Evidence-based Synthesis Program Systematic Review Protocol. Project Title: Benefits and harms of treating blood pressure in older adults

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Reginald Ethan Montgomery
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1 Evidence-based Synthesis Program Systematic Review Protocol Project Title: Benefits and harms of treating blood pressure in older adults I. Background Hypertension is a very common chronic illness in the United States with an estimated prevalence of 27% among adults over age 18 and as much as 67% in adults over age 60 in this country, and possibly higher prevalence among Veterans. 1 Hypertension management is known to modify the risk of cardiovascular disease, renal disease, cerebrovascular disease, and death. 2-5 The issue is of great relevance to the VA given the very high prevalence of hypertension and other vascular risk factors such as diabetes and hyperlipidemia in Veterans generally and the aging Veteran population more specifically. The benefit of some versus no blood pressure control has been shown to be consistent for older adults (age 60), even the oldest old (age 80). 6-8 The most beneficial blood pressure targets for patients of specific ages groups, however, has been a topic of some debate and controversy, stemming from concerns that the ratio of benefit to harm of a given blood pressure level may vary with age. Further, the disease-disease and disease-treatment interactions which can occur when treating hypertension in older adults with multiple chronic comorbidities remain unclear. This holds particular relevance for veterans over age 65, who experience an average of 5 comorbidities and for whom the most common comorbidity clusters in both men and women include hypertension. 9 In 2014, the JNC-8 published new guidelines for the treatment of hypertension as well as a new treatment goal for older individuals (age 60 and above) for systolic blood pressure of 150 rather than <140 mm Hg. 10 The new goal for those ages 60 and above has been very controversial and the issue of the appropriate (safest and most beneficial) goal for older people has been debated among experts with viewpoints supporting both higher and lower treatment goals. The objectives of this proposed review are to examine the benefits and harms of differing blood pressure targets among older adults (age 60) II. Key questions and inclusion/exclusion criteria The research questions for this systematic review were developed after a topic refinement process that included a preliminary review of published peer-reviewed literature, consultation with internal partners and investigators, and consultation with content experts and key stakeholders. The following table species the key questions (KQs) along with the relevant patient, intervention, comparator, and outcome criteria for each question. Portland Evidence-based Synthesis Program 1

2 Table. Key questions, inclusion criteria, and scope parameters Key Question In adults over age 60 with hypertension: KQ1. What are the health outcome effects of differing blood pressure targets? KQ2. How does age modify the benefits of differing blood pressure targets? KQ3. How does the patient burden of comorbidities modify the benefits of differing blood pressure targets? KQ3a: In patients who have suffered a TIA/stroke, does treatment of blood pressure to specific targets affect outcomes? KQ4. Do the harms of targeting lower blood pressure vary with age? KQ5. Do the harms of targeting lower blood pressure vary with patient burden of comorbidities? Population Adults aged 60 with hypertension Adults aged 60 with hypertension and CVA or other existing comorbidity Intervention Include: Pharmacologic treatment of hypertension to specified targets; or more intensive treatment of hypertension Exclude: Interventions for which hypertension management was not the primary objective, despite that secondary effects on hypertension may be reported. (Example: TNT for the j-curve effect; studies conducted in patients with heart failure for which vasoactive medications are being used for cardiac remodeling effects.) Non-pharmacologic interventions for blood pressure control Comparators Placebo or a higher blood pressure target Outcomes All-cause mortality Mortality related to stroke, CHD, CHF, and renal disease Morbidity including stroke, CHD, CHF, and renal disease Adults aged 60 with hypertension Adults aged 60 with hypertension and at least one comorbidity Include: Pharmacologic treatment of hypertension, not necessarily to specified targets Exclude: Non-pharmacologic interventions for blood pressure control Changes in cognition Falls Changes to quality of life Polypharmacy Hypotension Acute kidney injury (defined as doubling of serum creatinine or requiring renal replacement therapy) *Note: all-cause mortality and cardiovascular outcomes will NOT be examined using observational data. However, observational studies which did examine these outcomes may be identified and incorporated for the purposes of background and discussion.* **We will not include well-known drug-specific adverse effects including: -hypokalemia with diuretics -hyponatremia or gout with thiazide diuretics -cough with ace inhibitors Portland Evidence-based Synthesis Program 2

