Pharmacologic Treatment of Hypertension in Adults | Annals …

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Dr. Doreen M. Rabi, Dr. Stella S. Daskalopoulou, Dr Alexander A. Leung, Dr. George Dresser, Dr. Raj Padwal, Dr. Nadia Khan

Hypertension Canada

January 24, 2017

Hypertension Canada's Response to ACP/AAFP Guidelines

As contributors to Hypertension Canadas clinical practice guidelines, we have concerns about the American College of Physicians and the American Association of Family Physicians (ACP/AAFP) new recommendations on hypertension management in persons over 60-years (1).

The ACP/AAFP recommendations were based on a systematic review by Weiss et al. evaluating the impact of more vs. less intensive SBP-lowering on cardiovascular outcomes in adults over 60-years (2). While the study was well done, there were notable limitations. Namely that data were pooled by strategy (i.e., intensive vs. less intensive) rather than specific targets, blood pressure measurement methods were inconsistent across included studies, and the analytic approach to important sub-populations was inconsistent (diabetes and non-diabetes trials were pooled while stroke trials were analyzed separately). Furthermore, the Action to Control Cardiovascular Disease in Diabetes (3) trial was pooled despite evidence of an interaction effect of SBP treatment and glycemic control. Notwithstanding these limitations, Weiss et al. demonstrated a significant reduction in stroke with more intensive SBP-lowering (relative risk=0.79, 95% confidence interval=0.59-0.99). The point estimates for all-cause mortality and cardiac events favored intensive SBP-lowering but the confidence intervals were wide.

A larger review (n=42,000 individuals) demonstrated unambiguous benefit with intensive BP-lowering strategies on cardiovascular outcomes among older (62-years) individuals (4). Another meta-analysis of 123 hypertension trials noted a linear relationship between SBP-lowering and cardiovascular risk reduction, with every 10mmHg SBP reduction being associated with a decrease in cardiovascular events, stroke, and all-cause mortality by 20% 27%, and 13%, respectively (5). These meta-analyses suggest that lower SBP is associated with incrementally greater benefit, regardless of age. And among the elderly, the Systolic Blood Pressure Intervention Trial (SPRINT) indicates that intensive systolic blood pressure (SBP)-lowering (<120 mmHg, measured by automated method) leads to significant reductions in cardiovascular outcomes when compared to standard SBP-lowering (<140 mmHg), especially in the elderly (6), thus providing high-quality evidence for a specific target in older adults.

Safety concerns in older patients are understandable. While institutionalized elderly and those with severe orthostasis were excluded, SPRINT supports lower SBP targets even in frail individuals (6). While serious adverse-events were overall higher in the elderly SPRINT sub-population, the adverse-event rate did not differ by treatment assignment (intensive: 48.4%; standard: 48.3%) (6). Importantly, no significant increase in falls, fractures or adverse renal outcomes with intensive vs. less intensive strategy was noted in the Weiss et al. review.

Compelling evidence supports lower SBP targets in older patients. Intensive treatment guided by accurate blood pressure measurement will produce greater outcome reductions in older compared to younger patients. We commend the ACP/AAFP for encouraging meaningful communication with patients and the promotion of patient-centered treatment goals, but the best available evidence should also inform decisions.

Sincerely,

Dr. Doreen M. Rabi, Hypertension Canada Guidelines Task Force Chair

Dr. Stella S. Daskalopoulou, Hypertension Canada Central Review Committee Chair

Dr. Alexander A. Leung, Hypertension Canada Guidelines Task Force

Dr. George Dresser, Hypertension Canada Guidelines Task Force

Dr. Raj Padwal, Hypertension Canada Board Member

Dr. Nadia Khan, Hypertension Canada President

References1)Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA; for the Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians. Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians. Annals of Internal Medicine, 2017 January 17.2)Weiss J, MD, Freeman M, Low A, Fu R, Kerfoot A, Paynter R, et al. Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older: A Systematic Review and Meta-analysis. Annals of Internal Medicine, 2017 Jan 17.3)ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-85.4)Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435-43.5)Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387:957-67.6)Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al; SPRINT Research Group. Intensive vs. Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged 75 Years: A Randomized Clinical Trial. JAMA. 2016;315:2673-82..

William C. Cushman, MD, Karen C. Johnson, MD, MPH, William B. Applegate, MD, MPH, Jeffrey A. Cutler, MD, MPH

Memphis Veterans Affairs Medical Center, University of Tennessee Health Science Center, Wake Forest University, National Heart, Lung and Blood Institute, National Institutes of Health

February 15, 2017

Conflict of Interest: All authors are investigators in the Systolic Blood Pressure Intervention Trial (SPRINT); Dr. Cushman is an uncompensated consultant for Takeda and has an institutional grant with Eli Lilly. The content is solely the responsibility of the authors and does not necessarily represent the official views of the SPRINT Research Group, NIH, the U.S. Department of Veterans Affairs, or the United States Government.

Systolic blood goals pressure in older adults with hypertension

We read with interest the ACP-AAFP hypertension guidelines.(1) While we agree there is very strong evidence to support a systolic blood pressure goal <150 mm Hg in older hypertensive adults, we believe the guideline committee underestimated the strength of evidence for <120 mm Hg, based on the Systolic Blood pressure Intervention Trial (SPRINT), which demonstrated a highly significant reduction in mortality (-27%) and cardiovascular events (-25%).(2) In the accompanying meta-analysis,(3) for the group of trials with baseline blood pressure <160 mm Hg, both mortality and cardiac events were significantly reduced. However, the inclusion of trials in this meta-analysis that were clearly underpowered for major cardiovascular or mortality outcomes is questionable. In the supplement of the meta-analysis, for those trials that achieved a systolic blood pressure <140 mm Hg, total mortality, stroke, and cardiovascular events are all significantly reduced. We believe a meta-analysis including adequately powered trials that tested a systolic blood pressure goal <120-130 mm Hg would also demonstrate significant benefit.

