to tapering prednisone (e.g., existing or presumed adrenal insufficiency either primary or secondary). Corticosteroid was prescribed for another indication (e.g., malignancy, other inflammatory condition or extra-articular feature requiring steroid treatment, end-stage COPD). Patient refusal to taper Other documented physician reason why taper is inappropriate (e.g., presence of other significant comorbidities precluding other treatments, palliative patient for symptom control). Other specify Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Y1 Y2 Y1 Y2 Y1 Y2 Evidence of intent to taper steroids includes: A written plan in the chart or letter back to the primary care provider detailing the plan for taper A copy of a corticosteroid taper calendar in the chart or documentation that one was given to the patient Mention of initiating a taper Evidence that dose of corticosteroids was reduced or stopped over the 1 year measurement period 225

241 QI# 11: Communication About Risks/Benefits of Anti-Inflammatories in Patients at High Risk of Cardiovascular Events Not applicable (not on an NSAID) Numerator Chart Meets criteria Yes/No Date of Observation Y/M/D Comments Y1 Y2 Y1 Y2 Y1 Y2 Adult patients (18 years of age and older) with RA and known cardiovascular disease (or at intermediate or high risk for cardiovascular disease) who are prescribed antiinflammatories including non-steroidal antiinflammatory (NSAID) or Cox-2 inhibitors (COXIBS) and have a documented* discussion about the risks and benefits of using antiinflammatory drug in their medical record. Denominator Patients 18 years of age and older with a diagnosis of rheumatoid arthritis (RA) and known cardiovascular disease (or high risk for cardiovascular disease). Includes patients with but not limited to: Past history of myocardial infarction or ischemic heart disease Past history of Stroke History of peripheral vascular disease Intermediate or High risk based on a validated cardiovascular risk score Exclusions Unknown CVD risk level Other specify Documentation of the discussion of risks and benefits can include but is not limited to: - Documentation that a discussion of risks and benefits of NSAID and COXIB use occurred - Documentation that written information detailing the risks and benefits was provided to the patient - Documentation that cardiovascular risks were minimized by using an anti-inflammatory with a known lower or neutral cardiac risk profile - Documentation that the patient was informed of the risks and it was their preference to continue or start an antiinflammatory for symptom relief - Documentation that risks and benefits were considered but no other treatment options were viable for management of patient symptoms (other RA treatments maximized and other pain medications contraindicated for other reasons) 226

242 APPENDIX D: TOOLS FOR CARDIOVASCULAR QUALITY IMPROVEMENT 227

243 D.1. Prospective Cardiovascular Disease Screening Tool Initials of individual completing this form: Today s Date (Y/M/D): Patient Study Number: Birth Date (Y/M/D): Biological sex of patient: Male Female Does this patient have a cardiologist caring for their vascular risk factors: Yes No Cardiovascular risk factors Pre-existing CVD (Y/N) Specify Myocardial infarction Acute coronary syndrome Angina Stroke or TIA Peripheral vascular disease Other Family history of premature CVD: Y/N CVD in a male firstdegree relative <55 years or CVD in a female firstdegree relative <65 years Lifestyle Tobacco use: Never smoked Former smoker Current smoker Diabetes: Y/N* Last HgbA1C Date: *HgbA1C 6.5 or Fasting Plasma Glucose (FPG) 7.0mmol/L Guidelines for diagnosis of diabetes available from Chronic renal disease*: Y/N * GFR <60mL/min/1.73m 2 Is the patient on oral corticosteroids? Yes No If yes what dose: If yes is there a plan to taper? Yes No If no why Physical activity: Target: 30 min of moderateintensity activity most days of the week. Patient regularly meets target Patient occasionally meets target Patient never meets target Target not appropriate for this patient Pre-existing diagnosis of hypertension*: Y/N *Systolic BP of 140mmHg or a diastolic of 90mmHg on at least 3 occasions, or both, or taking antihypertensive therapies. Today s Blood pressure: If hypertension present what did you do? Recommended repeating the blood pressure and follow up with GP Tell the patient to follow up with GP Adjust or treat hypertension Weight Height: cm Weight: Kg BMI: Kg/m 2 CCS BMI calculator available at the App Store for free on smartphones Waist circumference: (optional) Patient normal weight Patient overweight Patient obese 228