3 Key Question In adults over age 60 with hypertension: KQ1. What are the health outcome effects of differing blood pressure targets? KQ2. How does age modify the benefits of differing blood pressure targets? KQ3. How does the patient burden of comorbidities modify the benefits of differing blood pressure targets? KQ3a: In patients who have suffered a TIA/stroke, does treatment of blood pressure to specific targets affect outcomes? KQ4. Do the harms of targeting lower blood pressure vary with age? KQ5. Do the harms of targeting lower blood pressure vary with patient burden of comorbidities? Timing Long term (>6 months) outcomes Any Study design Include: Controlled study designs (RCT and non-randomized controlled clinical trials) Include: Controlled study designs (RCT and non-randomized controlled clinical trials used for KQ1-3) Cohort extensions of trials that examined specific blood pressure targets Cohort studies that examined the effects of lower blood pressure in the context of antihypertensive medication Cohort studies that reported the effects of lower blood pressure despite that hypertension management was not the primary objective of the intervention studied. *Note: all study-designs may be specifically excluded on the basis of quality; for example, data from studies evaluated as poor quality may not contribute to conclusions.* Exclude: Case reports; case series; controlled before/after studies, RCTs with less than 6 month follow-up Portland Evidence-based Synthesis Program 3

4 III. Rationale for study design Our primary goal with this evidence review is not to duplicate work that has been done in a methodologically sound way, but instead to probe and expand upon that work to evaluate additional patient subgroups as well as harms of antihypertensive therapy in older adults. We have reviewed the methods used for the recent JNC-8 review and feel this process was methodologically sound. We have also reviewed trials included in recent meta-analyses of hypertension management; 11,12 we feel the likelihood of critical literature having been missed by these combined resources is exceedingly low, and repeating searches within the same timeline as that examined by these reviews would be repetitive and low-yield. For this reason, we have stipulated that the clinical trials within the references from these recent systematic reviews/metaanalyses are valuable and will be considered the main source of trial data for our review. We will conduct an auxiliary search for clinical trials published between 2012-current, as those trial would not have been captured by these recent meta-analyses or the systematic review for JNC-8. The combined studies identified from these resources yield over 60 controlled trials. In the presence of such numerous and robust trial data, we have elected to use trial data alone to evaluate the relationship between blood pressure management and important health outcomes (i.e. benefits, including reduction in mortality and cardiovascular events). We will not include observational data in our evaluation of the benefits of hypertension management, given the risk of confounding particularly surrounding very high and very low blood pressures and the availability of such diverse and numerous data from controlled trials. We will, however, incorporate cohort data to address potential harms of antihypertensive therapy. Because harms may be relatively infrequent and are not always immediate, the larger patient numbers and longer follow up of cohort studies may be more likely to identify important harms/adverse events of blood pressure management. Clinical uncertainty abounds regarding the value of a single, age-neutral management strategy for blood pressure control among all adults over age 60. Patients in this age group are a large, expanding, and diverse population with a high degree of multi-morbidity. 13,14 Medication burden and complexity of care increase with advancing age and degree of comorbidity, which in turn enhance the likelihood of competing risks and medication interactions that may affect the risk/benefit profile of achieving a specific blood pressure target Both advancing age and degree of comorbidity are also potential confounders in our understanding of the relationship between blood pressure control and mortality, as each may increase an individual s risk of death. 18,19 For these reasons, evaluation of available data on blood pressure management by age subgroups within the population over age 60 and by comorbidity burden may provide a more accurate reflection of the benefits and harms of blood pressure management for older adults. IV. Literature search strategies We plan to conduct a primary review of the literature by systematically searching, reviewing, and analyzing the scientific evidence as it pertains to the research questions. To identify relevant articles, we will begin by searching MEDLINE, Embase, and the Cochrane database of systematic reviews. We will further evaluate the bibliographies of included primary studies and any systematic or nonsystematic reviews that are identified. To identify in-progress or Portland Evidence-based Synthesis Program 4

