Perioperative β-Blockers for Cardiac Risk Reduction: Time for Clarity

TLDR: The acute hemodynamic effects of -blockers help explain the adverse events associated with perioperative -blockade, because postoperative stroke and death are associated with -blocker–mediated bradycardiaandhypotension.

Abstract: PERIOPERATIVE CARDIAC EVENTS ARE COMMON AND thought to result from coronary plaque rupture, myocardial oxygen supply-demand mismatch, or a combination of these processes. In theory, -blockers are ideal for preventing these events, because they decrease myocardial oxygen requirements (by lowering heart rate and reducing blood pressure) and are thought to stabilize atherosclerotic plaque. However, perioperative -blockade has become controversial because of conflicting results of recent studies. Based on the latest evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/ AHA) restricted the once-broad class I indication for perioperative -blockers to only patients already receiving this therapy. Why has the evidence not provided clarity? The underpinnings of the debate over perioperative -blockers may relate to fundamental differences among clinical studies. First, every trial of perioperative -blockers used unique inclusion criteria and risk-stratification methods (TABLE). For instance, the MSCPI study enrolled patients either “with or at risk for” coronary artery disease; cardiac risk was based on factors such as hyperlipidemia, hypertension, or tobacco use. The DECREASE I study included high-risk patients with active cardiac ischemia (wall-motion abnormalities on stress echocardiography) who were undergoing vascular surgery. The DECREASE IV study enrolled a heterogeneous group of patients at intermediate risk of cardiac events (determined by the Revised Cardiac Risk Index) who were undergoing various surgical procedures. The POISE study included patients undergoing vascular surgery who had varied risk factors including peripheral vascular disease, congestive heart failure, or need for emergency surgery. Given these variable inclusion criteria, operative interventions, and risk-stratification methods, unique cohorts are produced that are not directly comparable and may explain conflicting findings. In fact, a patient considered at high risk of cardiac events by one study could potentially be classified as at moderate risk by the standards of another. Second, the effects of -blockers vary according to agent, dose, duration of therapy, and pharmacological properties. Initiation time and dose titration influence the effectiveness and safety of perioperative -blockade. Even so, significant differences exist across studies in the manner in which -blockers were prescribed (Table). The acute hemodynamic effects of -blockers help explain the adverse events associated with perioperative -blockade (especially among patients naive to -blockers), because postoperative stroke and death are associated with -blocker–mediated bradycardiaandhypotension. Conversely, carefuldose titrationcoupled with the plaque-stabilizing effects of -blockers explains the benefit of these agents when time to achieve these results and attention to hemodynamic parameters are applied. Third,perioperative -blockerstudiesvariablydefine,measure, and report clinical outcomes. For instance, electrocardiographicchanges, intraoperativeHoltermonitoring,andmeasurement of biomarker levels have been used interchangeably to report cardiac ischemia. Some studies measure only early cardiacoutcomes,whereasothers report compositeoutcomes at 6-month and 1-year intervals. The MSCPI trial showed decreased incidence of myocardial ischemia during hospitalization and decreased mortality in the -blocker cohort. The study excluded immediate postoperative deaths, which (if included in the intent-to-treat analysis) would statistically negateanymortalitybenefit.Similarly,theunblindedDECREASE Istudywasprematurelyterminatedwheninterimanalysis(based on 20 outcomes) showed an incredible 90% relative-risk reduction in the composite outcome of cardiac death and nonfatal myocardial infarction. Thus, it is not surprising that a recent meta-analysis suggested that the beneficial effects of -blockers were driven mainly by trials with high risk of bias. Trials of perioperative -blockers have left clinicians with more questions than answers. Who should receive perioperative -blockers? Which agent should be used? When should these drugs be started and at what dose? Several recommendationsaresummarizedasfollows:(1)Perioperative -blockers protect patients at highest risk of cardiac events who are undergoinghigh-risksurgery. InaccordancewiththeACCF/AHA update,patientswithdemonstrableoractiveischemiaandthose already taking -blockers should receive perioperative -blockade but only if offered in a careful manner; (2) The approach of initiating -blockers days to weeks prior to surgery and individually adjusting dose to achieve a heart rate of 50/ minto70/min isasafe, logical, andcriticalaspectof implementation.Exposingpatientswithoutcoronarydiseaseorwithcoronary risk factors to large, standard preoperative doses of -blockers blunts protective responses to surgery and causes harm.Suchpractice isno longer justified; (3)Theevidence re-