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Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications:

A meta-analysis
  • Duminda N Wijeysundera
    Affiliations
    Department of Anesthesia (DNW, JSN, WSB), University of Toronto, and Toronto General Hospital (WSB), University Health Network, Toronto, Ontario, Canada
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  • Jennifer S Naik
    Affiliations
    Department of Anesthesia (DNW, JSN, WSB), University of Toronto, and Toronto General Hospital (WSB), University Health Network, Toronto, Ontario, Canada
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  • W Scott Beattie
    Correspondence
    Requests for reprints should be addressed to W. Scott Beattie, MD, PhD, Department of Anesthesia, University of Toronto, EN 3-453, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada
    Affiliations
    Department of Anesthesia (DNW, JSN, WSB), University of Toronto, and Toronto General Hospital (WSB), University Health Network, Toronto, Ontario, Canada
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      Abstract

      Purpose

      To investigate the effects of α2-adrenergic agonists on perioperative mortality and cardiovascular complications in adults undergoing surgery.

      Methods

      MEDLINE (1966 to May 2002), EMBASE (1980 to May 2002), the Cochrane Clinical Trials Register, the Science Citation Index, and bibliographies of included articles were searched without language restriction. Randomized trials comparing preoperative, intraoperative, or postoperative (first 48 hours) administration of clonidine, dexmedetomidine, or mivazerol with controls were included. Studies had to report any of the following outcomes: mortality, myocardial infarction, ischemia, or supraventricular tachyarrhythmia. Treatment effects were calculated using the fixed-effects model. Heterogeneity was assessed using the Q test.

      Results

      Twenty-three trials comprising 3395 patients were included. Overall, α2-adrenergic agonists reduced mortality (relative risk [RR] = 0.64; 95% confidence interval [CI]: 0.42 to 0.99; P = 0.05) and ischemia (RR = 0.76; 95% CI: 0.63 to 0.91; P = 0.003) significantly. They also reduced mortality (RR = 0.47; 95% CI: 0.25 to 0.90; P = 0.02) and myocardial infarction (RR = 0.66; 95% CI: 0.46 to 0.94; P = 0.02) during vascular surgery. During cardiac surgery, α2-adrenergic agonists reduced ischemia (RR = 0.71; 95% CI: 0.54 to 0.92; P = 0.01) and were associated with trends toward lower mortality (RR = 0.49; 95% CI: 0.12 to 1.98; P = 0.3) and a reduced risk of myocardial infarction (RR = 0.83; 95% CI: 0.35 to 1.96; P = 0.7).

      Conclusion

      Alpha-2 adrenergic agonists reduce mortality and myocardial infarction following vascular surgery. During cardiac surgery, they reduce ischemia and may also have effects on mortality and myocardial infarction. Large randomized trials are needed to evaluate these agents during cardiac and vascular surgery.
      Cardiovascular complications following cardiac and noncardiac surgery increase mortality, morbidity, and health care costs (
      • Carrier M.
      • Pellerin M.
      • Perrault L.P.
      • et al.
      Troponin levels in patients with myocardial infarction after coronary artery bypass grafting.
      ,
      • Force T.
      • Hibberd P.
      • Weeks G.
      • et al.
      Perioperative myocardial infarction after coronary artery bypass surgery. Clinical significance and approach to risk stratification.
      ,
      • Mangano D.T.
      Perioperative cardiac morbidity.
      ,
      • Mangano D.T.
      • Browner W.S.
      • Hollenberg M.
      • et al.
      Long-term cardiac prognosis following noncardiac surgery. The Study of Perioperative Ischemia Research Group.
      ). Approximately 4.5% of patients undergoing cardiac surgery will have a perioperative myocardial infarction (
      • Carrier M.
      • Pellerin M.
      • Perrault L.P.
      • et al.
      Troponin levels in patients with myocardial infarction after coronary artery bypass grafting.
      ), whereas about 30% of patients undergoing noncardiac surgery have, or are at risk of, coronary artery disease (
      • Mangano D.T.
      Perioperative cardiac morbidity.
      ). The direct health care costs of these complications have been estimated at U.S. $20 billion (
      • Mangano D.T.
      Perioperative cardiac morbidity.
      ).
      The surgical stress response is important in the pathogenesis of cardiovascular complications (
      • Halter J.B.
      • Pflug A.E.
      • Porte Jr, D.
      Mechanism of plasma catecholamine increases during surgical stress in man.
      ,
      • Roizen M.F.
      Should we all have a sympathectomy at birth? Or at least preoperatively?.
      ). The α2-adrenergic agonists currently used in clinical practice—clonidine, dexmedetomidine, and mivazerol—attenuate the stress response and therefore potentially reduce cardiovascular complications. Unlike α1-antagonists (e.g., prazosin), which act on peripheral adrenergic receptors to inhibit vasoconstriction directly, α2-agonists act on central and presynaptic receptors to inhibit central sympathetic outflow (
      • Muzi M.
      • Goff D.R.
      • Kampine J.P.
      • et al.
      Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans.
      ) and reduce peripheral norepinephrine release (
      • Ellis J.E.
      • Drijvers G.
      • Pedlow S.
      • et al.
      Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.
      ). Alpha-2 agonists dilate poststenotic coronary vessels (
      • Heusch G.
      • Schipke J.
      • Thamer V.
      Clonidine prevents the sympathetic initiation and aggravation of poststenotic myocardial ischemia.
      ) and attenuate the severity of perioperative hemodynamic abnormalities (
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      ,
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ), and consequently were conferred a grade IIb recommendation in the 2002 American College of Cardiology/American Heart Association Guideline Update on Perioperative Cardiovascular Evaluation for Noncardiac Surgery (
      • Eagle K.A.
      • Berger P.B.
      • Calkins H.
      • et al.
      ACC/AHA guideline update on perioperative cardiovascular evaluation for noncardiac surgery.
      ). This recommendation, however, was based on one study (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ).
      A prior meta-analysis concluded that clonidine reduced perioperative ischemia significantly (
      • Nishina K.
      • Mikawa K.
      • Uesugi T.
      • et al.
      Efficacy of clonidine for prevention of perioperative myocardial ischemia a critical appraisal and meta-analysis of the literature.
      ). However, the review was underpowered (664 patients in seven studies), searched only English-language literature, and reported effects only on ischemia, a surrogate outcome. It did not include trials of mivazerol or dexmedetomidine, which have enrolled up to 1900 patients (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ). A systematic review of perioperative α2-agonists is therefore justified.

