The Lancet MAY 31, 2008

Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial

Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, et al.

Bottom Line

In patients undergoing non-cardiac surgery, perioperative administration of extended-release metoprolol significantly reduced the risk of non-fatal myocardial infarction but resulted in a statistically significant increase in total mortality and stroke.

Key Findings

1. The primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest) occurred in 5.8% of the metoprolol group versus 6.9% in the placebo group (HR 0.84, 95% CI 0.70-0.99, p=0.0399).

2. Non-fatal myocardial infarction was significantly reduced in the metoprolol group (4.2% vs. 5.7%; HR 0.73, 95% CI 0.60-0.89, p=0.0017).

3. Total mortality was significantly higher in the metoprolol group (3.1% vs. 2.3%; HR 1.33, 95% CI 1.03-1.74, p=0.0317).

4. Stroke incidence was more than doubled in the metoprolol group (1.0% vs. 0.5%; HR 2.17, 95% CI 1.26-3.74, p=0.0053).

5. The increase in mortality and stroke was strongly associated with a higher incidence of clinically significant hypotension (15.0% vs. 9.7%; HR 1.55) and bradycardia (6.6% vs. 2.4%; HR 2.74) observed with metoprolol therapy.

Study Design

Design

RCT

Double-Blind

Sample

8,351

Patients

Duration

30 days

Median

Setting

Multicenter, 23 countries

Population Patients aged 45 or older with, or at risk of, atherosclerotic disease undergoing non-cardiac surgery.

Intervention Extended-release metoprolol succinate (100 mg 2-4 hours pre-op, followed by 100 mg 0-6 hours post-op and 200 mg daily for 30 days).

Comparator Placebo administered using the same regimen.

Outcome Composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest at 30 days.

Study Limitations

• The use of high-dose, fixed-regimen beta-blockade without individualized titration likely contributed to the adverse hemodynamic profile (hypotension and bradycardia).

• The study design included patients at risk of atherosclerotic disease, which may limit generalizability to lower-risk populations.

• The trial observed a significant increase in mortality, which forced a re-evaluation of the long-standing practice of empiric perioperative beta-blockade.

• The 30-day follow-up period may be insufficient to fully capture the long-term impact on mortality.

Clinical Significance

The POISE trial challenged the prevailing clinical practice of administering prophylactic perioperative beta-blockers to all high-risk patients. It demonstrated that while beta-blockers prevent myocardial infarction, they carry significant risks of stroke and death, emphasizing the need for individualized, hemodynamically-monitored therapy over routine administration.

Historical Context

Prior to POISE, clinical guidelines recommended perioperative beta-blockers based on smaller, unblinded trials from the 1990s that suggested large benefits. POISE was a landmark study that definitively showed these risks outweigh benefits in broad patient populations, leading to a major paradigm shift in perioperative management.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the physiological effects of beta-1 selective blockade, why would metoprolol succinate theoretically reduce the risk of myocardial infarction during the stress of surgery, yet paradoxically increase the risk of ischemic stroke?

Key Response

Beta-blockers decrease myocardial oxygen demand by reducing heart rate and contractility, protecting the heart from the catecholamine surge of surgery. However, this same reduction in cardiac output and systemic blood pressure can lead to intraoperative hypotension and cerebral hypoperfusion, which are primary drivers for the increased incidence of ischemic stroke observed in the POISE trial.

Resident

A 68-year-old beta-blocker-naive patient with a history of diabetes and stable angina is scheduled for an elective total hip arthroplasty tomorrow. Following the results of the POISE trial, how should you manage their perioperative beta-blockade strategy?

Key Response

The POISE trial demonstrated that starting high-dose extended-release metoprolol (100mg) immediately before surgery in beta-blocker-naive patients increases the risk of death and stroke. Therefore, you should NOT initiate beta-blockade on the day of surgery. If beta-blockade is indicated for long-term management, it should ideally be started and titrated weeks before the procedure to assess tolerance and avoid profound hypotension.

Fellow

The POISE trial results contrasted significantly with earlier, smaller trials such as DECREASE-I. What specific aspects of the POISE dosing protocol and the target heart rate might explain the higher mortality rate compared to earlier 'successes' in perioperative beta-blockade research?

