Association between NT-proBNP and ivabradine in patients after noncardiac surgery: a per-protocol analysis of the PREVENT-MINS study

BACKGROUND: The PREVENT-MINS trial investigated whether perioperative heart rate reduction with ivabradine could prevent myocardial injury after noncardiac surgery (MINS). Although ivabradine modestly reduced heart rate, it did not reduce the incidence of MINS in the intention-to-treat analysis. This per-protocol analysis of the PREVENT-MINS trial, with a post-hoc biomarker substudy, evaluated whether perioperative iva-bradine modifies postoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, a marker of perioperative cardiovascular risk. METHODS: This analysis included 2008 participants who received ≥ 1 dose of study drug, underwent surgery, and had NT-proBNP and troponin measured (ivabradine: n = 1,001; placebo: n = 1,007). Postoperative NT-proBNP levels and changes from baseline (ΔNT-proBNP) were compared by treatment allocation. Clinical outcomes and safety endpoints from the parent trial were evaluated. Analysis of covariance (ANCOVA) assessed ivabradine's effect on postoperative NT-proBNP after adjustment for baseline values and clinical covariates. RESULTS: MINS occurred in 17.7% of ivabradine-treated vs. 15.7% of placebo patients (RR 1.13; 95% CI: 0.93-1.37; P = 0.23). Median postoperative NT-proBNP was higher with ivabradine than with placebo (418.0 vs. 333.5 pg mL-1; P < 0.001), as were ΔNT-proBNP values (215.1 vs. 154.0 pg mL^-1; P < 0.001). After adjustment for baseline and relevant clinical covariates, ivabradine was independently associated with an approximately 82% increase in postoperative NT-proBNP (Δlog = 0.59 ± 0.19; 95% CI: 26-164). CONCLUSIONS: Ivabradine did not reduce the incidence of MINS and was associated with greater postoperative NT-proBNP release. Perioperative heart rate reduction with ivabradine may elevate markers of cardiac stress without measurable clinical benefit.