      Methods

      This review adhered to the recommendations of the Quality of Reporting of Meta-analyses (QUOROM) group (
      • Moher D.
      • Cook D.J.
      • Eastwood S.
      • et al.
      Improving the quality of reports of meta-analyses of randomised controlled trials the QUOROM statement. Quality of Reporting of Meta- analyses.
      ).

      Inclusion and exclusion criteria

      Eligible studies were published, randomized controlled trials that enrolled adults (age >18 years) who were undergoing surgery under general or neuroaxial (spinal or epidural) anesthesia. Trials that recruited patients undergoing local anesthesia or peripheral nerve blockade alone were excluded. We also excluded trials that recruited patients who were pregnant, organ transplant recipients, or suffering from substance withdrawal.
      The interventions assessed were preoperative (within 24 hours), intraoperative, or postoperative (within 48 hours) administration of clonidine, dexmedetomidine, or mivazerol via intravenous, intramuscular, oral, or transdermal routes. Trials had to report any of the following outcomes: death, myocardial infarction, myocardial ischemia, or supraventricular tachyarrhythmia. We did not employ a uniform definition of myocardial infarction given the lack of a standardized criterion in the literature. Ischemia was defined as ST-segment deviation on an electrocardiogram or new wall motion abnormalities on a transesophageal echocardiogram. Supraventricular tachyarrhythmias included atrial fibrillation, atrial flutter, and supraventricular tachycardia.

      Search strategy

      We identified eligible trials using MEDLINE (1966 to May 2002), EMBASE (1980 to May 2002), and the Cochrane Clinical Trials Register (The Cochrane Library, Issue 2, 2002) (

      Dickersin K, Larson K. Establishing and maintaining an international register of RCTs. In: The Cochrane Library. Oxford, UK: Update Software; 1996

      ). The search included the following medical subject headings: clonidine or dexmedetomidine or mivazerol and postoperative, perioperative, intraoperative, complications, period, preoperative, or care. Included trials were entered into the Science Citation Index to identify other articles. We also searched the bibliographies of included articles and published reviews. No language restrictions were applied. Unpublished trials were not sought, but authors of included studies were contacted for additional data.

      Methods of review

      Two reviewers independently performed the literature searches and assessed all identified full papers or abstracts for inclusion. The reasons for exclusion were documented for all excluded studies. Three reviewers independently abstracted the following onto data abstraction forms: number of patients, prior medications, type of surgery, and type of treatments, as well as the incidence of several outcomes, including deaths (all-cause), myocardial infarction, ischemia, supraventricular tachyarrhythmia, heart failure, hypotension (requiring pharmacologic or intra-aortic balloon pump treatment), and bradycardia (requiring pharmacologic or pacemaker treatment). Three reviewers rated study quality independently using the scale of Jadad et al (
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • et al.
      Assessing the quality of reports of randomized clinical trials is blinding necessary?.
      ). The minimum score required was 1. Reviewers were not blinded to the names of authors, institutions, or journals when performing data abstraction or quality assessment. Where possible, data were abstracted only for comparisons of α2-agonists with placebo. All disagreements were resolved by consensus.

      Statistical analysis

      Analyses were performed using Review Manager 4.1.1 (Cochrane Collaboration, Oxford, United Kingdom). We calculated the effects of α2-agonists on the primary outcome (mortality) and several secondary outcomes (myocardial infarction, ischemia, heart failure, hypotension, and bradycardia). Treatment effects were expressed as pooled relative risks, with 95% confidence intervals. Initially, heterogeneity was assessed using the Q statistic, with statistically significant heterogeneity defined by P values <0.1. In the absence of significant heterogeneity, relative risks were calculated using the fixed-effects model (
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ). If there was significant heterogeneity, the random-effects model (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ) was used; in addition, we carried out post hoc analyses to explain the heterogeneity. Statistical significance for treatment effects was defined by P values <0.05.
      Given that differences in preoperative medication use may confound the results, we compared the use of beta-blockers and calcium antagonists using meta-analytic methods. Differences in medication use were expressed as relative risks calculated with the fixed-effects model.

      Subgroup analyses

      Two subgroup analyses were performed to compare the treatment effects for each α2-agonist (clonidine, dexmedetomidine, and mivazerol) on mortality, myocardial infarction, and ischemia, as well as to study the effects of procedure type (cardiac, vascular, and nonvascular surgery) on these three outcomes. If several surgical procedures were included in a study, we attempted to obtain subgroup-specific results from the authors. If such data were not available, and more than 75% of patients underwent the same class of surgery, the study was allocated to that specific subgroup. Failing that, the study was excluded from the subgroup analysis involving procedure type.

      Sensitivity analyses

      Several sensitivity analyses were conducted to determine whether the choice of included studies or statistical model influenced treatment effects. The first analysis was restricted to analyses that had identified statistically significant treatment effects. We removed trials in increasing order of relative risks (i.e., trials favoring α2-agonists the most were removed first). We measured the proportion of studies and patients that were removed to make the treatment effect statistically nonsignificant. The second analysis assessed the relation between study quality and treatment effects. The meta-analyses were repeated in subgroups of high-quality studies (Jadad score ≥3) (
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • et al.
      Assessing the quality of reports of randomized clinical trials is blinding necessary?.
      ). The third analysis examined the effect of the statistical model on treatment effects. Analyses that employed the fixed-effects model were repeated using the random-effects model. The fourth analysis used funnel plots (
      • Egger M.
      • Davey S.G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ) to assess publication bias.

