Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial

Abstract

Aims: In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril.

Methods and results: In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001).

Conclusions: In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs.

Keywords: Chronic heart failure; Clinical trial; Neprilysin inhibitor; Sacubitril; Valsartan.

Figure 1

Kaplan–Meier curves showing primary outcome events by dose reduction status. Participants with a dose reduction had a higher risk of the primary event compared with those who remained on full study medication doses.

Figure 2

(A) Kaplan–Meier curves showing primary outcome events censored at dose reduction by treatment assignment. Individuals taking sacubitril/valsartan had fewer events compared with the enalapril group [hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.71–0.88]. (B) Kaplan–Meier curves showing primary outcome events following dose reduction by treatment assignment. Individuals randomized to sacubitril/valsartan had fewer events relative to enalapril after dose reduction (HR 0.80, 95% CI 0.70–0.93).

Figure 3

Hazard ratios (HR; sacubitril/valsartan relative to enalapril) of the primary outcome measure by time‐updated mean dose post‐randomization. Participants taking lower than target sacubitril/valsartan doses had a lower risk of the primary event compared with those taking lower than target doses of enalapril. CI, confidence interval.