Heart failure in the elderly: Urgent need for "real world" clinical trials

Heart failure is the leading cause of hospitalization among Medicare beneficiaries, and it is the most costly diagnosis-related group by a factor of 2.^1,2 In addition, half of heart failure hospitalizations occur in persons 75 years of age or older, and women comprise more than half of all heart failure admissions. ^1,2 Yet, despite these demographics, few heart failure clinical trials have included elderly patients, and women in particular have been markedly underrepresented.³ Moreover, most trials have excluded patients with preserved left ventricular systolic function, as well as patients with significant comorbidities, such as renal or hepatic insufficiency.

As a result, it is estimated that only about 25% of elderly heart failure patients would have met criteria for participation in most of the clinical trials, even if advanced age per se was not an exclusion.⁴ This is of critical importance because elderly patients are at increased risk for serious adverse effects from standard heart failure medications, including diuretics (electrolyte disorders, worsening renal function, dehydration), angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (worsening renal function, hyperkalemia), beta blockers (bradyarrhythmias), and aldosterone antagonists (hyperkalemia). The high prevalence of comorbid conditions and associated polypharmacy also increase the risk of adverse drug interactions (eg, nonsteroidal anti-inflammatory drugs for arthritis antagonize the effects of diuretics and ACE inhibitors and potentiate the risk for worsening renal function).

Taken together, these factors could substantially alter the risk—benefit ratio associated with specific pharmacotherapeutic interventions, implying that it may not be appropriate to extrapolate results of clinical trials conducted in younger and generally healthier (ie, those with fewer comorbidities) heart failure patients to the very elderly. Although subgroup analyses from clinical trials are reassuring in that outcomes are generally similar in older and younger patients, it must be recognized that older subjects enrolled in these trials are substantially different from typical elderly patients seen in routine clinical practice.⁵ In particular, the increased prevalence of preserved left ventricular systolic function in elderly heart failure patients is clinically problematic because there are currently no proven efficacious therapies.^6,7

An additional concern about existing data from clinical trials is that most studies have focused primarily on mortality, and there is a paucity of information on quality of life outcomes. Because the life-extending benefit of most current therapies is relatively modest (on the order of several months) and may be even less in the very elderly because of competing comorbidities, the effect of therapy on quality of life is of pivotal importance, especially for the very elderly, many of whom value quality over quantity of life.⁸

In light of major limitations in the existing evidence base, it must therefore be acknowledged that treatment of both systolic and diastolic heart failure in the very elderly remains largely empiric. Multidisciplinary interventions that offer individualized nurse case management, patient education to enhance self-management skills, and frequent follow-up are of proven efficacy in reducing hospitalizations in elderly heart failure patients, although their effect on other outcomes, including mortality and quality of life, is less clear.^9,10 With regard to drug and device therapy, I concur with Dr Gustafsson’s view that until proven otherwise, it is appropriate to manage elderly patients with systolic heart failure in a fashion similar to younger patients. This is based on best available evidence, recognizing, however, that such evidence is rather sparse, especially in very elderly patients with multiple comorbid conditions, and that it is essentially nonexistent in patients with heart failure and preserved left ventricular systolic function. Given the anticipated doubling in size of the elderly population in the United States over the next 25 years, it follows that there is an urgent need to conduct comprehensive clinical trials in the “real world” elderly heart failure population, with as few exclusion criteria as possible, and to prospectively assess relevant clinical outcomes, including quality of life, functional status, hospitalizations, and mortality.