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Eur J Heart Fail. 2016 Oct;18(10):1228-1234. doi: 10.1002/ejhf.580. Epub 2016 Jun 10.

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

Author information

1
Pharmacy Practice Division, University of Wisconsin School of Pharmacy, Madison, WI, USA.
2
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
3
Division of Cardiology; Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, USA.
4
Medical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center, Charleston, NC, USA.
5
Institut de Cardiologie de Montreal, Université de Montréal, Montreal, Canada.
6
University of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, UK.
7
University of California-San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
8
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
9
British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
10
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. ssolomon@rics.bwh.harvard.edu.

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

Comment in

PMID:
27283779
PMCID:
PMC5095784
DOI:
10.1002/ejhf.580
[Indexed for MEDLINE]
Free PMC Article

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