The publication of a large-scale randomised trial with extended-release metoprolol succinate (AstraZeneca’s Toprol XL) has re-ignited a debate over whether the recommended use of beta-blockers to reduce the risk of cardiovascular complications in people undergoing non-cardiac surgery may be doing more harm than good.

The initial results of the PeriOPerative ISchemic Evaluation (POISE) trial led by Dr Philip Devereaux of McMaster University in Hamilton, Canada were presented at an American Heart Association meeting last November. The key finding was that, while perioperative (i.e., around the time of surgery) administration of metoprolol reduced the risk of non-fatal myocardial infarctions (heart attacks) associated with non-cardiac surgery, it also significantly increased the risk of death or stroke.

“Patients who would place three times more value on avoiding a perioperative stroke than on avoiding a myocardial infarction, or who are unwilling to accept a probable increase in mortality, are unlikely to want perioperative extended-release metoprolol,” the authors concluded. “Current perioperative guidelines that recommend beta-blocker therapy to patients undergoing non-cardiac surgery should reconsider their recommendations in light of these findings.”

Every year more than 100 million adults have non-cardiac surgery and over one million of these are likely to encounter major cardiovascular complications. As the researchers explained, non-cardiac surgery raises levels of catecholamines – hormones released by the adrenal glands in situations of stress. This prompts an increase in heart rate, blood pressure and free fatty acid concentrations, which in turn boosts demand for myocardial oxygen.

The theory is that, as beta-blockers attenuate the effects of increased catecholamine levels, they may help to prevent perioperative cardiovascular complications. However, evidence to this effect from clinical trials has so far been patchy. Small non-cardiac surgery trials with atenolol and bisoprolol have suggested that beta-blockers may reduce the occurrence of major cardiovascular events, although these studies have methodological limitations, Devereaux et al noted.

On the other hand, recent moderate-sized randomised controlled trials of perioperative beta-blockers in non-cardiac surgery did not show benefit, they added. And a meta-analysis of randomised controlled trials involving non-cardiac surgery indicated that beta-blockers may prevent major cardiovascular events but also increase the risk of hypotension and brachycardia.

Less MI, more stroke

The POISE trial was conducted in 190 hospitals across 23 countries. A total of 8,351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery were randomised to either extended-release metoprolol succinate (4,174 patients) or placebo (4,177). Treatment with metoprolol 100mg was started two to four hours before surgery and continued for 30 days (the dose was raised to metoprolol 200mg per day 12 hours after the first post-operative dose). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal cardiac arrest.

Among the 8,331 patients who completed the 30-day follow-up, the primary endpoint was reached by 244 patients in the metoprolol group and 290 on placebo, a reduced risk of 16% for metoprolol. The risk reduction for myocardial infarction was 27%, with 176 patients in the metoprolol group reaching this endpoint compared with 239 in the placebo group.

However, there were more deaths on metoprolol (129) than in the placebo group, an increased risk of 33%. And the risk of stroke was more than doubled in the metoprolol group (41 strokes recorded) versus placebo (19).

“Our results suggest that for every 1,000 patients with a similar risk profile undergoing non-cardiac surgery, extended-release metoprolol would prevent 15 patients from having a myocardial infarction, three from undergoing cardiac revascularisation, and seven from developing new clinically significant atrial fibrillation,” the authors noted.

“The results also suggest that extended-release metoprolol would result in an excess of eight deaths, five patients having a stroke, 53 experiencing clinically significant hypotension, and 42 experiencing clinically significant bradycardia [slow heart beat] for every 1,000 treated,” they added.

Similar conclusions were drawn from a number of meta-analyses of trials involving perioperative beta-blockers that included events within a 30-day follow-up period. Post-hoc multivariate analyses indicated that hypotension may be to blame for the increased risk of stroke seen with beta-blockers in non-cardiac surgery, although identified risk factors explained only half of these events.

Risky assumption

The paper published in The Lancet highlights “the risk in assuming a perioperative beta-blocker regimen has benefit without substantial harm”, the authors commented. Given the high number of surgical procedures performed and the high risk of cardiovascular complications, “more large trials are needed urgently”, they said.

An accompanying comment piece in The Lancet took a more qualified stance, although both authors – Dr Lee Fleisher of the University of Pennsylvania School of Medicine in the US and Dr Don Poldermans of the Erasmus Medical Centre in Rotterdam, the Netherlands – had a stake in defending prior recommendations that perioperative beta-blockers should be used in non-cardiac surgery.

Specifically, Dr Fleisher was part of an American College of Cardiology/American Heart Association task force that has recommended perioperative beta-blocker therapy in non-cardiac surgery patients at risk of cardiac events. Dr Poldermans was one of the researchers in the DECREASE series of trials, which found that the beta-blocker bisoprolol reduced perioperative cardiac death and myocardial infarction in high-risk patients undergoing major vascular surgery.

In their editorial, Fleisher and Poldermans did not dispute the outcomes of the POISE trial but questioned why they should differ so markedly from experience in the non-surgical setting, where beta-blockers are “the cornerstone in the treatment of coronary artery disease, improving survival in patients with angina pectoris, myocardial infarction, peripheral arterial disease and heart failure”.

One reason, they suggested, may be the treatment regimens used: for example, in the POISE study the starting dose of metoprolol was 2-8 times the commonly prescribed dose in non-surgical patients. By contrast, in the DECREASE trials the starting dose of bisoprolol was 25% of the maximum daily therapeutic dose in the initial studies and was lowered to 12% in the more recent studies.

The initiation time for beta-blocker therapy before surgery could be another important factor, Fleisher and Poldermans said. The incidence of perioperative stroke with a low-dose bisoprolol regimen started at least seven days before surgery in the DECREASE trials was 0.4% out of 3,994 patients, a comparable level to placebo.

“The current trial clearly shows that acute administration of higher-dose beta-blocker therapy in the perioperative period is associated with greater risk than benefit, but we believe that the protocol used in the DECREASE studies (low-dose long-acting agents titrated to effect at least seven days in advance) is associated with overall benefit compared to risk,” they commented.

The POISE trial was partly supported by AstraZeneca, which has seen Toprol XL sales plummet in the face of generic competition. Using the drug before cardiac surgery is not an approved indication, the company has pointed out.