      Results

      Twenty-three studies comprising 3395 patients were included (Table 1; Figure 1). A list of excluded studies is available from the authors.
      Table 1Characteristics of Included Studies
      First Author (Reference)Number of PatientsCoronary Artery DiseaseProcedureAlpha-2 AgonistControlBlindingConcealed AllocationJadad Score
      On a scale of 0 to 5.
      Cardiac surgery
      Abi-Jaoude
      • Abi-Jaoude F.
      • Brusset A.
      • Ceddaha A.
      • et al.
      Clonidine premedication for coronary artery bypass grafting under high-dose alfentanil anesthesia intraoperative and postoperative hemodynamic study.
      24+Coronary bypass graftingOral clonidine 5 μg/kg 120 minutes before surgeryPlacebo+Unclear3
      Boldt
      • Boldt J.
      • Rothe G.
      • Schindler E.
      • et al.
      Can clonidine, enoximone, and enalaprilat help to protect the myocardium against ischaemia in cardiac surgery?.
      44+Coronary bypass graftingIntravenous clonidine 0.05 μg/kg/min from induction to cardiopulmonary bypassPlacebo+Unclear3
      Dorman
      • Dorman B.H.
      • Zucker J.R.
      • Verrier E.D.
      • et al.
      Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery.
      43+Coronary bypass graftingOral clonidine 5 μg/kg 90 minutes before surgery, and 5 μg/kg before cardiopulmonary bypassPlacebo+Unclear3
      Ghignone
      • Ghignone M.
      • Quintin L.
      • Duke P.C.
      • et al.
      Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation.
      24+Coronary bypass graftingOral clonidine 5 μg/kg 90 minutes before surgeryControlUnclear1
      Helbo-Hansen
      • Helbo-Hansen S.
      • Fletcher R.
      • Lundberg D.
      • et al.
      Clonidine and the sympatico-adrenal response to coronary artery by-pass surgery.
      40+Coronary bypass graftingIntravenous clonidine 7 μg/kg in three divided intraoperative bolus dosesPlaceboUnclear1
      Jalonen
      • Jalonen J.
      • Hynynen M.
      • Kuitunen A.
      • et al.
      Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.
      80+Coronary bypass graftingIntravenous dexmedetomidine 50 ng/kg/min before surgery for 30 minutes, 7 ng/kg/min intraoperativelyPlacebo+Unclear3
      Loick
      • Loick H.M.
      • Schmidt C.
      • Van Aken H.
      • et al.
      High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting.
      45+Coronary bypass graftingIntravenous clonidine 4 μg/kg before surgery, 1 μg/kg/min intraoperatively, and 0.2–0.5 μg/kg/min for 48 hours postoperativelyControlUnclear2
      Myles
      • Myles P.S.
      • Hunt J.O.
      • Holdgaard H.O.
      • et al.
      Clonidine and cardiac surgery haemodynamic and metabolic effects, myocardial ischaemia and recovery.
      150+Coronary bypass graftingOral clonidine 5 μg/kg 90 minutes before surgery, and 5 μg/kg before coronary bypass graftingPlacebo+Unclear4
      Quintin
      • Quintin L.
      • Cicala R.
      • Kent M.
      • Thomsen B.
      Effect of clonidine on myocardial ischaemia a double-blind pilot trial [letter].
      26+Coronary bypass graftingOral clonidine 2.5 μg/kg 90 minutes before surgeryPlacebo+Unclear3
      Venn
      • Venn R.M.
      • Bradshaw C.J.
      • Spencer R.
      • et al.
      Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.
      105+Mixed (83% cardiac)Intravenous dexmedetomidine 1 μg/kg within 1 hour after surgery, and 0.2–0.7 μg/kg/h for 6–24 hoursPlacebo+Unclear4
      Noncardiac surgery
      Ellis
      • Ellis J.E.
      • Drijvers G.
      • Pedlow S.
      • et al.
      Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.
      61+Noncardiac surgery (82% vascular)Transdermal clonidine (0.2 mg/d) for 72 hours from night before surgery, and 0.3 mg orally 60–90 minutes before surgeryPlacebo++4
      Ghignone
      • Ghignone M.
      • Calvillo O.
      • Quintin L.
      Anesthesia and hypertension the effect of clonidine on perioperative hemodynamics and isoflurane requirements.
      30+Nonvascular surgeryOral clonidine 5 μg/kg 90 minutes before surgeryControlUnclear2
      Lipszye
      • Lipszyc M.
      • Engelman E.
      Clonidine does not prevent myocardial ischemia during noncardiac surgery.
      40+Carotid artery surgeryOral clonidine 4 μg/kg 90 minutes before surgeryPlacebo+Unclear2
      Mangano
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      317+Vascular surgeryTwo intravenous mivazerol regimens: low (2 μg/kg bolus and 0.75 μg/kg/h), high (4 μg/kg bolus and 1.5 μg/kg/h). Bolus given 20 minutes before surgery; infusion until 72 hours after surgeryPlacebo+Unclear4
      Matot
      • Matot I.
      • Sichel J.Y.
      • Yofe V.
      • Gozal Y.
      The effect of clonidine premedication on hemodynamic responses to microlaryngoscopy and rigid bronchoscopy.
      36UnclearAirway surgeryOral clonidine 300 μg 90 minutes before surgeryPlacebo+Unclear3
      Oliver
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      1897
      Results for additional 957 patients at risk for coronary artery disease were not presented.
      +Noncardiac surgeryIntravenous mivazerol 4 μg/kg 20 minutes before surgery, and 1.5 μg/kg/h for 72 hoursPlacebo++4
      Pluskwa
      • Pluskwa F.
      • Bonnet F.
      • Saada M.
      • et al.
      Effects of clonidine on variation of arterial blood pressure and heart rate during carotid artery surgery.
      30+Carotid artery surgeryOral clonidine 300 μg 90 minutes before surgeryPlacebo++5
      Quintin
      • Quintin L.
      • Bouilloc X.
      • Butin E.
      • et al.
      Clonidine for major vascular surgery in hypertensive patients a double-blind, controlled, randomized study.
      24+Aortic surgeryOral clonidine 6 μg/kg 120 minutes before surgery, and 3 μg/kg intravenously after surgeryPlacebo+Unclear4
      Stuhmeier
      • Stuhmeier K.D.
      • Mainzer B.
      • Cierpka J.
      • et al.
      Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery.
      297+Vascular surgeryOral clonidine 2 μg/kg 90 minutes before surgeryPlacebo+Unclear5
      Talke
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      25+Vascular surgeryIntravenous dexmedetomidine given in three doses [low (2.64 μg/kg), medium (5.31 μg/kg), high (8.03 μg/kg)] as 48-hour infusion from start of surgeryPlacebo+Unclear4
      Talke
      • Talke P.
      • Chen R.
      • Thomas B.
      • et al.
      The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery.
      41+Vascular surgeryIntravenous dexmedetomidine: 140 μg intraoperative infusion, and 0.15 μg/min until 48 hours after surgeryPlacebo+Unclear4
      Venn
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      20UnclearNonvascular surgeryIntravenous dexmedetomidine 2.5 μg/kg within 1 hour after surgery, and 0.2–0.5 μg/kg/h for 6–24 hoursIntravenous propofol 1 mg/kg and 1–3 mg/kg/h infusionUnclear2
      Mixed surgery types
      Triltsch
      • Triltsch A.E.
      • Welter M.
      • von Homeyer P.
      • et al.
      Bispectral index-guided sedation with dexmedetomidine in intensive care a prospective, randomized, double blind, placebo-controlled phase II study.
      30UnclearMixed (53% cardiac)Intravenous dexmedetomidine 6 μg/kg within 6 hours after surgery, and 0.4 μg/kg/h for 72 hoursPlacebo+Unclear4
      + = present; − = absent.
      * On a scale of 0 to 5.
      Results for additional 957 patients at risk for coronary artery disease were not presented.
      Figure thumbnail GR1
      Figure 1Flow diagram of meta-analysis.
      Ten studies involved cardiac surgery, eight involved vascular noncardiac surgery, and three involved nonvascular noncardiac surgery (Table 1). One noncardiac surgery study (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ) presented subgroup-specific results for both vascular and nonvascular procedures. Fifteen studies assessed clonidine, six assessed dexmedetomidine, and two assessed mivazerol. Treatment duration ranged from a single preoperative dose to a 72-hour course of treatment. All studies allowed for comparison of α2-agonists with placebo, with the exception of a nonvascular surgery trial (
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ) that compared intravenous dexmedetomidine with intravenous propofol. There were no direct comparisons of α2-agonists with beta-blockers.
      The mean age of participants ranged from 48 to 69 years. Men comprised 47% to 100% of participants. Approximately 74% of the studies were high quality (Jadad score ≥3). The median Jadad score was 3 (range, 1 to 5).

