Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial)

Submitted by:
Stephen M. Pastores, MD, FCCP
Steering Committee Member
Cardiovascular Medicine and Surgery NetWork

Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomized controlled trial. Lancet 2008; 371:1839-1847.

POISE Study Group, Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Málaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P.

The use of β-blockers in the perioperative setting has remained controversial and a subject of much debate. The POISE (Perioperative Ischemic Evaluation) trial was a randomized controlled trial conducted between October 2002 and July 2007 in 190 hospitals in 23 countries designed to further investigate the effects of perioperative β-blocker therapy.1 In this trial, 8,351 patients with, or at risk of, atherosclerotic disease who were undergoing noncardiac surgery were randomly assigned to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177). The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or cardiac arrest. Patients were eligible for the trial if they were undergoing noncardiac surgery, aged >45 years, had an expected length of hospital stay of at least 24 h, and fulfilled any one of the following criteria: history of coronary artery disease, peripheral vascular disease, stroke, hospitalization for congestive heart failure (CHF) within the previous 3 years, undergoing major vascular surgery (ie, vascular surgery except arteriovenous shunt, vein stripping procedures, and carotid endarterectomies), or any three of seven risk criteria (undergoing intrathoracic or intraperitoneal surgery, history of CHF, transient ischemic attack, diabetes, serum creatinine >175 μmol/L, age >70 years, or undergoing emergent or urgent surgery). Patients were excluded for heart rate <50 beats per minute (bpm); second- or third-degree heart block; asthma; if receiving a β-blocker or their physician planned to start one perioperatively; prior adverse reaction to a β-blocker; coronary artery bypass graft surgery in the preceding 5 years with no cardiac ischemia since that time; low-risk surgical procedure (based on individual physician's judgment); receiving verapamil; or previous enrollment in the POISE trial.

Patients received the first dose of oral extended-release metoprolol, 100 mg, or matching placebo 2 to 4 h before surgery. Study drug administration required a heart rate of >50 bpm and a systolic BP >100 mm Hg. If, at any time during the first 6 h after surgery, heart rate was >80 bpm and systolic BP was >100 mm Hg, patients received their first postoperative dose (extended-release metoprolol, 100 mg, or matched placebo) orally. If the study drug was not given during the first 6 h, patients received their first postoperative dose at 6 h after surgery. Twelve hours after the first postoperative dose, patients started taking oral extended-release metoprolol, 200 mg, or placebo every day for 30 days. If a patient's heart rate was consistently below 45 bpm or their systolic BP dropped <100 mm Hg, the study drug was withheld until their heart rate or systolic BP recovered; the study drug was then restarted at 100 mg once daily. Patients whose heart rate was consistently 45 to 49 bpm and whose systolic BP exceeded 100 mm Hg delayed taking the study drug for 12 h.

The study was designed to provide 85% power with 8,000 patients and 92% power with 10,000 patients to detect a relative risk reduction of 25% (two-sided α=0·05). 13 PJ Devereaux, H Yang and GH Guyatt et al., Rationale, design, and organization of the PeriOperative ISchemic Evaluation (POISE) trial: a randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery, Am Heart J 152 (2006), pp. 223–230.After more than 8,000 patients were enrolled, and with a higher than predicted event rate, the independent safety and monitoring committee decided to terminate recruitment on July 31, 2007, mainly because the remaining study drug expired in September 2007. Patients were analyzed on an intention-to-treat basis. Patients lost to follow-up without having the outcome of interest were censored on the last day their outcome status was known. All analyses used Cox proportional hazards models, except for new clinically significant atrial fibrillation; cardiac revascularization; CHF; clinically significant hypotension; and clinically significant bradycardia, for which a χ2 test was used. Primary and secondary subgroup analyses were prespecified on the basis of the revised cardiac risk index scoring system and on the basis of sex, type of surgery, and use of an epidural or spinal anesthetic, respectively. For all subgroup analyses, Cox proportional hazards models that incorporated tests for interactions was used and p<0.05 was considered significant.

The trial showed that the primary endpoint of cardiac death, nonfatal myocardial infarction or cardiac arrest, was reduced in the metoprolol study group compared with placebo (5.8% vs 6.9%; hazard ratio, 0.84; 95% confidence interval, 0.70 to 0.99; p=0.04). This beneficial effect resulted from fewer myocardial infarctions in the metoprolol group than in the placebo group (0.73, 0.60-0.89, p=0.0017). However, these improvements were at the cost of an increased incidence of total mortality and stroke. Stroke was associated with perioperative hypotension, bleeding, atrial fibrillation, and a history of stroke or transient ischemic attack in patients assigned to receive metoprolol.

In the accompanying editorial, Fleisher and Poldermans2 suggest that the POISE trial supports the results of the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo) trial and other trials of long-acting β-blocker agents in reducing perioperative cardiac events, although with an increased incidence of stroke.3, 4 The increased incidence of stroke may be related to the hypotension induced by β-blockers although other potential mechanisms may exist. Other randomized trials of acute initiation of β-blockers immediately before surgery also have shown an increased rate of stroke.

The results of this trial and prior metaanalyses suggest that clinicians should be cautious in using β-blockers to prevent adverse cardiac events in patients undergoing surgery and that more large studies are urgently needed. As the editorialists point out,2 the overriding theme is that tachycardia caused by perioperative events, such as bleeding, hypovolemia, inadequate control of pain, or infection, should not be initially treated with additional β-blocker therapy. They recommend that the underlying cause of these conditions should be treated first and, if tachycardia persists, a β-blocker can be used cautiously in high-risk patients with proven or suspected coronary artery disease. These patients preferably would be supervised in the perioperative setting by physicians who have experience with perioperative hemodynamics so that hypotension and other hemodynamic alterations, which might have led to the increased incidence of stroke or septic death, are avoided.
References:

1. POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008; 371:1839-1847. Epub 2008, May 12
2. Fleisher LA, Poldermans D. Perioperative β-blockade: where do we go from here? Lancet 2008; 371:1813-1814
3. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery: Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341:1789-1795
4. Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol 2006; 48:964-969. Epub 2006, Aug 17