This review assessed evidence from randomized controlled trials (RCTs) on whether beta-blockers reduce deaths or other serious events when given to people undergoing surgery other than heart surgery. The findings for heart surgery are covered in another review.
Background
Surgery increases stress in the body, which responds by releasing the hormones adrenaline and noradrenaline. Stress from surgery can lead to death or other serious events such as heart attacks, stroke, or an irregular heartbeat. For surgery that does not involve the heart, an estimated 8% of people may have injury to their heart around the time of surgery. Beta-blockers are drugs that block the action of adrenaline and noradrenaline on the heart. Beta-blockers can slow down the heart, and reduce blood pressure, and this may reduce the risk of serious events. However, beta-blockers may lead to a very low heart rate or very low blood pressure which could increase the risk of death or a stroke. Prevention of early complications after surgery is important, but using beta-blockers to prevent these complications is controversial.
Study characteristics
The evidence is current to 28 June 2019. We included 83 RCTs with 14,967 adults who were undergoing different types of surgery other than heart surgery. Eighteen studies are awaiting classification (because we did not have enough details to assess them), and three studies are ongoing. The types of beta-blockers used in the studies were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. Studies compared these beta-blockers with either a placebo (disguised to look like a beta-blocker but containing no medicine) or with standard care.
Key results
Beta-blockers may make little or no difference to the number of people who die within 30 days of surgery (16 studies, 11,446 participants; low-certainty evidence), have a stroke (6 studies, 9460 participants; low-certainty evidence), or experience ventricular arrhythmias (irregular heartbeat rhythms, starting in the main chambers of the heart, that are potentially life-threatening and may need immediate medical treatment; 5 studies, 476 participants; very low-certainty evidence). We found that beta-blockers may reduce atrial fibrillation (an irregular heartbeat, starting in the atrial chambers of the heart, that increases the risk of stroke if untreated; 9 studies, 9080 participants; low certainty-evidence), and the number of people who have a heart attack (12 studies, 10,520 participants; low-certainty evidence). However, taking beta-blockers may increase the number of people who experience a very low heart rate (49 studies, 12,239 participants; low-certainty evidence), or very low blood pressure (49 studies, 12,304 participants; moderate-certainty evidence), around the time of surgery.
In a few studies, we also found little or no difference in the number of people who died after 30 days, who died because of a heart problem, or had heart failure. We found no evidence of whether beta-blockers alter the length of time in hospital.
No studies assessed whether people who were given beta-blockers had a better quality of life after heart surgery.
Certainty of the evidence
The certainty of the evidence in this review was limited by including some studies that were at high risk of bias, and we noticed that some of our findings were different if we only included placebo-controlled studies or studies that reported how participants were randomized. We also found one large, well-conducted, international study that had different findings to the smaller studies. It showed a reduction in heart attacks and an increase in stroke and all-cause mortality when beta-blockers were used, whilst the other studies did not show a clear effect. We were also less certain of the findings for outcomes with few studies, such as for ventricular arrhythmias.
Conclusion
Although beta-blockers may make little or no difference to the number of people who die within 30 days, have a stroke, or have ventricular arrhythmias, they may reduce atrial fibrillation and heart attacks. Taking beta-blockers may increase the number of people with a very low heart rate or very low blood pressure around the time of surgery. Further evidence from large, placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life.
The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.
Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in an unselected population remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update, and assesses the evidence in non-cardiac surgery only.
To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing non-cardiac surgery.
We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles.
We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing non-cardiac surgery. If studies included surgery with different types of anaesthesia, we included them if 70% participants, or at least 100 participants, received general anaesthesia. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes.
Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.
We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period.
The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence).
We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants.