Ivabradine Fails to Prevent Myocardial Injury After Noncardiac Surgery in PREVENT-MINS Trial
核心洞察
The PREVENT-MINS (搜索) trial found that ivabradine did not reduce myocardial injury after noncardiac surgery (搜索) (MINS) compared to placebo in 2,101 patients aged ≥45 years with atherosclerotic disease (搜索) risk factors.
MINS (搜索) occurred in 17.0% of ivabradine patients versus 15.1% of placebo patients, with the trial terminated early for futility after showing no significant benefit.
Unexpectedly, ivabradine was associated with increased MINS (搜索) risk in patients with existing coronary artery disease (搜索), contrary to the original hypothesis.
The PREVENT-MINS (搜索) trial has delivered disappointing results for ivabradine as a potential preventive therapy for myocardial injury after noncardiac surgery (搜索) (MINS), with the heart rate-lowering drug failing to demonstrate efficacy in a large randomized controlled study presented at ESC Congress 2025.
Trial Design and Rationale
The double-blind, placebo-controlled PREVENT-MINS (搜索) trial was conducted across 26 hospitals in Poland, enrolling patients aged ≥45 years with established atherosclerotic disease (搜索) or substantial risk factors. The study was based on the hypothesis that increased heart rate during surgery leads to higher myocardial oxygen consumption and supply-demand mismatch, resulting in myocardial injury.
"It has been proposed that increased heart rate at the time of surgery leads to higher myocardial oxygen consumption, a supply-demand mismatch and myocardial injury," explained Principal Investigator Professor Wojciech Szczeklik from Jagiellonian University Medical College (搜索), Krakow, Poland. "Giving beta-blockers (搜索) around the time of surgery lowers heart rate and decreases the risk of myocardial infarction (搜索), but these benefits may be offset by increased risk of hypotension, death and stroke (搜索)."
Ivabradine was selected for investigation because it more selectively slows heart rate than beta-blockers (搜索), potentially offering cardiovascular protection without the associated risks of hypotension and stroke (搜索).
Study Population and Methodology
The trial randomized 2,101 participants in a 1:1 ratio to receive either ivabradine (5 mg orally twice daily for up to 7 days, starting one hour before surgery) or placebo. The median age was 70.0 years, and 49.4% were women. Eligible patients had either established atherosclerotic disease (搜索) including coronary artery disease (搜索), peripheral artery disease (搜索), or prior stroke (搜索), or substantial risk factors such as diabetes (搜索), hypertension (搜索), and age ≥70 years.
The primary outcome was MINS (搜索) within 30 days from randomization. Originally designed to enroll approximately 2,500 patients, the trial was terminated early in March 2025 following a recommendation from the independent Data Monitoring Committee based on a prespecified interim analysis showing futility.
Primary Results Show No Benefit
The results revealed no significant difference in MINS (搜索) occurrence between treatment groups. MINS occurred in 17.0% of patients in the ivabradine group compared to 15.1% in the placebo group (relative risk [RR] 1.12; 95% confidence interval [CI] 0.92 to 1.37; p=0.25).
Physiologically, ivabradine achieved its intended effect of heart rate reduction, with the intraoperative mean heart rate being 3.2 beats per minute lower in the ivabradine group compared to placebo. However, this modest reduction did not translate into clinical benefit, and there was no difference in intraoperative mean arterial pressure between groups.
Unexpected Subgroup Findings
Perhaps most concerning were the prespecified subgroup analyses, which revealed an unexpected pattern. Among patients with a history of coronary artery disease (搜索), ivabradine was associated with an increased risk of MINS (搜索) (RR 1.49; 95% CI 1.03 to 2.16). This finding was not observed in patients without a history of coronary artery disease (RR 0.98; 95% CI 0.78 to 1.24).
The drug also demonstrated a safety signal, with clinically important bradycardia (搜索) being more common in the ivabradine group (RR 1.18; 95% CI 1.00 to 1.40).
Clinical Implications and Future Directions
The failure of ivabradine to prevent MINS (搜索) represents a significant setback in addressing this common and serious surgical complication. MINS has been found to account for approximately 13% of all deaths within 30 days of surgery, making it a critical target for intervention.
"Ivabradine did not reduce the risk of MINS (搜索) in patients undergoing noncardiac surgery. Heart-rate lowering was modest and the possible higher MINS incidence in patients with known coronary artery disease (搜索) is contrary to our original hypothesis," Professor Szczeklik concluded. "Further research is needed to establish a method to safely control the heart's stress associated with noncardiac surgery."
The results challenge the assumption that selective heart rate reduction would provide cardiovascular protection during noncardiac surgery and highlight the complex pathophysiology underlying MINS (搜索). The unexpected increased risk in patients with existing coronary artery disease (搜索) suggests that the mechanisms contributing to perioperative myocardial injury may be more complex than previously understood, requiring alternative therapeutic approaches.