Sacubitril/valsartan versus valsartan initiation in patients naïve to renin-angiotensin system inhibitors: Insights from PARAGLIDE-HF

AIMS: Whether prior treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) modifies efficacy and safety of sacubitril/valsartan (Sac/Val) in patients with heart failure (HF) and ejection fraction (EF) >40% is unclear, thus Sac/Val according to ACEi/ARB status at baseline was assessed.

METHODS AND RESULTS: This was a pre-specified analysis of Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF (PARAGLIDE-HF), a double-blind, randomized controlled trial of Sac/Val versus valsartan, categorizing patients according to baseline ACEi/ARB status. The primary endpoint was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Secondary analyses included a win-ratio analysis of the hierarchical outcome of (i) cardiovascular death; (ii) HF hospitalizations; (iii) urgent HF visits; and (iv) time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8, in addition to safety outcomes. Among 466 patients, 107 (23%) were ACEi/ARB naïve at the time of randomization. NT-proBNP favoured Sac/Val irrespective of ACEi/ARB status (naïve: 0.76, 95% confidence interval [CI] 0.51-1.13; users: 0.88, 95% CI 0.74-1.05; pinteraction = 0.52). The win ratio of the hierarchical outcome was 1.13 (95% CI 0.86-1.49) for ACEi/ARB users and 1.38 (95% CI 0.81-2.37) for ACEi/ARB naïve (pinteraction = 0.51). Safety endpoints showed non-significant interactions by ACEi/ARB status, with odds ratio of 1.79 (95% CI 0.68-4.72) and 0.71 (95% CI 0.29-1.78) for symptomatic hypotension and worsening renal function, respectively for ACEi/ARB naïve.

CONCLUSION: In HF with EF >40% stabilized after worsening HF, safety and efficacy were similar irrespective of ACEi/ARB status at baseline, supporting early initiation irrespective of prior ACEi/ARB use.