American Heart Journal
Volume 146, Issue 2 , Pages 194-196, August 2003

Heart failure and the elderly: disease diversity, data, and delivery of care

  • Karen P. Alexander, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • Corresponding Author InformationReprint requests: Karen P. Alexander, MD, Duke Clinical Research Institute, Room 7068, PO Box 17969, Durham, NC 27715, USA.
    • ,
  • Mimi S. Biswas, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA

Article Outline

 

The concept of evidence-based medicine emphasizes the judicious use of the “best evidence” from clinical research in the treatment of the individual patient. Rendering evidence-based care successfully requires several key steps, however. One must arrive at the correct diagnosis for the constellation of signs and symptoms, have proven beneficial therapies for the disease in question, and encounter few barriers to treatment at the level of the individual, such as drug contraindications, adverse effects, and cost barriers. Evidence-based care of elderly patients with heart failure is challenged along all 3 steps in this continuum from evidence to practice. In this issue of the Journal, Masoudi and colleagues look at the degree to which the evidence for beneficial therapies applies to elderly heart failure patients in the community setting.1 They compared the characteristics of patients with heart failure in a Medicare population with the population enrolled in 3 large randomized controlled clinical trials of treatments for heart failure and found that surprisingly few Medicare patients fit the profiles of the patients with heart failure enrolled in these trials. In the 3 major heart failure trials, Studies of Left Ventricular Dysfunction (SOLVD), Metroprolol CR/LX Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), and Randomized Aldactone Evaluation Study (RALES), 18%, 13%, and 25%, respectively, of an unselected heart failure population met the criteria for enrollment.2, 3, 4 Although under-enrollment of elderly patients in cardiovascular trials has been previously highlighted, until this point, the magnitude and reasons for this discordance between trial and community patients has been speculation.5, 6, 7 This analysis highlights the diversity of heart failure in elderly patients and their under-representation in existing trials and reflects many of the issues faced in treating elderly patients with heart failure in contemporary community practice.

The first point of interest in considering this work is the diversity of heart failure in the community, particularly among elderly patients. “Heart failure” describes a constellation of characteristic signs and symptoms that result from the inability of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues. As such, there is a large diversity of pathologic processes that result in this hemodynamic insufficiency. Heart failure is the final common pathway of several disease processes more common in aging patients, like hypertension and valvular or ischemic heart disease, but it can also be the result of physiologic changes associated with age itself. In elderly patients, diastolic heart failure and left ventricular (LV) hypertrophy develop in response to the progressive increases in afterload that accompany the age-related changes in central artery compliance. Abnormal diastolic relaxation patterns are also more common with age because of abnormal calcium flux and ischemia. For these reasons, reports have shown that 50% of heart failure in patients >70 years is from diastolic dysfunction, compared with only 8% of heart failure in patients <65 years. The authors found that preserved LV function was the most common reason for exclusion of elderly patients from clinical trials, affecting 54% of the patients with heart failure in the National Heart Foundation (NHF) project. Diastolic heart failure has been reported to have a mortality rate that is intermediate between that of systolic heart failure and that of normal heart function. Because congestive heart failure remains the leading cause of hospitalization in patients >65 years, despite the higher mortality rate seen with reduced ejection fraction (EF), patients with diastolic heart failure account for more deaths because of their greater prevalence.8, 9 Although diastolic heart failure has similarities to systolic heart failure in its symptoms of congestion and neurohormonal activation, it is fundamentally different in its etiology and primary hemodynamic abnormality. Thus, there is an urgent need for basic and clinical heart failure studies in elderly patients, particularly those with diastolic heart failure.

The authors found that the second most common reason for exclusion of elderly patients was age, affecting 40% of the NHF project population. The under-representation of elderly patients in all trials of heart disease was recently documented. Lee et al5 found that 40% of the 593 randomized trials in coronary artery disease published between 1991 and 2000 had explicit exclusions on the basis of age. Even though the most trials did not have exclusions on the basis on age, only 9% of the enrollment consisted of patients ≥75 years. This is well below the representation of patients ≥75 years in the United States with myocardial infarction (37%), and this percentage has not changed significantly compared with the prior decade. However, in addition to chronologic age, elderly patients are also more likely to have drug-specific exclusions, such as elevated creatinine level, active ischemic heart disease, or aortic stenosis. In the NHF registry, 45% of patients who met age and EF inclusions for the RALES trial were not eligible because of drug-specific exclusions. This results in elderly patients being excluded in greater proportions than by just age alone. Although these exclusions are important to ensure patient safety, they may also exclude some patients who are at higher risk and also have the most to gain. For this same reason, investigators may be hesitant to offer enrollment in clinical trials to elderly patients because they are concerned about excess risk caused by a comorbidity that is not exclusionary, or simply because of age alone. However, studies have shown that elderly patients, when approached, report a high degree of willingness to consider participation in clinical trials.10 As our aged population increases, we must continue to make concerted efforts to offer inclusion and encourage participation in randomized trials to increase applicability of the findings.

