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1 Supplementary Online Content James PA, Oparil S, Carter BL, et al evidence-based guideline for the management of high blood pressure in adults: report by the panel appointed to the Eighth Joint National Committee (JNC 8). JAMA. doi: /jama Supplement. Supplement to 2014 Evidence-based guideline for the management of high blood pressure in adults: report by the panel appointed to the Eighth Joint National Committee (JNC 8) This supplementary material has been provided by the authors to give readers additional information about their work.

2 Supplement to 2014 Evidence Based Guideline for the Management of High Blood Pressure in Adults: Report by the Panel Appointed to the Eighth Joint National Committee (JNC 8)

3 PANEL MEMBERS Panel Co Chairs Paul A. James, MD, University of Iowa Suzanne Oparil, MD, University of Alabama at Birmingham School of Medicine Panel Members Barry L. Carter, PharmD, University of Iowa William C. Cushman, MD, Memphis Veterans Affairs Medical Center and the University of Tennessee Cheryl Dennison Himmelfarb, RN, ANP, PhD, Johns Hopkins University School of Nursing Joel Handler, MD, Southern California Kaiser Permanente Medical Group Daniel T. Lackland, DrPH, Medical University of South Carolina Michael L. LeFevre, MD, MSPH, University of Missouri Thomas D. MacKenzie, MD, MSPH, Denver Health and Hospital Authority and the University of Colorado School of Medicine Olugbenga Ogedegbe, MD, MPH, MS, New York University School of Medicine Sidney C. Smith, Jr., MD, University of North Carolina at Chapel Hill Laura P. Svetkey, MD, MHS, Duke University Sandra J. Taler, MD, Mayo Clinic College of Medicine Raymond R. Townsend, MD, University of Pennsylvania Jackson T. Wright, Jr., MD, PhD, Case Western Reserve University Andrew S. Narva, MD, National Institute of Diabetes and Digestive and Kidney Diseases Eduardo Ortiz, MD, MPH, At the time of this project, Dr. Ortiz was a Senior Medical Officer with the National Heart, Lung, and Blood Institute. He is currently Director of Clinical Development and Informatics with ProVation Medical, Wolters Kluwer Health. Support Staff Cory V. Evans, MPP. At the time of this project, Ms. Evans was a Senior Research Analyst and Contract Lead for JNC 8 with Leidos (formerly, Science Applications International Corporation). She is currently a Research Associate at the Kaiser Permanente Center for Health Research. Linda J. Lux, MPA, Senior Research Associate at RTI International iii

4 TABLE OF CONTENTS Executive Summary Figure: 2014 Guideline Hypertension Management Algorithim Table 1: Comparison of Current Recommendations with JNC 7 Guidelines Table 2: Evidence Quality Rating Table 3: Strength of Recommendation Table 4: Evidence Based Dosing for Antihypertensive Drugs Table 5: Strategies to Dose Antihypertensive Drugs Table 6: Guideline Comparisons of Goal BP and Initial Drug Therapy for Adults with Hypertension Background Panel Members Disclosures Methods How Were the Questions Selected? Rationale for the Questions Selected Questions Inclusion/Exclusion Criteria for the Evidence Review Literature Search Yields Populations Addressed in this Guideline Definition of High Blood Pressure or Hypertension Evidence Statements Recommendations Additional Content Measurement and Monitoring of Blood Pressure Appropriate Dosing of Antihypertensive Medications Research Gaps Recommendations from the Lifestyle Working Group Lifestyle Workgroup Diet Recommendations Lifestyle Physical Activity Recommendation Lifestyle for Prevention and Treatment of High Blood Pressure History of this Guideline Development Process References iv

5 Appendix Exhibit A: Evidence from randomized controlled trials on initiating antihypertensive pharmacological therapy at SBP thresholds 160 mmhg Exhibit B: Evidence from randomized controlled trials on initiating antihypertensive pharmacological therapy at DBP thresholds 90 mmhg Exhibit C: Evidence from randomized controlled trials on treatment with antihypertensive pharmacological therapy to specified SBP goals Exhibit D: Evidence from randomized controlled trials on treatment with antihypertensive pharmacological therapy to specified DBP goals Exhibit E: Evidence from randomized controlled trials on treatment with antihypertensive pharmacological therapy to mixed SBP and DBP goals Exhibit F: Evidence from randomized controlled trials on treatment with antihypertensive pharmacological therapy to BP goals in patients with chronic kidney disease Exhibit G: Evidence from randomized controlled trials on treatment with antihypertensive pharmacological therapy to BP goals in patients with chronic kidney disease by baseline proteinuria subgroups Exhibit H: Evidence from randomized controlled trials on treatment with antihypertensive pharmacological therapy to BP goals in patients with diabetes Exhibit I: Evidence from randomized controlled trials of initial antihypertensive drug therapy with diuretics versus other drugs Exhibit J: Evidence from randomized controlled trials of initial antihypertensive drug therapy with beta blockers versus other drugs Exhibit K: Evidence from randomized controlled trials of initial antihypertensive drug therapy with calcium channel blockers versus other drugs Exhibit L: Evidence from randomized controlled trials of initial antihypertensive drug therapy with ACE inhibitors versus other drugs Exhibit M: Evidence from randomized controlled trials of initial antihypertensive drug therapy with ARBs versus other drugs Exhibit N: Evidence from randomized controlled trials of antihypertensive drug therapy with combination drugs Search Strategy Overview and Syntax of Queries Question 1 Search Strategy Study Type Query Boolean Search Boolean Filter v

6 Question 1 Search Strategy Results and PRISMA Diagram Question 2 Search Strategy Study Type Query Boolean Search Boolean Filter Question 2 Search Strategy Results and PRISMA Diagram Question 3 Search Strategy Study Type Query Boolean Search Boolean Filter Question 3 Search Strategy Results and PRISMA Diagram Critical Questions identified by the Panel Questions 1 through 3 are the questions that form the basis of this report Questions for which search criteria were developed, but a literature search and evidence review were not conducted include Questions 4 and 5: Question Question 4 Inclusion/Exclusion Criteria Question Question 5 Inclusion/Exclusion Criteria Questions for which no search criteria was developed: Question Question Question Question Question Question Question Question Question Question Question Question vi

7 Question Question Question Question Question Question vii

8 Executive Summary Unstructured Abstract: Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

9 Executive Summary 9

10 EXECUTIVE SUMMARY BACKGROUND Hypertension remains one of the most important preventable contributors to disease and death. Abundant evidence from randomized controlled trials (RCTs) has shown benefit of antihypertensive drug treatment in reducing important health outcomes in persons with hypertension. 1-3 Clinical guidelines are at the intersection between research evidence and clinical actions that can improve patient outcomes. The Institute of Medicine Report Clinical Practice Guidelines We Can Trust outlined a pathway to guideline development and is the approach that this panel aspired to in the creation of this report. 4 The panel members appointed to the Eighth Joint National Committee (JNC 8) used rigorous evidencebased methods, developing Evidence Statements and recommendations for blood pressure (BP) treatment based on a systematic review of the literature to meet user needs, especially the needs of the primary care clinician. This report is an executive summary of the evidence and is designed to provide clear recommendations for all clinicians. Major differences from the previous JNC report are summarized in Table 1. The complete evidence summary and detailed description of the evidence review and methods are provided online (see Supplement). THE PROCESS The panel members appointed to JNC 8 were selected from more than 400 nominees based on expertise in hypertension (n = 14), primary care (n = 6), including geriatrics (n = 2), cardiology (n = 2), nephrology (n = 3), nursing (n = 1), pharmacology (n = 2), clinical trials (n = 6), evidence-based medicine (n = 3), epidemiology (n = 1), informatics (n = 4), and the development and implementation of clinical guidelines in systems of care (n = 4). The panel also included a senior scientist from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a senior medical officer from the National Heart, Lung, and Blood Institute (NHLBI), and a senior scientist from NHLBI who withdrew from authorship prior to publication. Two members left the panel early in the process before the evidence review because of new job commitments that prevented them from continuing to serve. Panel members disclosed any potential conflicts of interest including studies evaluated in this report and relationships with industry. Those with conflicts were allowed to participate in discussions as long as they declared their relationships, but they recused themselves from voting on evidence statements and recommendations relevant to their relationships or conflicts. Four panel members (24%) had relationships with industry or potential conflicts to disclose at the outset of the process. In January 2013, the guideline was submitted for external peer review by NHLBI to 20 reviewers, all of whom had expertise in hypertension, and to 16 federal agencies. Reviewers also had expertise in cardiology, 10

11 nephrology, primary care, pharmacology, research (including clinical trials), biostatistics, and other important related fields. Sixteen individual reviewers and 5 federal agencies responded. Reviewers comments were collected, collated, and anonymized. Comments were reviewed and discussed by the panel from March through June 2013 and incorporated into a revised document. (Reviewers comments and suggestions, and responses and disposition by the panel are available on request from the authors.) QUESTIONS GUIDING THE EVIDENCE REVIEW This evidence-based hypertension guideline focuses on the panel s 3 highest-ranked questions related to high BP management identified through a modified Delphi technique. 5 Nine recommendations are made reflecting these questions. These questions address thresholds and goals for pharmacologic treatment of hypertension and whether particular antihypertensive drugs or drug classes improve important health outcomes compared with other drug classes. 1. In adults with hypertension, does initiating antihypertensive pharmacologic therapy at specific BP thresholds improve health outcomes? 2. In adults with hypertension, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? THE EVIDENCE REVIEW The evidence review focused on adults aged 18 years or older with hypertension and included studies with the following prespecified subgroups: diabetes, coronary artery disease, peripheral artery disease, heart failure, previous stroke, chronic kidney disease (CKD), proteinuria, older adults, men and women, racial and ethnic groups, and smokers. Studies with sample sizes smaller than 100 were excluded, as were studies with a follow-up period of less than 1 year, because small studies of brief duration are unlikely to yield enough healthrelated outcome information to permit interpretation of treatment effects. Studies were included in the evidence review only if they reported the effects of the studied interventions on any of these important health outcomes: Overall mortality, cardiovascular disease (CVD) related mortality, CKD-related mortality Myocardial infarction, heart failure, hospitalization for heart failure, stroke Coronary revascularization (includes coronary artery bypass surgery, coronary angioplasty and coronary stent placement), other revascularization (includes carotid, renal, and lower extremity revascularization) End-stage renal disease (ESRD) (ie, kidney failure resulting in dialysis or transplantation), doubling of creatinine level, halving of glomerular filtration rate (GFR). 11

12 The panel limited its evidence review to RCTs because they are less subject to bias than other study designs and represent the gold standard for determining efficacy and effectiveness. 6 The studies in the evidence review were from original publications of eligible RCTs. These studies were used to create evidence tables and summary tables that were used by the panel for their deliberations (see Supplement). Because the panel conducted its own systematic review using original studies, systematic reviews and meta-analyses of RCTs conducted and published by other groups were not included in the formal evidence review. Initial search dates for the literature review were January 1, 1966, through December 31, The search strategy and PRISMA diagram for each question is in the online Supplement. To ensure that no major relevant studies published after December 31, 2009, were excluded from consideration, 2 independent searches of PubMed and CINAHL between December 2009 and August 2013 were conducted with the same MeSH terms as the original search. Three panel members reviewed the results. The panel limited the inclusion criteria of this second search to the following. (1) The study was a major study in hypertension (eg, ACCORD- BP, SPS3; however, SPS3 did not meet strict inclusion criteria because it included nonhypertensive participants. SPS3 would not have changed our conclusions/recommendations because the only significant finding supporting a lower goal for BP occurred in an infrequent secondary outcome). 7,8 (2) The study had at least 2000 participants. (3) The study was multicentered. (4) The study met all the other inclusion/exclusion criteria. The relatively high threshold of 2000 participants was used because of the markedly lower event rates observed in recent RCTs such as ACCORD, suggesting that larger study populations are needed to obtain interpretable results. Additionally, all panel members were asked to identify newly published studies for consideration if they met the above criteria. No additional clinical trials met the previously described inclusion criteria. Studies selected were rated for quality using NHLBI s standardized quality rating tool (see Supplement) and were only included if rated as good or fair. An external methodology team performed the literature review, summarized data from selected papers into evidence tables, and provided a summary of the evidence. From this evidence review, the panel crafted evidence statements and voted on agreement or disagreement with each statement. For approved evidence statements, the panel then voted on the quality of the evidence (Table 2). Once all evidence statements for each critical question were identified, the panel reviewed the evidence statements to craft the clinical recommendations, voting on each recommendation and on the strength of the recommendation (Table 3). For both evidence statements and recommendations, a record of the vote count (for, against, or recusal) was made without attribution. The panel attempted to achieve 100% consensus whenever possible, but a two-thirds majority was considered acceptable, with the exception of recommendations based on expert opinion, which required a 75% majority agreement to approve. 12