      Mortality and cardiovascular complications

      Fifteen studies reported deaths, with an incidence of 2.5% (n = 78) among 3128 patients (Figure 2). Alpha-2 agonists reduced mortality (relative risk [RR] = 0.64; 95% confidence interval [CI]: 0.42 to 0.99; P = 0.05), without statistically significant heterogeneity (P = 0.92). Clonidine (RR = 0.48; 95% CI: 0.15 to 1.60; P = 0.2), dexmedetomidine (RR = 0.57; 95% CI: 0.17 to 1.88; P = 0.4), and mivazerol (RR = 0.69; 95% CI: 0.42 to 1.15; P = 0.15) had similar effects on mortality.
      Figure thumbnail GR2
      Figure 2Effect of α2-agonists on mortality during all types of surgery, with a combined analysis of these results. Squares represent point estimates. The area of a square correlates with its contribution towards the weighted summary estimate. Horizontal lines denote 95% confidence intervals (CI), some of which extend beyond the limits of the scale. The overall effect, represented by the diamond, was a relative risk of 0.64 (95% CI: 0.42 to 0.99; P for heterogeneity = 0.92).
      Thirteen studies reported myocardial infarctions, with an incidence of 6% (n = 188) among 3090 patients (Figure 3). Alpha-2 agonists were associated with a nonsignificant reduction in myocardial infarction (RR = 0.85; 95% CI: 0.65 to 1.11; P = 0.2). There was no statistically significant heterogeneity for this analysis (P = 0.55), although clonidine (RR = 0.61; 95% CI: 0.25 to 1.48; P = 0.3) and dexmedetomidine (RR = 0.47; 95% CI: 0.11 to 2.03; P = 0.3) appeared to reduce infarction to a greater degree than did mivazerol (RR = 0.91; 95% CI: 0.68 to 1.21; P = 0.5).
      Figure thumbnail GR3
      Figure 3Effect of α2-agonists on myocardial infarction during all types of surgery, with a combined analysis of these results. Squares represent point estimates. The area of a square correlates with its contribution towards the weighted summary estimate. Horizontal lines denote 95% confidence intervals (CI), some of which extend beyond the limits of the scale. The overall effect, represented by the diamond, was a relative risk of 0.85 (95% CI: 0.65 to 1.11; P for heterogeneity = 0.55).
      Sixteen studies reported ischemia, with an incidence of 25.5% (n = 336) among 1320 patients (Figure 4). Alpha-2 agonists reduced ischemia (RR = 0.76; 95% CI: 0.63 to 0.91; P = 0.003), without statistically significant heterogeneity (P = 0.59). Clonidine appeared to reduce ischemia (RR = 0.67; 95% CI: 0.54 to 0.84; P = 0.0005) to a greater degree than did dexmedetomidine (RR = 0.85; 95% CI: 0.57 to 1.27; P = 0.4) or mivazerol (RR = 1.14; 95% CI: 0.67 to 1.97; P = 0.6).
      Figure thumbnail GR4
      Figure 4Effect of α2-agonists on myocardial ischemia during all types of surgery, with a combined analysis of these results. Squares represent point estimates. The area of a square correlates with its contribution towards the weighted summary estimate. Horizontal lines denote 95% confidence intervals (CI), some of which extend beyond the limits of the scale. The overall effect, represented by the diamond, was a relative risk of 0.76 (95% CI: 0.63 to 0.91; P for heterogeneity = 0.59).
      Four studies reported supraventricular tachyarrhythmias (
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ,
      • Jalonen J.
      • Hynynen M.
      • Kuitunen A.
      • et al.
      Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.
      ,
      • Venn R.M.
      • Bradshaw C.J.
      • Spencer R.
      • et al.
      Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.
      ,
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ), with an incidence of 12% (n = 33) among 243 patients. Alpha-2 agonists had little effect on supraventricular tachyarrhythmia (RR = 1.04; 95% CI: 0.56 to 1.93; P = 0.9), without statistically significant heterogeneity (P = 0.87).
      There were no obvious trends in treatment efficacy by dosage, duration of treatment, or event rate.

      Cardiac surgery

      Alpha-2 agonists reduced myocardial ischemia significantly (RR = 0.71; 95% CI: 0.54 to 0.92; P = 0.01). They also reduced mortality (RR = 0.49; 95% CI: 0.12 to 1.98; P = 0.3) and myocardial infarction (RR = 0.83; 95% CI: 0.35 to 1.96; P = 0.7), although these estimates did not achieve statistical significance. There was no statistically significant heterogeneity for effects on death (P = 0.47), infarction (P = 0.86), and ischemia (P = 0.88).

