Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery.

BACKGROUND: The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may help prevent postoperative cardiac complications. OBJECTIVES: To determine the efficacy and safety of α-2 adrenergic agonists for reducing mortality and cardiac complications in adults undergoing cardiac surgery and non-cardiac surgery. SEARCH METHODS: We searched CENTRAL (2017, Issue 4), MEDLINE (1950 to April Week 4, 2017), Embase (1980 to May 2017), the Science Citation Index, clinical trial registries, and reference lists of included articles. SELECTION CRITERIA: We included randomized controlled trials that compared α-2 adrenergic agonists (i.e. clonidine, dexmedetomidine or mivazerol) against placebo or non-α-2 adrenergic agonists. Included trials had to evaluate the efficacy and safety of α-2 adrenergic agonists for preventing perioperative mortality or cardiac complications (or both), or measure one or more relevant outcomes (i.e. death, myocardial infarction, heart failure, acute stroke, supraventricular tachyarrhythmia and myocardial ischaemia). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality, extracted data and independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. We evaluated included studies using the Cochrane 'Risk of bias' tool, and the quality of the evidence underlying pooled treatment effects using GRADE methodology. Given the clinical heterogeneity between cardiac and non-cardiac surgery, we analysed these subgroups separately. We expressed treatment effects as pooled risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included 47 trials with 17,039 participants. Of these studies, 24 trials only included participants undergoing cardiac surgery, 23 only included participants undergoing non-cardiac surgery and eight only included participants undergoing vascular surgery. The α-2 adrenergic agonist studied was clonidine in 21 trials, dexmedetomidine in 24 trials and mivazerol in two trials.In non-cardiac surgery, there was high quality evidence that α-2 adrenergic agonists led to a similar risk of all-cause mortality compared with control groups (1.3% with α-2 adrenergic agonists versus 1.7% with control; RR 0.80, 95% CI 0.61 to 1.04; participants = 14,081; studies = 16). Additionally, the risk of cardiac mortality was similar between treatment groups (0.8% with α-2 adrenergic agonists versus 1.0% with control; RR 0.86, 95% CI 0.60 to 1.23; participants = 12,525; studies = 5, high quality evidence). The risk of myocardial infarction was probably similar between treatment groups (RR 0.94, 95% CI 0.69 to 1.27; participants = 13,907; studies = 12, moderate quality evidence). There was no associated effect on the risk of stroke (RR 0.93, 95% CI 0.55 to 1.56; participants = 11,542; studies = 7; high quality evidence). Conversely, α-2 adrenergic agonists probably increase the risks of clinically significant bradycardia (RR 1.59, 95% CI 1.18 to 2.13; participants = 14,035; studies = 16) and hypotension (RR 1.24, 95% CI 1.03 to 1.48; participants = 13,738; studies = 15), based on moderate quality evidence.There was insufficient evidence to determine the effect of α-2 adrenergic agonists on all-cause mortality in cardiac surgery (RR 0.52, 95% CI 0.26 to 1.04; participants = 1947; studies = 16) and myocardial infarction (RR 1.01, 95% CI 0.43 to 2.40; participants = 782; studies = 8), based on moderate quality evidence. There was one cardiac death in the clonidine arm of a study of 22 participants. Based on very limited data, α-2 adrenergic agonists may have reduced the risk of stroke (RR 0.37, 95% CI 0.15 to 0.93; participants = 1175; studies = 7; outcome events = 18; low quality evidence). Conversely, α-2 adrenergic agonists increased the risk of bradycardia from 6.4% to 12.0% (RR 1.88, 95% CI 1.35 to 2.62; participants = 1477; studies = 10; moderate quality evidence), but their effect on hypotension was uncertain (RR 1.19, 95% CI 0.87 to 1.64; participants = 1413; studies = 9; low quality evidence).These results were qualitatively unchanged in subgroup analyses and sensitivity analyses. AUTHORS' CONCLUSIONS: Our review concludes that prophylactic α-2 adrenergic agonists generally do not prevent perioperative death or major cardiac complications. For non-cardiac surgery, there is moderate-to-high quality evidence that these agents do not prevent death, myocardial infarction or stroke. Conversely, there is moderate quality evidence that these agents have important adverse effects, namely increased risks of hypotension and bradycardia. For cardiac surgery, there is moderate quality evidence that α-2 adrenergic agonists have no effect on the risk of mortality or myocardial infarction, and that they increase the risk of bradycardia. The quality of evidence was inadequate to draw conclusions regarding the effects of alpha-2 agonists on stroke or hypotension during cardiac surgery.