13 RESULTS (RECOMMENDATIONS) The following recommendations are based on the systematic evidence review described above (Box). Recommendations 1 through 5 address questions 1 and 2 concerning thresholds and goals for BP treatment. Recommendations 6, 7, and 8 address question 3 concerning selection of antihypertensive drugs. Recommendation 9 is a summary of strategies based on expert opinion for starting and adding antihypertensive drugs. The evidence statements supporting the recommendations are in the online Supplement. RECOMMENDATION 1 In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher and treat to a goal SBP lower than 150 mm Hg and goal DBP lower than 90 mm Hg. Strong Recommendation Grade A COROLLARY RECOMMENDATION In the general population aged 60 years or older, if pharmacologic treatment for high BP results in lower achieved SBP (for example, <140 mm Hg) and treatment is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted. Expert Opinion Grade E Recommendation 1 is based on evidence statements 1 through 3 from question 2 in which there is moderate- to high-quality evidence from RCTs that in the general population aged 60 years or older, treating high BP to a goal of lower than 150/90 mm Hg reduces stroke, heart failure, and coronary heart disease (CHD). There is also evidence (albeit low quality) from evidence statement 6, question 2 that setting a goal SBP of lower than 140 mm Hg in this age group provides no additional benefit compared with a higher goal SBP of 140 to 160 mm Hg or 140 to 149 mm Hg. 9,10 To answer question 2 about goal BP, the panel reviewed all RCTs that met the eligibility criteria and that either compared treatment with a particular goal vs no treatment or placebo or compared treatment with one BP goal with treatment to another BP goal. The trials on which these evidence statements and this recommendation are based include HYVET, Syst-Eur, SHEP, JATOS, VALISH, and CARDIO-SIS. 1-3,9-11 Strengths, limitations, and other considerations related to this evidence review are presented in the evidence statement narratives and clearly support the benefit of treating to a BP lower than 150 mm Hg. The corollary to recommendation 1 reflects that there are many treated hypertensive patients aged 60 years or older in whom SBP is currently lower than 140 mm Hg, based on implementation of previous guideline 13

14 recommendations. 12 The panel s opinion is that in these patients, it is not necessary to adjust medication to allow BP to increase. In 2 of the trials that provide evidence supporting an SBP goal lower than 150 mm Hg, the average treated SBP was 143 to 144 mm Hg. 2,3 Many participants in those studies achieved an SBP lower than 140 mm Hg with treatment that was generally well tolerated. Two other trials 9,10 suggest there was no benefit for an SBP goal lower than 140 mm Hg, but the confidence intervals around the effect sizes were wide and did not exclude the possibility of a clinically important benefit. Therefore, the panel included a corollary recommendation based on expert opinion that treatment for hypertension does not need to be adjusted if treatment results in SBP lower than 140 mm Hg and is not associated with adverse effects on health or quality of life. While all panel members agreed that the evidence supporting recommendation 1 is very strong, the panel was unable to reach unanimity on the recommendation of a goal SBP of lower than 150 mm Hg. Some members recommended continuing the JNC 7 SBP goal of lower than 140 mm Hg for individuals older than 60 years based on expert opinion. 12 These members concluded that the evidence was insufficient to raise the SBP target from lower than 140 to lower than 150 mm Hg in high-risk groups, such as black persons, those with CVD including stroke, and those with multiple risk factors. The panel agreed that more research is needed to identify optimal goals of SBP for patients with high BP. RECOMMENDATION 2 In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at DBP of 90 mm Hg or higher and treat to a goal DBP of lower than 90 mm Hg. For ages 30 through 59 years, Strong Recommendation Grade A For ages 18 through 29 years, Expert Opinion Grade E Recommendation 2 is based on high-quality evidence from 5 DBP trials (HDFP, Hypertension-Stroke Cooperative, MRC, ANBP, and VA Cooperative) that demonstrate improvements in health outcomes among adults aged 30 through 69 years with elevated BP Initiation of antihypertensive treatment at a DBP threshold of 90 mm Hg or higher and treatment to a DBP goal of lower than 90 mm Hg reduces cerebrovascular events, heart failure, and overall mortality (question 1, evidence statements 10, 11, 13; question 2, evidence statement 10). In further support for a DBP goal of lower than 90 mm Hg, the panel found evidence that there is no benefit in treating patients to a goal of either 80 mm Hg or lower or 85 mm Hg or lower compared with 90 mm Hg or lower based on the HOT trial, in which patients were randomized to these 3 goals without statistically significant differences between treatment groups in the primary or secondary outcomes (question 2, evidence statement 14). 19 In adults younger than 30 years, there are no good- or fair-quality RCTs that assessed the benefits of treating elevated DBP on health outcomes (question 1, evidence statement 14). In the absence of such 14

15 evidence, it is the panel s opinion that in adults younger than 30 years, the DBP threshold and goal should be the same as in adults 30 through 59 years of age. RECOMMENDATION 3 In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg. Expert Opinion Grade E Recommendation 3 is based on expert opinion. While there is high-quality evidence to support a specific SBP threshold and goal for persons aged 60 years or older (See recommendation 1), the panel found insufficient evidence from good- or fair-quality RCTs to support a specific SBP threshold or goal for persons younger than 60 years. In the absence of such evidence, the panel recommends an SBP treatment threshold of 140 mm Hg or higher and an SBP treatment goal of lower than 140 mm Hg based on several factors. First, in the absence of any RCTs that compared the current SBP standard of 140 mm Hg with another higher or lower standard in this age group, there was no compelling reason to change current recommendations. Second, in the DBP trials that demonstrated the benefit of treating DBP to lower than 90 mm Hg, many of the study participants who achieved DBP of lower than 90 mm Hg were also likely to have achieved SBPs of lower than 140 mm Hg with treatment. It is not possible to determine whether the outcome benefits in these trials were due to lowering DBP, SBP, or both. Third, given the recommended SBP goal of lower than 140 mm Hg in adults with diabetes or CKD (recommendations 4 and 5), a similar SBP goal for the general population younger than 60 years may facilitate guideline implementation. RECOMMENDATION 4 In the population aged 18 years or older with CKD, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher or DBP of 90 mm Hg or higher and treat to goal SBP of lower than 140 mm Hg and goal DBP lower than 90 mm Hg. Expert Opinion Grade E Based on the inclusion criteria used in the RCTs reviewed by the panel, this recommendation applies to individuals younger than 70 years with an estimated GFR or measured GFR less than 60 ml/min/1.73 m2 and in people of any age with albuminuria defined as greater than 30 mg of albumin/g of creatinine at any level of GFR. Recommendation 4 is based on evidence statements from question 2. In adults younger than 70 years with CKD, the evidence is insufficient to determine if there is a benefit in mortality, or cardiovascular or cerebrovascular health outcomes with antihypertensive drug therapy to a lower BP goal (for example, <130/80 mm Hg) compared with a goal of lower than 140/90 mm Hg (question 2, evidence statement 15). There is 15

16 evidence of moderate quality demonstrating no benefit in slowing the progression of kidney disease from treatment with antihypertensive drug therapy to a lower BP goal (for example, <130/80 mm Hg) compared with a goal of lower than 140/90 mm Hg (question 2, evidence statement 16). Three trials that met our criteria for review addressed the effect of antihypertensive drug therapy on change in GFR or time to development of ESRD, but only one trial addressed cardiovascular disease end points. Blood pressure goals differed across the trials, with 2 trials (AASK and MDRD) using mean arterial pressure and different targets by age, and 1 trial (REIN-2) using only DBP goals None of the trials showed that treatment to a lower BP goal (for example, <130/80 mm Hg) significantly lowered kidney or cardiovascular disease end points compared with a goal of lower than 140/90 mm Hg. For patients with proteinuria (>3 g/24 hours), post hoc analysis from only 1 study (MDRD) indicated benefit from treatment to a lower BP goal (<130/80 mm Hg), and this related to kidney outcomes only. 22 Although post hoc observational analyses of data from this trial and others suggested benefit from the lower goal at lower levels of proteinuria, this result was not seen in the primary analyses or in AASK or REIN-2 (question 2, evidence statement 17). 20,21 Based on available evidence the panel cannot make a recommendation for a BP goal for people aged 70 years or older with GFR less than 60 ml/min/1.73m2. The commonly used estimating equations for GFR were not developed in populations with significant numbers of people older than 70 years and have not been validated in older adults. No outcome trials reviewed by the panel included large numbers of adults older than 70 years with CKD. Further, the diagnostic criteria for CKD do not consider age-related decline in kidney function as reflected in estimated GFR. Thus, when weighing the risks and benefits of a lower BP goal for people aged 70 years or older with estimated GFR less than 60 ml/min/1.73m2, antihypertensive treatment should be individualized, taking into consideration factors such as frailty, comorbidities, and albuminuria. RECOMMENDATION 5 In the population aged 18 years or older with diabetes, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher or DBP of 90 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg and goal DBP lower than 90 mm Hg. Expert Opinion Grade E Recommendation 5 is based on evidence statements from question 2, which address BP goals in adults with both diabetes and hypertension. There is moderate-quality evidence from 3 trials (SHEP, Syst-Eur, and UKPDS) that treatment to an SBP goal of lower than 150 mm Hg improves cardiovascular and cerebrovascular health outcomes and lowers mortality (see question 2, evidence statement 18) in adults with diabetes and hypertension No RCTs addressed whether treatment to an SBP goal of lower than 140 mm Hg compared with a higher goal (for example, <150 mm Hg) improves health outcomes in adults with diabetes 16

17 and hypertension. In the absence of such evidence, the panel recommends an SBP goal of lower than 140 mm Hg and a DBP goal lower than 90 mm Hg in this population based on expert opinion, consistent with the BP goals in recommendation 3 for the general population younger than 60 years with hypertension. Use of a consistent BP goal in the general population younger than 60 years and in adults with diabetes of any age may facilitate guideline implementation. This recommendation for an SBP goal of lower than 140 mm Hg in patients with diabetes is also supported by the ACCORD-BP trial, in which the control group used this goal and had similar outcomes compared with a lower goal. 7 The panel recognizes that the ADVANCE trial tested the effects of treatment to lower BP on major macrovascular and microvascular events in adults with diabetes who were at increased risk of CVD, but the study did not meet the panel s inclusion criteria because participants were eligible irrespective of baseline BP, and there were no randomized BP treatment thresholds or goals. 26 The panel also recognizes that an SBP goal of lower than 130 mm Hg is commonly recommended for adults with diabetes and hypertension. However, this lower SBP goal is not supported by any RCT that randomized participants into 2 or more groups in which treatment was initiated at a lower SBP threshold than 140 mm Hg or into treatment groups in which the SBP goal was lower than 140 mm Hg and that assessed the effects of a lower SBP threshold or goal on important health outcomes. The only RCT that compared an SBP treatment goal of lower than 140 mm Hg with a lower SBP goal and assessed the effects on important health outcomes is ACCORD-BP, which compared an SBP treatment goal of lower than 120 mm Hg with a goal lower than 140 mm Hg. 7 There was no difference in the primary outcome, a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. There were also no differences in any of the secondary outcomes except for a reduction in stroke. However, the incidence of stroke in the group treated to lower than 140 mm Hg was much lower than expected, so the absolute difference in fatal and nonfatal stroke between the 2 groups was only 0.21% per year. The panel concluded that the results from ACCORD-BP did not provide sufficient evidence to recommend an SBP goal of lower than 120 mm Hg in adults with diabetes and hypertension. The panel similarly recommends the same goal DBP in adults with diabetes and hypertension as in the general population (<90 mm Hg). Despite some existing recommendations that adults with diabetes and hypertension should be treated to a DBP goal of lower than 80 mm Hg, the panel did not find sufficient evidence to support such a recommendation. For example, there are no good- or fair-quality RCTs with mortality as a primary or secondary prespecified outcome that compared a DBP goal of lower than 90 mm Hg with a lower goal (evidence statement 21). In the HOT trial, which is frequently cited to support a lower DBP goal, investigators compared a DBP goal of 90 mm Hg or lower vs a goal of 80 mm Hg or lower. 19 The lower goal was associated with a reduction in a composite CVD outcome (question 2, evidence statement 20), but this was a post hoc analysis of a small 17

