Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM‐HF trial. (10th June 2016)

• Record Type: Journal Article
• Authors: Vardeny, Orly; Claggett, Brian; Packer, Milton; Zile, Michael R.; Rouleau, Jean; Swedberg, Karl; Teerlink, John R.; Desai, Akshay S.; Lefkowitz, Martin; Shi, Victor; McMurray, John J.V.; Solomon, Scott D.
• Is Part Of: European journal of heart failure. Volume 18:Number 10(2016)
• Page Start: 1228
• Page End: 1234
• Publication Date: 2016-06-10
• Subjects: Chronic heart failure -- Neprilysin inhibitor -- Clinical trial -- Sacubitril -- Valsartan; Heart failure -- Periodicals; Heart Failure -- Periodicals; Insuffisance cardiaque -- Périodiques; Heart failure; Periodicals; 616.129005
• DOI: 10.1002/ejhf.580
• Languages: English
• ISSNs: 1388-9842

Abstract

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.