244 Tobacco Intervention: Patient advised to quit smoking Referred for smoking cessation counselling Medication prescribed Advised general practitioner to address Other Today s cardiovascular risk assessment Lipids Lipid levels done within last year? Yes No If No is patient lowrisk for CVD based on a valid risk score? Intervention: Lipid levels ordered today? Yes No Directed GP to order lipids No they were already done within the last year No patient is low risk and these will be repeated at a later date Other Was a risk assessment done today? Yes No Patient told to followup with their GP or other physician about their lipids Physical Activity Intervention: Patient directed to a physiotherapist for physical activity assessment and recommendation Patient directed to community or hospital physical activity program Discussion about national physical activity guidelines Advised patient to increase physical activity Other Risk Assessment (primary prevention only and not already on statin therapy) 10-year CHD risk= % Canadian cardiovascular society risk calculator available at the App Store for free on smartphones Patient is Low risk Intermediate risk High risk Don t know I have asked GP or other practitioner to calculate risk and manage Intervention (If patient is intermediate or high risk): Documentation in a letter back to GP that the patient is at higher risk for CVD and they need to consider treatment according to national guidelines Documentation the patient was notified about their risk level and told to follow-up with their GP I added a statin or recommended intensive lifestyle advice (if appropriate) and will follow their lipid levels and Intervention if patient overweight BMI >30: Patient referred to a dietician Patient told to follow national food guidelines A Mediterranean diet or DASH diet discussed Weight reduction advised Increased physical activity advised Follow-up with GP Other Screening for diabetes Has a fasting glucose or a Hemoglobin A1C been done in the last year? Yes No No this was done in last 2 years and patient is low risk Are any of the following risk factors for diabetes present? Family history of type 2 diabetes in a first degree relative History of metabolic syndrome Obesity or overweight (body mass index 25 kg/m2) Steroid use History of gestational diabetes or a macrosomic infant History of impaired fasting glucose History of hypertension Member of a high risk population (e.g., aboriginal, Asian, Hispanic, South Asian, African, Pacific Islanders) High risk based on validated diabetes risk calculators High or intermediate cardiovascular risk based on cardiovascular risk calculators Intervention: If a patient had any of the above risk factors have you ordered screening tests for diabetes? 229

245 No patient already on statin therapy modifiable risk factors Yes No NSAIDS Is the patient on a prescribed or over the counter NSAID or COXIB? Yes No Didn t ask specifically Agent Dose If Yes did you discuss the potential CVD risks of these agents with the patient? Yes No No as patient is not at intermediate or high risk of CV. Patients with RA are at increased cardiovascular risk. Have you notified/reminded this patient s general practitioner in a letter at least once in the last 2 years that they may be at increased risk for cardiovascular disease OR completed a formal cardiovascular risk assessment on the patient yourself? Yes No Specify: You notified the general practitioner of the increased cardiovascular risk in RA You conducted a formal cardiovascular risk assessment on the patient If you answered no to the above question, why 230

246 D.2. Simplified Cardiovascular Disease Quality Indicator Audit Tool Instructions: The following chart audit tool is designed for collection of quality indicators (QIs) for cardiovascular care for patients with rheumatoid arthritis (RA) over a one-year collection period. For each quality measure please mark whether the indicator is met (yes), or not (no) or whether it is not applicable (N/A). For complete specifications for the indicator describing exclusions please see Appendix B. Please note, these indicators have been simplified from their original format for the purposes of physician chart audit and some of the measurement periods differ from the original description (i.e., for the purposes of this chart audit, a one year collection period is suggested for all QIs). It is suggested that the QIs are measured in consecutive charts (between charts) for patients aged (as in Canada our cardiovascular risk score, the Framingham Risk Score, is most appropriately interpreted in this risk group). 231

247 Chart Audit Tool for Cardiovascular Quality Indicators in Rheumatoid Arthritis Chart number Age Note to Primary Care Provider (PCP) that patients with RA have increased CVD risk Fasting Lipids done CVD risk assessment done Diabetes (DM) screening (fasting glucose or HgA1C) If abnormal DM screen, patient treated or PCP notified Smoking status captured If current smoker advised to quit smoking Blood Pressure (BP) measured at 80% of visits or more within last year If BP above target ( 140/90) then PCP was notified Physical activity discussed at least once yearly Body Mass Index (BMI) documented in chart at least once yearly If abnormal BMI ( 25) lifestyle counselling provided If on corticosteroids, plan for taper documented If intermediate or high risk for CVD and on NSAID, documented risk discussion 232

248 APPENDIX E: CO-AUTHOR & PUBLISHER PERMISSIONS 233

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