Perioperative beta-blockers for preventing surgery-related mortality and morbidity
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Hans Van Brabandt
The Cochrane Collaboration issued a meta-analysis on the clinical effectiveness of perioperative beta-blockers for preventing surgery-related mortality and morbidity.1 The primary outcome was all-cause mortality, defined as death due to any cause occurring up to 30 days postoperatively. Secondary outcomes included the incidence of acute myocardial infarction, stroke, arrhythmias, hypotension, congestive heart failure, and length of stay. Outcomes were evaluated separately for cardiac and non-cardiac surgery.
After cardiac surgery there was no evidence of an effect of beta-blockers on death. These drugs had a protective effect against both ventricular and supraventricular rhythm disturbances. The study found no evidence of an effect on the occurrence of myocardial infarction, stroke or heart failure after cardiac surgery. In non-cardiac surgery, beta-blockers increased the risk of death and stroke when high-quality trials were considered.
Cardiovascular complications are reported in 15 to 24% of patients undergoing surgery with perioperative myocardial infarction occurring in up to 6% of them. Even in non-cardiac surgery, an estimated 4% of patients will have a perioperative cardiac complication. It has been suggested that these cardiac adverse events are related to increases in heart rate and myocardial oxygen consumption, induced by the sympathetic response that is associated with surgery. Perioperative blockade of beta-adrenergic receptors therefore has been proposed to reduce the risk of perioperative complications.1
In 2009, the European Society of Cardiology (ESC) guidelines on perioperative care endorsed a class I recommendation (“There is evidence and/or general agreement that this treatment is beneficial, useful, effective”) for the use of beta-blockers in patients undergoing high-risk surgery and in those diagnosed with ischaemic heart disease.2 Later on, it appeared that this recommendation was essentially based on a fraudulent study.3 In an updated 2014 ESC guideline, the latter study was no longer taken into consideration and the class of recommendation was downgraded to level IIb (“usefulness/efficacy is less well established”).4 The Cochrane review that is discussed in the present document also excluded this fraudulent study.
Meta-analysis performed by the Cochrane Collaboration
The objective of this review was to analyse the effects of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing any type of surgery while under general anaesthesia.
The perioperative period was defined as 30 days before to 30 days after surgery. Administration of beta-blockers could occur via any route. They could be started before surgery, during surgery or at the latest by the end of the first day after surgery. Events were classified as “perioperative” if they occurred during or after surgery (from the time of induction of anaesthesia until 30 days after surgery).
We critically appraised the methodology followed by the authors of this systematic review by means of the AMSTAR instrument. This resulted in a 10/11 score, demonstrating its top quality.
Only randomised controlled trials (RCTs) were considered. Up to June 2013, 89 RCTs enrolling 19 211 participants were identified: 53 cardiac surgery trials and 36 trials in other types of surgery.
The primary outcome was all-cause mortality up to 30 days postoperatively (or before hospital discharge whichever came latest). Secondary outcomes were long-term all-cause mortality, cardiac mortality, the incidence of acute myocardial infarction (AMI), myocardial ischemia, cerebrovascular complications (transient ischemic attack, stroke), malignant ventricular arrhythmias, supraventricular arrhythmias (atrial fibrillation, flutter), severe bradycardia, hypotension, congestive heart failure, length of hospital stay, quality of life, and cost of care.
Studies and data were independently extracted by two researchers. For each outcome, data were pooled and meta-analysed. The GRADE methodology was used to assess the body of evidence.
In cardiac surgery, there was no clear evidence of an effect of beta-blockers on all-cause mortality: the relative risk (RR) was 0.73 [95% CI 0.35 to 1.52]. These drugs significantly reduced the occurrence of ventricular arrhythmias (RR 0.37 [95% CI: 0.24 to 0.58]), with a number needed to treat (NNT) for an additional beneficial outcome of 29. They also reduced the occurrence of supraventricular arrhythmias (RR 0.44 [95% CI: 0.36 to 0.53]) and a NNT of 6. There was no clear evidence of an effect on the other outcomes studied.
In non-cardiac surgery, beta-blockers were found to potentially increase all-cause mortality. Whereas no clear evidence of an effect on all-cause mortality was noted when all studies were analysed (RR 1.24, [95% CI 0.99 to 1.54]), restricting the meta-analysis to low risk of bias studies revealed a significant increase in all-cause mortality with the use of beta-blockers: RR 1.27 [95% CI: 1.01 to 1.59]); the number needed to harm (NNH) was 189. Similarly, beta-blockers in non-cardiac surgery were found to potentially increase cerebrovascular events. Meta-analysis of the low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09 [95% CI: 1.14 to 3.82], with a NNH of 255. Beta-blockers also significantly increased the occurrence of hypotension and bradycardia.
In non-cardiac surgery, beta-blockers reduced the occurrence of acute myocardial infarction: RR 0.73 [95% CI: 0.61 to 0.87], with a NNT of 72. Supraventricular arrhythmias were also significantly reduced with beta-blockers: RR 0.72 [95% CI: 0.56 to 0.92], with a NNT of 111.
Conclusions of the authors
The perioperative application of beta-blockers still plays a role in cardiac surgery as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear.
In non-cardiac surgery, evidence from high quality trials shows an increase in all-cause mortality and stroke with the use of beta-blockers. This is likely to offset the substantial reduction in supraventricular arrhythmias and AMI in this setting. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn.
1. Blessberger H, Kammler J, Domanovits H, Schlager O, Wildner B, Azar D, et al. Perioperative beta-blockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst Rev. 2014;9:CD004476.
2. The Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA). Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. Eur Heart J. 2009;30(22):2769-812.
3. Cole GD, Francis DP. Perioperative beta blockade: guidelines do not reflect the problems with the evidence from the DECREASE trials. BMJ. 2014;349:g5210.
4. The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Guidelines on non-cardiac surgery: cardiovascular assessment and management: Eur Heart J. 2014;35(35):2383-431.