Ivabradine Fails to Reduce Myocardial Injury After Noncardiac Surgery: Insights from a Large RCT

Highlight

This randomized controlled trial evaluated whether ivabradine, a selective heart rate–lowering agent, reduces myocardial injury after noncardiac surgery (MINS). Despite significant intraoperative heart rate reduction without hemodynamic compromise, ivabradine did not lower MINS incidence compared to placebo. The trial was halted early for futility after enrolling 2101 patients at risk for atherosclerotic disease undergoing major noncardiac surgery.

Study Background and Disease Burden

Cardiovascular complications remain a leading cause of morbidity and mortality following noncardiac surgery, particularly in patients with underlying atherosclerotic risk factors or established cardiovascular disease. Myocardial injury after noncardiac surgery (MINS) is a common and prognostically important event associated with increased 30-day mortality. Traditionally, perioperative beta-blockers have been used to lower heart rate and reduce myocardial oxygen demand, thus decreasing myocardial infarction risk. However, beta-blocker therapy frequently increases the risk of perioperative hypotension, stroke, and even death due to their systemic hemodynamic effects.

Ivabradine is a selective inhibitor of the cardiac pacemaker If current, acting specifically to reduce heart rate without adversely affecting myocardial contractility or systemic blood pressure. This pharmacodynamic profile suggests ivabradine might reduce perioperative myocardial injury while avoiding the hemodynamic instability sometimes seen with beta-blockers. Yet, evidence supporting ivabradine’s efficacy in the perioperative setting has been lacking prior to this trial.

Study Design

The PERI-CRIT trial was a multicenter, double-blind, placebo-controlled randomized clinical trial. It enrolled 2101 patients aged 45 years or older, all with established or at-risk atherosclerotic disease, scheduled for elective major noncardiac surgery. Eligible patients were randomly assigned in a 1:1 ratio to receive either ivabradine (5 mg orally twice daily) or placebo. Study drug administration commenced one hour before surgery and continued for up to seven days postoperatively.

The primary endpoint was the occurrence of MINS within 30 days of randomization, defined per established criteria including elevations in cardiac troponin levels indicative of myocardial injury. Secondary endpoints included intraoperative heart rate and blood pressure, other cardiovascular events, and safety outcomes.

Key Findings

The intention-to-treat population comprised all 2101 randomized patients, with 1050 assigned to ivabradine and 1051 to placebo. The incidence of MINS was 17.0% (178 patients) in the ivabradine group versus 15.1% (159 patients) in the placebo group. The relative risk was 1.12 (95% confidence interval [CI], 0.92 to 1.37; p=0.25), indicating no statistically significant difference. Due to the lack of benefit and a conditional power of 6%—well below the predefined futility threshold of 20%—the trial was stopped early at a planned interim analysis.

Intraoperative analyses showed that ivabradine effectively reduced mean heart rate by 3.2 beats per minute compared to placebo (95% CI, -4.07 to -2.36). Importantly, this heart rate reduction was not accompanied by a statistically or clinically significant difference in mean arterial pressure, indicating hemodynamic stability was maintained.

No differences were noted between groups in other perioperative cardiovascular events or adverse safety outcomes, reinforcing ivabradine’s tolerability in this setting.

Expert Commentary

These findings illustrate the complex nature of perioperative myocardial injury and underscore that selective heart rate reduction alone—without broader modulation of hemodynamic stress or myocardial oxygen supply-demand balance—may not suffice to reduce MINS risk. While ivabradine safely lowered heart rate without provoking hypotension, it did not translate into clinical benefit, contrasting with some benefits observed with beta-blockade albeit at the risk of adverse events.

The trial’s rigor, sizable sample, and pragmatic design provide high-quality evidence to guide clinical practice. However, it remains unknown whether different dosing regimens, combination therapies, or targeted patient subgroups might derive benefit from ivabradine. Further mechanistic studies are warranted to understand the pathophysiology of MINS and explore alternative strategies to improve cardiovascular outcomes in the perioperative period.

Current clinical guidelines should continue to emphasize individualized perioperative risk stratification and cautious use of beta-blockers while recognizing the limited role of ivabradine in this context based on existing evidence.

Conclusion

The PERI-CRIT randomized trial demonstrated that ivabradine, despite effectively lowering heart rate without causing hypotension, did not reduce the incidence of myocardial injury after noncardiac surgery in patients at risk of atherosclerotic cardiovascular disease. This negative result tempers enthusiasm for selective heart rate reduction as a standalone strategy in the perioperative period and highlights the ongoing need for effective, safe interventions to mitigate MINS.

Clinicians should continue adhering to established perioperative cardiovascular risk management practices, balancing benefits and risks of beta-blockade case by case. Future research should focus on elucidating underlying mechanisms of MINS, refining risk prediction, and developing multifaceted prevention strategies beyond heart rate control alone.

References

1. Szczeklik W, Fronczek J, Putowski Z, et al; PERI-CRIT investigators. Ivabradine in Patients Undergoing Noncardiac Surgery: a Randomized Controlled Trial. Circulation. 2025 Aug 30. doi: 10.1161/CIRCULATIONAHA.125.076704. Epub ahead of print. PMID: 40884771.