Perioperative Beta-Blocker Management

Current European and American guidelines recommend the perioperative initiation of a course of &#x3b2;-blockers in those at risk of cardiac events undergoing high- or intermediate-risk surgery or vascular surgery. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) family of trials, the bedrock of evidence for this, are no longer secure. We therefore conducted a meta-analysis of randomised controlled trials of &#x3b2;-blockade on perioperative mortality, non-fatal myocardial infarction, stroke and hypotension in non-cardiac surgery using the secure data. The randomised controlled trials of initiation of &#x3b2;-blockers before non-cardiac surgery were examined. Primary outcome was all-cause mortality at 30 days or at discharge. The DECREASE trials were separately analysed. Nine secure trials totalling 10 529 patients, 291 of whom died, met the criteria. Initiation of a course of &#x3b2;-blockers before surgery caused a 27% risk increase in 30-day all-cause mortality (p=0.04). The DECREASE family of studies substantially contradict the meta-analysis of the secure trials on the effect of mortality (p=0.05 for divergence). In the secure trials, &#x3b2;-blockade reduced non-fatal myocardial infarction (RR 0.73, p=0.001) but increased stroke (RR 1.73, p=0.05) and hypotension (RR 1.51, p<0.00001). These results were dominated by one large trial. Guideline bodies should retract their recommendations based on fictitious data without further delay. This should not be blocked by dispute over allocation of blame. The well-conducted trials indicate a statistically significant 27% increase in mortality from the initiation of perioperative &#x3b2;-blockade that guidelines currently recommend. Any remaining enthusiasts might best channel their energy into a further randomised trial which should be designed carefully and conducted honestly.

Trials of beta blockers in patients undergoing non-cardiac surgery have reported conflicting results. This randomised controlled trial, done in 190 hospitals in 23 countries, was designed to investigate the effects of perioperative beta blockers. We randomly assigned 8351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177), by a computerised randomisation phone service. Study treatment was started 2-4 h before surgery and continued for 30 days. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00182039. All 8351 patients were included in analyses; 8331 (99.8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5.8%] patients in the metoprolol group vs 290 [6.9%] in the placebo group; hazard ratio 0.84, 95% CI 0.70-0.99; p=0.0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4.2%] vs 239 [5.7%] patients; 0.73, 0.60-0.89; p=0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] vs 97 [2.3%] patients; 1.33, 1.03-1.74; p=0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] vs 19 [0.5%] patients; 2.17, 1.26-3.74; p=0.0053). Our results highlight the risk in assuming a perioperative beta-blocker regimen has benefit without substantial harm, and the importance and need for large randomised trials in the perioperative setting. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.

Despite limited evidence from randomized trials, perioperative treatment with beta-blockers is now widely advocated. We assessed the use of perioperative beta-blockers and their association with in-hospital mortality in routine clinical practice. We conducted a retrospective cohort study of patients 18 years of age or older who underwent major noncardiac surgery in 2000 and 2001 at 329 hospitals throughout the United States. We used propensity-score matching to adjust for differences between patients who received perioperative beta-blockers and those who did not receive such therapy and compared in-hospital mortality using multivariable logistic modeling. Of 782,969 patients, 663,635 (85 percent) had no recorded contraindications to beta-blockers, 122,338 of whom (18 percent) received such treatment during the first two hospital days, including 14 percent of patients with a Revised Cardiac Risk Index (RCRI) score of 0 and 44 percent with a score of 4 or higher. The relationship between perioperative beta-blocker treatment and the risk of death varied directly with cardiac risk; among the 580,665 patients with an RCRI score of 0 or 1, treatment was associated with no benefit and possible harm, whereas among the patients with an RCRI score of 2, 3, or 4 or more, the adjusted odds ratios for death in the hospital were 0.88 (95 percent confidence interval, 0.80 to 0.98), 0.71 (95 percent confidence interval, 0.63 to 0.80), and 0.58 (95 percent confidence interval, 0.50 to 0.67), respectively. Perioperative beta-blocker therapy is associated with a reduced risk of in-hospital death among high-risk, but not low-risk, patients undergoing major noncardiac surgery. Patient safety may be enhanced by increasing the use of beta-blockers in high-risk patients.

&#x3b2;-Blockers are useful drugs in several clinical cardiologic scenarios. Their use in the perioperative period and in critically ill patients is increasing, but their effect on clinically relevant outcomes remains controversial. Long-acting &#x3b2;-blockers can have detrimental effects that are difficult to be counteracted in these settings. The authors describe the possible clinical uses of ultra-short-acting &#x3b2;-blockers (esmolol and landiolol) in the perioperative period and in critically ill patients because these drugs have the beneficial effects of &#x3b2;-blockers, but do not have the detrimental effects of long-acting agents. This narrative review focuses on ultra-short-acting &#x3b2;-blockers in the following clinical settings: prevention and treatment of arrhythmias and myocardial ischemia in noncardiac and cardiac surgery, usage as cardioplegia adjuvants or to test the reversibility of systolic anterior motion of the mitral valve in cardiac surgery, medical treatment of aortic dissection before surgery, improvement of microcirculation and oxygenation in critically ill patients experiencing sepsis or undergoing extracorporeal membrane oxygenation, anesthesia induction, and coronary computed tomography angiography.