      Vascular surgery

      Among patients undergoing vascular surgery, α2-agonists reduced mortality (RR = 0.47; 95% CI: 0.25 to 0.90; P = 0.02; Figure 5) and myocardial infarction (RR = 0.66; 95% CI: 0.46 to 0.94; P = 0.02; Figure 6). Alpha-2 agonists were associated with trends toward reduced ischemia (RR = 0.83; 95% CI: 0.64 to 1.07; P = 0.15). There was no statistically significant heterogeneity for effects on death (P = 0.82), infarction (P = 0.21), and ischemia (P = 0.16).
      Figure thumbnail GR5
      Figure 5Effect of α2-agonists on mortality during vascular surgery, with a combined analysis of these results. Squares represent point estimates. The area of a square correlates with its contribution towards the weighted summary estimate. Horizontal lines denote 95% confidence intervals (CI), some of which extend beyond the limits of the scale. The overall effect, represented by the diamond, was a relative risk of 0.47 (95% CI: 0.25 to 0.90; P for heterogeneity = 0.82).
      Figure thumbnail GR6
      Figure 6Effect of α2-agonists on myocardial infarction during vascular surgery, with a combined analysis of these results. Squares represent point estimates. The area of a square correlates with its contribution towards the weighted summary estimate. Horizontal lines denote 95% confidence intervals (CI), some of which extend beyond the limits of the scale. The overall effect, represented by the diamond, was a relative risk of 0.66 (95% CI: 0.46 to 0.94; P for heterogeneity = 0.21).

      Nonvascular surgery

      The studies that reported deaths following nonvascular surgery (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ,
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ) found that α2-agonists had little effect on mortality (RR = 1.05; 95% CI: 0.52 to 2.09; P = 0.9), without statistically significant heterogeneity (P = 0.55). The one study that reported infarction (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ) within this subgroup found that α2-agonists increased the incidence of infarction (RR = 1.35; 95% CI: 0.83 to 2.21; P = 0.2), although this estimate was not statistically significant. Alpha-2 agonists were, however, associated with a nonsignificant reduction in ischemia (RR = 0.20; 95% CI: 0.02 to 1.62; P = 0.13).

      Prior medication use

      Fourteen studies reported calcium antagonist use (
      • Ellis J.E.
      • Drijvers G.
      • Pedlow S.
      • et al.
      Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.
      ,
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      ,
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ,
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ,
      • Abi-Jaoude F.
      • Brusset A.
      • Ceddaha A.
      • et al.
      Clonidine premedication for coronary artery bypass grafting under high-dose alfentanil anesthesia intraoperative and postoperative hemodynamic study.
      ,
      • Boldt J.
      • Rothe G.
      • Schindler E.
      • et al.
      Can clonidine, enoximone, and enalaprilat help to protect the myocardium against ischaemia in cardiac surgery?.
      ,
      • Dorman B.H.
      • Zucker J.R.
      • Verrier E.D.
      • et al.
      Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery.
      ,
      • Helbo-Hansen S.
      • Fletcher R.
      • Lundberg D.
      • et al.
      Clonidine and the sympatico-adrenal response to coronary artery by-pass surgery.
      ,
      • Jalonen J.
      • Hynynen M.
      • Kuitunen A.
      • et al.
      Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.
      ,
      • Matot I.
      • Sichel J.Y.
      • Yofe V.
      • Gozal Y.
      The effect of clonidine premedication on hemodynamic responses to microlaryngoscopy and rigid bronchoscopy.
      ,
      • Myles P.S.
      • Hunt J.O.
      • Holdgaard H.O.
      • et al.
      Clonidine and cardiac surgery haemodynamic and metabolic effects, myocardial ischaemia and recovery.
      ,
      • Quintin L.
      • Cicala R.
      • Kent M.
      • Thomsen B.
      Effect of clonidine on myocardial ischaemia a double-blind pilot trial [letter].
      ,
      • Quintin L.
      • Bouilloc X.
      • Butin E.
      • et al.
      Clonidine for major vascular surgery in hypertensive patients a double-blind, controlled, randomized study.
      ,
      • Stuhmeier K.D.
      • Mainzer B.
      • Cierpka J.
      • et al.
      Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery.
      ), with an overall prevalence of 45% (n = 1373) among 3043 patients. There was no difference in calcium antagonist use between α2-agonist and control arms (RR = 0.95; 95% CI: 0.88 to 1.03; P = 0.2; P for heterogeneity = 0.94).
      Fifteen studies reported beta-blocker use (
      • Ellis J.E.
      • Drijvers G.
      • Pedlow S.
      • et al.
      Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.
      ,
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      ,
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ,
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ,
      • Abi-Jaoude F.
      • Brusset A.
      • Ceddaha A.
      • et al.
      Clonidine premedication for coronary artery bypass grafting under high-dose alfentanil anesthesia intraoperative and postoperative hemodynamic study.
      ,
      • Boldt J.
      • Rothe G.
      • Schindler E.
      • et al.
      Can clonidine, enoximone, and enalaprilat help to protect the myocardium against ischaemia in cardiac surgery?.
      ,
      • Dorman B.H.
      • Zucker J.R.
      • Verrier E.D.
      • et al.
      Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery.
      ,
      • Helbo-Hansen S.
      • Fletcher R.
      • Lundberg D.
      • et al.
      Clonidine and the sympatico-adrenal response to coronary artery by-pass surgery.
      ,
      • Jalonen J.
      • Hynynen M.
      • Kuitunen A.
      • et al.
      Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.
      ,
      • Loick H.M.
      • Schmidt C.
      • Van Aken H.
      • et al.
      High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting.
      ,
      • Matot I.
      • Sichel J.Y.
      • Yofe V.
      • Gozal Y.
      The effect of clonidine premedication on hemodynamic responses to microlaryngoscopy and rigid bronchoscopy.
      ,
      • Myles P.S.
      • Hunt J.O.
      • Holdgaard H.O.
      • et al.
      Clonidine and cardiac surgery haemodynamic and metabolic effects, myocardial ischaemia and recovery.
      ,
      • Quintin L.
      • Cicala R.
      • Kent M.
      • Thomsen B.
      Effect of clonidine on myocardial ischaemia a double-blind pilot trial [letter].
      ,
      • Quintin L.
      • Bouilloc X.
      • Butin E.
      • et al.
      Clonidine for major vascular surgery in hypertensive patients a double-blind, controlled, randomized study.
      ,
      • Stuhmeier K.D.
      • Mainzer B.
      • Cierpka J.
      • et al.
      Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery.
      ). The overall prevalence was 34% (n = 1037) among 3088 patients, with patients in α2-agonist arms more likely to receive beta-blockers (RR = 1.11; 95% CI: 1.01 to 1.22; P = 0.04; P for heterogeneity = 0.82). In a post hoc analysis, patients in cardiac surgery trials who were assigned to α2-agonist arms were as likely to receive beta-blockers as were those assigned to control arms (RR = 1.05; 95% CI: 0.91 to 1.21; P = 0.5). In noncardiac surgery trials, however, patients assigned to α2-agonist arms were significantly more likely to receive beta-blockers (RR = 1.13; 95% CI: 1.00 to 1.27; P = 0.05).
      Given that beta-blockers decrease perioperative mortality following noncardiac surgery (
      • Mangano D.T.
      • Layug E.L.
      • Wallace A.
      • Tateo I.
      Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group.
      ,
      • Poldermans D.
      • Boersma E.
      • Bax J.J.
      • et al.
      The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.
      ), we carried out post hoc analyses to estimate the change in mortality attributable to differential beta-blocker use. During noncardiac surgery, the prevalence of beta-blocker use was 31% in α2-agonist arms and 27% in control arms. Assuming that beta-blockers are associated with an 80% reduction in the risk of cardiac death and myocardial infarction (
      • Poldermans D.
      • Boersma E.
      • Bax J.J.
      • et al.
      The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.
      ), differential beta-blocker use accounted for a 4% relative risk reduction in mortality.

