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GUEST EDITORIAL |
Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri.
Address correspondence to Michael W. Rich, MD, Cardiovascular Division, Washington University, 660 S. Euclid Ave., Box 8086, St. Louis, MO 63110. E-mail: mrich{at}im.wustl.edu
HEART failure is the quintessential disorder of cardiovascular aging, reflecting the convergence of age-associated reductions in cardiovascular reserve and the increasing prevalence of hypertension and coronary heart disease, the two leading causes of heart failure in industrialized nations (1). In the United States, heart failure is the leading cause of hospitalization in older adults, and over 50% of all heart failure admissions occur in persons aged 75 years or older (2). As a result, heart failure is the most costly medical illness in the Medicare age group by a factor of almost two, and Medicare expenditures for heart failure exceed those for acute myocardial infarction and all cancers—combined (3). In addition, despite widely publicized declines in mortality rates from coronary heart disease and stroke, hospitalization rates for heart failure have increased by more than 2.5-fold over the past 20 years (4,5), and it is projected that population aging will result in a further doubling of the number of persons with heart failure by 2030 (1).
These observations and statistics, coupled with the fact that elderly heart failure patients comprise a markedly heterogeneous population (6), lend credence to the view that heart failure—like falls, incontinence, frailty, and other age-associated conditions—represents a true geriatric syndrome (7). Moreover, heart failure in very elderly people differs in many important respects from heart failure occurring during middle age (Table 1), and it should not be assumed that management strategies and drug therapies proven to be efficacious in middle-aged patients will necessarily confer equivalent benefits in elderly persons. Unfortunately, most of the major heart failure trials have enrolled predominantly middle-aged men with systolic heart failure (i.e., heart failure with reduced left ventricular ejection fraction); older patients, women, racial and ethnic minority groups, and patients with diastolic heart failure (heart failure with preserved left ventricular systolic function) have been markedly underrepresented in these trials (8). Indeed, a recent analysis found that only approximately 18% of older heart failure patients in the community would have met criteria for the major angiotensin-converting enzyme (ACE) inhibitor trials—even if older age were eliminated as an exclusion criterion (9). As a result, the generalizability of the findings of the heart failure trials to patients 75 years of age or older, especially women and those with diastolic heart failure, remains uncertain, and several studies have attempted to provide insight into this important issue.
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Recognizing the limitations of randomized trials with respect to their applicability to very elderly persons, several observational studies have examined the impact of ACE inhibitors on clinical outcomes in elderly heart failure patients. In one study, Ahmed and colleagues analyzed data on 1090 Alabama Medicare beneficiaries discharged from the hospital with a diagnosis of heart failure (11). The mean age of the study population was 79 ± 7.5 years, 60% were women, 18% were black, 25% had diabetes, and 9% were admitted from a nursing home. Overall, 48% of patients were discharged on an ACE inhibitor. During a 3-year follow-up period, patients treated with an ACE inhibitor experienced a significant 23% reduction in mortality compared with patients not taking an ACE inhibitor, and this difference persisted after adjusting for clinical and therapeutic differences between groups.
In another study, Johnson and colleagues reviewed data on 11,854 patients aged 65 years or older discharged with a diagnosis of heart failure from hospitals in Alberta, Canada during the period 1994–2000 (12). The mean age was 79 years and 53% were women. Overall, 43% of patients were discharged on an ACE inhibitor or angiotensin receptor blocker (ARB). Compared with patients not receiving these drugs, 1-year mortality was 26% lower in patients treated with an ACE inhibitor or ARB.
In the current issue of the Journal, Pedone and colleagues provide additional evidence in support of the effectiveness of ACE inhibitors in elderly heart failure patients (13). In this study, the authors collected prospective data on 818 heart failure patients aged 65 years or older discharged from the hospital in 1998 and followed for 1 year. The mean age of the study population was 79 years, 24% were aged 85 years or older, 50% were women, one third were cognitively impaired, one sixth were incontinent, and more than 50% were receiving 6 or more medications prior to the index hospitalization. In addition, approximately one fourth of patients had a Cumulative Illness Rating Scale (CIRS) score of 14 or higher, reflecting a high level of comorbidity. At discharge, 67% of patients were prescribed ACE inhibitors, with older age and physical disability being associated with a lower likelihood of ACE inhibitor use. However, even after adjusting for these and other baseline differences, ACE inhibitor prescription at discharge was associated with a 44% lower 1-year mortality than nontreatment with an ACE inhibitor. Moreover, the benefit of ACE inhibitors extended not only to patients aged 75–85 years (45% mortality reduction), but also to those aged 85 years or older (49% reduction).
The principal virtue of the studies by Ahmed, Johnson, and Pedone is that they are population based, thereby reflecting "real world" clinical practice (11–13). Taken together, these three studies provide strong support for routine prescription of ACE inhibitors in heart failure patients of all ages, as currently recommended by both the American College of Cardiology/American Heart Association and the European Society of Cardiology practice guidelines for management of chronic heart failure (14,15). At the same time, it is important to recognize that these studies are not without significant limitations. In particular, the fact that ACE inhibitors were not prescribed randomly implies that selection bias may have contributed to the apparent beneficial effects of ACE inhibitor therapy; i.e., patients prescribed these drugs may have had a more favorable prognosis to start with (e.g., younger age and less physical disability, as in the study reported by Pedone and colleagues), or patients most likely to benefit from these drugs may have been preferentially selected for treatment (confounding by indication). One approach to minimizing these effects is propensity analysis, a statistical methodology that attempts to simulate randomization in observational studies (16). Unfortunately, none of the studies cited above incorporated propensity analysis into the study design.
How should the current body of evidence be interpreted, and what are the practical implications for the use of ACE inhibitors in very elderly people? The skeptic might argue that, at the present time, there is no compelling evidence from randomized clinical trials that ACE inhibitors are beneficial in patients aged older than 75 years, and that, indeed, the systematic review cited above suggests that the benefit of these agents is, at best, modest and substantially less than in younger patients (10). It should be noted, however, that, in the analysis by Flather and colleagues, there was no significant interaction between age and treatment effect (p = 0.47), indicating that the effects in patients aged older than 75 years were statistically similar to those in younger patients (10). In contrast, several large population-based studies that have included a substantial number of very old patients provide firm and convincing support for the use of ACE inhibitors in elderly heart failure patients, including those aged older than 85 years (11–13). In addition, although older age is often used as a rationale for prescribing lower dosages of ACE inhibitors, there is good evidence that dosages approximating those used in the clinical trials are associated with better outcomes than lower doses, even in elderly patients (17). Therefore, based on the available evidence, my response to the question "Are ACE inhibitors indicated for the routine treatment of elderly heart failure patients," is, to put it mildly, "you bet your booties, granny!"
Received February 27, 2004
Accepted March 4, 2004
References
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