The effectiveness of perioperative &#x3b2;-blockade in patients undergoing noncardiac surgery remains controversial. To determine the associations of early perioperative exposure to &#x3b2;-blockers with 30-day postoperative outcome in patients undergoing noncardiac surgery. A retrospective cohort analysis evaluating exposure to &#x3b2;-blockers on the day of or following major noncardiac surgery among a population-based sample of 136,745 patients who were 1:1 matched on propensity scores (37,805 matched pairs) treated at 104 VA medical centers from January 2005 through August 2010. All cause 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction). Overall 55,138 patients (40.3%) were exposed to &#x3b2;-blockers. Exposure was higher in the 66.7% of 13,863 patients undergoing vascular surgery (95% CI, 65.9%-67.5%) than in the 37.4% of 122,882 patients undergoing nonvascular surgery (95% CI, 37.1%-37.6%; P < .001). Exposure increased as Revised Cardiac Risk Index factors increased, with 25.3% (95% CI, 24.9%-25.6%) of those with no risk vs 71.3% (95% CI, 69.5%-73.2%) of those with 4 risk factors or more exposed to &#x3b2;-blockers (P < .001). Death occurred among 1.1% (95% CI, 1.1%-1.2%) and cardiac morbidity occurred among 0.9% (95% CI, 0.8%-0.9%) of patients. In the propensity matched cohort, exposure was associated with lower mortality (relative risk [RR], 0.73; 95% CI, 0.65-0.83; P < .001; number need to treat [NNT], 241; 95% CI, 173-397). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, &#x3b2;-blocker exposure was associated with significantly lower mortality among patients with 2 factors (RR, 0.63 [95% CI, 0.50-0.80]; P < .001; NNT, 105 [95% CI, 69-212]), 3 factors (RR, 0.54 [95% CI, 0.39-0.73]; P < .001; NNT, 41 [95% CI, 28-80]), or 4 factors or more (RR, 0.40 [95% CI, 0.25-0.73]; P < .001; NNT, 18 [95% CI, 12-34]). This association was limited to patients undergoing nonvascular surgery. &#x3b2;-Blocker exposure was also associated with a lower rate of nonfatal Q-wave infarction or cardiac arrest (RR, 0.67 [95% CI, 0.57-0.79]; P < .001; NNT, 339 [95% CI, 240-582]), again limited to patients undergoing nonvascular surgery. Among propensity-matched patients undergoing noncardiac, nonvascular surgery, perioperative &#x3b2;-blocker exposure was associated with lower rates of 30-day all-cause mortality in patients with 2 or more Revised Cardiac Risk Index factors. Our findings support use of a cumulative number of Revised Cardiac Risk Index predictors in decision making regarding institution and continuation of perioperative &#x3b2;-blockade. A multicenter randomized trial involving patients at a low to intermediate risk by these factors would be of interest to validate these observational findings.

An enduring controversy surrounds perioperative beta-blocker use in noncardiac surgery, in particular with regard to the cerebrovascular risks associated with long-term preoperative beta-blocker use. Although perioperative stroke is uncommon, its consequences are severe, and the growing recognition of covert perioperative stroke, affecting up to 7-12% of older patients, substantially magnifies its clinical significance. The debate was shaped principally by the POISE trial, which showed that acute initiation of high-dose extended-release metoprolol reduced myocardial infarction but significantly increased stroke and mortality. Subsequent evidence suggests that stroke risk depends on timing, dose, and drug class rather than beta-blockade per se. Current guidelines support continuation of chronic beta-blocker therapy while discouraging acute perioperative initiation, a position now challenged by emerging data. We discuss the recent findings of Rudolph and colleagues, who used causal inference methods in a large multicentre retrospective cohort of nearly 290&#x2009;000 patients to show that long-term preoperative beta-blocker prescription was independently associated with increased postoperative ischaemic stroke risk at 30 and 365 days. This association was most pronounced in lower-risk patients and was absent in those with severe heart failure, suggesting important effect modification by baseline cardiovascular status. We explore the pathophysiological mechanisms that could underline this association, address the methodological strengths and limitations of causal inference applied to large observational datasets, and advocate for a nuanced, individualised approach to perioperative beta-blocker management, particularly in patients without established cardiac indications.