Targeting Doses of Guideline-Directed Medical Therapy in Heart Failure

Volume 20, Issue 3

The therapeutics of heart failure have evolved rapidly in the last 7 years, starting with the approval of sacubitril/valsartan for heart failure with a reduced ejection fraction (HFrEF) in 2015. This was the first new agent approved for heart failure in decades, and its approval was based on a proven benefit in reducing rates of cardiovascular death and heart failure hospitalizations with this agent vs enalapril.

What hasn’t changed in the field of heart failure is the notion that guideline-directed medical therapy (GDMT) should be titrated to maximally tolerated doses in order to optimize the benefits in reducing mortality and hospitalizations. This has been historically true for ACE inhibitors and beta-blockers. The dose-response benefit for new agents like sacubitril/valsartan have not been robustly analyzed.

In this week’s issue of Talking Therapeutics, we examine a new paper that addressed this very salient issue.

Point 1: No Clear Signal for a Dose Benefit

This new study used data from the PROVE-HF trial, which followed 794 patients with HFrEF for 1 year. In this paper, doses of sacubitril/valsartan were averaged over the study period, and then patients were divided into a low-dose (112 mg), moderate-dose (342 mg), and high-dose (379 mg) tertiles. The outcomes of interest for this paper were changes from baseline to 12 months in biomarkers (N-terminal pro–B-type natriuretic peptide, high-sensitivity cardiac troponin T, etc), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, etc).

The study found there was no difference between the tertiles for any of the outcomes assessed, which suggests that significant benefit can be achieved with relatively lower doses of sacubitril/valsartan.

Point 2: Clinical Data Needed

These results are encouraging; however, this study was not designed to assess the dose-response relationship for hard clinical endpoints like mortality and hospitalization for heart failure.

If these data are confirmed in a larger trial with hard clinical endpoints, they could change the practice of heart failure management. If sacubitril/valsartan doses did not need to be titrated aggressively to maximize benefit, then the focus could shift to titrating beta-blockers more aggressively, given that these agents have a very clear linear dose-response relationship in patients with HFrEF.