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The experts debate: Perioperative beta-blockade for noncardiac surgery—proven safe or not?

November 1, 2009|Cleveland Clinic Journal of Medicine
Don Poldermans, MD, PhD;P.J. Devereaux, MD, PhD
Author and Disclosure Information

Don Poldermans, MD, PhD
Professor of Perioperative Care, Department of Anesthesiology, Erasmus Medical Center, Rotterdam, The Netherlands

P.J. Devereaux, MD, PhD
Associate Professor and Joint Member in Departments of Clinical Epidemiology & Biostatistics and Medicine (Cardiology), McMaster University, Hamilton, ON, Canada

Correspondence: Don Poldermans, MD, PhD, Department of Anesthesiology, Erasmus MC’s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands (d.poldermans@erasmusmc.nl) and P.J. Devereaux, MD, PhD, McMaster University, Faculty of Health Sciences, 1200 Main Street West, Room 2C8, Hamilton, ON, Canada L8N 3Z5 (philipj@mcmaster.ca)

Dr. Poldermans has indicated that he has received grants/research support from Novartis, Pfizer, and Merck.

Dr. Devereaux has indicated that he has served on an advisory board meeting for GlaxoSmithKline and an expert panel for AstraZeneca and has received grants/research support from AstraZeneca and Roche Diagnostics. All conflicts of interest have been resolved.

This article was developed from an audio transcript of a debate between the authors at the 4th Annual Perioperative Medicine Summit. The transcript was edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Drs. Poldermans and Devereaux.

ABSTRACT

Guidelines on perioperative management of patients undergoing noncardiac surgery recommend the use of prophylactic perioperative beta-blockers in high-risk patients who are not already taking them, and their continuance in patients on chronic beta-blockade prior to surgery. These recommendations were challenged recently by results of the Perioperative Ischemic Evaluation (POISE), a large randomized trial of extended-release metoprolol succinate started immediately before noncardiac surgery in patients at high risk for atherosclerotic disease. While metoprolol significantly reduced myocardial infarctions relative to placebo in POISE, it also was associated with significant excesses of both stroke and mortality. The merits and limitations of POISE and its applicability in light of other trials of perioperative beta-blockade are debated here by two experts in the field—Dr. Don Poldermans and Dr. P.J. Devereaux (co-principal investigator of POISE).

ANSWERING THE CRITICS

Several criticisms have been raised about POISE, as detailed below.

Beta-blocker dose

Some contend that a lower dose of beta-blocker would provide benefit and minimize risk, but this assertion must be supported by evidence from a large clinical trial. The targeted dosage of metoprolol in POISE represents 50% of the maximum daily therapeutic dose. Further, the protocol called for decreasing the dosage to 100 mg/day if SBP dropped to less than 100 mm Hg or if heart rate fell to less than 45 beats per minute.

The two small trials on which guideline recommendations for perioperative beta-blockade are primarily based1,3 had a sample size that was 4% of that in POISE, which calls into question the reliability of their results. The study by Mangano et al used atenolol at a target dosage that was 50% of the maximum daily therapeutic dose,1 the same as with metoprolol in POISE. DECREASE initiated bisoprolol at 25% of the maximum daily therapeutic dose, and allowed for titration to 50% of the maximum daily therapeutic dose.3

As the second largest study of perioperative beta-blockade, the Diabetic Postoperative Mortality and Morbidity (DIPOM) trial enrolled 921 patients who were assigned to placebo or controlled-release metoprolol with a target dosage that was 25% of the maximum daily therapeutic dose.4 The 30-day outcomes from DIPOM showed a trend toward an excess of death and stroke despite using only one-half the dosage in POISE and the same dosage as in DECREASE.

Timing of beta-blocker initiation

Another contention is that earlier beta-blocker initiation would be better. The issue with timing of initiation is not benefit, as POISE showed that starting a beta-blocker hours before surgery results in a reduction in the risk of MI. The issue is whether giving a beta-blocker earlier makes administering the drug safer. Nearly 10% of placebo recipients in POISE developed clinically significant hypotension, which suggests that the titrated dosage of a beta-blocker that appears effective preoperatively is unlikely to inform a safe dose after surgery, when hypotension is common.

The practicality of titrating the dose of beta-blocker prior to surgery also comes into play. Most patients referred to my institution for surgery are seen 1 to 2 weeks in advance, at the earliest. Real-world practice at present simply does not afford us the luxury of seeing patients three to four times before surgery in order to titrate the beta-blocker dose.

POISE did not address chronic beta-blocker therapy

It is important to remember that POISE excluded patients on chronic beta-blocker therapy and thus did not attempt to address the perioperative management of such patients who undergo noncardiac surgery. My suspicion is that perioperative continuation of beta-blockade in these patients is the best course of action, but this too has not been studied robustly, so we need a large controlled trial to confirm that this practice is indeed safe. 

CONCLUSIONS

The POISE results suggest that for every 1,000 patients treated, perioperative metoprolol would:

  • Prevent 15 MIs, 3 cardiac revascularizations, and 7 new cases of atrial fibrillation
  • Result in 8 excess deaths, 5 strokes, 53 cases of clinically significant hypotension, and 42 cases of clinically significant bradycardia.

The central take-away message is that patients are unlikely to want a perioperative beta-blocker if they are unwilling to accept a probable increase in mortality or if they place three times more value on avoiding a perioperative stroke than on avoiding an MI.

It has been 10 years since the recommendation to use perioperatove beta-blockers was incorporated into perioperative practice guidelines. Assuming only 10% of physicians acted on this recommendation, 100 million patients have received a perioperative beta-blocker over this time as a result. If the POISE results are applicable, a full 800,000 of these patients died and another 500,000 suffered perioperative strokes as a result of being given a beta-blocker. This issue is not to be taken lightly, given the evidence to suggest harm.

Though it is possible that an alternative beta-blocker regimen to the one used in POISE may provide benefit without substantial harm, the data suggest this is not probable. The POISE data highlight the risk of making assumptions, as well as the importance of and need for large, high-quality randomized trials in the perioperative setting.

It is time for perioperative medicine to enter the age of evidence-based practice and embrace one of its central tenets: only large trials are reliable when it comes to therapeutic questions.

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