ACCEL: The Perioperative Ischemic Evaluation (POISE) trial: A randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery

The prevalence of cardiovascular disease increases with age, as does the need for noncardiac surgery. As the number of persons older than 65 years in the United States increases over the next 30 years, the number of noncardiac surgical procedures performed in this population likely will increase from the current 6 million to nearly 12 million per year, and nearly one-fourth of these - major intra-abdominal, thoracic, vascular, and orthopedic procedures - have been associated with significant perioperative cardiovascular morbidity, mortality, and consequent cost. In a review of the magnitude of the problem, as well as the pathophysiology of the events, P.J. Devereaux, MD, and colleagues, noted, for example, that patients experiencing myocardial infarction (MI) after noncardiac surgery have a hospital mortality rate of 15%-25%, and nonfatal perioperative MI is an independent risk factor for cardiovascular death and nonfatal MI during the 6 months following surgery. Cardiac complications after noncardiac surgery result in substantial cost because these events prolong hospitalization by a mean of 11 days. Perioperative beta-blocker therapy has been evaluated to prevent cardiovascular events following noncardiac surgery. However, these have been small, underpowered studies with conflicting results. In a 2002 review of the data, investigators noted that despite the heterogeneity of trials, "a growing literature suggests a benefit of beta blockade in preventing perioperative cardiac morbidity." In a study of 200 patients undergoing general surgery randomized to a combination of intravenous and oral atenolol versus placebo for 7 days, there was no difference in perioperative MI or death, but there were significantly fewer episodes of ischemia by Holter monitoring in the atenolol versus placebo groups. During follow-up of these patients, the investigators documented fewer deaths in the atenolol group over the subsequent 6 months (1% vs. 10%; p < 0.001). Moreover, patients with postoperative episodes of myocardial ischemia were more likely to die in the next 2 years (p = 0.025). However, methodologic and statistical problems rendered the conclusions difficult to interpret. In another study of 103 patients without previous MI who had infrarenal vascular surgery, myocardial ischemia was evident in a high proportion (one-third) of the patients after surgery, but perioperative beta-blockade with metoprolol did not reduce 30-day cardiovascular events, although it did decrease the time from surgery to discharge. Such patients undergoing vascular surgery comprise the highest-risk group for perioperative cardiac mortality and morbidity after noncardiac procedures. However, in the larger Metoprolol after Vascular Surgery (MaVS) trial (∼500 patients), this approach was not effective in reducing 30-day and 6-month postoperative cardiac event rates in vascular surgery patients (Slide 1). Patients with diabetes, who are considered at higher risk of cardiovascular events, were evaluated in a trial by Juul et al. They randomized 921 diabetic subjects undergoing a range of non-cardiac operations to either 100 mg of extended-release metoprolol or placebo in the Diabetic Postoperative Mortality and Morbidity (DIPOM) study. There was no significant difference in the composite primary outcome measure (time to all-cause mortality, acute MI, unstable angina, or congestive heart failure) nor was there any difference in mortality during a median follow-up of 18 months (Slide 2). After evaluating the available evidence, the American College of Cardiology/American Heart Association (ACC/AHA) 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery found that the data "strongly suggest but do not definitively prove that when possible, beta-blockers should be started days to weeks before elective surgery." (Slide 3 reviews the guideline recommendations for perioperative beta-blocker therapy).