      Adverse events

      Nine studies reported heart failure (
      • Ellis J.E.
      • Drijvers G.
      • Pedlow S.
      • et al.
      Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.
      ,
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      ,
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ,
      • Abi-Jaoude F.
      • Brusset A.
      • Ceddaha A.
      • et al.
      Clonidine premedication for coronary artery bypass grafting under high-dose alfentanil anesthesia intraoperative and postoperative hemodynamic study.
      ,
      • Jalonen J.
      • Hynynen M.
      • Kuitunen A.
      • et al.
      Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.
      ,
      • Matot I.
      • Sichel J.Y.
      • Yofe V.
      • Gozal Y.
      The effect of clonidine premedication on hemodynamic responses to microlaryngoscopy and rigid bronchoscopy.
      ,
      • Myles P.S.
      • Hunt J.O.
      • Holdgaard H.O.
      • et al.
      Clonidine and cardiac surgery haemodynamic and metabolic effects, myocardial ischaemia and recovery.
      ,
      • Triltsch A.E.
      • Welter M.
      • von Homeyer P.
      • et al.
      Bispectral index-guided sedation with dexmedetomidine in intensive care a prospective, randomized, double blind, placebo-controlled phase II study.
      ,
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ). Alpha-2 agonists were associated with a reduction in heart failure that was not significant (RR = 0.82; 95% CI: 0.49 to 1.36; P = 0.4). There was no statistically significant heterogeneity for this analysis (P = 0.91).
      Twelve studies reported hypotension (
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      ,
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ,
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ,
      • Abi-Jaoude F.
      • Brusset A.
      • Ceddaha A.
      • et al.
      Clonidine premedication for coronary artery bypass grafting under high-dose alfentanil anesthesia intraoperative and postoperative hemodynamic study.
      ,
      • Boldt J.
      • Rothe G.
      • Schindler E.
      • et al.
      Can clonidine, enoximone, and enalaprilat help to protect the myocardium against ischaemia in cardiac surgery?.
      ,
      • Ghignone M.
      • Calvillo O.
      • Quintin L.
      Anesthesia and hypertension the effect of clonidine on perioperative hemodynamics and isoflurane requirements.
      ,
      • Matot I.
      • Sichel J.Y.
      • Yofe V.
      • Gozal Y.
      The effect of clonidine premedication on hemodynamic responses to microlaryngoscopy and rigid bronchoscopy.
      ,
      • Myles P.S.
      • Hunt J.O.
      • Holdgaard H.O.
      • et al.
      Clonidine and cardiac surgery haemodynamic and metabolic effects, myocardial ischaemia and recovery.
      ,
      • Pluskwa F.
      • Bonnet F.
      • Saada M.
      • et al.
      Effects of clonidine on variation of arterial blood pressure and heart rate during carotid artery surgery.
      ,
      • Quintin L.
      • Bouilloc X.
      • Butin E.
      • et al.
      Clonidine for major vascular surgery in hypertensive patients a double-blind, controlled, randomized study.
      ,
      • Triltsch A.E.
      • Welter M.
      • von Homeyer P.
      • et al.
      Bispectral index-guided sedation with dexmedetomidine in intensive care a prospective, randomized, double blind, placebo-controlled phase II study.
      ,
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ). The incidence of hypotension, although increased, was not significant (RR = 1.09; 95% CI: 0.94 to 1.27; P = 0.20; P for heterogeneity = 0.15). Hypotension was significantly increased among patients who received α2-agonists during cardiac surgery (RR = 1.76; 95% CI: 1.04 to 2.96; P = 0.03; P for heterogeneity = 0.52), but not during noncardiac surgery (RR = 1.03; 95% CI: 0.89 to 1.21; P = 0.7; P for heterogeneity = 0.22).
      Thirteen studies reported bradycardia (
      McSPI-EUROPE Research Group
      Perioperative sympatholysis beneficial effects of the α2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
      ,
      • Talke P.
      • Li J.
      • Jain U.
      • et al.
      Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group.
      ,
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ,
      • Boldt J.
      • Rothe G.
      • Schindler E.
      • et al.
      Can clonidine, enoximone, and enalaprilat help to protect the myocardium against ischaemia in cardiac surgery?.
      ,
      • Dorman B.H.
      • Zucker J.R.
      • Verrier E.D.
      • et al.
      Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirement, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery.
      ,
      • Loick H.M.
      • Schmidt C.
      • Van Aken H.
      • et al.
      High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting.
      ,
      • Matot I.
      • Sichel J.Y.
      • Yofe V.
      • Gozal Y.
      The effect of clonidine premedication on hemodynamic responses to microlaryngoscopy and rigid bronchoscopy.
      ,
      • Myles P.S.
      • Hunt J.O.
      • Holdgaard H.O.
      • et al.
      Clonidine and cardiac surgery haemodynamic and metabolic effects, myocardial ischaemia and recovery.
      ,
      • Pluskwa F.
      • Bonnet F.
      • Saada M.
      • et al.
      Effects of clonidine on variation of arterial blood pressure and heart rate during carotid artery surgery.
      ,
      • Quintin L.
      • Bouilloc X.
      • Butin E.
      • et al.
      Clonidine for major vascular surgery in hypertensive patients a double-blind, controlled, randomized study.
      ,
      • Stuhmeier K.D.
      • Mainzer B.
      • Cierpka J.
      • et al.
      Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery.
      ,
      • Triltsch A.E.
      • Welter M.
      • von Homeyer P.
      • et al.
      Bispectral index-guided sedation with dexmedetomidine in intensive care a prospective, randomized, double blind, placebo-controlled phase II study.
      ,
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ). The increase in bradycardia associated with α2-agonist use was not significant (RR = 1.36; 95% CI: 0.91 to 2.04; P = 0.13); however, there was significant heterogeneity (P = 0.009). Post hoc subgroup analyses did not explain this heterogeneity.

