Letters

unwell. However, a different set of financial rules results in my hospital not getting paid if the patient has no acute need for the hospital day. Although great emphasis is placed on being patient centered, we need better alignment between payments and our patients’ values and needs. Mitchell H. Katz, MD

Karen L. Margolis, MD, MPH Joshua I. Barzilay, MD Ann V. Schwartz, PhD Author Affiliations: HealthPartners Institute for Education and Research, Minneapolis, Minnesota (Margolis); Kaiser Permanente of Georgia, Atlanta, Georgia (Barzilay); University of California, San Francisco (Schwartz). Corresponding Author: Karen Margolis, MD, MPH, 8170 33rd Ave S, MS21111R, Minneapolis, MN 55425 ([email protected]).

Conflict of Interest Disclosures: None reported. 1. Howard-Anderson J, Lonowski S, Vangala S, Tseng C-h, Busuttil A, Afsar-manesh N. Readmissions in the era of patient engagement [published online September 29, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed .2014.4782.

Conflict of Interest Disclosures: None reported. 1. Tinetti ME, Han L, Lee DS, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med. 2014;174(4):588-595. 2. Peters R, Beckett N, Burch L, et al. The effect of treatment based on a diuretic (indapamide) +/- ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Age Ageing. 2010;39(5):609-616.

COMMENT & RESPONSE

Risks and Benefits of Antihypertensive Medications in Older Adults To the Editor The recent observational study by Tinetti et al1 reported that treatment with antihypertensive medications is associated with an increased risk of serious fall injuries among community-living older adults with a mean age of 80 years. One reason for this study was to examine a population that may be less healthy than those enrolled in clinical trials and who may have had a higher risk of serious injuries from falls. Approximately 9% of the cohort experienced a serious injury over the follow-up period, most of which were fractures. Although the mean follow-up time is not stated, the annual rate of fractures appears to have been approximately 1.5% to 2.0%. In the Hypertension in the Very Elderly Trial (HYVET), among 3845 participants (mean age, 83 years) followed up for 2.1 years, the annual fracture rate was roughly similar at approximately 1.3%.2 In HYVET, the risk of fractures was not higher in the group randomized to receive antihypertensive treatment (42 fractures) compared with the group randomized to receive placebo (60 fractures [hazard ratio, 0.69; 95% CI, 0.46-1.05; P = .086). In contrast to the null findings for fractures, the trial was stopped early because of a significant reduction in stroke, total mortality, and other serious cardiovascular events in the actively treated group.3 The number of cardiovascular events (n = 331) was more than triple the number of fractures (n = 102). Likewise, the Systolic Hypertension in the Elderly Trial, which compared the thiazide-like diuretic chlorthalidone vs placebo, found a reduction in the risk of stroke and other serious cardiovascular events in the actively treated group, but no difference in falls and fractures.4,5 We agree with Tinetti et al1 that it is critical to determine the overall balance of risks and benefits of antihypertensive treatment in representative populations of elderly patients. However, randomized trials in elderly patients have demonstrated net benefit with reductions in stroke and other cardiovascular events that are not accompanied by increased fractures or falls. The present evidence of harms is observational and more equivocal. More high-quality evidence regarding the net effects of treatment is needed to inform guidelines and clinical decision making.

3. Beckett NS, Peters R, Fletcher AE, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18): 1887-1898. 4. Curb J, Applegate W, Vogt T, et al; Systolic Hypertension in the Elderly Program Cooperative Group. Antihypertensive therapy and falls and fractures in the systolic hypertension in the elderly program. J Am Geriatr Soc. 1993;41(10) (suppl):SA15. 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 (24):3255-3264.

In Reply We appreciate the opportunity to respond to the comments by Margolis et al regarding our article.1 The low rates of serious injuries such as fractures observed in several randomized clinical trials (RCTs) of older adults all included samples that are healthier than average clinical populations of older adults. The authors correctly note that the purpose of our study was to determine the risk of experiencing serious fall injuries among representative samples of older adults. The estimate for the annual fall injury rate or incidence proportion in our sample is 4.3%, based on the total number of participants experiencing at least 1 event (446) and the mean time to first serious fall injury (772 days), not 1.5% to 2.0% as the reviewers suggested. Therefore, our annual serious fall injury rate is 3.3 times higher than the 1.3% annual rate observed in the Hypertension in the Very Elderly Trial (HYVET) population.2 The rate would be higher if we accounted for recurrent serious fall injuries (446 participants experienced 540 serious injury events). In a second observational study of this nationally representative cohort of older adults, after adjusting for propensity score and other covariates, neither moderate (adjusted hazard ratio, 1.08 [95% CI, 0.89-1.32]) nor high (1.16 [95% CI, 0.94-1.43]), antihypertensive intensity was associated with experiencing cardiovascular events.3 During the follow-up of up to 3 years, 407 of 4961 participants (8.2%) had coronary events, while 270 participants (5.4%) experienced strokes, comparable to the rates of serious fall injury. The hazard ratio for death was 0.79 (95% CI, 0.65-0.97) in the moderate-intensity group and 0.72 (95% CI, 0.58-0.91) in the high-intensity group compared with those receiving no antihypertensives, suggesting a survival benefit. The relationship between antihypertensive medications and relevant clinical outcomes is complicated in older adults who have more chronic conditions and are at risk for more com-

jamainternalmedicine.com

JAMA Internal Medicine November 2014 Volume 174, Number 11

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a Tulane University User on 05/18/2015

