Perioperative beta-blocker controversy begins again with new meta-analysis

London, UK - The debate over the perioperative use of beta-blockers in noncardiac surgery is flaring up once again with the publication of a new meta-analysis suggesting their use increases the risk of death [1]. In an analysis that excluded discredited clinical trials, investigators report that treatment of patients undergoing noncardiac surgery with beta-blockers resulted in a statistically significant 27% increased mortality risk.

"I would urge all my colleagues to consider the analysis in this paper and reconsider very carefully whether they wish to routinely use perioperative beta-blockade," senior researcher Dr Darrel Francis (Imperial College London, UK) told heartwire

Published online July 31, 2013 in Heart, the findings are likely to stir up more controversy, given that the 2009 European Society of Cardiology (ESC) guidelines state beta-blockers are a class I indication (with dose titration based on heart rate) in patients with established coronary artery disease or ischemia on a preoperative stress test or in patients undergoing high-risk surgery [2]. They are a class IIa indication in patients undergoing intermediate-risk surgery.

The ESC guidelines, along with the 2009 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) class IIa indication for patients undergoing vascular surgery [3], are based, in part, on data from the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo (DECREASE) studies. Dr Don Poldermans, formerly of Erasmus Medical Center, was best known for his work in using beta-blockers in surgery patients and published the first DECREASE paper in 1999 on the use of bisoprolol. He also authored subsequent DECREASE studies, including DECREASE IV, which addressed the perioperative use of beta-blockers. 

As has been reported extensively by heartwire and other media outlets, Poldermans was fired for violations of academic integrity and resigned from the ESC Committee for Practice Guidelines. Subsequent investigations into his research have questioned the validity of his findings, particularly the DECREASE studies. Complicating the whole matter further, Poldermans chaired the 2009 ESC guidelines for perioperative management in noncardiac surgery.

To heartwireDr Sripal Bangalore (New York University School of Medicine) said the newest meta-analysis raises important concerns about the safety and efficacy of perioperative beta-blockers, especially given the controversy surrounding the research by Poldermans. Irrespective of the DECREASE fiasco, Bangalore said his group already showed that the risk/benefit trade-off of perioperative beta-blocker use was unfavorable back in 2008 when they published a meta-analysis in the Lancet. In addition, the Perioperative Ischemic Evaluation(POISE) trial highlighted these same concerns. 

"In our meta-analysis, we found that the benefits, if any, were driven by trials with high risk for bias, including the DECREASE trial," Bangalore commented. 

As a result of the 2008 meta-analysis, the ACCF/AHA downgraded the recommendations from class I to IIa, but it is "surprising that the ESC guidelines still have a class I recommendation for perioperative beta-blockade," he added. Bangalore believes that neither now nor before the 2009 ESC guidelines were published did any solid evidence exist for beta-blocker use in this setting. 

Excluding the DECREASE studies

In the newest meta-analysis, with first author Dr Sonia Bouri (Imperial College London), the researchers included nine randomized controlled trials of beta-blockers given prior to noncardiac surgery. The nine trials, which involved 10 529 patients, excluded the DECREASE studies. The largest trial included in the meta-analysis was POISE, a study reported by heartwire, which first suggested beta-blockers may do more harm than good. 

After excluding DECREASE I and DECREASE IV, given questions about the integrity of these trials, perioperative treatment of noncardiac surgical patients with a beta-blocker increased the risk of death by 27%. Similarly, perioperative beta-blockade also increased the risk of stroke and hypotension. 

End points: Secure trials only (excludes DECREASE and DECREASE IV)

End point       Risk ratio (95% CI) 
Mortality       1.27 (1.01-1.60)
Nonfatal MI       0.73 (0.61-0.88)
Nonfatal stroke       1.73 (1.00-2.99)
Hypotension       1.51 (1.37-1.67)

To heartwire, Francis said the ESC guidelines recommending beta-blockade in noncardiac-surgery patients are based on analyses that include the now-discredited DECREASE I and IV studies. When these trials are included in the meta-analysis, the risk of mortality with beta-blockers is not statistically significant.

"The trouble is that DECREASE messed it all up," said Francis. "Once DECREASE is added to the mix, you could argue that the mortality risk is inconclusive, that there is no significant increased risk. So, what do you do next? You look at the risk of myocardial infarction, and here there is no controversy. Even I think myocardial infarction is reduced with beta-blockers. That is clear from the POISE trial. So we are right to think that it protects the heart, but it also does some other bad stuff, which unfortunately, is more important for the average patient." He added that the "heart is not the only game in town."

A fictitious adjudication committee

Francis said the investigation into Poldermans and the DECREASE studies found that the DECREASE IV study included a "fictitious adjudication committee" of a cardiologist, anesthesiologist, and surgeon, but the adjudications were made by the surgeon alone. Most important, documented clinical events, including MI, did not match hospital records or clinical discharge reports. However, the paper was never officially retracted and as a result the guidelines have remained in place. 

He has been waiting since the Poldermans"s investigation for updated ESC guidelines.

"Every day, as a cardiologist, I am called to advise on some surgical disaster," said Francis. "They ask what can be done. We can’t take them to the cardiac cath lab for a stent because they’ll be out of action for a minimum of four weeks because of clopidogrel. It was lovely to recommend beta-blockers because we thought we"d reduce their mortality and then we’d sort out their heart afterward. Unfortunately, we"ve been killing them."