5 unpublished studies, we will also search ClinicalTrials.gov. Search strategies will be developed in consultation with a research librarian. Using pre-specified inclusion/exclusion criteria, titles and abstracts will be reviewed for potential relevance to the key questions. At the full-text screening stage, two independent reviewers must agree on a final inclusion/exclusion decision. For articles excluded, full-text reviews must also agree on the reason for exclusion. Articles meeting eligibility criteria will be included for data abstraction. V. Data abstraction Data from published reports will be abstracted into a customized database by one reviewer and over-read by a second reviewer. From each study, we will abstract the following: study design objectives setting demographic variables (including sex, age) comorbidities (burden of comorbiditiy, medication #/burden at baseline, baseline cognitive function) subject eligibility and exclusion criteria number of subjects years of enrollment duration of follow-up the study and comparator interventions (including screening intervals, antihypertensive agents used, blood pressure targets) important co-interventions health outcomes (all-cause mortality, mortality/morbidity related to CVA, CHD, CHF, renal disease) and adverse events (including changes in cognitive status, falls, changes in quality of life, polypharmacy, aki, all-cause mortality) Additional study result characteristics of interest will include achieved blood pressures (systolic and diastolic), documented cognitive changes, number of antihypertensive medications required VI. Assessment of methodological quality of individual studies Two reviewers will independently assess the quality of each trial using a tool developed by the Cochrane Collaboration. 20 Disagreements will be resolved through discussion. Each trial will be given an overall summary assessment of low, high, or unclear risk of bias. The risk of bias within a given study can vary according to outcome. For instance, the risk of bias associated with lack of blinding might be low for mortality outcomes, but high for more subjective outcomes such as quality of life or functional status. Data on outcomes including mortality and cardiovascular disease have been explored reasonably well for older adults among randomized controlled trials, but data on harms in particular may be Portland Evidence-based Synthesis Program 5

6 more clearly delineated in long-term and relatively large cohort studies. We believe broad inclusion of this evidence base coupled with critical appraisal of each study will provide the most transparent approach to defining the strength of this body of evidence VII. Data synthesis We will query the literature for previous patient-level or study-level meta-analyses which may address part or all of the key questions developed for this review. If none are available or if key questions are incompletely addressed by available meta-analyses, we will contact study investigators for the Blood Pressure Trialists Treatment Collaborative (BPTTC) as well as investigators from key trials not included within the BPTTC (eg: SHEP) to request patient-level or study level data that these investigators may be willing/able to share. 21 We will determine the feasibility of completing a quantitative synthesis (i.e., meta-analysis, patient- or study-level) to estimate summary effects depending on the completeness and homogeneity of available data. If this is not possible, we will perform a systematic review to summarize the primary literature by abstracting relevant data, developing data tables, and qualitatively synthesizing the literature for each key question. VIII. Assessing the overall body of evidence We will assess the overall quality of evidence for outcomes using a method developed by the GRADE Working Group. 22 The GRADE method considers the consistency, coherence, and applicability of a body of evidence, as well as the internal validity of individual studies, to classify the grade of evidence across outcomes as follows: High = Further research is very unlikely to change our confidence on the estimate of effect. Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low = Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very Low = Any estimate of effect is very uncertain. IX. Timeline Project start: October 2014 First call with technical expert panel: December 15, 2014 (projected date) Abstract review due: January 15, 2015 Internal draft report due: May 1, 2015 Anticipated draft report due: June 1, 2015 Reviewer feedback: Summer 2014 Anticipated final report submitted: Sept 1, 2015 Portland Evidence-based Synthesis Program 6