18 subgroup (8%) of the study population that was not prespecified. As a result, the evidence was graded as low quality. Another commonly cited study to support a lower DBP goal is UKPDS, 25 which had a BP goal of lower than 150/85 mm Hg in the more-intensively treated group compared with a goal of lower than 180/105 mm Hg in the less-intensively treated group. UKPDS did show that treatment in the lower goal BP group was associated with a significantly lower rate of stroke, heart failure, diabetes-related end points, and deaths related to diabetes. However, the comparison in UKPDS was a DBP goal of lower than 85 mm Hg vs lower than105 mm Hg; therefore, it is not possible to determine whether treatment to a DBP goal of lower than 85 mm Hg improves outcomes compared with treatment to a DBP goal of lower than 90 mm Hg. In addition, UKPDS was a mixed systolic and diastolic BP goal study (combined SBP and DBP goals), so it cannot be determined if the benefits were due to lowering SBP, DBP, or both. RECOMMENDATION 6 In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensinconverting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). Moderate Recommendation Grade B For this recommendation, only RCTs that compared one class of antihypertensive medication to another and assessed the effects on health outcomes were reviewed; placebo-controlled RCTs were not included. However, the evidence review was informed by major placebo-controlled hypertension trials, including 3 federally funded trials (VA Cooperative Trial, HDFP, and SHEP), that were pivotal in demonstrating that treatment of hypertension with antihypertensive medications reduces cardiovascular or cerebrovascular events and/or mortality. 3,13,18 These trials all used thiazide-type diuretics compared with placebo or usual care as the basis of therapy. Additional evidence that BP lowering reduces risk comes from trials of β-blocker vs placebo 16,27 and CCB vs placebo. 1 Each of the 4 drug classes recommended by the panel in recommendation 6 yielded comparable effects on overall mortality and cardiovascular, cerebrovascular, and kidney outcomes, with one exception: heart failure. Initial treatment with a thiazide-type diuretic was more effective than a CCB or ACEI (question 3, evidence statements 14 and 15), and an ACEI was more effective than a CCB (question 3, evidence statement 1) in improving heart failure outcomes. While the panel recognized that improved heart failure outcomes was an important finding that should be considered when selecting a drug for initial therapy for hypertension, the panel did not conclude that it was compelling enough within the context of the overall body of evidence to preclude the use of the other drug classes for initial therapy. The panel also acknowledged that the evidence 18

19 supported BP control, rather than a specific agent used to achieve that control, as the most relevant consideration for this recommendation. The panel did not recommend β-blockers for the initial treatment of hypertension because in one study use of β-blockers resulted in a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to use of an ARB, a finding that was driven largely by an increase in stroke (question 3, evidence statement 22). 28 In the other studies that compared a β-blocker to the 4 recommended drug classes, the β-blocker performed similarly to the other drugs (question 3, evidence statement 8) or the evidence was insufficient to make a determination (question 3, evidence statements 7, 12, 21, 23, and 24). α-blockers were not recommended as first-line therapy because in one study initial treatment with an α- blocker resulted in worse cerebrovascular, heart failure, and combined cardiovascular outcomes than initial treatment with a diuretic (question 3, evidence statement 13). 29 There were no RCTs of good or fair quality comparing the following drug classes to the 4 recommended classes: dual α β-blocking agents (eg, carvedilol), vasodilating β-blockers (eg, nebivolol), central α 2 -adrenergic agonists (eg, clonidine), direct vasodilators (eg, hydralazine), aldosterone receptor antagonists (eg, spironolactone), adrenergic neuronal depleting agents (reserpine), and loop diuretics (eg, furosemide) (question 3, evidence statement 30). Therefore, these drug classes are not recommended as first-line therapy. In addition, no eligible RCTs were identified that compared a diuretic vs an ARB, or an ACEI vs an ARB. ONTARGET was not eligible because hypertension was not required for inclusion in the study. 30 Similar to those for the general population, this recommendation applies to those with diabetes because trials including participants with diabetes showed no differences in major cardiovascular or cerebrovascular outcomes from those in the general population (question 3, evidence statements 36-48). The following important points should be noted. First, many people will require treatment with more than one antihypertensive drug to achieve BP control. While this recommendation applies only to the choice of the initial antihypertensive drug, the panel suggests that any of these 4 classes would be good choices as addon agents (recommendation 9). Second, this recommendation is specific for thiazide-type diuretics, which include thiazide diuretics, chlorthalidone, and indapamide; it does not include loop or potassium-sparing diuretics. Third, it is important that medications be dosed adequately to achieve results similar to those seen in the RCTs (Table 4). Fourth, RCTs that were limited to specific nonhypertensive populations, such as those with coronary artery disease or heart failure, were not reviewed for this recommendation. Therefore, recommendation 6 should be applied with caution to these populations. Recommendations for those with CKD are addressed in recommendation 8. 19

20 RECOMMENDATION 7 In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB. For general black population: Moderate Recommendation Grade B For black patients with diabetes: Weak Recommendation Grade C Recommendation 7 is based on evidence statements from question 3. In cases for which evidence for the black population was the same as for the general population, the evidence statements for the general population apply to the black population. However, there are some cases for which the results for black persons were different from the results for the general population (question 3, evidence statements 2, 10, and 17). In those cases, separate evidence statements were developed. This recommendation stems from a prespecified subgroup analysis of data from a single large trial (ALLHAT) that was rated good.31 In that study, a thiazide-type diuretic was shown to be more effective in improving cerebrovascular, heart failure, and combined cardiovascular outcomes compared to an ACEI in the black patient subgroup, which included large numbers of diabetic and nondiabetic participants (question 3, evidence statements 10, 15 and 17). Therefore, the recommendation is to choose thiazide-type diuretics over ACEI for black patients. Although a CCB was less effective than a diuretic in preventing heart failure in the black subgroup of this trial (question 3, evidence statement 14), there were no differences in other outcomes (cerebrovascular, CHD, combined cardiovascular, and kidney outcomes, or overall mortality) between a CCB and a diuretic (question 3, evidence statements 6, 8, 11, 18, and 19). Therefore, both thiazide-type diuretics and CCBs are recommended as first-line therapy for hypertension in black patients. The panel recommended a CCB over an ACEI as first-line therapy in black patients because there was a 51% higher rate (relative risk, 1.51; 95% CI, ) of stroke in black persons in ALLHAT with the use of an ACEI as initial therapy compared with use of a CCB (question 3, evidence statement 2). 32 The ACEI was also less effective in reducing BP in black individuals compared with the CCB (question 3, evidence statement 2). 32 There were no outcome studies meeting our eligibility criteria that compared diuretics or CCBs vs β- blockers, ARBs, or other renin-angiotensin system inhibitors in black patients. The recommendation for black patients with diabetes is weaker than the recommendation for the general black population because outcomes for the comparison between initial use of a CCB compared to initial use of an ACEI in black persons with diabetes were not reported in any of the studies eligible for our evidence review. Therefore, this evidence was extrapolated from findings in the black participants in ALLHAT, 46% of whom had diabetes. Additional support comes from a post hoc analysis of black participants in ALLHAT that met the criteria for the metabolic syndrome, 68% of whom had diabetes. 33 However, this study 20

21 did not meet the criteria for our review because it was a post hoc analysis. This recommendation also does not address black persons with CKD, who are addressed in recommendation 8. RECOMMENDATION 8 In the population aged 18 years or older with CKD and hypertension, initial (or add-on) antihypertensive treatment should include an ACEI or ARB to improve kidney outcomes. This applies to all CKD patients with hypertension regardless of race or diabetes status. Moderate Recommendation Grade B The evidence is moderate (question 3, evidence statements 31-32) that treatment with an ACEI or ARB improves kidney outcomes for patients with CKD. This recommendation applies to CKD patients with and without proteinuria, as studies using ACEIs or ARBs showed evidence of improved kidney outcomes in both groups. This recommendation is based primarily on kidney outcomes because there is less evidence favoring ACEI or ARB for cardiovascular outcomes in patients with CKD. Neither ACEIs nor ARBs improved cardiovascular outcomes for CKD patients compared with a β-blocker or CCB (question 3, evidence statements 33-34). One trial (IDNT) did show improvement in heart failure outcomes with an ARB compared with a CCB, but this trial was restricted to a population with diabetic nephropathy and proteinuria (question 3, evidence statement 5). 34 There are no RCTs in the evidence review that directly compared ACEI to ARB for any cardiovascular outcome. However, both are renin-angiotensin system inhibitors and have been shown to have similar effects on kidney outcomes (question 3, evidence statements 31-32). Recommendation 8 is specifically directed at those with CKD and hypertension and addresses the potential benefit of specific drugs on kidney outcomes. The AASK study showed the benefit of an ACEI on kidney outcomes in black patients with CKD and provides additional evidence that supports ACEI use in that population. 21 Additional trials that support the benefits of ACEI or ARB therapy did not meet our inclusion criteria because they were not restricted to patients with hypertension. 35,36 Direct renin inhibitors are not included in this recommendation because there were no studies demonstrating their benefits on kidney or cardiovascular outcomes. The panel noted the potential conflict between this recommendation to use an ACEI or ARB in those with CKD and hypertension and the recommendation to use a diuretic or CCB (recommendation 7) in black persons: what if the person is black and has CKD? To answer this, the panel relied on expert opinion. In black patients with CKD and proteinuria, an ACEI or ARB is recommended as initial therapy because of the higher likelihood of progression to ESRD. 21 In black patients with CKD but without proteinuria, the choice for initial therapy is less clear and includes a thiazide-type diuretic, CCB, ACEI, or ARB. If an ACEI or ARB is not used as the initial drug, then an ACEI or ARB can be added as a second-line drug if necessary to achieve goal BP. 21

22 Because the majority of patients with CKD and hypertension will require more than 1 drug to achieve goal BP, it is anticipated that an ACEI or ARB will be used either as initial therapy or as second-line therapy in addition to a diuretic or CCB in black patients with CKD. Recommendation 8 applies to adults aged 18 years or older with CKD, but there is no evidence to support renin-angiotensin system inhibitor treatment in those older than 75 years. Although treatment with an ACEI or ARB may be beneficial in those older than 75 years, use of a thiazide-type diuretic or CCB is also an option for individuals with CKD in this age group. Use of an ACEI or an ARB will commonly increase serum creatinine and may produce other metabolic effects such as hyperkalemia, particularly in patients with decreased kidney function. Although an increase in creatinine or potassium level does not always require adjusting medication, use of renin-angiotensin system inhibitors in the CKD population requires monitoring of electrolyte and serum creatinine levels, and in some cases, may require reduction in dose or discontinuation for safety reasons. RECOMMENDATION 9 The main objective of hypertension treatment is to attain and maintain goal BP. If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a second drug from one of the classes in recommendation 6 (thiazide-type diuretic, CCB, ACEI, or ARB). The clinician should continue to assess BP and adjust the treatment regimen until goal BP is reached. If goal BP cannot be reached with 2 drugs, add and titrate a third drug from the list provided. Do not use an ACEI and an ARB together in the same patient. If goal BP cannot be reached using the drugs in recommendation 6 because of a contraindication or the need to use more than 3 drugs to reach goal BP, antihypertensive drugs from other classes can be used. Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attained using the above strategy or for the management of complicated patients for whom additional clinical consultation is needed. Expert Opinion Grade E Recommendation 9 was developed by the panel in response to a perceived need for further guidance to assist in implementation of recommendations 1 through 8. Recommendation 9 is based on strategies used in RCTs that demonstrated improved patient outcomes and the expertise and clinical experience of panel members. This recommendation differs from the other recommendations because it was not developed in response to the 3 critical questions using a systematic review of the literature. The Figure is an algorithm summarizing the recommendations. However, this algorithm has not been validated with respect to achieving improved patient outcomes. How should clinicians titrate and combine the drugs recommended in this report? There were no RCTs and thus the panel relied on expert opinion. Three strategies (Table 5) have been used in RCTs of high BP 22

