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Efficacy of novel HF drug persists at lower doses

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NATIONAL HARBOR, Md. — Patients with HF treated with lower doses of an angiotensin receptor-neprilysin inhibitor exhibited reductions in risk for CV-related death and HF hospitalization compared with patients treated with lower doses of enalapril, according to a new analysis of the PARADIGM-HF trial.

Researchers evaluated data collected from patients with HF and reduced ejection fraction enrolled in PARADIGM-HF. Patients were treated with the angiotensin receptor blocker valsartan bonded to the neprilysin inhibitor sacubitril (Entresto, Novartis; target dose, 200 mg twice daily) or the ACE inhibitor enalapril (target dose, 10 mg twice daily).

The trial was terminated early after sacubitril/valsartan was shown to significantly reduce the risk for the primary composite outcome of CV-related death or first incidence of HF-related hospitalization compared with enalapril.

The goal of the present analysis was to compare the effects of sacubitril/valsartan and enalapril when patients received doses lower than the study target as a result of dose reduction due to treatment intolerance.

According to results presented at the Heart Failure Society of America Annual Scientific Meeting, dose reduction occurred in 42% of the sacubitril/valsartan group and 43% of the enalapril group during the course of the study. Hypotension was the most cited reason for dose reduction in the sacubitril/valsartan group and cough in the enalapril group. Dose reduction was more common in patients who were older, sicker, had higher levels of serum creatinine and NT-proBNP at baseline, and had an implantable cardioverter defibrillator or cardiac resynchronization therapy device, according to Orly Vardeny, PharmD, MS, from the University of Wisconsin-Madison School of Pharmacy.

Patients who did not require dose reduction had significantly reduced risk for the primary outcome with sacubitril/valsartan compared with enalapril (HR = 0.79; 95% CI, 0.71-0.88; P < .001). However, patients treated with reduced-dose sacubitril/valsartan also had a significantly lower risk for events compared with patients treated with a similarly reduced dose of enalapril: sacubitril/valsartan dose of 100 mg to 200 mg twice daily vs. enalapril 5 mg to 10 mg twice daily  (HR = 0.8; 95% CI, 0.67-0.94; P = .008); sacubitril/valsartan dose below 100 mg twice daily vs. enalapril less than 5 mg twice daily (HR = 0.76; 95% CI, 0.58-0.99; P = .043).

"Among those unable to remain on the target dose of either study drug, patients treated with [sacubitril/valsartan] still had a better outcome compared to those treated with enalapril," Vardeny said. "These data suggest that the efficacy of [sacubitril/valsartan] relative to enalapril was maintained even at lower than target doses, however clinicians should always aim for the target doses tested in this trial."– by Adam Taliercio

Reference:

Vardeny O, et al. Rapid-Fire Abstracts I. Presented at: Heart Failure Society of America Annual Scientific Meeting; Sept. 26-29, 2015; National Harbor, Md.

Vardeny O, et al. J Card Fail. 2015;doi:10.1016/j.cardfail.2015.06.067.

Disclosure: Vardeny reports receiving speaker fees/honoraria from Novartis.