1873

Letters

peting outcomes than the healthy RCT populations. As we noted in our article,1 no single observational study can be considered definitive, and we cannot exclude unmeasured confounding. Neither can we, however, continue to assume that the treatment benefits and harms seen in RCTs of healthy populations generalize to less healthy clinical populations. The inappropriateness of this extrapolation is increasingly apparent.4 In our article,1 we highlighted the need for RCTs in representative samples of older adults, preferably with risk stratification to detect net benefits and harms in relevant subgroups. Alternatively, real-time clinical registries may shed further light on harms and benefits in key subgroups. The adverse effects of serious fall injuries such as fractures and head injuries on survival and function are comparable to cardiovascular events. The onus, therefore, is on those recommending treatment to show evidence of benefit and lack of harm in the populations for whom they recommend treatment. This is particularly true because, as Fried et al5 found, older persons’ willingness to take medication for prevention of cardiovascular disease is less related to potential benefits than to potential adverse effects. Mary E. Tinetti, MD Ling Han, MD, PhD Gail J. McAvay, PhD Author Affiliations: Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut. Corresponding Author: Mary E. Tinetti, MD, Yale School of Medicine, Internal Medicine, 333 Cedar St, PO Box 208025, New Haven, CT, 06520-8025 (mary [email protected]). Conflict of Interest Disclosures: None reported. 1. Tinetti ME, Han L, Lee DS, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med. 2014;174(4):588-595. 2. Peters R, Beckett N, Burch L, et al. The effect of treatment based on a diuretic (indapamide) +/- ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Age Ageing. 2010;39(5):609-616. 3. Tinetti ME, Han L, McAvay GJ, et al. Anti-hypertensive medications and cardiovascular events in older adults with multiple chronic conditions. PLoS One. 2014;9(3):e90733. doi:10.1371/journal.pone.0090733. 4. O’Hare AM, Hotchkiss JR, Kurella Tamura M, et al. Interpreting treatment effects from clinical trials in the context of real-world risk information: end-stage renal disease prevention in older adults. JAMA Intern Med. 2014;174 (3):391-397. 5. Fried TR, Tinetti ME, Towle V, O’Leary JR, Iannone L. Effects of benefits and harms on older persons’ willingness to take medication for primary cardiovascular prevention. Arch Intern Med. 2011;171(10):923-928.

New EMA Policy—Further Measures Needed to Support Comparative Effectiveness Assessments To the Editor We agree with Dr Steinbrook1(p373) that implementation of the new policy of the European Medicines Agency (EMA) on the proactive release of clinical trial data means that “a new era of clinical trial data as a public good will begin.” However, the policy has a major flaw: it will not apply to drugs approved before the effective date.2 A previous transparency initiative, the Food and Drug Administration Amendments Act of 2007, also has the same problem.3 Thus, despite the recent EMA initiative, although comprehensive information will be available on newer drugs in the future, published informa1874

tion on established drugs (ie, approved before the effective date of the policy) will still remain biased, even though they will account for the lion’s share of drugs prescribed in clinical practice for years to come. This imbalance will hamper a meaningful comparison of established and newer drugs and therefore devaluate comparative effectiveness research (especially when indirect comparisons are required). In addition, open questions on established drugs will never be answered. This is particularly relevant for drugs with a large public health impact such as Tamiflu (oseltamivir phosphate; Genentech): it took independent researchers several years to obtain all of the relevant clinical trial data. With the technical possibilities regulatory agencies offer, it would be easy to fill the existing evidence gap and post clinical study reports of all established drugs (or drugs that were never approved) in a central repository. Pharmaceutical companies could also release further reports never submitted to regulatory agencies, thus underlining their commitment to transparency. Unfortunately, EMA’s move towards transparency is again open for discussion. After public consultation on a promising draft policy in 2013,1 in May 2014, EMA—in a step widely criticized as a U-turn—suggested a revised version of the policy, which restricted access to clinical study reports to a view-onscreen-only mode, allowed for redaction of study methods and results, and included restrictive terms of use.4,5 Even after EMA withdrew some of the restrictions on data access, the Agency’s management board was unable to reach a resolution. Further debate and possible adoption of the policy are now planned for October 2014. The initiative by EMA could represent a major breakthrough for transparency in clinical research. However, even after implementation, in many cases independent researchers will still have insufficient information to produce a complete and unbiased comparative effectiveness assessment of a drug. In the interest of patient care, we should make sure we do not give up our pursuit of transparency before reaching the goal line. Beate Wieseler, PhD Natalie McGauran Thomas Kaiser, MD Author Affiliations: Institute for Quality and Efficiency in Health Care, Cologne, Germany. Corresponding Author: Beate Wieseler, PhD, Head of Drug Assessment Department, Institute for Quality and Efficiency in Health Care, Im Mediapark 8, 50670 Cologne, Germany ([email protected]) Conflict of Interest Disclosures: All authors are employees of Institute for Quality and Efficiency in Health Care. In order to produce unbiased health technology assessment reports, the institute depends on access to all of the relevant data on the topic under investigation. The authors therefore support public access to clinical study reports submitted to regulatory authorities. 1. Steinbrook R. The European Medicines Agency and the brave new world of access to clinical trial data. JAMA Intern Med. 2013;173(5):373-374. 2. European Medicines Agency. Draft Policy 70: publication and access to clinical-trial data. 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages %2Fincludes%2Fdocument%2Fdocument_detail.jsp%3FwebContentId %3DWC500144730&mid=WC0b01ac058009a3dc. Accessed September 22, 2014.

JAMA Internal Medicine November 2014 Volume 174, Number 11

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a Tulane University User on 05/18/2015

jamainternalmedicine.com

Risks and benefits of antihypertensive medications in older adults.

Risks and benefits of antihypertensive medications in older adults. - PDF Download Free
64KB Sizes 2 Downloads 8 Views