23 treatment but were not compared with each other. Based on the evidence reviewed for questions 1 through 3 and on the expert opinion of the panel members, it is not known if one of the strategies results in improved cardiovascular outcomes, cerebrovascular outcomes, kidney outcomes, or mortality compared with an alternative strategy. There is not likely to be evidence from well-designed RCTs that compare these strategies and assess their effects on important health outcomes. There may be evidence that different strategies result in more rapid attainment of BP goal or in improved adherence, but those are intermediate outcomes that were not included in the evidence review. Therefore, each strategy is an acceptable pharmacologic treatment strategy that can be tailored based on individual circumstances, clinician and patient preferences, and drug tolerability. With each strategy, clinicians should regularly assess BP, encourage evidence-based lifestyle and adherence interventions, and adjust treatment until goal BP is attained and maintained. In most cases, adjusting treatment means intensifying therapy by increasing the drug dose or by adding additional drugs to the regimen. To avoid unnecessary complexity in this report, the hypertension management algorithm (Figure) does not explicitly define all potential drug treatment strategies. Finally, panel members point out that in specific situations, one antihypertensive drug may be replaced with another if it is perceived not to be effective or if there are adverse effects. LIMITATIONS This evidence-based guideline for the management of high BP in adults is not a comprehensive guideline and is limited in scope because of the focused evidence review to address the 3 specific questions (Table 1). Clinicians often provide care for patients with numerous comorbidities or other important issues related to hypertension, but the decision was made to focus on 3 questions considered to be relevant to most physicians and patients. Treatment adherence and medication costs were thought to be beyond the scope of this review, but the panel acknowledges the importance of both issues. The evidence review did not include observational studies, systematic reviews, or meta-analyses, and the panel did not conduct its own meta-analysis based on prespecified inclusion criteria. Thus, information from these types of studies was not incorporated into the evidence statements or recommendations. Although this may be considered a limitation, the panel decided to focus only on RCTs because they represent the best scientific evidence and because there were a substantial number of studies that included large numbers of patients and met our inclusion criteria. Randomized controlled trials that included participants with normal BP were excluded from our formal analysis. In cases in which high-quality evidence was not available or the evidence was weak or absent, the panel relied on fair-quality evidence, panel members knowledge of the published literature beyond the RCTs reviewed, and personal experience to make recommendations. The duration of the guideline development process following completion of the systematic search may have caused the panel to miss studies published after our literature review. However, a bridge search was performed 23

24 through August 2013, and the panel found no additional studies that would have changed the recommendations. Many of the reviewed studies were conducted when the overall risk of cardiovascular morbidity and mortality was substantially higher than it is today; therefore, effect sizes may have been overestimated. Further, RCTs that enrolled prehypertensive or nonhypertensive individuals were excluded. Thus, our recommendations do not apply to those without hypertension. In many studies focused on DBP, participants also had elevated SBP so it was not possible to determine whether the benefit observed in those trials arose from lowering DBP, SBP, or both. In addition, the ability to compare studies from different time periods was limited by differences in clinical trial design and analytic techniques. While physicians use cost, adherence, and often observational data to make treatment decisions, medical interventions should whenever possible be based first and foremost on good science demonstrating benefits to patients. Randomized controlled trials are the gold standard for this assessment and thus were the basis for providing the evidence for our clinical recommendations. Although adverse effects and harms of antihypertensive treatment documented in the RCTs were considered when the panel made its decisions, the review was not designed to determine whether therapy-associated adverse effects and harms resulted in significant changes in important health outcomes. In addition, this guideline was not endorsed by any federal agency or professional society prior to publication and thus is a departure from previous JNC reports. The panel anticipates that an objective assessment of this report following publication will allow open dialogue among endorsing entities and encourage continued attention to rigorous methods in guideline development, thus raising the standard for future guidelines. DISCUSSION The recommendations based on RCT evidence in this guideline differ from recommendations in other currently used guidelines supported by expert consensus (Table 6). For example, JNC 7 and other guidelines recommended treatment to lower BP goals in patients with diabetes and CKD based on observational studies. 12 Recently, several guideline documents such as those from the American Diabetes Association have raised the systolic BP goals to values that are similar to those recommended in this evidence-based guideline Other guidelines such as those of the European Society of Hypertension/European Society of Cardiology also recommend a systolic BP goal of lower than 150 mm Hg, but it is not clear at what age cutoff this goal specifically applies. 37 This changing landscape is understandable given the lack of clear RCT evidence in many clinical situations. HISTORY of JNC 8 The panel was originally constituted as the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8). In March 2008 NHLBI sent letters inviting the co-chairs and committee members to serve on JNC 8. The charge to the committee was as follows: 24

25 The JNC 8 will review and synthesize the latest available scientific evidence, update existing clinical recommendations, and provide guidance to busy primary care clinicians on the best approaches to manage and control hypertension in order to minimize patients risk for cardiovascular and other complications. The committee was also asked to identify and prioritize the most important questions for the evidence review. In June 2013, NHLBI announced its decision to discontinue developing clinical guidelines including those in process, instead partnering with selected organizations that would develop the guidelines. 43,44 Importantly, participation in this process required that these organizations be involved in producing the final content of the report. The panel elected to pursue publication independently to bring the recommendations to the public in a timely manner while maintaining the integrity of the predefined process. This report is therefore not an NHLBI sanctioned report and does not reflect the views of NHLBI. CONCLUSIONS It is important to note that this evidence-based guideline has not redefined high BP, and the panel believes that the 140/90 mm Hg definition from JNC 7 remains reasonable. The relationship between naturally occurring BP and risk is linear down to very low BP, but the benefit of treating to these lower levels with antihypertensive drugs is not established. For all persons with hypertension, the potential benefits of a healthy diet, weight control, and regular exercise cannot be overemphasized. These lifestyle treatments have the potential to improve BP control and even reduce medication needs. Although the authors of this hypertension guideline did not conduct an evidence review of lifestyle treatments in patients taking and not taking antihypertensive medication, we support the recommendations of the 2013 Lifestyle Work Group. 45 The recommendations from this evidence-based guideline from panel members appointed to the Eighth Joint National Committee (JNC 8) offer clinicians an analysis of what is known and not known about BP treatment thresholds, goals, and drug treatment strategies to achieve those goals based on evidence from RCTs. However, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient. We hope that the algorithm will facilitate implementation and be useful to busy clinicians. The strong evidence base of this report should inform quality measures for the treatment of patients with hypertension. 25

26 Acknowledgements: Funding/Support and Role of Sponsor. The evidence review for this project was funded by the National Heart, Lung, and Blood Institute (NHLBI). The design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication are the responsibilities of the authors alone and independent of NHLBI. The views expressed do not represent those of the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, or the Federal Government. Data Access and Responsibility. Dr. Paul James and Dr. Suzanne Oparil had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The Panel wishes to thank Cory V. Evans, MPP, who at the time of the project was a Senior Research Analyst and Contract Lead for JNC 8 with Leidos (formerly Science Applications International Corporation) and Linda J. Lux, MPA, with RTI International for their support. The Panel also wishes to thank Lawrence J. Fine, MD, DrPH, with the National Heart, Lung, and Blood Institute, for his work with the Panel. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Cushman reports receipt of institutional grant support from Merck, Lilly and Novartis; and consulting fees from Novartis, Sciele Pharmaceuticals, Takeda, Sanofi-aventis, Gilead, Calpis, Pharmacopeia, Theravance, Daiichi-Sankyo, Noven, Astra Zeneca Spain, Merck, Omron, and Janssen. Dr. Wright reports receipt of consulting fees from Medtronics, CVRX, Takeda, Daiichi-Sankyo, Novartis and Take Care Health. Dr. Oparil reports individual and institutional payment related to Board membership for Bayer, Daiichi Sankyo, Novartis, Medtronic and Takeda; and individual consulting fees from Backbeat, Bayer, 26

27 Boehringer-Ingelheim, Bristol Myers-Squibb, Daiichi Sankyo, Eli Lilly, Medtronic, Merck and Co, Pfizer and Takeda; and receipt of institutional grant funding from AstraZeneca AB, Daiichi Sankyo, Eisai Inc, Gilead, Medtronic Inc., Merck, Novartis, Takeda Global Research and Development Inc.; and individual payment for lectures from Daiichi Sankyo, Merck, Novartis and Pfizer; and individual and institutional payment for development of educational presentations from ASH/ASHR (Daiichi Sankyo, Inc.); and individual and institutional payment from Amarin Pharma Inc., Daiichi Sankyo, Inc., and LipoScience, Inc. for educational grant(s) for the Annual UAB Vascular Biology & Hypertension Symposium; sponsorship. Dr. Townsend reports Board membership with Medtronic, consultancy for Janssen, GSK and Merck, and educational related payments from Merck, UpToDate, and Medscape. The other authors report no disclosures. 27

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30 27. The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens. 1985;3(4): Dahlöf B, Devereux RB, Kjeldsen SE, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311): Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2003;42(3): Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15): ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288(23): Leenen FH, Nwachuku CE, Black HR, et al; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Hypertension. 2006;48(3): Wright JT Jr, Harris-Haywood S, Pressel S, et al. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2008;168(2): Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12): Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12): Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; The Collaborative Study Group. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329(20): Mancia G, Fagard R, Narkiewicz K, et al ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28): Hypertension without compelling indications: 2013 CHEP recommendations. Hypertension Canada website. Accessed October 30,

31 39. American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2013;36(suppl 1):S11-S Kidney Disease; Improving Global (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012;2(5): National Institute for Health and Clinical Excellence. Hypertension (CG127). Accessed October 30, Flack JM, Sica DA, Bakris G, et al; International Society on Hypertension in Blacks. Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5): Gibbons GH, Harold JG, Jessup M, Robertson RM, Oetgen WJ. The next steps in developing clinical practice guidelines for prevention. J Am Coll Cardiol. 2013;62(15): Gibbons GH, Shurin SB, Mensah GA, Lauer MS. Refocusing the agenda on cardiovascular guidelines: an announcement from the National Heart, Lung, and Blood Institute. Circulation. 2013;128(15): Eckel RH, Jakicic JM, Ard JD, et al. AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation doi: /01.cir d1. 31

32 Tables and Figures 32

33 Figure Hypertension Guideline Management Algorithm Adult aged 18 years with hypertension Implement lifestyle interventions (continue throughout management). Set blood pressure goal and initiate blood pressure lowering-medication based on age, diabetes, and chronic kidney disease (CKD). General population (no diabetes or CKD) Diabetes or CKD present Age 60 years Age <60 years All ages Diabetes present No CKD All ages CKD present with or without diabetes Blood pressure goal SBP <150 mm Hg DBP <90 mm Hg Blood pressure goal SBP <140 mm Hg DBP <90 mm Hg Blood pressure goal SBP <140 mm Hg DBP <90 mm Hg Blood pressure goal SBP <140 mm Hg DBP <90 mm Hg Nonblack Black All races Initiate thiazide-type diuretic or ACEI or ARB or CCB, alone or in combination. a Initiate thiazide-type diuretic or CCB, alone or in combination. Initiate ACEI or ARB, alone or in combination with other drug class. a Select a drug treatment titration strategy A. Maximize first medication before adding second or B. Add second medication before reaching maximum dose of first medication or C. Start with 2 medication classes separately or as fixed-dose combination. At goal blood pressure? No Yes Reinforce medication and lifestyle adherence. For strategies A and B, add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class not previously selected and avoid combined use of ACEI and ARB). For strategy C, titrate doses of initial medications to maximum. At goal blood pressure? Yes Reinforce medication and lifestyle adherence. Add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class not previously selected and avoid combined use of ACEI and ARB). No At goal blood pressure? No Yes Reinforce medication and lifestyle adherence. Add additional medication class (eg, β-blocker, aldosterone antagonist, or others) and/or refer to physician with expertise in hypertension management. No At goal blood pressure? Yes Continue current treatment and monitoring. b SBP indicates systolic blood pressure; DBP, diastolic blood pressure; ACEI, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; and CCB, calcium channel blocker. a ACEIs and ARBs should not be used in combination. b If blood pressure fails to be maintained at goal, reenter the algorithm where appropriate based on the current individual therapeutic plan. 33

34 Table 1: Comparison of Current Recommendations with JNC 7 Guidelines Topic JNC Hypertension Guideline Methodology Nonsystematic literature review by expert committee including a range of study designs Recommendations based on consensus Critical questions and review criteria defined by expert panel with input from methodology team Initial systematic review by methodologists restricted to RCT evidence Subsequent review of RCT evidence and recommendations by the panel according to a standardized protocol Definitions Defined hypertension and prehypertension Definitions of hypertension and prehypertension not addressed, but thresholds for pharmacologic treatment were defined Treatment goals Lifestyle recommendati ons Drug therapy Separate treatment goals defined for uncomplicated hypertension and for subsets with various comorbid conditions (diabetes and CKD) Recommended lifestyle modifications based on literature review and expert opinion Recommended 5 classes to be considered as initial therapy but recommended thiazide type diuretics as initial therapy for most patients without compelling indication for another class Specified particular antihypertensive medication classes for patients with compelling indications, ie, diabetes, CKD, heart failure, myocardial infarction, stroke, and high CVD risk Included a comprehensive table of oral antihypertensive drugs including names and usual dose ranges Similar treatment goals defined for all hypertensive populations except when evidence review supports different goals for a particular subpopulation Lifestyle modifications recommended by endorsing the evidencebased Recommendations of the Lifestyle Work Group Recommended selection among 4 specific medication classes (ACEI or ARB, CCB or diuretics) and doses based on RCT evidence Recommended specific medication classes based on evidence review for racial, CKD, and diabetic subgroups Panel created a table of drugs and doses used in the outcome trials 34

