A recent meta-analysis7
included 11 RCTs that studied the use of perioperative β-blocker therapy; a total of 866 patients were enrolled in the trials, of whom 475 received β-blocker therapy. Only 7 of the 11 RCTs reported any major adverse events within the first 30 days of surgery; overall, there were only 20 deaths (of which 15 were cardiac) and 18 cases of nonfatal myocardial infarction. The meta-analysis failed to include a nonfatal myocardial infarction that occurred in 1 of the RCTs8
and incorrectly assumed that the myocardial infarctions in another trial9
were nonfatal. provides an overview of these results.
The 7 β-blocker trials did not demonstrate a significant impact on the total number of deaths, but suggested a reduction in the number of deaths from cardiac events, as well as nonfatal myocardial infarctions. In the meta-analysis, there were 3 cardiac deaths in the β-blocker group and 12 in the control group; 11 of these 15 deaths, and 9 of the 18 nonfatal myocardial infarctions, occurred in a trial by Poldermans and colleagues.8
The results from these trials are promising, but they warrant cautious interpretation in light of the very small number of events and the substantial reliance on the results of 1 small trial.8
If even 1 or 2 “negative” trials remain unpublished, this could undermine the findings of the meta-analysis. To establish moderate (25%) relative risk reductions convincingly, given a control event rate of 10%, an RCT would require at least 350, and ideally 650, events.10
The perioperative β-blocker RCT data included only 38 events.
Furthermore, the relative risk reductions of 75%–80% in this meta-analysis are inconsistent with the results of RCTs that showed benefits of cardiovascular therapies, which have generally demonstrated relative risk reductions in the order of 20%–35%. A host of mechanisms, including increases in adrenergic activity, free fatty acid levels, platelet reactivity, plasminogen activator inhibitor I, factor VIII-related antigen levels, inflammation, and decreases in antithrombin III levels, probably mediate perioperative cardiovascular events.8,11,12,13,14
Only a few of these mechanisms (e.g., decreasing adrenergic activity and free fatty acid levels) are targeted by β-blockers. Given the number of important pathogenic mechanisms that are unaffected by β-blockers, relative risk reductions much greater than 25% are implausible.
The RCT by Poldermans and colleagues that dominates the meta-analysis warrants further scrutiny. This trial evaluated the efficacy of bisoprolol therapy in patients with a positive dobutamine echocardiography study who were undergoing elective vascular surgery. There are a number of reasons for concern about their findings: the study included only 112 patients; few events occurred (20 total); and the trial was not blinded. The investigators terminated the trial because interim analysis suggested a large benefit. Empirical data caution us to be skeptical about unexpected large treatment effects in studies that are terminated early.15
Further, the benefits appear too good to be true (relative risk reductions of 100% for nonfatal myocardial infarction, and 80% for cardiac death). These results are inconsistent with those of RCTs of β-blocker therapy in tens of thousands of patients with acute myocardial infarction and chronic congestive heart failure, which have consistently demonstrated relative risk reductions of 15%–35%. If this were true, we would be seeing virtually no cardiac events in patients treated with β-blockers in clinical practice. But this is not the case. Although the findings of this trial are important, they need to be confirmed in a large, well-designed RCT.
With respect to long-term benefits, a single RCT involving 200 patients undergoing noncardiac surgery became the basis for the recommendation for perioperative β-blocker therapy by the authors of the ACP guidelines.9
In this trial, atenolol or placebo was administered to patients for a maximum of 7 postoperative days. After 2 years of follow-up, 9 deaths had occurred in the atenolol group and 21 in the placebo group (a relative risk reduction of 55%, p
However, the authors included only deaths that occurred after patients had stopped taking the trial medication. Given that perioperative β-blockers have the greatest potential for impact during the period when patients are taking these drugs, it is inappropriate to exclude these events from the analysis. Including the data from the first 7 postoperative days (when patients were receiving the trial medication) gives a total of 13 deaths in the atenolol group and 23 in the placebo group (a true intention-to-treat analysis), and the difference loses statistical significance (p
= 0.1). The paucity of events, the implausibly large magnitude of the effect and the nonsignificant results when one includes all deaths during the 2-year follow-up call into question this trial's conclusions.