| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
2- and ß-adrenergic antagonists reduce perioperative cardiac events
1 Hamilton, Ontario
2 Melbourne, Australia
 |
Article appraised |
|---|
 TOP Article appraised Structured abstractCommentary by P. J....References |
|---|
|
Structured abstract |
|---|
|
TOPArticle appraisedStructured abstractCommentary by P. J....References |
|---|
Data sources: Studies were identified by computerized searches (MEDLINE, EMBASE, Cochrane Library) up to November 2002 and citation review. No language restrictions were applied.
Study selection: Studies were selected if they were randomized controlled trials (RCTs) comparing a cardioprotective drug to placebo or another cardioprotective drug in patients undergoing major non-cardiac surgery, followed patients over the entire intraoperative period or longer, enrolled at least ten patients per group, initiated the drug regimen no later than 24 hr after surgery, and did not focus on cardiovascular responses during the induction of anesthesia.
Data extraction: Data were extracted in triplicate on trial design, surgical setting, patient characteristics, drug regimens, length of postoperative follow-up, prevalence of previous MI, and outcomes including adverse events. The main outcomes were intraoperative myocardial ischemia, postoperative myocardial ischemia, perioperative nonfatal MI, and cardiac mortality.
Main results: Twenty-one trials with a total of 3,646 patients met the selection criteria. Studied drugs included ß-blockers (11 RCTs, 866 patients), 2-agonists (six RCTs, 2,614 patients), calcium channel blockers (three RCTs, 121 patients), and nitrates (one RCT, 45 patients). All compared a single cardioprotective drug with placebo. Meta-analyses were only performed for drugs tested in at least two trials. ß-blockers and 2-agonists reduced intraoperative ischemia; ß-blockers also reduced postoperative ischemia (Table
). ß-blockers reduced the risk of nonfatal MI (odds ratio [OR] 0.19; 95% confidence interval [CI] 0.08-0.48; Table). This effect was not significant when the two trials with extremely high control event rates were excluded. ß-blockers and 2-agonists reduced the risk of cardiac mortality (Table). Again, this effect was not significant for ß-blockers when the single trial with extremely high baseline risk was excluded. ß-blockers and calcium channel blockers increased the risk of bradycardia compared to placebo (Table).
|
2-agonists reduce the risk of perioperative cardiac events in patients undergoing major non-cardiac surgery; the magnitude of risk reduction with ß-blockers appears to be dependent on the baseline risk. Funding: Prosper Grant No. 3233-051939.97/2, Swiss National Research Foundation.
Correspondence: Dr. M.R. Tramèr, Division of Anesthesiology, Department APSIC, Geneva University Hospitals, CH-1211 Geneva 14, Switzerland. Email: martin.tramer{at}hcuge.ch
|
Commentary by P. J. Devereaux and K. Leslie |
|---|
|
TOPArticle appraisedStructured abstractCommentary by P. J....References |
|---|
Dr. Stevens and colleagues concluded, "this systematic review indicates that ß-blockers and 2-agonists offer significant protection against cardiac morbidity in patients undergoing noncardiac surgery".1 We, however, caution that a number of considerations raise concerns as to the reliability of their conclusions.
There was an error in their beta-blocker meta-analysis which missed one nonfatal myocardial infarction in one randomized controlled trial (RCT)2 and incorrectly assumed that the myocardial infarctions in another trial, by Wallace and colleagues,3 were nonfatal. Therefore, there were two nonfatal myocardial infarctions in the beta-blocker group and 16 in the placebo group.
The perioperative beta-blocker data, whilst encouraging, should be viewed with skepticism for a number of reasons. First, the treatment effects (i.e., reducing the risk of cardiac death and nonfatal myocardial infarction by 75–80%) are implausibly large and inconsistent with other cardiovascular interventions tested in large RCTs. Indeed beta-blocker RCTs of 10,000s of patients in acute myocardial infarction and congestive heart failure have consistently demonstrated relative risk reduction of 20 to 35%. Furthermore, given that several important pathogenic mechanisms, through which perioperative cardiovascular events are thought to occur (e.g., increases in platelet reactivity, plasminogen activator inhibitor I (PAI-I), factor VIII-related antigen levels, and inflammation, and decreases in antithrombin III levels), are unaffected by beta-blockers, relative risk reductions much greater than 25% are not realistic. Second, there have been very few events in the perioperative beta-blocker RCTs (i.e., 20 deaths of which 15 were cardiac and 18 nonfatal myocardial infarctions). To convincingly establish realistic (i.e., 25%) risk reductions, trials need a minimum of 350, and ideally 650, events.4 Third, the results are completely reliant on the results of one small RCT that has several limitations.2 This RCT, by Poldermans and colleagues, included only 112 patients, had very few events (11 deaths and nine nonfatal myocardial infarctions), was unblinded, and stopped after an interim analysis suggested large treatment effects that appear too good to be true (i.e., relative risk reductions of 100% for nonfatal myocardial infarction and 80% for cardiac death). There are strong theoretical reasons and empiric data that caution us to remain skeptical about unexpected large treatment effects in studies terminated early.5 Fourth, when the supportive evidence for an intervention comes from nothing more than a small number of positive trials with very few events, publication bias may seriously distort the evidence.
Similar to the perioperative beta-blocker data the perioperative 2-agonists data should be considered promising but the results warrant cautious interpretation. The failure of 2-agonists to demonstrate an effect on nonfatal myocardial infarctions was inconsistent with the reported 50% reduction in the risk of cardiac death. This occurred despite there being four times as many nonfatal myocardial infarctions as there were cardiac deaths.
The systematic review by Stevens and colleagues highlights the need for large adequately powered RCTs to provided definitive evidence regarding the potential benefits and risks of perioperative beta-blockers and 2-agonists.
|
Footnotes |
|---|
|
References |
|---|
|
TOPArticle appraisedStructured abstractCommentary by P. J....References |
|---|
2 Poldermans D, Boersma E, Bax JJ, 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. N Engl J Med 1999; 341: 1789–94.
3 Wallace A, Layug B, Tateo I, et al. Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. Anesthesiology 1998; 88: 7–17.[Medline]
4 Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984; 3: 409–22.[Medline]
5 Wheatley K, Clayton D. Be skeptical about unexpected large apparent treatment effects: the case of an MRC AML12 randomization. Control Clin Trials 2003; 24: 66–70.[Medline]
This article has been cited by other articles:
 |
|
 |
|
  P.J. Devereaux, K. Leslie, and H. Yang The effect of perioperative beta-blockers on patients undergoing noncardiac surgery - is the answer in?/L'effet des beta-blo-quants perioperatoires sur les patients de chirurgie non cardiaque - avons-nous la reponse ? Can J Anesth, October 1, 2004; 51(8): 749 - 755. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