35 Scope of topics Review process prior to publication Addressed multiple issues (blood pressure measurement methods, patient evaluation components, secondary hypertension, adherence to regimens, resistant hypertension, and hypertension in special populations) based on literature review and expert opinion Reviewed by the National High Blood Pressure Education Program Coordinating Committee, a coalition of 39 major professional, public, and voluntary organizations and 7 federal agencies Evidence review of RCTs addressed a limited number of questions, those judged by the panel to be of highest priority. Reviewed by experts including those affiliated with professional and public organizations and federal agencies; no official sponsorship by any organization should be inferred Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; CVD, cardiovascular disease; JNC, Joint National Committee; RCT, randomized controlled trial. 35

36 Table 2: Evidence Quality Rating Type of Evidence Well designed, well executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomes Quality Rating a High Well conducted meta analyses of such studies Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect RCTs with minor limitations affecting confidence in, or applicability of, the results Well designed, well executed non randomized controlled studies and well designed, well executed observational studies Well conducted meta analyses of such studies Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate RCTs with major limitations Non randomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports) Physiological studies in humans Meta analyses of such studies Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate. Moderate Low Abbreviation: RCT, randomized controlled trial. a The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute s (NHLBI s) Evidence Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI CVD guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. 36

37 Table 3: Strength of Recommendation Grade A B C D E N Strength of Recommendation Strong Recommendation There is high certainty based on evidence that the net benefit a is substantial. Moderate Recommendation There is moderate certainty based on evidence that the net benefit is moderate to substantial or there is high certainty that the net benefit is moderate. Weak Recommendation There is at least moderate certainty based on evidence that there is a small net benefit. Recommendation against There is at least moderate certainty based on evidence that it has no net benefit or that risks/harms outweigh benefits. Expert Opinion ( There is insufficient evidence or evidence is unclear or conflicting, but this is what the committee recommends. ) Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the committee thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area. No Recommendation for or against ( There is insufficient evidence or evidence is unclear or conflicting. ) Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the committee thought no recommendation should be made. Further research is recommended in this area. The strength of recommendation grading system used in this guideline was developed by the National Heart, Lung, and Blood Institute s (NHLBI s) Evidence Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI CVD guideline panels and work groups during this project. Additional details regarding the strength of recommendation grading system are available in the online Supplement. a Net benefit is defined as benefits minus the risks/harms of the service/intervention. 37

38 Table 4: Evidence Based Dosing for Antihypertensive Drugs Antihypertensive Medication Initial Daily Dose, mg Target Dose in RCTs Reviewed, mg No. of Doses per Day ACE inhibitors Captopril Enalapril Lisinopril Angiotensin receptor blockers Eprosartan Candesartan Losartan Valsartan Irbesartan β Blockers Atenolol Metoprolol Calcium channel blockers Amlodipine Diltiazem extended release Nitrendipine Thiazide type diuretics Bendroflumethiazide Chlorthalidone Hydrochlorothiazide a 1 2 Indapamide Abbreviations: ACE, angiotensin converting enzyme; RCT, randomized controlled trial. a Current recommended evidence based dose that balances efficacy and safety is mg daily. 38

39 Table 5: Strategies to Dose Antihypertensive Drugs Strategy Description Details A Start one drug, titrate to maximum dose, and then add a second drug If goal BP is not achieved with the initial drug, titrate the dose of the initial drug up to the maximum recommended dose to achieve goal BP If goal BP is not achieved with the use of one drug despite titration to the maximum recommended dose, add a second drug from the list (thiazide type diuretic, CCB, ACEI, or ARB) and titrate up to the maximum recommended dose of the second drug to achieve goal BP If goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide type diuretic, CCB, ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximum recommended dose to achieve goal BP B C Start one drug and then add a second drug before achieving maximum dose of the initial drug Begin with 2 drugs at the same time, either as 2 separate pills or as a single pill combination Start with one drug then add a second drug before achieving the maximum recommended dose of the initial drug, then titrate both drugs up to the maximum recommended doses of both to achieve goal BP If goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide type diuretic, CCB, ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximum recommended dose to achieve goal BP Initiate therapy with 2 drugs simultaneously, either as 2 separate drugs or as a single pill combination. Some committee members recommend starting therapy with 2 drugs when SBP is >160 mm Hg and/or DBP is >100 mm Hg, or if SBP is >20 mm Hg above goal and/or DBP is >10 mm Hg above goal. If goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide type diuretic, CCB, ACEI, or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximum recommended dose. Abbreviations: ACEI, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; DBP, diastolic blood pressure; SBP, systolic blood pressure. a This table is not meant to exclude other agents within the classes of antihypertensive medications that have been recommended but reflects those agents and dosing used in randomized controlled trials that demonstrated improved outcomes. 39

40 Table 6: Guideline Comparisons of Goal BP and Initial Drug Therapy for Adults with Hypertension Goal BP, Guideline Population mm Hg Initial Drug Treatment Options 2014 Hypertension guideline General 60 y <150/90 General <60 y <140/90 Nonblack: thiazide type diuretic, ACEI, ARB, or CCB; black: thiazide type diuretic or CCB Diabetes <140/90 Thiazide type diuretic, ACEI, ARB, or CCB CKD <140/90 ACEI or ARB ESH/ESC General nonelderly <140/90 General elderly <80 y <150/90 Diuretic, β blocker, CCB, ACEI, or ARB General 80 y <150/90 Diabetes <140/85 ACEI or ARB CKD no proteinuria <140/90 CKD + proteinuria <130/90 CHEP General <80 y <140/90 General 80 y <150/90 ACEI or ARB Thiazide, β blocker (age <60y), ACEI (nonblack), or ARB Diabetes <130/80 ACEI or ARB with additional CVD risk CKD <140/90 ACEI or ARB ACEI, ARB, thiazide, or DHPCCB without additional CVD risk 40

41 Guideline Population Goal BP, mm Hg Initial Drug Treatment Options ADA Diabetes <140/80 ACEI or ARB KDIGO CKD no proteinuria 140/90 CKD + proteinuria 130/80 ACEI or ARB NICE General <80 y <140/90 <55 y: ACEI or ARB General 80 y <150/90 55 y or black: CCB ISHIB Black, lower risk <135/85 Target organ damage or CVD risk <130/80 Diuretic or CCB Abbreviations: ADA, American Diabetes Association; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CHEP, Canadian Hypertension Education Program; CKD, chronic kidney disease; CVD, cardiovascular disease; DHPCCB, dihydropyridine calcium channel blocker; ESC, European Society of Cardiology; ESH, European Society of Hypertension; ISHIB, International Society for Hypertension in Blacks; JNC, Joint National Committee; KDIGO, Kidney Disease: Improving Global Outcome; NICE, National Institute for Health and Clinical Excellence. 41

42 Box. Recommendations for Management of Hypertension Recommendation 1 In the general population aged 60 years, initiate pharmacologic treatment to lower blood pressure (BP) at systolic blood pressure (SBP) 150 mm Hg or diastolic blood pressure (DBP) 90 mm Hg and treat to a goal SBP <150 mm Hg and goal DBP <90 mm Hg. (Strong Recommendation Grade A) Corollary Recommendation In the general population aged 60 years, if pharmacologic treatment for high BP results in lower achieved SBP (eg, <140 mm Hg) and treatment is well tolerated and without adverse effects on health or quality of life, treatment does not need to be adjusted. (Expert Opinion Grade E) Recommendation 2 In the general population <60 years, initiate pharmacologic treatment to lower BP at DBP 90 mm Hg and treat to a goal DBP <90 mm Hg. (For ages years, Strong Recommendation Grade A; For ages years, Expert Opinion Grade E) Recommendation 3 In the general population <60 years, initiate pharmacologic treatment to lower BP at SBP 140 mm Hg and treat to a goal SBP <140 mm Hg. (Expert Opinion Grade E) Recommendation 4 In the population aged 18 years with chronic kidney disease (CKD), initiate pharmacologic treatment to lower BP at SBP 140 mm Hg or DBP 90 mm Hg and treat to goal SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion Grade E) Recommendation 5 In the population aged 18 years with diabetes, initiate pharmacologic treatment to lower BP at SBP 140 mm Hg or DBP 90 mm Hg and treat to a goal SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion Grade E) Recommendation 6 In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). (Moderate Recommendation Grade B) 42

43 Recommendation 7 In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide type diuretic or CCB. (For general black population: Moderate Recommendation Grade B; for black patients with diabetes: Weak Recommendation Grade C) Recommendation 8 In the population aged 18 years with CKD, initial (or add on) antihypertensive treatment should include an ACEI or ARB to improve kidney outcomes. This applies to all CKD patients with hypertension regardless of race or diabetes status. (Moderate Recommendation Grade B) Recommendation 9 The main objective of hypertension treatment is to attain and maintain goal BP. If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a second drug from one of the classes in recommendation 6 (thiazide type diuretic, CCB, ACEI, or ARB). The clinician should continue to assess BP and adjust the treatment regimen until goal BP is reached. If goal BP cannot be reached with 2 drugs, add and titrate a third drug from the list provided. Do not use an ACEI and an ARB together in the same patient. If goal BP cannot be reached using only the drugs in recommendation 6 because of a contraindication or the need to use more than 3 drugs to reach goal BP, antihypertensive drugs from other classes can be used. Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attained using the above strategy or for the management of complicated patients for whom additional clinical consultation is needed. (Expert Opinion Grade E) 43

44 Background 44

45 BACKGROUND Hypertension remains one of the most important preventable contributors to disease and death. Abundant evidence from randomized controlled trials (RCTs) has shown the benefit of antihypertensive drug treatment in reducing important health outcomes in hypertensive persons. [Staessen, 1997; Beckett, 2008; Shep 1991] Clinical guidelines sit at the intersection between research evidence and clinical actions that can improve patient outcomes. The Institute of Medicine Report Clinical Practice Guidelines We Can Trust outlined a pathway to guideline development and is an approach that the JNC 8 Panel aspired to in the creation of this Report. [IOM (Institute of Medicine) 2011] The Panel used rigorous evidence based methodology, developing Evidence Statements (ESs) and Recommendations for blood pressure (BP) treatment based on a systematic review of the literature to meet user needs, especially the needs of the primary care clinician. This Report is designed to be userfriendly and to provide clear recommendations for all clinicians. Major differences from the previous JNC Reports are summarized in Table 1. Panel Members Panel members were selected from over 400 nominees. Panel members were selected based on their expertise in hypertension, primary care, cardiology, nephrology, clinical trials, research methodology, evidence based medicine, epidemiology, guideline development and implementation, nutrition/lifestyle, nursing, pharmacology, systems of care, and informatics. The Panel also included senior scientists from NHLBI and NIDDK with expertise in hypertension, clinical trials, translational research, nephrology, primary care, guideline development, and evidence based methodology. In assembling the Panel, we sought to achieve a balance of expertise and perspectives. The Panel met for the first time in September Panel Members Co Chair: Paul A. James, MD Professor and Head, Department of Family Medicine in the Carver College of Medicine, Professor of Occupational and Environmental Health in the College of Public Health, Donald J. and Anna M. Ottilie Endowed Chair in Family Medicine University of Iowa Co Chair: Suzanne Oparil, MD Professor of Medicine Professor of Cell, Developmental and Integrative Biology Director, Vascular Biology and Hypertension Program Division of Cardiovascular Disease, Department of Medicine University of Alabama at Birmingham School of Medicine Barry L. Carter, PharmD Professor, Department of Pharmacy Practice and Science, College of Pharmacy Professor and Associate Head, Research Department of Family Medicine University of Iowa 45

46 William C. Cushman, MD, FACP, FAHA, FASH Chief, Preventive Medicine, Memphis Veterans Affairs Medical Center Lead Consultant in Hypertension to VA Medical Service Professor, Preventive Medicine and Medicine University of Tennessee Cheryl Dennison Himmelfarb, RN, ANP, PhD, FAAN Associate Professor Department of Health Systems and Johns Hopkins University School of Nursing Division of Health Sciences Informatics Johns Hopkins University School of Medicine Joel Handler, MD Clinical Lead for Hypertension Care Management Institute, Kaiser Permanente Southern California Permanente Medical Group Department of Internal Medicine Daniel T. Lackland, DrPH Professor, Epidemiology and Medicine Department of Neurosciences Medical University of South Carolina Michael L. LeFevre, MD, MSPH Professor, Department of Family and Community Medicine University of Missouri Thomas D. MacKenzie, MD, MSPH, FACP Chief Medical Officer, Denver Health and Hospital Authority Associate Professor of Medicine University of Colorado School of Medicine Olugbenga Ogedegbe, MD, MPH, MS, FAHA Professor of Medicine and Population Health Division of Health and Behavior Department of Population Health New York University School of Medicine Sidney C. Smith, Jr., MD, FACC, FAHA, FESC Director, Center for Cardiovascular Science and Medicine Professor of Medicine University of North Carolina at Chapel Hill Laura P. Svetkey, MD, MHS Director, Duke Hypertension Center Director of Clinical Research at the Sarah W. Stedman Nutrition and Metabolism Center 46

