Drug therapy for heart failure with reduced ejection fraction: what is the 'right' dose?

Abstract

New guidelines have emphasized the primacy of starting the four key life-saving therapies for patients with heart failure and reduced ejection fraction as quickly as possible, with titration to 'target dose' of these, as secondary consideration. In this article, we examine the reasons for this change in emphasis and revisit the evidence regarding the dosing of pharmacological therapy in heart failure. We demonstrate the early benefits obtained with even low doses of most of the foundational therapies for heart failure and reduced ejection fraction. We also clarify that the 'target dose' of those therapies requiring titration was a goal based on tolerability and often not reached in trials, i.e. the proven benefits of our foundational therapies were demonstrated with an average dose that was less than target and many patients in these trials were treated with sub-target doses.

Keywords: Drug therapy; Heart failure with reduced ejection fraction.

Figure 1

Kaplan–Meier analysis for the composite of all‐cause death or hospitalization for heart failure up to 4 weeks in trials using an angiotensin receptor blocker (ARB) (CHARM‐HFrEF trials) and a mineralocorticoid receptor antagonist (MRA) (EMPHASIS‐HF). CI, confidence interval.

Figure 2

(A) Effect of candesartan compared with placebo on the composite of all‐cause death or hospitalization for heart failure over the first 4 weeks after randomization. The horizontal blue line shows a continuous hazard ratio and the interrupted lines the 95% confidence interval. The upper 95% confidence interval falls below 1 after 15 days and remains under 1 thereafter. (B) Effect of eplerenone compared with placebo on the composite of all‐cause death or hospitalization for heart failure over the first 4 weeks after randomization. The horizontal blue line shows a continuous hazard ratio and the interrupted lines the 95% confidence interval. The upper 95% confidence interval falls below 1 after 24 days and remains under 1 thereafter. ARB, angiotensin receptor blocker: MRA, mineralocorticoid receptor antagonist.