Blessberger H, Kammler J, Domanovits H, et al. Perioperative beta-blockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst Rev. 2018 Mar 13;3:CD004476. doi: 10.1002/14651858.CD004476.pub3.
Area Score
Surgery - Thoracic
Cardiology
Surgery - Vascular
Surgery - Gastrointestinal
Surgery - General
Hospital Doctor/Hospitalists
Internal Medicine
Anesthesiology
Surgery - Cardiac
Surgery - Orthopaedics
Surgery - Neurosurgery
Surgery - Head and Neck
Abstract

BACKGROUND: Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue.

OBJECTIVES: The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia.

SEARCH METHODS: We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, Embase , the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature.

SELECTION CRITERIA: We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers.

MAIN RESULTS: We included 88 randomized controlled trials with 19,161 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery.CARDIAC SURGERY (53 trials)We found no clear evidence of an effect of beta-blockers on the following outcomes.• All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality evidence.• Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality evidence.• Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality evidence.• Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality evidence.• Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality evidence.• Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality evidence.Beta-blockers significantly reduced the occurrence of the following endpoints.• Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB five, 6420 participants, high quality evidence.• On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality evidence).NON-CARDIAC SURGERY (35 trials)Beta-blockers significantly increased the occurrence of the following adverse events.• All-cause mortality: RR 1.25, 95% CI 1.00 to 1.57, 11,413 participants, low quality of evidence, number needed to treat for an additional harmful outcome (NNTH) 167.• Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 16, 10,947 participants, high quality evidence.• Bradycardia: RR 2.23, 95% CI 1.48 to 3.36, NNTH 21, 11,033 participants, moderate quality evidence.We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.• Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality evidence.Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta-analysis to 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, NNTH 265, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.• AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 76, 10,958 participants, high quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.34 to 0.77, NNTB nine, 978 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.73, 95% CI 0.57 to 0.94, NNTB 112, 8744 participants, high quality evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.• Ventricular arrhythmias: RR 0.68, 95% CI 0.31 to 1.49, 476 participants, moderate quality evidence.• Congestive heart failure: RR 1.18, 95% CI 0.94 to 1.48, 9173 participants, moderate quality evidence.• Length of hospital stay: mean difference -0.45 days, 95% CI -1.75 to 0.84, 551 participants, low quality evidence.

AUTHORS' CONCLUSIONS: According to our findings, perioperative application of beta-blockers still plays a pivotal 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 shows an association of beta-blockers with increased all-cause mortality. Data from low risk of bias trials further suggests an increase in stroke rate with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke.

Comments from MORE raters

Anesthesiology rater

This Cochrane review evaluates the use of perioperative beta-blockers in preventing surgery-related morbidity and mortality. The authors evaluated RCTs where participants were given either a beta-blocker or placebo. They found 88 randomized trials with 19,161 participants. Studies show no clear evidence of an effect in cardiac surgery patients for all-cause mortality, acute MI, myocardial ischemia, CV events, hypotension, bradycardia, or congestive heart failure. With non-cardiac surgery, beta-blockers increased all-cause mortality, hypotension, bradycardia, and CV events. In non-cardiac surgery, beta-blockers reduced AMI, myocardial ischemia, and SVT. They also showed no effect on ventricular arrhythmias, CHF, and hospital stay. Beta-blockers increase all-cause mortality and stroke rate. Anesthesiologists know about the problems with beta-blocker use in selected populations and about the increase in stroke and mortality with their perioperative use.

Anesthesiology rater

The circle is complete. I remember when everyone undergoing non-cardiac surgery received beta-blockers. However, the benefit of a decreased risk for MI in non-cardiac surgery is offset by an increased risk for stroke. Clinicians should maintain patients on beta-blockers, but there is no benefit to starting them in the perioperative period.

Hospital Doctor/Hospitalists rater

This Cochrane review provides additional information to inform general internists about the magnitude of benefit expected when recommending peri-operative beta-blockers for cardiac and non-cardiac surgery. The risk-benefit trade-offs would favor beta-blockers for most patients having cardiac surgery (reduced rate of arrhythmias). The results are more ambiguous for patients having non-cardiac surgery. The review does not review subsets where perioperative beta-blockers might be more beneficial (e.g., patients with heart failure, renal insufficiency, diabetes). The Surgical Care Improvement Project measure (SCIP-Card-2) focused on patients who were taking a beta-blocker prior to admission as the group to receive the medication during the perioperative period, which is a different patient population than addressed by this Cochrane review. I believe the review may prompt internists to consider restricting their recommendations for peri-operative beta-blockers to specific populations.

Internal Medicine rater

This appears to include major studies about this issue with some helpful conclusions.

Internal Medicine rater

For non-cardiac surgery, the summary doesn't do justice here as the results seem entirely driven by POISE, which gave patients a very large dose of long-acting metoprolol to beta-blocker-naïve patients right before surgery. In fact, Analysis 4.2 shows an improvement in long-term mortality among high-risk patients undergoing non-cardiac surgery. (The debate continues.)

Surgery - Cardiac rater

Beta blockers are still used around the peri-operative period. This is one of the most important SCIP measures and one gets penalized for not using this. However, several studies have shown only adverse outcome and in spite of the evidence against it, it is still a measure. It is time to abandon the use except for selected patients. Even the rhythm control after cardiac surgery is not practicable.

Surgery - Gastrointestinal rater

More evidence needed before this can be introduced for widespread use.

Surgery - General rater

This is on par with recent guidelines.

Surgery - General rater

I was of the impression that perioperative beta-blockade was something to consider in my pre-op patients with cardiac issues. Obviously, this contradicts that notion for patients undergoing non-cardiac surgery. While decreasing the incidence of acute MI, myocardial ischemia, and supraventricular tachycardia, perioperative beta-blockade increased all-cause mortality, hypotension, and bradycardia, and potentially increased cerebrovascular events.

Surgery - Head and Neck rater

As an otolaryngologist, this is relevant to my clinical practice. Routine use of beta-blockers is not useful and may be harmful for patients undergoing non-cardiac surgery.

Surgery - Neurosurgery rater

This is a high quality systematic review, however it is the standard of care for neurosurgical practice in my country that patients older than 35 years are evaluated by a cardiologist before undergoing any operation which is why I don't think reading this will affect my colleagues decision of preoperative care, since we already follow the final recommendation which is a case by case evaluation of the cases before surgery.

Surgery - Neurosurgery rater

In non-cardiac surgery, starting a beta-blocker before surgery to counter the rise in catecholamines is an obvious way to decrease the risk for MI during the perioperative period. The increase in deaths and strokes at one year, which offsets the early benefits, might be dose-related. More studies, therefore, should be done to determine what causes these late negative effects.

Surgery - Thoracic rater

This is a very interesting review about an issue of relevance in management.

Surgery - Vascular rater

I appreciate the enormous undertaking to compile all of these studies regarding beta-antagonists. In most cases, surgeons are not going to stop beta-antagonists peri-op, and since most patients are already taking them, the utility of this information is limited to confirmation that established practice patterns can continue with the trade-offs in outcomes after non-cardiac surgery as described. It remains somewhat concerning that the cardiac benefits may be outweighed by risks of other problems that impact peri-op mortality.