47 Professor of Medicine Duke University Sandra J. Taler, MD Professor of Medicine Division of Nephrology and Hypertension Mayo Clinic College of Medicine Raymond R. Townsend, MD Director, Hypertension Section Professor of Medicine Department of Internal Medicine Renal University of Pennsylvania Jackson T. Wright, Jr., MD, PhD Director, Clinical Hypertension Program Director, William T. Dahms Clinical Research Unit, University Hospitals Case Medical Center Professor of Medicine Case Western Reserve University Andrew S. Narva, MD Director, National Kidney Disease Education Program Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Eduardo Ortiz, MD, MPH (Non Voting Member) At the time of this project, Dr. Ortiz was a Senior Medical Officer with the National Heart, Lung, and Blood Institute (NHLBI). He was also the Program Coordinator for JNC 8 and NHLBI s Evidence Based Methodology Lead. He is currently Director of Clinical Development and Informatics with ProVation Medical, Wolters Kluwer Health. Support Staff Cory V. Evans, MPP, At the time of this project, Ms. Evans was a Senior Research Analyst and Contract Lead for JNC 8 with Leidos (formerly, Science Applications International Corporation). She is currently a Research Associate with the Kaiser Permanente Center for Health Research. Linda J. Lux, MPA, Senior Research Associate with RTI International Note: The Panel also recognizes the significant contributions of Lawrence J. Fine, MD, DrPH, with the National Heart, Lung, and Blood Institute, for his work with the Panel. DISCLOSURES Panel members disclosed their relationships with industry and potential conflicts of interest and recused themselves from voting on evidence statements and recommendations relevant to their relationships/potential conflicts. Four Panel members had relationships or potential conflicts to disclose. 47

48 For more information, refer to: Guideline Executive Committee Policy on Disclosures: rwi_policy.htm Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Cushman reports receipt of institutional grant support from Merck, Lilly and Novartis; and consulting fees from Novartis, Sciele Pharmaceuticals, Takeda, Sanofi aventis, Gilead, Calpis, Pharmacopeia, Theravance, Daiichi Sankyo, Noven, Astra Zeneca Spain, Merck, Omron, and Janssen. Dr. Wright reports receipt of consulting fees from Medtronics, CVRX, Takeda, Daiichi Sankyo, Novartis and Take Care Health. Dr. Oparil reports individual and institutional payment related to Board membership for Bayer, Daiichi Sankyo, Novartis, Medtronic and Takeda; and individual consulting fees from Backbeat, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Medtronic, Merck and Co, Pfizer and Takeda; and receipt of institutional grant funding from AstraZeneca AB, Daiichi Sankyo, Eisai Inc, Gilead, Medtronic Inc., Merck, Novartis, Takeda Global Research and Development Inc.; and individual payment for lectures from Daiichi Sankyo, Merck, Novartis and Pfizer; and individual and institutional payment for development of educational presentations from ASH/ASHR (Daiichi Sankyo, Inc.); and individual and institutional payment from Amarin Pharma Inc., Daiichi Sankyo, Inc., and LipoScience, Inc. for educational grant(s) for the Annual Vascular Biology & Hypertension Symposium; sponsorship. Dr. Townsend reports Board membership with Medtronic, consultancy for Janssen, GSK and Merck, and educational related payments from Merck, UpToDate, and Medscape. The other authors report no disclosures. Other Acknowledgments The evidence review for this project was funded by the National Heart, Lung, and Blood Institute. The views expressed do not represent those of the National Heart, Lung, and Blood Institute, the National Institute of Diabetes, Digestive and Kidney Disease, the National Institutes of Health, or the Federal Government. 48

49 Methods 49

50 METHODS Description of How Panel Members Were Selected The NHLBI initiated a public call for nominations for panel membership to ensure adequate representation of key specialties and stakeholders and appropriate expertise. A nomination form was posted on the NHLBI website for several weeks and was also distributed to a Guidelines Leadership Group that had given advice to the NHLBI on its guideline efforts. Information from nomination forms, including contact information and areas of clinical and research expertise, was entered into a database. After the close of the call for nominations, NHLBI staff reviewed the database and selected potential cochairs. The potential co chairs provided the NHLBI Conflict of Interest (COI) disclosures and copies of their curriculum vitae. The NHLBI Ethics Office reviewed the COI disclosures of the potential co chairs. The selected chairs then were formed into a Guidelines Executive Committee, which worked with thenhlbi to select panel members from the list of nominees. The NHLBI received 440 nominations for panel members. Panel members were selected based on their expertise in hypertension, primary care, cardiology, nephrology, clinical trials, research methodology, evidence based medicine, epidemiology, guideline development and implementation, nutrition/lifestyle, nursing, pharmacology, systems of care, and informatics. The panel also included senior scientists from NHLBI and NIDDK with expertise in hypertension, clinical trials, translational research, nephrology, primary care, guideline development, and evidence based methodology. Description of How the Panel Developed, Prioritized, and Formatted Questions The Panel Co Chairs and NHLBI staff developed an initial set of questions based on their expertise, a brief literature review, and speaking with colleagues to identify topics of the greatest relevance and impact for the target audience of the guideline: primary care providers. These questions were sent to panel members to review and revise, including adding or deleting questions, based on what they thought were the most important clinical questions in hypertension. This process resulted in 23 questions, which were sent to all panel members. Panel members discussed these questions on multiple conference calls and then independently ranked the top 5 questions felt to be of highest priority. The five highest ranked questions were discussed further and prioritized. This report is focused on the three highest ranked questions. With support from the methodologist and systematic review team, the highest priority questions were formatted using the PICOTSS framework, and inclusion and exclusion criteria (I/E criteria) were defined. PICOTSS is a standardized framework for a structured research question that is commonly used when conducting evidence based systematic reviews and includes the following components in the statement of the question or in the question s inclusion and exclusion criteria: P I C O T S S person or population intervention or exposure comparator outcome timing setting study design 50

51 Inclusion and exclusion criteria define the parameters for conducting the literature search for a particular question. Inclusion and exclusion criteria were developed with input from the methodologist and systematic review team to ensure that criteria were clear and precise and could be applied consistently across literature identified in the search. The final questions and criteria were submitted to the literature search team for search strategy development. How Were the Questions Selected? Panel Chairs and NHLBI staff developed an initial set of questions based on their expertise, a brief literature review, and speaking with colleagues. These questions were then sent to Panel members to review and revise, including adding or deleting questions, based on what they thought were the most important clinical questions in hypertension. This process resulted in 23 questions, which were sent to all Panel members. Panel members discussed these questions on multiple conference calls then independently ranked the top 5 questions felt to be of highest priority. The five highest ranked questions were discussed further and prioritized. This report is focused on the three highest ranked questions Rationale for the Questions Selected The rationale for the questions selected by the Panel was based on the following: Interest among Panel members regarding the evidence supporting 140/90 mm Hg as a treatment threshold and/or goal for the general population. Interest in whether the treatment threshold or goal should be lower than in the general population for those with diabetes, chronic kidney disease, coronary artery disease, stroke, or other comorbidities or risks, including older adults. Concern that having a threshold for initiating treatment that differs from the treatment goal may be confusing to people. Interest in the selection of pharmacologic therapy, including whether treatment to lower blood pressure with a particular drug or drug class improves important health outcomes when compared to another drug or drug class. QUESTIONS 1. In adults with hypertension, does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes? 2. In adults with hypertension, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? 51

52 Inclusion/Exclusion Criteria for the Evidence Review The Panel decided to limit its evidence review to Randomized Controlled Trials (RCTs) because they are subject to less bias than other types of clinical studies and represent the gold standard for determining efficacy and effectiveness [IOM, 2011]. All of the studies in the evidence review were from original publications of eligible RCTs. These studies were used to create Evidence Tables and Summary Tables that were used by the Panel as the basis for their deliberations. Because the Panel conducted its own systematic review using original studies, systematic reviews and meta analyses (SR/MA) of RCTs published by other groups were not used in the evidence review (i.e., they were not abstracted and included in the Evidence Tables and Summary Tables). Pilot studies were also excluded. Pilot studies were defined as trials where the specific aims were to conduct a pilot or feasibility study for the purpose of informing a larger clinical trial that occurred later. The evidence review focused on adults 18 years of age or older with hypertension and included studies with the following prespecified subgroups: diabetes, coronary artery disease, peripheral artery disease, heart failure, previous stroke, chronic kidney disease, proteinuria, older adults, men and women, racial and ethnic groups, and smokers. Studies with sample sizes less than 100 were excluded, as were studies with a follow up period of less than one year. Initial search dates for the literature review were January 1, 1966 to December 31, In order to ensure that no major relevant studies published after December 31, 2009 were excluded from consideration; two independent searches of PubMed and CINAHL between December 2009 and August 2013 were conducted with the same MeSH terms as the original search. Three Panel members reviewed the results. The Panel limited the inclusion criteria of this second search to the following: 1) The study was a major study in the field (e.g., ACCORD BP, SPS3 ) {{728 ACCORD Study Group 2010; 729 SPS3 Study Group 2013}} 2) It had at least 2,000 participants; 3) It was multi centered; and 4) It met all the other inclusion/exclusion criteria. Additionally, all Panel members were asked to identify newly published studies for consideration if they met the above criteria. There were no additional clinical trials that fit the previously described inclusion criteria. Studies selected were rated for quality using NHLBI s standardized quality rating tool and were only included if rated as Good or Fair. Studies selected in this manner were also rated for quality using NHLBI s standardized quality rating tool and were only included if rated as Good or Fair. Although the Panel understands that this approach may result in selection bias for studies identified after December 31, 2009, the Panel thought that it was important to identify and include seminal studies like ACCORD that were published after the end of the literature search. Although it would have been ideal to continually update the literature search until publication of this report, such an approach was not feasible. The Panel only included studies that measured the effects of the studied interventions on the following important health outcomes: Overall mortality, mortality related to CVD, mortality related to chronic kidney disease (CKD) Myocardial infarction, heart failure, hospitalization for heart failure, stroke SPS3 did not meet strict inclusion criteria because it included non-hypertensive participants. It would not have changed our conclusions/recommendations since the only significant finding supporting a lower goal occurred in an infrequent secondary outcome. 52

53 Coronary revascularization (includes coronary artery bypass surgery, coronary angioplasty and coronary stent placement), peripheral revascularization (includes carotid, renal, and lower extremity revascularization) End stage renal disease (i.e., kidney failure resulting in dialysis or transplant), doubling of creatinine, halving of estimated glomerular filtration rate (egfr) For Question 1, we originally looked for studies that randomized participants into groups where pharmacologic therapy to lower blood pressure was initiated at different blood pressure thresholds. For example, we looked for studies where treatment was initiated at a systolic blood pressure of 160 mm Hg in one group and compared to treatment initiated at a systolic BP of 140 mm Hg in another group. We found that no RCTs had been conducted that compared two or more different treatment thresholds. Therefore, we had to broaden the inclusion criteria to include RCTs that had a specific criterion for initiating treatment in one group (e.g., initiating treatment if systolic blood pressure was > = 160 mm Hg) and compared it to a group that received placebo, usual care, or no treatment. Evidence statements were graded for quality as high, moderate, or low using a grading system developed by NHLBI s Evidence Based Methodology Lead with input from NHLBI staff, the external methodology team and the Guideline Panels and Work Groups. This grading system was adapted (with modifications) from the approach used by the United States Preventive Services Task Force. Recommendations were graded as Strong Recommendation (Grade A), Moderate Recommendation (Grade B), Weak Recommendation (Grade C), Recommendation Against (Grade D), Expert Opinion (Grade E), or No Recommendation for or Against (Grade N), which also was adapted (with modifications) from the United States Preventive Services Task Force. Literature Search Infrastructure, Search Strategy Development and Validation The literature search was performed using an integrated suite of search engines that explored a central repository of citations and full text journal articles. The central repository, search engines, search results, and web based modules for literature screening and data abstraction were integrated within a technology platform called the Virtual Collaborative Workspace (VCW). The VCW was custom developed for the NHLBI guidelines initiative. The central repository consisted of 1.9 million citations and 71,000 full text articles related to cardiovascular disease risk reduction. Citations were acquired from: PubMed, Embase, Cinahl, Cochrane, PsycInfo, Wilson Science, and Biological Abstracts databases. Literature searches were conducted using a collection of search engines including: TeraText, Content Analyst, Collexis, and Lucene. These engines were used for executing search strategies, and Lucene was used in correlating the search with screening results. For every question, literature search and screening were conducted according to the understanding of the question and the inclusion/exclusion criteria that provided specific characteristics of studies relevant to the question. Criteria were framed in the PICOTSS format specifying Population, Intervention, 53

