RAAS Blockade in Heart Failure

RAAS blockade valsartan heart failure ARNI

Jun 4, 4:54 PM

Surveyed evidence on ARNI versus RAAS blockade in heart failure and refined the search plan.

Your query terms point at the sacubitril/valsartan story, so here's what the evidence says about ARNI on top of (or instead of) conventional RAAS blockade in heart failure.

HFrEF — ARNI beats ACEi.

PARADIGM-HF randomized 8,399 patients with NYHA II–IV symptoms and LVEF ≤40% to sacubitril/valsartan vs. enalapril on top of guideline therapy, with a median 27-month follow-up. Sacubitril/valsartan cut cardiovascular death by about 20% (HR 0.80, 95% CI 0.72–0.89), driven by reductions in both sudden cardiac death and death from worsening heart failure (Desai et al. 2015). A 2023 meta-analysis of 10 studies confirms lower all-cause and cardiovascular mortality vs. ACEi/ARB controls, with no significant difference in LVEF change or HF hospitalization in that pooled set, but a higher rate of symptomatic hypotension on ARNI (Haseeb et al. 2023). Net: ARNI is now first-line over ACEi/ARB for HFrEF.

HFpEF — formally negative, but with a signal.

PARAGON-HF tested sacubitril/valsartan against valsartan alone in patients with LVEF ≥45%, elevated natriuretic peptides, and structural heart disease. The primary composite of CV death + HF hospitalization missed statistical significance overall, but a pre-specified subgroup analysis showed a reduction in HF hospitalizations in patients with LVEF below the trial median (~57%) — i.e., the "mildly reduced" range (Gronda et al. 2020). This is what shifted guidelines toward considering ARNI in HFmrEF and lower-range HFpEF, though the overall HFpEF result remains a miss.

Post-MI.

PARADISE-MI extended the ARNI question to acute MI without prior HF; that trial did not show a significant reduction in the primary composite vs. ramipril — I'd flag this as a real boundary on where ARNI helps (She et al. 2021) (the retrieved abstract only frames the comparison; the published trial reported HR ~0.90, non-significant — worth pulling the primary paper if you want the exact numbers).

A few caveats on what I pulled: this was an abstract-level search, so I'm not seeing the full PARADIGM-HF primary endpoint numbers (the famous 20% reduction in CV death/HF hospitalization composite) or the PARAGON-HF subgroup hazard ratios verbatim — happy to fetch full text if you want exact effect sizes.