      Sensitivity analyses

      Sequential exclusion of the most favorable studies (i.e., studies with low relative risks) had variable effects on statistically significant treatment effects (Table 2). Treatment effects were generally unaffected by study quality and choice of statistical model (Table 3). Funnel plots revealed no obvious publication bias with regard to reporting of death, infarction, or ischemia.
      Table 2Effect of Removing Favorable Studies on Estimated Treatment Effects
      Type of SurgeryOutcomeInitial AnalysisFavorable Trials Removed to Eliminate Statistical Significance
      TrialsPatientsTrials RemainingNo. of Patients (% Initial Sample)
      AllDeath153128142978 (95.2)
      AllIschemia16132010860 (65.2)
      CardiacIschemia95396442 (82.0)
      VascularDeath7164841525 (92.5)
      VascularInfarction6161651258 (77.8)
      Table 3Effect of Study Quality and Statistical Model on Estimated Treatment Effects
      Type of SurgeryOutcomeAll TrialsHigh-Quality Trials
      Jadad score ≥3.
      Random-Effects Model
      Relative Risk (95% Confidence Interval)P ValueRelative Risk (95% Confidence Interval)P ValueRelative Risk (95% Confidence Interval)P Value
      AllMortality0.64 (0.42–0.99)0.050.59 (0.38–0.93)0.020.64 (0.41–1.01)0.05
      AllInfarction0.85 (0.65–1.11)0.20.84 (0.64–1.10)0.20.88 (0.67–1.16)0.4
      AllIschemia0.76 (0.63–0.91)0.0030.75 (0.62–0.91)0.0040.75 (0.62–0.90)0.002
      CardiacMortality0.49 (0.12–1.98)0.30.28 (0.05–1.68)0.160.50 (0.11–2.37)0.4
      CardiacInfarction0.83 (0.35–1.96)0.70.71 (0.27–1.86)0.50.85 (0.34–2.15)0.7
      CardiacIschemia0.71 (0.54–0.92)0.010.72 (0.54–0.97)0.030.68 (0.52–0.89)0.005
      VascularMortality0.47 (0.25–0.90)0.020.47 (0.25–0.90)0.020.46 (0.23–0.90)0.02
      VascularInfarction0.66 (0.46–0.94)0.020.66 (0.46–0.94)0.020.47 (0.20–1.10)0.08
      VascularIschemia0.83 (0.64–1.07)0.150.79 (0.61–1.03)0.080.92 (0.64–1.34)0.7
      * Jadad score ≥3.
      Because results may have been highly influenced by a single large study (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ), we estimated treatment effects when this study was excluded. Effects on mortality during all surgical procedures (RR = 0.65; 95% CI: 0.30 to 1.40; P = 0.3) and vascular surgery (RR = 0.66; 95% CI: 0.22 to 2.00; P = 0.5) were qualitatively unchanged, but effects on myocardial infarction during all surgical procedures (RR = 0.47; 95% CI: 0.25 to 0.91; P = 0.02) and vascular surgery (RR = 0.21; 95% CI: 0.07 to 0.66; P = 0.008) were improved.