54 Comparator,, Timing, Settings, and Study Design. The question and PICOTSS components were translated into a search strategy involving Boolean and conceptual queries. A Boolean query encodes both inclusion and exclusion rules. It grants access to the maximum quantity of citations, which are then analyzed by text analytics tools and ranked to produce a selection for literature screening that was conducted by two independent reviewers in the VCW s web based module. Boolean queries select citations by matching words in titles and abstracts, as well as Medical Subject Headings (MeSH) and subheadings. The number of citations resulting from Boolean queries ranged from a few hundred to several thousand depending on the question. The text analytics tools suite included: A natural language processing module for automated extraction of data elements in support of application of inclusion/exclusion criteria. Frequently extracted and utilized data elements were study size and intervention follow up period. Content Analyst for automatically expanding vocabulary of queries, conceptual retrieval, and conceptual clustering. The conceptual query engine employed in Content Analyst leverages word frequency features and co occurrence in similar contexts to index, select and rank results. The indexing utilizes the Singular Value Decomposition (SVD) algebraic method. TeraText for ranking search results and a variety of fast operations on the inverted index. Search strategy development was intertwined with the results of literature screening, which provided feedback on search quality and context. Screened literature was categorized into two subsets: relevant or not relevant to the question. Next, results were analyzed to determine the characteristics of relevant versus not relevant citations. Additional keywords and MeSH terms were used to expand or contract the scope of the query as driven by characteristics of relevant citations. If a revised search strategy produced more citations than the original strategy, the new citations resulting from the larger result set were added for literature review. The search strategy refinement/literature review cycle was repeated until all citations covered by the most recent Boolean query were screened. Each search strategy was developed and implemented in the VCW. The search strategy was reviewed by the methodologist and panel members, and was available for viewing and printing at any time by panel members and staff collaborating on the systematic review. It was available for execution and supplying literature updates until the literature search and screening cut off date. Search strategies for a sample of questions were validated by an independent methodology team. This validation process involved the methodology team developing and executing a separate search strategy and screening a random sample of citations against I/E criteria. These results were compared to the search and screening results developed by the systematic review team. Based on the validation process, the searches were considered appropriate. As an additional validation method, studies identified in systematic reviews and meta analyses were cross checked against a question s include list to ensure completeness of the search strategy. Literature Review Process Using results of the search strategy, criteria were applied to screen the literature for inclusion or exclusion in the evidence base for the question. The I/E criteria addressed the parameters in the PICOTSS framework and determined the types of studies that were eligible and appropriate to answer the question. Additional criteria such as sample size restrictions were included by the panel to fit the context of the question. 54

55 Pilot Literature Screening During Pilot Literature Screening, two reviewers independently screened the first 50 titles/abstracts in the search strategy results by applying I/E criteria. Reviewers voted to include or exclude the publication for full text review. Reviewers compared their results to ensure that I/E criteria were applied consistently. Discrepancies in votes were discussed and clarification on criteria was sought from the panel where appropriate. For example, if criteria were not specific enough to be clearly applied to include or exclude a citation, guidance was sought to define the criteria more explicitly. During this phase, reviewers provided feedback to the literature search team about the relevance of search strategy results; this feedback was used to further refine and optimize the search. Phase 1: Title and Abstract Screening Phase After completion of the Pilot Mode, two reviewers independently screened the search results at the title and abstract level by applying the I/E criteria. Reviewers voted to include or exclude the publication for full text review. Titles and abstracts that one or both reviewers voted to include advanced to Phase 2: Full Text Screening. Titles and abstracts that both reviewers voted to exclude were not reviewed further. These citations were maintained in the VCW and marked as excluded at the title/abstract phase. Phase 2: Full Text Screening Phase Titles and abstracts that at least one reviewer voted to include were reviewed at the full text level in Phase 2. In this Phase, two reviewers independently applied the I/E criteria to the full text article and voted as follows: include, exclude, or undecided. The reviewer had to specify the rationale for exclusion in this phase. Articles that both reviewers voted to include were moved to the Include List. Articles that both reviewers voted to exclude were moved to the Exclude List. These citations were maintained in the VCW and identified as excluded at the full article phase. The rationale for exclusion was noted. Any article with discrepant votes (i.e., one include and one undecided, one include and one exclude, etc.) advanced to Phase 3. Phase 3: Resolution and Consultation Phase In this phase, reviewers discussed their vote (include, exclude, or undecided) and cited the relevant criteria for their decision. The two reviewers attempted to achieve consensus through collaborative discussion. If consensus was not reached by the two reviewers, input was sought from the methodologist. If a decision was not reached after consultation with the methodologist, input was sought from the panel. However the methodologist had the final decision. The final disposition of the article (include or exclude) was recorded in the VCW along with comments from the adjudication process. All the citations that were screened for each question were maintained in the VCW, along with the votes and comments of each reviewer. Description of Methods for Assessing the Quality of Individual Studies Articles meeting the criteria after the three phase literature review process were then quality rated independently by two trained raters. Studies rated Good or Fair were included in the evidence review. 55

56 Design of the Quality Assessment Tools Appraisal of individual study quality was based on six quality assessment tools developed jointly by NHLBI and the methodology team. The development of these tools was guided by an initial review of methods and tools that have been used by others working in the field of systematic reviews and evidence based medicine, including AHRQ s Evidence Based Practice Centers, United States Preventive Services Task Force, The Cochrane Collaborative, and the National Health Service Centre for Reviews and Dissemination, adapted to meet the needs of this project. These quality assessment tools were used in the evidence reviews for the High Blood Pressure, High Blood Cholesterol, and Overweight/Obesity Panels and the Lifestyle and Risk Assessment Work Groups. These tools were designed to assist reviewers in focusing on key concepts for critical appraisal of the internal validity of a study but were not designed to generate a numeric score. The tools were specific to individual types of included study designs. Because the Panel limited its evidence review to RCTs, only the quality assessment tool for controlled intervention studies was used for the questions addressed by the Panel. This quality assessment tool is provided in Exhibit 1. The tools include items for evaluation of potential flaws in study methods or implementation, such as sources of bias (e.g., selection, performance, attrition, or detection bias), confounding, study power, and strength of causality in the association between interventions and outcomes. Quality reviewers could select yes, no, or cannot determine (CD)/not reported (NR)/not applicable (NA) in response to each item in the tool. For each item where no was checked, reviewers were instructed to consider the potential risk of bias that could be introduced by that flaw in study design or implementation. CD and NR were also noted as representing potential flaws. A detailed guidance document accompanied each of the six quality assessment tools. The guidance documents were specific to each tool and provided more detailed descriptions and examples of application of the items for evaluation of potential flaws in study methods or implementation, as well as justifications for item inclusion. For some items, examples were provided to clarify the intent of the question and the appropriate rater response. Significance of the Quality Ratings of Good, Fair, or Poor Reviewers used the study ratings on the range of items included in each tool to judge each study to be of good, fair, or poor quality. The ratings on the different items were used by the reviewers to assess the risk of bias in the study due to flaws in study design or implementation. In general terms, a good study has the least risk of bias, and results are considered to be valid. A fair study is susceptible to some bias that may be of concern, but the risk of bias is not deemed sufficient to invalidate its results. The fair quality category is likely to be broad, so studies with this rating will vary in their strengths and weaknesses. A poor rating indicates that there is a significant risk of bias. Studies rated poor were excluded from the body of evidence used by the panel to deliberate, draw conclusions, and make recommendations. The only exception allowed for this general policy of excluding poor studies was if there was no other evidence available; in such cases, poor quality studies could be considered. However, this exception did not apply to the questions addressed by the Panel because there were good and/or fair quality studies that met the I/E criteria for each question. 56

57 Training on the Use of the Quality Assessment Tools The methodology team conducted a series of training sessions on the use of the quality assessment tools. Initial training consisted of two two day, in person training sessions. Individuals trained in quality rating were Masters or PhD level staff with backgrounds in public health or the health sciences. Training sessions provided instruction on identifying correct study designs, the theory behind evidence based research and quality assessment, explanations and rationales for the items in each tool, and methods for achieving overall judgments regarding quality ratings of good, fair, or poor. Participants engaged in interactive training exercises where they evaluated multiple articles, first with the instructors and then working together in groups. Reviewers were also instructed to refer to related articles on study methods if such papers were cited in the articles being rated. Following the in person training sessions, the methodology team assigned several articles with pertinent study designs to test the abilities of each reviewer. The reviewers were asked to individually identify the correct study design, complete the appropriate quality assessment tool, and submit it to the methodology team for grading against a methodologist developed key. A second round of training sessions was then conducted via conference calls to review the results and resolve any remaining issues. Quality Assessment Process Each article that met the inclusion criteria for a question was rated for quality by two independent reviewers using the appropriate tool for the assigned article. If the ratings differed, the reviewers discussed the article in an effort to reach consensus. If consensus was not achieved, the article was forwarded to a methodologist for quality adjudication. Panel members could appeal the quality rating of a particular study or publication and make their case for why they disagreed with the initial quality rating. Any issues of concern would then be discussed on a panel call, and if other panel members agreed that the quality rating should be re assessed, the reviewers would conduct another assessment of the study or publication with input from the lead methodologist. However, all final decisions on quality ratings were made by the methodology team, not by panel members, to ensure the objectivity of the quality rating process. Quality Assessment Tool for Controlled Intervention Studies The quality assessment tool for controlled intervention studies is included below in Exhibit 1. The guidance document for the tool is also included in Exhibit 1. Because the Panel decided to limit its evidence review to RCTs, only the quality assessment tool for controlled intervention studies was used for the questions addressed by the Panel. This tool addresses 14 elements of quality assessment. They include randomization and allocation concealment, similarity of compared groups at baseline, use of intention to treat (ITT) analysis, adequacy of blinding, the overall percentage of study participants lost to follow up, the differential rates of loss to follow up between the intervention and control groups, and other factors. 57

58 EXHIBIT 1 Quality Assessment of Controlled Intervention Studies Criteria Yes No Other (CD, NR, NA)* 1. Was the study described as randomized, a randomized trial, a randomized clinical trial, or an RCT? 2. Was the method of randomization adequate (i.e., use of randomly generated assignment)? 3. Was the treatment allocation concealed (so that assignments could not be predicted)? 4. Were study participants and providers blinded to treatment group assignment? 5. Were the people assessing the outcomes blinded to the participants group assignments? 6. Were the groups similar at baseline on important characteristics that could affect outcomes (e.g., demographics, risk factors, co morbid conditions)? 7. Was the overall drop out rate from the study at endpoint 20% or lower of the number allocated to treatment? 8. Was the differential drop out rate (between treatment groups) at endpoint 15 percentage points or lower? 9. Was there high adherence to the intervention protocols for each treatment group? 10. Were other interventions avoided or similar in the groups (e.g., similar background treatments)? 11. Were outcomes assessed using valid and reliable measures, implemented consistently across all study participants? 12. Did the authors report that the sample size was sufficiently large to be able to detect a difference in the main outcome between groups with at least 80% power? 13. Were outcomes reported or subgroups analyzed prespecified (i.e., identified before analyses were conducted)? 14. Were all randomized participants analyzed in the group to which they were originally assigned, i.e., did they use an intention to treat analysis? Quality Rating (Good, Fair, Poor) (see guidance) Rater #1 initials: Additional Comments (If POOR, please state why): Rater #2 initials: *CD: cannot determine; NA: not applicable; NR: not reported Guidance for Assessing the Quality of Controlled Intervention Studies 58

