American College of Cardiology -- Anaheim, California

Heart Failure Trials: Extracting the Clinically Relevant Information


In his presentation at the American College of Cardiology 46th Scientific Session, Dr. Robert Cody explained that one thing that hampers the extraction of truly relevant information from clinical trials is the use of unsound methodologies, since they provide skewed conclusions which are often largely inapplicable to the general population of patients. For example, a preponderance of CHF trials have routinely excluded heart-failure patients with diastolic dysfunction, active coexisting hypertension (one of the major causes of heart failure) and, till recently, patients over 70 years-of-age.

In addition, he emphasized the need for cardiologists to keep benefit managers informed about the drugs which they believe should be recommended for managing CHF and the fact that new drug therapies need to be implemented as they become available. He advocated that physicians should turn their attention to:

– improving myocardial function by primary prevention and secondary effects in the post-MI, acute MI, and hypertensive population;
– managing sodium and water retention more intelligently with dietary sodium control, factors that block vasopressin, the renin system, or potentiate vasoactive natriuretic peptides and, by eventually finding a compound that could improve glomerular filtration rates; and by
– modulating the adverse myocardial, vascular, and growth maladaptation by blocking the known pathways, and continue to aggressively attack this using not only drug therapies, but gene-guided therapy, as well.

On the way to making these recommendations, Dr. Cody provided an overview of current drug therapies:

Digitalis
By itself, digitalis has a neutral effect on survival. A positive inotropic agent, digoxin increases ejection fraction, slows the heart rate, stabilizes membranes, suppresses the renin angiotensin system and corrects barrier receptor abnormalities, and these effects all contribute to the long-term benefit. Trials assessing the efficacy of digoxin, the oldest treatment for CHF, have indicated that patients treated concomitantly with angiotensin converting enzyme (ACE) inhibitors enjoy the best outcome.

Diuretics
Given the propensity for diuretics to exert adverse effects, more attention should be paid to eliminating excessive sodium
consumption rather than providing drugs which treat edema and sodium retention. Loop diuretics vary pharmacokinetically and pharmacodynamically but all are capable of inducing hypertrophy of the distal nephron of the kidney, an action which completely offsets any beneficial effects.

ß-blockers
Despite the belief since 1978 that positive inotropic agents increase ejection fraction rates, it now appears that only ß-blockers (negative inotropic agents) – via their effects on autonomic activity – do so consistently compared to placebo, and that no positive inotropic agent administered orally can actually make that claim. Digoxin also increases ejection fractions, but it now appears that this may, in fact, be unrelated to its positive inotropic activity. Carbetalol, recently approved in the U.S. for the treatment of CHF, has been shown to improve survival vs placebo in at least one clinical trial. However, it is only indicated for reducing the clinical effects of and hospitalisation for CHF, not mortality.

Calcium Channel Blockers
Studies assessing the use of CCBs in hypertension have shown that those which are short-acting may be deleterious, whereas long-acting agents, such as amlodipine, are not. The Prospective Randomized Amlodlpine Survival Evaluation (PRAISE) trial has suggested that CCBs have no effect on mortality overall, although, quite unexpectedly, they do appear to reduce mortality in the nonischemic subset of CHF patients. Given these findings, nonischemic cardiomyopathy patients are being studied to determine if amlodipine will, in fact, reduce their mortality.

ACE Inhibitors
Since they consistently have been shown to be better than CCBs in the treatment of CHF, ACE inhibitors should be the drug of choice for all stages and all forms of heart failure, according to Dr. Cody. Although they have some of the properties of vasodilators, ACE inhibitors have much broader effects on remodeling and other issues. Perhaps due to the higher mortality rates associated with direct-acting vasodilators, no new ones have been introduced for a long time. Preliminary findings in small, limited-patient studies comparing ACE inhibitors and angiotensin II antagonists indicate that the latter may be even more effective in reducing mortality and sudden death.