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


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.
Pharmacy Practice Division, University of Wisconsin School of Pharmacy, Madison, WI, USA.
Orly
O
Vardeny
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
Brian
B
Claggett
Division of Cardiology; Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, USA.
Milton
M
Packer
Medical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center, Charleston, NC, USA.
Michael R
MR
Zile
Institut de Cardiologie de Montreal, Université de Montréal, Montreal, Canada.
Jean
J
Rouleau
University of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, UK.
Karl
K
Swedberg
University of California-San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
John R
JR
Teerlink
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
Akshay S
AS
Desai
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Martin
M
Lefkowitz
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Victor
V
Shi
British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
John J V
JJ
McMurray
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. ssolomon@rics.bwh.harvard.edu.
Scott D
SD
Solomon
D000368:Aged; D000613:Aminobutyrates / Q000008:administration & dosage*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004656:Enalapril / Q000008:administration & dosage*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D013318:Stroke Volume / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage*; D000068756:Valsartan
D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
Chronic heart failure; Clinical trial; Neprilysin inhibitor; Sacubitril; Valsartan