In the meantime, the extent to which trial results can be extended to non-studied groups depends on the extent to which the disease pathophysiology and manifestations are similar. The influence of disease diversity on the magnitude of benefit from drug therapy has been shown in several studies. For example, the mortality benefit from the calcium channel blocker, Amlodipine, in patients with heart failure in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) I study was greatest in patients with an non-ischemic etiology of their LV dysfunction.11 Although this was not subsequently confirmed in the follow-up PRAISE II study, in which the patients without ischemia had clean coronary arteries, it raises questions about the possible anti-anginal effect of Amlodipine on subclinical disease in the “non-ischemics” in PRAISE I.12 The Yusuf meta-analysis of angiotensin-converting enzyme (ACE) inhibitor trials in heart failure showed a greater treatment effect in younger patients than in patients >75 years.13 Although elderly patients gain symptomatic benefits from traditional therapies for heart failure, studies have shown that their LV dimensions do not significantly change with therapy, unlike LV dimensions in younger patients.14 A recent subgroup analysis from the Digitalis Investigation Group (DIG) trial found no evidence of benefit in women treated with digoxin. Women enrolled in the DIG trial who received digoxin had a rate of death that was 4% higher than that of women who received placebo. The absolute difference in the effect of digoxin on mortality rate between men and women was 5.8%.15 These and other studies demonstrate that heart failure is the final common pathway of a diverse and dynamic process involving neurohumoral and mechanical factors. The diversity in response to treatment should further emphasize the importance of identifying groups requiring particular study, such as patients with diastolic heart failure. In addition, the exclusion criteria of systolic heart failure trials should be reviewed to ensure representation by a broad range of patients to better approximate the real world.

Drug treatment of elderly patients in clinical practice is complex and is impacted by more than age alone. Elderly patients are not eligible for many drugs because of comorbidities, including renal failure, hypotension, and sinus node dysfunction. Drug metabolism is also altered with aging, so that the target doses that have been proven effective in younger populations may not be the safe or effective in older patients. The pharmacokinetics of the drug may enable lower doses for equivalent biologic effects with fewer adverse effects. The average Medicare patient with heart failure who is taking an ACE inhibitor is also taking 8 other medications. In addition, only 22% of patients taking an ACE inhibitor are receiving the target dose studied in clinical trials.16 The issues of polypharmacy and drug interactions are also of particular importance in elderly patients. There has been a suggestion that other commonly used medications, such as aspirin, may, in elderly patients, counteract the effectiveness of medications such as ACE inhibitors.17 Although there are several proven agents for the treatment of heart failure, most are studied in addition to standard therapy including ACE inhibitors and diuretics. Unanticipated interactions may exist between drug classes. For example, in a subgroup analysis from the Valsartan-Heart Failure Trial (ValHeFT) study, the angiotensin receptor blocker, Valsartan, was beneficial when used with either an ACE inhibitor or β-blocker alone, but was harmful in patients taking both of these medications.18 The ability to identify the agents of greatest benefit to each individual patient on the basis of the etiology of their heart failure and other confounders would be of great benefit in reducing cost and potential drug-drug interaction. Attention should also be given to the issues of drug interactions with non-cardiac medications. These issues of delivery of care are specifically important to elderly patients with heart failure with a limited budget who may be on numerous costly medications . In this setting, it becomes vitally important to know that each medication will incrementally affect disease outcomes. In addition, post-marketing surveillance of possible drug interactions should be conducted when a new agent is added to the existing pharmaceutical terrain.

In the continuum of evidence to practice, the ultimate goal of research is to improve the clinical care of all our patients. Narrow inclusion and exclusion criteria ensure homogeneity in clinical trial populations and reduce unexpected variations in drug efficacy and safety. When carefully applying the enrollment criteria for 3 clinical trials in heart failure, only 33% of 20,388 patients in the NHF project who were being treated in the community would have been eligible for enrollment. This represents a substantial gap between the patients in the real-world and patients in clinical studies. Research must take into consideration the diversity of heart failure etiology, presentation, and response to treatment. In this case, studies specifically targeting diastolic heart failure are urgently needed. Until the evidence gap for heart failure treatment in elderly patients narrows, physicians will have to practice within this divide of uncertainty, bridging it through the art of medical judgment in applying the existing evidence.

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References 

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PII: S0002-8703(03)00190-X

doi:10.1016/S0002-8703(03)00190-X

American Heart Journal
Volume 146, Issue 2 , Pages 194-196, August 2003

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