Initiating therapy for heart failure: Must ontogeny recapitulate phylogeny?

Cardiology Review® Online, October 2005, Volume 22, Issue 10

The treatment of heart failure (HF) has undergone a revolution over the past

20 years with the recognition of the importance of neurohormonal activation in the development and progression of HF. This has led to the use of angiotensin-converting en-

zyme (ACE) inhibitors and beta-blocking agents as the cornerstone of therapy for HF associated with systolic dysfunction (ie, reduced ejection fraction). Because ACE inhibitor treatment for HF was the first neurohormonal therapy studied and demonstrated to have

a benefit, ACE inhibitors are initiated first in the treatment of HF, and beta blockers, which were studied later, are subsequently added to the patient’s regimen. The important study of Sliwa (page 24) suggests that we may have it backwards.1

Between 1987 and 1992, the Cooperative North Scandinavian Enalapril Survival Study, Studies of Left Ventricular Dysfunction, and the Vasodilator Heart Failure Trial demonstrated that ACE inhibitor therapy was beneficial in patients with left ventricular systolic dysfunction of all symptomatic classes.2-5 Based on the compelling data demonstrating the benefit of ACE inhibitors in these patients, there has been a concerted effort to implement this evidence-based medicine.6 Everyone has been encouraged to “get with the guidelines.” This has culminated in each hospital’s quality of care being graded by the percentage of patients with decreased ejection fraction who are discharged on an ACE inhibitor. Each hospital’s score can be found at The average for all reporting hospitals is 74%.

After the landmark ACE inhibitor trials, the next advancement in the treatment of HF was the recognition that beta blockade had a powerful added effect in patients with systolic HF. These studies demonstrated that beta blockade, begun at a low dose and subsequently titrated up, improved survival, decreased hospitalization, and produced favorable remodeling in patients with systolic HF.7-10 Most of these patients were already on an ACE inhibitor when they entered the trials. It is notable that these studies demonstrated that the addition of a beta blocker in patients with systolic dysfunction has a greater effect on left ventricular remodeling than an ACE inhibitor.

Sliwa performed a single-center, prospective, open-label study in 78 patients with HF due to a dilated cardiomyopathy who were randomly assigned to therapy with a beta blocker (carvedilol, Coreg) or an ACE inhibitor (perindopril, Aceon).1 Only patients with presumed idiopathic dilated cardiomyopathy were studied; patients with ischemic cardiomyopathy were excluded. The second agent was added after 6 months. After 12 months, patients in the group that received carvedilol as the initial therapy were tolerating a higher dose of beta blocker, were using a lower dose of diuretic, had greater improvement in symptoms and ejection fraction, and had a lower plasma N-terminal pro-brain natriuretic peptide concentration.

The provocative implication of this study is that beta adrenergic blockade should be the initial therapy in patients with systolic HF. As with all clinical studies, there are some limitations to this important investigation. First, only 78 patients were enrolled from a single center in South Africa. Second, the study was not blinded. Third, there was a 6-month delay before adding the second agent to the patient’s regimen.

Despite these limitations, this study suggests, but does not prove, the hypothesis that beta blockade should be the initial therapy (before adding ACE inhibition) in patients with systolic HF. The ultimate evaluation of this hypothesis will depend upon a much larger, multicenter, blinded study. Fortunately, such a study has been conducted, and the results should be available soon.11

In the interim, how should we initiate treatment in a patient with HF? Should the patient initially diagnosed with systolic HF be discharged on a beta blocker and not on an ACE inhibitor? This, of course, would lead to a poor score for your hospital on the Web site and expose the clinician to the charge of not practicing evidence-based medicine in compliance with current guidelines. Despite these concerns, the initial use of a beta blocker before an ACE inhibitor may be the optimal method of management for certain individual patients with HF (for example, those with evidence of a hyperadrenergic state).6 An alternate approach is to initiate therapy with an ACE inhibitor, but begin beta blockade soon thereafter. Certainly, the study of Sliwa indicates that one should not wait 6 months before initiating a beta blocker.1

In conclusion, the provocative study of Sliwa suggests that we may move beyond recapitulating the evolution of our therapeutic knowledge, as we initiate the treatment of patients with HF.