Perioperative beta blockade in noncardiac surgery: a systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

OBJECTIVE: To review the literature systematically to determine whether initiation of beta blockade within 45 days prior to noncardiac surgery reduces 30-day cardiovascular morbidity and mortality rates. METHODS: PubMed (up to April 2013), Embase (up to April 2013), Cochrane Central Register of Controlled Trials (up to March 2013), and conference abstracts (January 2011 to April 2013) were searched for randomized controlled trials (RCTs) and cohort studies comparing perioperative beta blockade with inactive control during noncardiac surgery. Pooled relative risks (RRs) were calculated under the random-effects model. We conducted subgroup analyses to assess how the DECREASE-I (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography), DECREASE-IV, and POISE-1 (Perioperative Ischemic Evaluation) trials influenced our conclusions. RESULTS: We identified 17 studies, of which 16 were RCTs (12 043 participants) and 1 was a cohort study (348 participants). Aside from the DECREASE trials, all other RCTs initiated beta blockade within 1 day or less prior to surgery. Among RCTs, beta blockade decreased nonfatal myocardial infarction (MI) (RR: 0.69; 95% confidence interval [CI]: 0.58 to 0.82) but increased nonfatal stroke (RR: 1.76; 95% CI: 1.07 to 2.91), hypotension (RR: 1.47; 95% CI: 1.34 to 1.60), and bradycardia (RR: 2.61; 95% CI: 2.18 to 3.12). These findings were qualitatively unchanged after the DECREASE and POISE-1 trials were excluded. Effects on mortality rate differed significantly between the DECREASE trials and other trials. Beta blockers were associated with a trend toward reduced all-cause mortality rate in the DECREASE trials (RR: 0.42; 95% CI: 0.15 to 1.22) but with increased all-cause mortality rate in other trials (RR: 1.30; 95% CI: 1.03 to 1.64). Beta blockers reduced cardiovascular mortality rate in the DECREASE trials (RR: 0.17; 95% CI: 0.05 to 0.64) but were associated with trends toward increased cardiovascular mortality rate in other trials (RR: 1.25; 95% CI: 0.92 to 1.71). These differences were qualitatively unchanged after the POISE-1 trial was excluded. CONCLUSIONS: Perioperative beta blockade started within 1 day or less before noncardiac surgery prevents nonfatal MI but increases risks of stroke, death, hypotension, and bradycardia. Without the controversial DECREASE studies, there are insufficient data on beta blockade started 2 or more days prior to surgery. Multicenter RCTs are needed to address this knowledge gap.

Perioperative beta blockade in noncardiac surgery: a systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.

OBJECTIVE: To review the literature systematically to determine whether initiation of beta blockade within 45 days prior to noncardiac surgery reduces 30-day cardiovascular morbidity and mortality rates. METHODS: PubMed (up to April 2013), Embase (up to April 2013), Cochrane Central Register of Controlled Trials (up to March 2013), and conference abstracts (January 2011 to April 2013) were searched for randomized controlled trials (RCTs) and cohort studies comparing perioperative beta blockade with inactive control during noncardiac surgery. Pooled relative risks (RRs) were calculated under the random-effects model. We conducted subgroup analyses to assess how the DECREASE-I (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography), DECREASE-IV, and POISE-1 (Perioperative Ischemic Evaluation) trials influenced our conclusions. RESULTS: We identified 17 studies, of which 16 were RCTs (12,043 participants) and 1 was a cohort study (348 participants). Aside from the DECREASE trials, all other RCTs initiated beta blockade within 1 day or less prior to surgery. Among RCTs, beta blockade decreased nonfatal myocardial infarction (MI) (RR: 0.69; 95% confidence interval [CI]: 0.58 to 0.82) but increased nonfatal stroke (RR: 1.76; 95% CI:1.07 to 2.91), hypotension (RR: 1.47; 95% CI: 1.34 to 1.60), and bradycardia (RR: 2.61; 95% CI: 2.18 to 3.12). These findings were qualitatively unchanged after the DECREASE and POISE-1 trials were excluded. Effects on mortality rate differed significantly between the DECREASE trials and other trials. Beta blockers were associated with a trend toward reduced all-cause mortality rate in the DECREASE trials (RR: 0.42; 95% CI: 0.15 to 1.22) but with increased all-cause mortality rate in other trials (RR: 1.30; 95% CI: 1.03 to 1.64). Beta blockers reduced cardiovascular mortality rate in the DECREASE trials (RR:0.17; 95% CI: 0.05 to 0.64) but were associated with trends toward increased cardiovascular mortality rate in other trials (RR: 1.25; 95% CI: 0.92 to 1.71). These differences were qualitatively unchanged after the POISE-1 trial was excluded. CONCLUSIONS: Perioperative beta blockade started within 1 day or less before noncardiac surgery prevents nonfatal MI but increases risks of stroke, death, hypotension, and bradycardia. Without the controversial DECREASE studies, there are insufficient data on beta blockade started 2 or more days prior to surgery. Multicenter RCTs are needed to address this knowledge gap.