59 Descriptions by question # in the controlled intervention study tool: 1. Described as randomized Literally, was the study described as randomized? A study does not satisfy quality criteria as randomized simply because the authors call it randomized. But as a first step, did the authors of the study say it was randomized? 2 3. Treatment Allocation two interrelated pieces Adequate randomization: the randomization is adequate if it occurred according to the play of chance (e.g., computer generated sequence in more recent studies, or random number table in older studies). Inadequate randomization: randomization is inadequate if there is a pre set plan (e.g., alternation where every other subject is assigned to treatment arm or another method of allocation is used such as time or day of hospital admission or clinic visit, zip code, phone number, etc.). In fact, this is not randomization at all it is another method of assignment to groups. If assignment is not by the play of chance then the answer is NO. There may be some tricky scenarios that will require careful reading and consideration for the role of chance in assignment. For example, sites are randomized to receive treatment or not so all individuals at the site are thereby assigned to a treatment group. This scenario used for group randomized trials GRTs, which can be truly randomized, but often are quasi experimental studies with comparison groups rather than true control groups. (We anticipate few if any GRTs in this evidence review.) Allocation concealment This means that one does not know in advance, or cannot guess accurately, to what group the next person eligible for randomization will be assigned. Methods include sequentially numbered opaque sealed envelopes, numbered or coded containers, central randomization by a coordinating center, and computer generated randomization that is not revealed ahead of time Blinding Blinding means that one does not know to which group intervention or control the participant is assigned. It is also sometimes called masking. You are looking to see if each of the following is blinded to knowledge of treatment assignment: the person assessing the primary outcome(s) for the study (e.g., taking the measurements, examining medical records to determine type of event as in an adjudication committee); the person receiving the intervention (e.g., patient or study participant); and the person providing the intervention (e.g., physician, nurse, pharmacist, or behavioral interventionist). Generally placebo controlled medication studies are blinded to patient, provider, and outcome assessors; behavioral or lifestyle studies may often be blinded only to the outcome assessors. Sometimes the person providing the intervention is the same person doing the outcome assessment. If so, make note of it in your comments section. 6. Similarity of groups at baseline This question relates to whether the intervention and control groups have similar characteristics on average. The whole point of doing a randomized trial is to create similar groups to enable valid comparisons of intervention effects between groups. If there is a significant difference, you should see it 59

60 when you abstract baseline characteristics. Baseline characteristics for intervention groups are usually presented in a table in the article (often Table 1). Groups can differ at baseline without raising red flags if: (1) the differences would not be expected to have any bearing on the interventions and outcomes; or (2) the differences are not statistically significant. If you have any concerns about baseline difference in the groups, write them down in the comments section and consider them in your overall determination of the study quality Drop out By drop out we mean participants for whom there are no endpoint measurements the most common reason being that they dropped out of the study (for whatever reason) and were lost to follow up. Generally, an acceptable overall dropout rate is considered 20% or less of participants who were randomized/allocated into each group, and an acceptable differential drop out is considered an absolute difference between groups of 15 percentage points at most (calculated by subtracting the drop out rate of one group minus the drop out rate of the other group). However, these are general rates, and higher overall drop out rates may be acceptable under certain circumstances. If you are conducting a systematic review on the comparative efficacy of antidepressants, then setting the cap at 20% for an overall dropout is appropriate. On the other hand, if you are looking at joint space narrowing for targeted immune modulators (TIMs), where studies comparing TIMs for this outcome are generally of longer duration and drop outs are more likely, it may be reasonable to raise the cap for defining an acceptable overall dropout rate. This type of decision should be made with input from the content experts and decided before conducting your systematic review. The same flexibility does not apply to the differential drop out rate, which should be capped at 15%. If you have a differential drop out rate of 15% or higher between study arms, there is a high risk of bias, which constitutes a fatal flaw resulting in a Poor quality rating for the study. 9. Adherence Did participants in each treatment group adhere to the protocols for assigned interventions? For example, if Group 1 was assigned to 10 mg/day of Drug A, did most of them take 10 mg/day of drug A? Another example is a study evaluating the difference between a 30 lb weight loss and a 10 lb weight loss on specific clinical outcomes (for example, heart attacks), but the 30 lb weight loss group did not achieve its intended weight loss target. A third example is whether a large percentage of participants assigned to one group crossed over and received the intervention provided to the other group. A final example is when one group that was assigned to receive a particular drug at a particular dose had a large percentage of participants who didn t end up taking the drug or the dose as designed in the protocol. 10. Avoid other interventions Changes that occur in the study outcomes being assessed should be attributable to the interventions being compared in the study. If participants in any of the groups receive other interventions that are not part of the study protocol and that could affect the outcomes being assessed, and they receive these interventions differentially, there is cause for concern, as it could bias the results. For example, if you had a study comparing two different dietary interventions on serum cholesterol, but one of the groups had a significantly higher percentage of participants taking statin drugs, it could unduly influence the results of the study because you wouldn t know whether the difference in outcome was due to the dietary intervention or the drugs. 60

61 11. Outcome measures assessment What tools or methods were used to measure outcomes in the study? Were the tools/methods accurate and reliable for example, have they been validated, or are they objective? This is important as it indicates the confidence you can have in the reported outcomes. Perhaps even more important is whether the outcomes were assessed in the same manner within groups and between groups. One example is that a self report of dietary salt intake is not as valid and reliable as testing urine for sodium content. Another example is measurement of blood pressure that just uses clinicians usual measurement approaches rather than measurers being trained on a standard approach using the same instrument and taking BP multiple times. In each of these cases, the question would get a NO for the former and a YES for the latter scenario. Another example of a NO is when an intervention group is seen much more often, enabling more opportunities to report clinical events, than the control group. 12. Power calculation Generally, a paragraph in the methods section of the study will explain sample size needed to detect differences in primary outcomes. The current standard is at least 80% power to detect a clinicallyrelevant difference in an outcome using a two sided alpha of Often, however, older studies will not report anything about power. 13. Prespecified outcomes reported in the study must have been prespecified in order to be hypothesis testing which is the whole purpose of doing a RCT. If they are not prespecified, then the study may be reporting ad hoc analyses, simply looking for differences that support the findings they wanted. In addition to outcomes, the subgroups being examined should be prespecified in order to be considered hypothesis testing. Most RCTs conduct numerous post hoc analyses as a way of exploring findings and generating additional hypotheses. The intent of this question is to give more weight to reports that are not simply exploratory in nature. 14. Intention to treat (ITT) analysis Intention to treat means everybody who was randomized is analyzed according to the original group to which they are assigned. This is an extremely important concept, because doing an ITT analysis preserves the whole reason for doing a randomized trial that is to compare groups that differ only in the intervention being tested. Once the ITT philosophy is not followed, you are not really sure that the main reason for doing an RCT is upheld as the groups being compared may no longer be the same. If a study does not use an ITT analysis, it should probably be rated as poor. However, if some other analysis is used and you think it is valid, explain in the other box of the quality review form. Some studies will use a completers analysis (analyzes only the participants that completed the intervention and the study), which introduces significant potential for bias. Characteristics of participants who do not complete the study are unlikely to be the same as those who do. The likely impact of participants who withdraw from the study treatment must be considered carefully. ITT analysis provides a more conservative (potentially less biased) estimate of effectiveness. Some general guidance for determining the overall quality rating The questions on the form are designed to help you to focus on the key concepts for evaluating the internal validity of a study. They are not intended to create a list that you simply tally up to arrive at a summary judgment of quality. 61

62 Internal validity is the extent to which the results (effects) reported in a study can truly be attributed to the intervention being evaluated and not to flaws in the design or conduct of the study in other words the ability for the study to draw causal conclusions about the effects of the intervention being tested. Any such flaws can increase the risk of bias. Critical appraisal involves considering the risk of potential for allocation bias, measurement bias, or confounding (the mixture of exposures that one cannot tease out from each other examples of confounding include co interventions, differences at baseline in patient characteristics, and other issues throughout the questions above). High potential for risk of bias translates to a rating of poor quality. Low potential for risk of bias translates to a rating of good quality. (Again, the greater the risk of bias, the lower the quality rating of the study.) Fatal flaws: if a study has a fatal flaw then risk of bias is significant and the study is of poor quality. Examples of fatal flaws in RCTs include high drop out, high differential drop out, no ITT analysis or/unsuitable statistical analysis (e.g., completers only analysis). Generally, when you evaluate a study you will not see a fatal flaw, but you will find some risk of bias. By focusing on the concepts underlying the questions in the tool, you should ask yourself about the potential for bias in the study you are critically appraising. For any box where you check no you should ask what the potential for bias is as a result. That is, does this factor cause you to doubt the results that are reported in the study? We can provide some background reading for you on critical appraisal. But the best approach is for you to think about the questions in the tool and how each tells you something about the potential for bias for any study. We are reluctant to give you general rules as each study has nuances that are a little bit different. The more you familiarize yourself with the key concepts, the more comfortable you will be with critical appraisal. We will provide you some examples of studies that fall into each of the categories: good/fair/poor. But again, these will be examples. Each study must be assessed on its own given the details that are reported. Data Abstraction and Review Process Articles rated good or fair during the quality rating process were abstracted into the VCW using a webbased data entry form. Requirements for abstraction were specified in an Evidence Table template that was developed by the methodologist for each question. The Evidence Table template included data elements relevant to the question such as study characteristics, interventions, population demographics, and outcomes. The abstractor carefully read the article and entered the required information into the web based tool. Once abstraction was complete, an independent quality control review was conducted. During this review, data were checked for accuracy, completeness, and the use of standard formatting. Development of Evidence Tables, Summary Tables, and Exhibits Evidence Tables For each question, methodologists worked with the Panel to identify the key data elements needed to answer the question. Using the PICOTSS criteria as the foundation, Panel members determined what information was needed from each study to be able to understand the design, sample and baseline characteristics in order to interpret the outcomes of interest. A template for a standard evidence table was created and then populated with data from several example studies for review by the Panel to ensure 62

63 that all of the appropriate study characteristics were being considered. Once a final template was agreed upon, evidence tables were generated by pulling the appropriate data elements from the master abstraction database for those studies that met the inclusion criteria for the question. Only studies rated Good and Fair were included in the Evidence Tables. The templates for the Panel s questions included the following data elements: Study Characteristics: author, year, study name, country and setting, funding, study design, research objective, year study began, overall study N, quality rating Criteria for Study Inclusion/Exclusion and Endpoints: inclusion/exclusion criteria for the study, primary outcome, secondary outcome, composite outcome definitions Study Design Details: treatment groups, description of interventions, duration of treatment, duration of follow up, run in, wash out, sample size Baseline Population Characteristics: age, sex, race/ethnicity, mean blood pressure, coronary heart disease, cerebrovascular disease, heart failure, diabetes, chronic kidney disease, peripheral artery disease, smoking status, previous antihypertensive therapy, history of MI, history of stroke, mean heart rate, mean GFR, mean serum creatinine, mean creatinine clearance Results: outcomes of interest as prespecified in the criteria for the question, adverse events, attrition, adherence Studies were listed in alphabetical order by study name (if none, the first author s last name). For secondary articles related to a primary article for a study (i.e., a prespecified subgroup analysis published in a separate paper), entries were made in chronological order after the primary article. Summary Tables To enable a more targeted focus on the specific aspects of a question, methodologists developed summary tables, or abbreviated evidence tables, in concert with the Panel. A summary table presents a smaller set of data elements than the Evidence Tables and might be designed to address the general population or a specific subpopulation, such as patients with diabetes. Templates generally provided the following information: Study Characteristics: study name, author/year, design, overall study numbers, quality rating Sample Characteristics: relevant inclusion criteria Study Design Details: intervention doses and duration Results: outcomes, attrition, adherence The ordering of studies in the Summary Tables was determined by the question addressed by the Table. For Question 1, studies were listed by ascending blood pressure treatment initiation threshold; separate Summary Tables were created for systolic, diastolic, and mixed systolic/diastolic treatment initiation thresholds. For Question 2, studies were listed by ascending blood pressure treatment goal; separate Summary Tables were created for systolic, diastolic, and mixed systolic/diastolic treatment goals. For Question 3, studies were listed in alphabetical order of the intervention drug, and by ascending dose order within drugs; separate Summary Tables were created for each drug class. Exhibits The Panel used an even more concise view of the eligible evidence to summarize evidence and develop evidence statements. These materials were called exhibits. In exhibits, each outcome was given a color 63

64 coded symbol that was designed to enable panel members to quickly compare and summarize outcomes across trials in a one to two page view. A sample exhibit used for Question 1 is provided in Exhibit 2 below. An outcome was given a circle symbol if it was the primary outcome of the study; a triangle was used if the outcome was secondary or not specified. The symbol was green if the p value between the intervention and comparison group was <0.05; yellow if the p value was p 0.05 and 0.10; clear if the p value was >0.10; and blue if the p value was not reported. 64

65 EXHIBIT 2: SAMPLE OF EVIDENCE EXHIBIT 65