POISE: Perioperative Beta-Blockade in Noncardiac Surgery (2008)

“In patients undergoing non-cardiac surgery, metoprolol succinate extended-release was associated with a reduced risk of myocardial infarction but an increased risk of death and stroke.”

  • The POISE Study Group

1. Publication Details

  • Trial Title: Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial
  • Citation: POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371(9627):1839-1847. DOI: 10.1016/S0140-6736(08)60601-7
  • Published: May 31, 2008, in The Lancet
  • Author: The POISE Study Group
  • Funding: Canadian Institutes of Health Research; and others.

2. Keywords

  • Perioperative Care, Beta-Blockers, Metoprolol, Myocardial Infarction, Noncardiac Surgery, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients undergoing noncardiac surgery who are at risk for atherosclerotic disease (Population), does a strategy of perioperative extended-release metoprolol (Intervention) compared to placebo (Comparison) reduce the composite risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest at 30 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Myocardial infarction is a leading cause of death after noncardiac surgery. The stress of surgery causes a catecholamine surge, leading to tachycardia and hypertension, which increase myocardial oxygen demand. Beta-blockers, by controlling heart rate and blood pressure, were thought to be a promising prophylactic strategy.
  • Knowledge Gap: Previous trials on perioperative beta-blockade were small, often single-center, and had produced conflicting results. A large, definitive, multicenter trial was needed to clarify the true risk-benefit balance of this common practice.
  • Proposed Hypothesis: The authors hypothesized that perioperative metoprolol would be superior to placebo in reducing the risk of major cardiovascular events.

5. Study Design and Methods

  • Design: A very large, international, multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 190 hospitals in 23 countries.
  • Trial Period: Enrollment ran from July 2000 to July 2007.
  • Population:
    • Inclusion Criteria: Adult patients (≥45 years) undergoing noncardiac surgery who were at risk for cardiovascular complications (e.g., known coronary artery disease, peripheral vascular disease, history of stroke, or major surgery).
    • Exclusion Criteria: Included patients already taking a beta-blocker, those with a heart rate <50 bpm, or systolic blood pressure <100 mm Hg.
  • Intervention: Patients received extended-release metoprolol succinate (100 mg) 2-4 hours before surgery, another 100 mg within 6 hours after surgery, and then 200 mg daily for 30 days.
  • Control: Patients received a matching placebo on the same schedule.
  • Management Common to Both Groups: All other aspects of perioperative care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 8000 patients would provide 90% power to detect a 25% relative risk reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: A composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest at 30 days.
    • Secondary Outcomes: Included all-cause mortality, stroke, and the incidence of clinically significant hypotension and bradycardia.

6. Key Results

  • Enrollment and Baseline: 8351 patients were randomized (4174 to metoprolol and 4177 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The primary composite outcome occurred in a significantly lower proportion of patients in the metoprolol group: 244 of 4174 patients (5.8%) in the metoprolol group met the primary endpoint, compared with 290 of 4177 patients (6.9%) in the placebo group (p=0.04).
  • Secondary Outcomes: The benefit was driven by a significant reduction in nonfatal myocardial infarction. However, all-cause mortality was significantly higher in the metoprolol group (3.1% vs. 2.3%; p=0.03). The risk of stroke was also significantly higher in the metoprolol group (1.0% vs. 0.5%; p=0.005).
  • Adverse Events: The incidence of clinically significant hypotension and bradycardia was significantly higher in the metoprolol group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a Cox proportional-hazards model.
  • Primary Outcome Analysis: The primary outcome was a time-to-event analysis of the composite endpoint.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for the primary outcome: 0.84 (95% CI, 0.70 to 0.99; P-value: 0.04).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the result as 0.84.
      • Clinical Meaning: The HR of 0.84 means that patients in the metoprolol group had a 16% lower risk of the primary composite outcome at any given time point compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.70 to 0.99.
      • Clinical Meaning: Since this entire range is below the line of no effect (1.0), it confirms that the result is statistically significant.
    • P-value: The p-value of 0.04 is below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for mortality):
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 3.1% – 2.3% = 0.8%.
      • Clinical Meaning: For every 1000 patients treated with this metoprolol regimen, about 8 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.008 = 125.
      • Clinical Meaning: You would need to treat 125 patients with this metoprolol regimen to cause one additional death.
  • Subgroup Analyses: The risks of death and stroke were consistent across subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of a very large, global population of patients make the findings highly generalizable.
  • Statistical Power: The enormous sample size provided definitive power to detect even small but clinically important differences in outcomes.
  • Patient-Centered Outcomes: The study focused on the most important patient-centered outcomes: death, MI, and stroke.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of at-risk patients undergoing noncardiac surgery.
  • Other: The “fixed-dose” regimen, without titration to hemodynamic response, is a key point of discussion and may have contributed to the increased rates of hypotension and bradycardia.

10. Conclusion of the Authors

  • The authors concluded that in patients undergoing noncardiac surgery, a perioperative regimen of extended-release metoprolol reduced the risk of myocardial infarction but increased the risk of death and stroke.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that the routine, protocolized use of high-dose, fixed-regimen beta-blockers in the perioperative period is harmful and should be avoided.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult patients at risk for cardiovascular complications undergoing noncardiac surgery.
    • Actionable Intervention: Do not initiate a fixed, high-dose beta-blocker regimen immediately before surgery.
    • Expected Benefit: Avoiding this therapy prevents one additional death for every 125 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that beta-blockers have no role in the perioperative period. It only argues against a “one-size-fits-all,” fixed-dose initiation strategy. Continuing a patient’s chronic beta-blocker therapy is still recommended.
  • Implementation Caveats: The key takeaway is the critical importance of avoiding hypotension and bradycardia in the perioperative period. If beta-blockers are to be initiated, they should be started well before surgery and carefully titrated to the patient’s hemodynamic response.

12. Context and Related Studies

  • Building on Previous Evidence: The POISE trial (2008) was designed to provide a definitive answer to a question that had been explored in many smaller, conflicting studies.
  • Influence on Subsequent Research: The definitive finding of harm in this trial has been highly influential in shaping all subsequent international anesthesiology and cardiology guidelines, which now strongly recommend against the routine initiation of beta-blockers immediately before surgery.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal strategy for initiating and titrating beta-blockers in the days or weeks beforenoncardiac surgery remains an area of investigation.
  • Future Directions: The results of this trial have shifted the focus of research towards other strategies for reducing perioperative cardiac risk, such as preoperative risk stratification and the management of other risk factors.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a very common and physiologically plausible intervention to reduce a major cause of postoperative morbidity and mortality.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for providing a definitive answer. The pragmatic design ensured high external validity.
  • Results: The study reported a complex primary outcome, with a benefit in one component (MI) but a significant increase in harm for others (death and stroke). The finding of a significant increase in overall mortality (NNH of 125) is the most critical result.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial is a landmark in perioperative medicine and a classic example of how a therapy can have a beneficial effect on a surrogate or component endpoint (MI) but still cause an overall increase in patient-centered harm (death). Its findings are broadly applicable and have become a cornerstone of modern perioperative care.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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