Therefore, the guidelines failure to recommend a systolic blood pressure goal <120-130 mm Hg was apparently because there was only one definitive trial (SPRINT). (2) We believe one high quality large trial should be sufficient to inform guideline recommendations. For example, when the Veterans Administration Cooperative Hypertension Study demonstrated benefit for treating diastolic blood pressure 90 mm Hg in 1970,(4) guideline committees recommended treatment of diastolic hypertension and clinical practice changed. Similarly, after the Systolic Hypertension in the Elderly Program (SHEP) trial was reported in 1991,(5) it was considered by most as definitive and guidelines then recommended treating systolic blood pressure. Although subsequent trials addressed similar questions, they were often considered by many as unethical to conduct, since benefit had already been proven for the control groups. Therefore, the desire for guideline committees to have multiple trials showing the same thing for a strong recommendation is questionable and does not follow previous hypertension guideline development procedures. One could also question the ethical stance of not treating populations similar to SPRINT to a systolic BP <120 mm Hg.

We would urge clinicians to consider treating older hypertensive patients at higher risk for cardiovascular disease, at least those similar to the SPRINT trial participants, to a lower level of systolic blood pressure than is recommended by the ACP-AAFP hypertension guidelines, and we would recommend guidelines now reflect the strength of evidence from SPRINT.

References:1.Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA; Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians. Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017 Jan 17. doi: 10.7326/M16-1785. [Epub ahead of print]2.Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-16. doi:10.1056/NEJMoa15119393.Weiss J, Freeman M, Low A, Fu R, Kerfoot A, Paynter R, et al. Benefits and harms of intensive blood pressure treatment in adults aged 60 years or older. A systematic review and meta-analysis. Ann Intern Med. 2017. [Epub ahead of print]. doi:10.7326/M16-17544.Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;17;213:1143-52.5.SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-64.

Devan Kansagara, MD, MCR, Timothy J. Wilt, MD, MPH, Jennifer Frost, MD, Amir Qaseem, MD, PhD

ACP

March 8, 2017

Author's Response

IN RESPONSE: We thank Drs. Rabi and colleagues for their comments and careful review of the guideline and accompanying systematic review. ACP and AAFP Clinical Guidelines are based on best available evidence (1) and meet the GIN/IOM Standards for Guidelines (2, 3). We wholeheartedly agree that there are important differences among the studies addressing hypertension treatment goals. Drs. Rabi and colleagues point out that blood pressure measurement techniques are one source of clinical heterogeneity amongst the studies, but there are many other dramatic differences among the studies which also need to be considered.

We have read in detail the two meta-analyses mentioned (4, 5), both of which are acknowledged and discussed in our evidence review (1). There are important differences between these meta-analyses and our evidence review, and there are trade-offs in any meta-analytic approach. Very large meta-analyses have the power to reveal important findings, but can also obscure differences across studies and hamper application of the evidence to clinical practice. For example, the vast majority of studies suggesting benefit from antihypertensive treatment in patients with baseline blood pressure < 140 mmHg in the Ettehad review included patients with heart failure or acute myocardial infarction. The benefit of antihypertensive medications in these patients is not in dispute and is not necessarily derived from lowering blood pressure. Since the clinical questions addressed by the evidence review and the ACP/AAFP guideline (1, 6) centered on blood pressure treatment targets rather than clinical management of distinct clinical conditions (such as acute myocardial infarction or congestive heart failure), we excluded studies of these patient populations. We disagree with Drs. Rabi and colleagues that the data support a broad-based systolic treatment target of < 130 mmHg.

We agree that a lower blood pressure target may be appropriate for older patients at high cardiovascular risk. The evidence in support of a lower treatment target largely comes from the SPRINT trial (7), though results have not been consistent across studies. As the review and guideline report, there are several potential reasons for the inconsistencies. A weak recommendation in support of a lower treatment target in specific patient populations is not a recommendation against more aggressive treatment in these populations. Rather, a weak recommendation emphasizes the need for individual decision making and accounting for the magnitude of benefits, harms, and treatment burden; it may still support more aggressive treatment in some patients.

Devan Kansagara, MD, MCRPortland Evidence-based Synthesis Program and Portland VA Medical Center

Timothy J. Wilt, MD, MPHMinneapolis VA Center for Chronic Disease Outcomes Research and University of Minnesota School of MedicineJennifer Frost, MDAmerican Academy of Family Physicians; Leawood, Kansas

Amir Qaseem, MD, PhDAmerican College of Physicians; Philadelphia, Pennsylvania

References

1.Weiss J, Freeman M, Low A, et al. Benefits and harms of intensive blood pressure treatment in adults aged 60 years or older: A systematic review and meta-analysis. Annals of Internal Medicine. 2017.2.Qaseem A, Forland F, Macbeth F, et al. Guidelines international network: Toward international standards for clinical practice guidelines. Annals of Internal Medicine. 2012;156(7):525-31.3.Institute of MedicineClinical Practice Guidelines We Can Trust.Washington, DC. National Academies Pr 2011.4.Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. The Lancet;387(10022):957-67.5.Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. The Lancet;387(10017):435-43.6.Qaseem A, Wilt TJ, Rich R, et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: A clinical practice guideline from the american college of physicians and the american academy of family physicians. Annals of Internal Medicine. 2017.7.Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years: A randomized clinical trial. JAMA. 2016.

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