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

Research output: Contribution to journalArticle

63 Citations (Scopus)

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

Fingerprint

Enalapril
Heart Failure
Confidence Intervals
Proportional Hazards Models
LCZ 696
Therapeutics
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Vardeny, O., Claggett, B., Packer, M., Zile, M. R., Rouleau, J., Swedberg, K., ... 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

Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction : the PARADIGM-HF trial. / 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.; for the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Investigators.

In: European Journal of Heart Failure, Vol. 18, No. 10, 01.10.2016, p. 1228-1234.

Research output: Contribution to journalArticle

Vardeny, O, Claggett, B, Packer, M, Zile, MR, Rouleau, J, Swedberg, K, Teerlink, JR, Desai, AS, Lefkowitz, M, Shi, V, McMurray, JJV, Solomon, SD & 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, vol. 18, no. 10, pp. 1228-1234. https://doi.org/10.1002/ejhf.580
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. ; for the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Investigators. / Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction : the PARADIGM-HF trial. In: European Journal of Heart Failure. 2016 ; Vol. 18, No. 10. pp. 1228-1234.
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AU - Shi, Victor

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