Key Response

POISE utilized a high-dose, fixed-regimen (100mg metoprolol CR) initiated only 2-4 hours before surgery without a titration period. In contrast, earlier trials that showed benefit often used lower doses started days or weeks in advance. The rapid, high-dose administration in POISE likely caused acute hemodynamic instability and blunted the compensatory tachycardia required to maintain cardiac output during surgical hemorrhage or systemic inflammatory response.

Attending

POISE is a classic example of a 'positive' trial for a primary composite endpoint that resulted in 'negative' clinical practice changes. How do you interpret the 'Net Clinical Benefit' when a treatment significantly reduces non-fatal myocardial infarction (HR 0.73) but increases all-cause mortality (HR 1.33)?

Key Response

This highlights the importance of hierarchical endpoints. A reduction in a non-fatal event (MI) does not justify a treatment if it increases the risk of a definitive, irreversible event like death. In clinical teaching, this emphasizes that we must treat the patient's survival rather than just an isolated surrogate or organ-specific complication.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of a fixed-dose titration protocol in the POISE trial from a pharmacodynamic perspective. How might the lack of an individualized dose-response assessment threaten the external validity of the study's conclusions regarding the beta-blocker class as a whole?

Key Response

By using a fixed 100mg dose of metoprolol succinate, the trial may have tested a 'toxic' dosing strategy rather than the pharmacological class effect. The study design lacks an arm for 'optimal' clinical care (slow titration to effect), meaning the results may only be generalizable to aggressive, fixed-dose protocols rather than the more cautious initiation strategies often used in clinical practice, potentially overestimating the harm of the drug class itself.

Journal Editor

As a reviewer, if the authors of POISE had chosen to emphasize only the 27% reduction in myocardial infarction in their abstract conclusions, what specific threats to transparency and reporting standards (such as CONSORT) would you cite in your revision request?

Key Response

Emphasizing the MI reduction while downplaying the increase in mortality and stroke would constitute 'spin.' An editor must insist that the 'Harm' outcomes be given equal or greater prominence in the conclusion because the hazard ratio for mortality (1.33) and stroke (2.17) carries more clinical weight than the reduction in non-fatal MI. Failure to do so would mislead readers regarding the safety-efficacy trade-off.

Guideline Committee

How did the POISE trial influence the evolution of ACC/AHA guidelines regarding the 'Class of Recommendation' for initiating beta-blockers in the immediate perioperative period for non-cardiac surgery?

Key Response

Before POISE, guidelines were more permissive regarding perioperative beta-blockade. Following the trial, ACC/AHA and ESC guidelines were updated to state that initiating beta-blockers on the day of surgery is a Class III (Harm) recommendation. Current guidelines (e.g., 2014 ACC/AHA) specify that beta-blockers should not be started on the day of surgery in naive patients, but should be continued in those already taking them chronically (Class I).

Clinical Landscape

Noteworthy Related Trials

1999

DECREASE-I Trial

n = 112 · JAMA

Tested

Bisoprolol

Population

Vascular surgery patients with high risk of cardiac events

Comparator

Placebo

Endpoint

Cardiac death and nonfatal myocardial infarction

Key result: Bisoprolol significantly reduced the incidence of perioperative cardiac death and myocardial infarction in high-risk patients.

2006

DIPOM Trial

n = 921 · Diabetes Care

Tested

Metoprolol succinate

Population

Patients with type 2 diabetes undergoing major noncardiac surgery

Comparator

Placebo

Endpoint

Composite of mortality and cardiac morbidity

Key result: Metoprolol did not significantly reduce the 30-day incidence of the primary endpoint in diabetic patients undergoing noncardiac surgery.

2014

POISE-2 Trial

n = 10,000 · NEJM

Tested

Clonidine

Population

Patients undergoing noncardiac surgery at risk of perioperative cardiovascular events

Comparator

Placebo

Endpoint

Composite of death or nonfatal myocardial infarction at 30 days

Key result: Clonidine did not reduce the rate of death or nonfatal myocardial infarction but increased the risk of clinically significant hypotension.

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