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ARNI Based on HF History and Use of Angiotensin Antagonists
Quick Takes
- In a prespecified subgroup analysis of the PIONEER-HF trial, patients receiving sacubitril-valsartan had lower NT-proBNP levels at 8 weeks compared with enalapril, irrespective of duration of HFrEF (i.e., de novo vs. chronic worsening).
- Patients receiving sacubitril-valsartan had lower NT-proBNP levels at 8 weeks compared with enalapril, irrespective of previous ACE inhibitor/ARB use.
- Incidence of adverse events with sacubitril-valsartan compared with enalapril was no different.
Study Questions:
What is the safety and efficacy of sacubitril-valsartan (S/V) compared to enalapril in two subgroups not studied in the PARADIGM-HF trial: 1) de novo heart failure (HF) versus worsening chronic HF, and 2) patients on angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), irrespective of dose, compared to those not treated with an ACE inhibitor or ARB?
Methods:
This was a prespecified subgroup analysis of the PIONEER-HF trial, which was a randomized, double-blinded, placebo-controlled trial that examined in-hospital initiation of S/V compared with enalapril in HF with reduced ejection fraction (HFrEF). Hospitalized adults with EF ≤40%, and N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥1600 pg/ml or BNP ≤400 pg/ml were enrolled between 24 hours and 10 days of initial presentation. The primary endpoint was change in NT-proBNP from baseline through 4 and 8 weeks. Safety endpoints included worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema.
Results:
At the time of enrollment, 576 patients (66%) had worsening HFrEF and 303 patients (34%) had de novo HFrEF. Overall, 63 patients (21%) with de novo HFrEF and 358 patients (62%) with worsening chronic HFrEF were on an ACE inhibitor/ARB. Patients not treated with an ACE inhibitor/ARB were younger, less likely to be Black, with a lower prevalence of comorbidities. NT-proBNP levels declined significantly in all four subgroups with greater decreases among those receiving S/V compared with enalapril. There was no interaction between prior HF history or ACE inhibitor/ARB use. Among patients with de novo HFrEF and worsening chronic HFrEF, those receiving S/V had a lower incidence of composite of cardiovascular death or HF rehospitalization. The incidence of adverse events was similar with S/V compared to enalapril in all four subgroups.
Conclusions:
In this prespecified subgroup analysis of the PIONEER-HF trial, S/V was associated with lower NT-proBNP levels at 8 weeks compared with enalapril among patients, irrespective of HF duration (i.e., de novo or worsening chronic HF) and irrespective of prior use of ACE inhibitor/ARB versus not. The incidence of adverse events was comparable between S/V and enalapril across all four subgroups.
Perspective:
Following the PARADIGM-HF trial, current guidelines endorse use of sacubitril/valsartan over ACE inhibitors and ARB in patients with HFrEF. However, patients enrolled in this trial included ambulatory HF patients able to tolerate a high dose of enalapril. Accordingly, there are no data supporting safety and efficacy of S/V in hospitalized patients with de novo HFrEF and among those not on ACE inhibitor/ARB. This prespecified subgroup analysis of PIONEER-HF attempts to bridge these gaps in knowledge. S/V was associated with lower NT-proBNP levels compared with enalapril irrespective of prior HF history or previous ACE inhibitor/ARB use. Clinical endpoints including HF rehospitalization or cardiovascular deaths were lower among patients receiving S/V compared to enalapril among those with de novo and worsening chronic HFrEF. Incidence of adverse events was no different compared to enalapril among patients receiving S/V in all subgroups. These results support extended use of S/V among HFrEF patients not enrolled in the PARADIGM-HF trial (i.e., those hospitalized with de novo HFrEF and those not on ACE inhibitor/ARB).
Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Angiotensin-Converting Enzyme Inhibitors, Angiotensins, Enalapril, Heart Failure, Hyperkalemia, Hypotension, Natriuretic Peptide, Brain, Neprilysin, Peptidyl-Dipeptidase A, Renal Insufficiency, Renin-Angiotensin System, Stroke Volume
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