ARNI for Heart Failure: Earlier Is Better

Earlier is better for the initiation of angiotensin receptor-neprilysin inhibition (ARNI) therapy in people hospitalized for acute decompensated heart failure (ADHF), according to data from the open-label extension phase of the 8-week PIONEER-HF trial.

Among patients with heart failure with reduced ejection fraction (HFrEF), those who were assigned sacubitril/valsartan (Entresto) right before discharge saw a further 17.2% decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) during the 4-week extension, reported Adam DeVore, MD, MHS, of Duke Clinical Research Institute in Durham, North Carolina, and colleagues.

Those who had been randomized to enalapril (Vasotec) for the 8 weeks of the main study saw a 37.4% reduction in NT-proBNP after switching to sacubitril/valsartan during the extension (P<0.001 comparing the two groups' extension-phase results), DeVore's team said in JAMA Cardiology.

Moreover, rates of heart failure rehospitalizations or cardiovascular death over the entire 12 weeks of follow-up were lower among patients who got sacubitril/valsartan from the start rather than beginning at 8 weeks (13.0% vs 18.1%, HR 0.69, 95% CI 0.49-0.97).

This study "further informs us that the optimal time to implement sacubitril/valsartan for hospitalized patients with HF is now," according to an accompanying editorial by Jane Wilcox, MD, MSc, of Northwestern University Feinberg School of Medicine, Chicago.

"At first glance, the study by DeVore and colleagues could feel incremental. The parent study of this secondary analysis was not powered to clinical end points, but rather reduction in biomarkers only; thus, the reduction in clinical events seen during this open-label extension phase must not be overstated," Wilcox wrote.

Still, the sacubitril/valsartan story remains consistent, she suggested: the drug has been tied to clinical benefit across the spectrum of reduced ejection fraction, regardless of heart failure etiology (non-ischemic vs ischemic) or the presence of background medical therapy among stable outpatients with slight-to-marked limitation of physical activity. Now, it appears that inpatients with ADHF who have achieved hemodynamic stability also derive clinical benefit from ARNI therapy.

"Early implementation of sacubitril/valsartan in clinical practice has the potential to reduce the overall burden of HF. We must learn from the past, move forward, and embrace ARNI therapy as the new frontier," she urged.

The main finding from PIONEER-HF had been that patients stabilized after ADHF tolerated the in-hospital initiation of sacubitril/valsartan and experienced better outcomes than with enalapril.

This was a multicenter, randomized, double-blind trial that had 881 patients randomized to 8 weeks of sacubitril/valsartan (97 or 103 mg twice daily) or the ACE inhibitor enalapril (10 mg twice daily).

Another 4 weeks of sacubitril/valsartan was taken among the 832 patients who continued on to PIONEER-HF's open-label extension.

All had been admitted for acute decompensated HFrEF and reached hemodynamic stability. They had no history of recent treatment with ACE inhibitors or angiotensin receptor blockers.

Mean age was 61 years and 27.7% were women. The overall trial cohort was notable for its large proportion of black patients (35.7%).

That the investigators didn't get everyone from PIONEER-HF to participate in the extension phase was a limitation of the secondary analysis, they acknowledged, adding that the extension phase itself was relatively short.

"Despite the growing body of evidence demonstrating the benefits of ARNI therapy over standard of care, too few eligible patients are actually prescribed sacubitril/valsartan," Wilcox lamented.

She advocated for better understanding of the barriers to ARNI uptake.

"Examples of such barriers may include practitioners' unfamiliarity with sacubitril/valsartan, whether sacubitril/valsartan is on the hospital formulary, concerns about hospital length of stay (i.e., a 36-hour washout during an ADHF episode), reimbursement issues, and safety concerns," according to the editorialist.