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

Orly Vardeny, Brian Claggett, Milton Packer, Michael R. Zile, Jean Rouleau, Karl Swedberg, John R. Teerlink, Akshay S. Desai, Martin Lefkowitz, Victor Shi, John J V McMurray, Scott D. Solomon, for the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Investigators

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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.

Original languageEnglish (US)
Pages (from-to)1228-1234
Number of pages7
JournalEuropean Journal of Heart Failure
Volume18
Issue number10
DOIs
StatePublished - Oct 1 2016

Keywords

  • Chronic heart failure
  • Clinical trial
  • Neprilysin inhibitor
  • Sacubitril
  • Valsartan

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Vardeny, O., Claggett, B., Packer, M., Zile, M. R., Rouleau, J., Swedberg, K., Teerlink, J. R., Desai, A. S., Lefkowitz, M., Shi, V., McMurray, J. J. V., Solomon, S. D., & for the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Investigators (2016). Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. European Journal of Heart Failure, 18(10), 1228-1234. https://doi.org/10.1002/ejhf.580