      Discussion

      Our results show that α2-agonists reduce perioperative mortality and myocardial ischemia following cardiac and noncardiac surgery. No single treatment regimen was clearly superior. These perioperative benefits may depend largely on the surgical procedure involved, with the largest benefits observed in patients undergoing vascular and cardiac surgery. Compared with a prior systematic review of perioperative clonidine (
      • Nishina K.
      • Mikawa K.
      • Uesugi T.
      • et al.
      Efficacy of clonidine for prevention of perioperative myocardial ischemia a critical appraisal and meta-analysis of the literature.
      ), our meta-analysis included all commonly used α2-agonists, used a more extensive literature search, utilized a larger data set, and calculated treatment effects on important clinical outcomes, namely mortality and myocardial infarction.
      Among noncardiac surgical procedures, vascular surgery is associated with the highest risk of cardiovascular complications (
      • Lee T.H.
      • Marcantonio E.R.
      • Mangione C.M.
      • et al.
      Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery.
      ). Alpha-2 agonists reduced mortality and myocardial infarction significantly following vascular surgery. Treatment effects on mortality were unaffected by study quality and choice of statistical model, and remained statistically significant even when 35% to 45% of the most favorable studies were removed. Alpha-2 agonists were not associated with significant increases in bradycardia or hypotension during vascular surgery.
      During cardiac surgery, α2-agonists reduced myocardial ischemia significantly, but not mortality and myocardial infarction, which is likely due to the inadequate power of the subgroup analysis. Nonetheless, α2-agonists were associated with significant increases in hypotension during cardiac surgery.
      There are limited data to support the use of α2-agonists during nonvascular surgery. Only two trials reported effects on death or myocardial infarction within this subgroup (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ,
      • Venn R.M.
      • Grounds R.M.
      Comparison between dexmedetomidine and propofol for sedation in the intensive care unit patient and clinician perceptions.
      ). Furthermore, the estimates of treatment effect were uncertain, with wide 95% confidence intervals.
      The dose and duration of α2-agonist regimens were similar and did not appear to affect treatment efficacy. The effective dose of clonidine appears to be a single oral or intravenous dose of 2 to 6 μg/kg before surgery. There is no evidence of added benefit from additional intraoperative or postoperative doses of clonidine, which has a half-life of 12 hours (
      • Lowenthal D.T.
      • Matzek K.M.
      • MacGregor T.R.
      Clinical pharmacokinetics of clonidine.
      ). Dexmedetomidine should be administered as a 1- to 6-μg/kg intravenous bolus during or immediately after surgery, followed by a 0.2- to 0.7- μg/kg/h infusion for 48 hours. The effective mivazerol treatment regimen appears to be a 4-μg/kg intravenous bolus before surgery, followed by a 1.5-μg/kg/h infusion for 72 hours. Nonetheless, further study is needed to determine the optimal timing for initiating and terminating perioperative therapy.
      Alpha-2 agonists are generally safe. Aside from hypotension during cardiac surgery, this analysis did not find statistically significant increases in hypotension, bradycardia, or heart failure. The effect on bradycardia, although statistically nonsignificant, should be viewed cautiously in light of its heterogeneity and wide 95% confidence intervals. Although discontinuation of long-term α2-agonist therapy has been associated with rebound hypertension (
      • Webster J.
      • Koch H.F.
      Aspects of tolerability of centrally acting antihypertensive drugs.
      ) and mortality (
      • Webster J.
      • Jeffers A.
      • Galloway D.B.
      • Petrie J.C.
      Withdrawal of antihypertensive therapy [letter].
      ), these adverse effects did not appear to be clinically important during perioperative therapy.
      This study has several limitations. The overall results were dominated by a single large study (
      • Oliver M.F.
      • Goldman L.
      • Julian D.G.
      • Holme I.
      Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease the European Mivazerol Trial (EMIT).
      ). Exclusion of this study did not qualitatively change the results. The meta-analysis also lacked sufficient power to examine the effects of α2-agonists on specific subgroups (e.g., cardiac surgery, nonvascular surgery) and outcomes (e.g., supraventricular tachyarrhythmia, heart failure, bradycardia). Our results may have been biased by the different use of beta-blockers among studies, which decrease mortality after cardiac (
      • Ferguson Jr, T.B.
      • Coombs L.P.
      • Peterson E.D.
      Preoperative beta-blocker use and mortality and morbidity following CABG surgery in North America.
      ) and noncardiac (
      • Mangano D.T.
      • Layug E.L.
      • Wallace A.
      • Tateo I.
      Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group.
      ,
      • Poldermans D.
      • Boersma E.
      • Bax J.J.
      • et al.
      The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.
      ) surgery. In noncardiac surgery trials, patients assigned to α2-agonist arms were more likely to have received beta-blockers preoperatively. Nonetheless, differential beta-blocker use accounted for only a 4% relative risk reduction in mortality, and does not explain the 53% relative risk reduction in mortality during vascular surgery.
      We did not include any direct comparisons of α2-agonists and beta-blockers. Prior meta-analyses (
      • Crystal E.
      • Connolly S.J.
      • Sleik K.
      • et al.
      Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery a meta-analysis.
      ,
      • Andrews T.C.
      • Reimold S.C.
      • Berlin J.A.
      • Antman E.M.
      Prevention of supraventricular arrhythmias after coronary artery bypass surgery. A meta-analysis of randomized control trials.
      ) have shown that beta-blockers reduce supraventricular tachyarrhythmias during cardiac surgery; however, these analyses did not report effects on death or infarction. A systematic review (
      • Auerbach A.D.
      • Goldman L.
      Beta-blockers and reduction of cardiac events in noncardiac surgery scientific review.
      ) of beta-blocker use during noncardiac surgery identified five randomized controlled trials (
      • Mangano D.T.
      • Layug E.L.
      • Wallace A.
      • Tateo I.
      Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group.
      ,
      • Poldermans D.
      • Boersma E.
      • Bax J.J.
      • et al.
      The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.
      ,
      • Stone J.G.
      • Foex P.
      • Sear J.W.
      • et al.
      Myocardial ischemia in untreated hypertensive patients effect of a single small oral dose of a beta-adrenergic blocking agent.
      ,
      • Raby K.E.
      • Brull S.J.
      • Timimi F.
      • et al.
      The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery.
      ,
      • Urban M.K.
      • Markowitz S.M.
      • Gordon M.A.
      • et al.
      Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia.
      ) comprising 586 patients. The numbers needed to treat for beta-blockers to prevent a perioperative cardiovascular complication ranged from 2.5 (ischemia) (
      • Raby K.E.
      • Brull S.J.
      • Timimi F.
      • et al.
      The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery.
      ), to 3.2 (cardiac death or myocardial infarction, 18% event rate) (
      • Poldermans D.
      • Boersma E.
      • Bax J.J.
      • et al.
      The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.
      ), to 3.8 (myocardial infarction, 10% event rate) (
      • Stone J.G.
      • Foex P.
      • Sear J.W.
      • et al.
      Myocardial ischemia in untreated hypertensive patients effect of a single small oral dose of a beta-adrenergic blocking agent.
      ). In contrast, the numbers needed to treat for α2-agonists to prevent a postoperative death following vascular surgery ranged from 19 (10% event rate) to 38 (5% event rate). We were also unable to determine if α2-agonists have synergistic or additive effects when used with beta-blockers. The combination of the medications is unlikely to have adverse effects, given that α2- agonists continue to have beneficial effects among patients concurrently receiving beta-blockers.
      The quality of included trials may have biased treatment effects (
      • Moher D.
      • Pham B.
      • Jones A.
      • et al.
      Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?.
      ). The majority of studies were double-blind, placebo-controlled trials with Jadad scores of 3 or greater. However, we found that allocation concealment was generally poorly described, which may have increased estimates of treatment benefit (
      • Moher D.
      • Pham B.
      • Jones A.
      • et al.
      Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?.
      ).
      Our results support the use of α2-agonists for preventing perioperative cardiovascular complications following vascular or cardiac surgery. The most compelling evidence shows that α2-agonists decrease perioperative mortality and myocardial infarction during vascular surgery. Their potential in improving perioperative outcomes should be clarified in large randomized controlled trials.

      Acknowledgements

      We thank the following authors for providing additional information regarding their publications: Dr. M. Fischler (Hôpital Foch, Suresnes, France), Dr. R. M. Venn (Worthing Hospital, West Sussex, United Kingdom), Dr. R. M. Grounds (St George’s Hospital, London, United Kingdom), Dr. H. M. Loick (Marien-Hospital Euskirchen, Euskirchen, Germany), Dr. I. Matot (Hadassah Hebrew University Medical Center, Jerusalem, Israel), Dr. P. Myles (Alfred Hospital, Melbourne, Victoria, Australia), Dr. M. Oliver (late of National Heart & Lung Institute, London, United Kingdom), Dr. L. Quintin (School of Medicine, Lyon, France), Dr. C. Spies (University Hospital Charité, Berlin, Germany), and Dr. P. Talke (University of California, San Francisco, San Francisco, California).

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