7 X. Stakeholders and technical experts Topic nominators: Dawn Bravata, MD Glenn D. Graham, MD, PhD Joe Francis, MD M. Eric Rodgers, PhD, FNP, BC William Cushman, MD Technical Expert Panel: Seemant Chaturvedi, MD Peter Glassman, MBBS, MSc, FACP Mary Goldstein, MD, MS Phil Gorelick, MD Linda Humphrey, MD Lois Katz, MD Lilian Min, MD Amir Qaseem, MD, PhD, MHA, FACP Jeff Whittle, MD, MPH XI. Citations 1. Nwankwo T., Yoon SS., Burt V GQ. Hypertension among adults in the united states: National health and nutrition examination survey, NCHS data brief, no 133. hyattsville, MD: National center for health statistics Effects of treatment on morbidity in hypertension. results in patients with diastolic blood pressures averaging 115 through 129 mm hg. JAMA. 1967;202(11): Effects of treatment on morbidity in hypertension. II. results in patients with diastolic blood pressure averaging 90 through 114 mm hg. JAMA. 1970;213(7): The australian therapeutic trial in mild hypertension. report by the management committee. Lancet. 1980;1(8181): Medical research council trial of treatment of hypertension in older adults: Principal results. MRC working party. BMJ. 1992;304(6824): Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. final results of the systolic hypertension in the elderly program (SHEP). SHEP cooperative research group. JAMA. 1991;265(24): Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. the systolic hypertension in europe (syst-eur) trial investigators. Lancet. 1997;350(9080): Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18): Steinman MA, Lee SJ, John Boscardin W, et al. Patterns of multimorbidity in elderly veterans. J Am Geriatr Soc. 2012;60(10): James PA, Oparil S, Carter BL, et al evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA. 2014;311(5): Portland Evidence-based Synthesis Program 7

8 11. Blood Pressure Lowering Treatment Trialists' Collaboration, Sundstrom J, Arima H, et al. Blood pressure-lowering treatment based on cardiovascular risk: A meta-analysis of individual patient data. Lancet. 2014;384(9943): Briasoulis A, Agarwal V, Tousoulis D, Stefanadis C. Effects of antihypertensive treatment in patients over 65 years of age: A meta-analysis of randomised controlled studies. Heart. 2014;100(4): Kinsella K, Wan H. An aging world: U S Census Bureau, International Population Reports. 2009;U.S. Government Printing Office(Washington, DC). 14. Wolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med. 2002;162(20): Fried TR, McGraw S, Agostini JV, Tinetti ME. Views of older persons with multiple morbidities on competing outcomes and clinical decision-making. J Am Geriatr Soc. 2008;56(10): Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003;348(16): Field TS, Gurwitz JH, Harrold LR, et al. Risk factors for adverse drug events among older adults in the ambulatory setting. J Am Geriatr Soc. 2004;52(8): Gijsen R, Hoeymans N, Schellevis FG, Ruwaard D, Satariano WA, van den Bos GA. Causes and consequences of comorbidity: A review. J Clin Epidemiol. 2001;54(7): Kane RL, Shamliyan T, Talley K, Pacala J. The association between geriatric syndromes and survival. J Am Geriatr Soc. 2012;60(5): Higgins JPT, Green S, et al. "Part 2, chapter 8: Assessing risk of bias in included studies." cochrane handbook for systematic review of interventions. version the cochrane collaboration, updated march Updated 2011Accessed 6/12/ Protocol for prospective collaborative overviews of major randomized trials of bloodpressure-lowering treatments. world health organization-international society of hypertension blood pressure lowering treatment trialists' collaboration. J Hypertens. 1998;16(2): Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490. Portland Evidence-based Synthesis Program 8

Int. J. Pharm. Sci. Rev. Res., 36(1), January February 2016; Article No. 06, Pages: JNC 8 versus JNC 7 Understanding the Evidences

Int. J. Pharm. Sci. Rev. Res., 36(1), January February 2016; Article No. 06, Pages: JNC 8 versus JNC 7 Understanding the Evidences Research Article JNC 8 versus JNC 7 Understanding the Evidences Anns Clara Joseph, Karthik MS, Sivasakthi R, Venkatanarayanan R, Sam Johnson Udaya Chander J* RVS College of Pharmaceutical Sciences, Coimbatore,