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Frequently Asked Questions

Are perioperative beta blockers effective in preventing cardiovascular complications in non-cardiac surgery?

Background

The most common and potentially life-threatening complications of surgery are cardiovascular events.1 These include myocardial infarction (MI), cardiac death, pulmonary edema, arrhythmias, and heart block. It is thought that these complications are the result of myocardial ischemia (imbalance between oxygen supply and demand) and an increase in catecholamine levels during the first 48 hours after surgery.1,2 Patients with coronary artery disease (CAD), a history of MI, congestive heart failure, hypertension, and diabetes are at the greatest risk for perioperative cardiovascular complications.1 In these patients, the body compensates for the imbalance of myocardial oxygen supply or demand by increasing the contractility of the heart thus causing an increase in heart rate. In surgical patients, this effect is compounded by the release of catecholamines, which have similar effects on the heart.1,2 Previous studies have shown a cardio-protective role of beta blockers, specifically those that affect beta1 receptors, in non-cardiac surgery.1-3 The exact mechanism by which beta blockers may prevent cardiovascular complications following surgery has not been determined; however, it is thought that by decreasing heart rate and blood pressure, beta blockade prevents plaque rupture and coronary thrombosis.1

Literature evaluation

The results of 2 recently published studies and 1 meta-analysis have sparked controversy over the use of perioperative beta blockers in non-cardiac surgery.2-4 The PeriOperative Ischemic Evaluation (POISE trial) was a randomized, double-blind, placebo-controlled, multi-center trial of 8351 patients with, or at risk for, atherosclerotic disease who were undergoing non-cardiac surgery.3 Patients with a heart rate ≥50 bpm and systolic blood pressure ≥100 mmHg received extended-release metoprolol 100 mg or matching placebo 2 to 4 hours before surgery. Within 6 hours post-surgery, patients with a heart rate ≥80 bpm and systolic blood pressure ≥100 mmHg were started on metoprolol 100 mg. Twelve hours after the first postoperative dose, patients were started on metoprolol 200 mg daily or placebo for 30 days. The primary outcome was a composite of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest after 30 days. Secondary outcomes included non-fatal stroke, cardiac revascularization, new onset atrial fibrillation, and clinically significant hypotension and bradycardia.

There was a statistically significant difference in the number of MIs in the metoprolol group vs. placebo [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.6 to 0.89; p=0.0017].3 There was a greater number of strokes seen in patients treated with metoprolol (HR 2.17, 95% CI 1.26 to 3.74; p=0.0053). More people in the metoprolol group died compared to placebo (HR 1.33, 95% CI 1.03 to 1.74; p=0.0317). Non-fatal MI was higher in the placebo group while non-fatal stroke was higher in the metoprolol group (HR 0.7, 95% CI 0.57 to 0.86; p=0.008) and (HR 1.94, 95% CI 1.01 to 3.69; p=0.045), respectively. At hospital discharge, patients in the metoprolol group had a lower heart rate and blood pressure compared with those in the placebo group (p<0.001 for both measures), which resulted in a greater number of patients with clinically significant hypotension and bradycardia. The results of the POISE trial showed that for every 1000 patients treated with metoprolol for non-cardiac surgery, MI would be prevented in 15 patients, cardiac revascularization would be prevented in 3 patients, and atrial fibrillation in 7 patients. Additionally, metoprolol treatment would result in an excess of 8 deaths, 5 strokes, 53 episodes of clinical hypotension, and 42 episodes of clinical bradycardia. The authors of the POISE trial concluded that although metoprolol was better than placebo for some outcome measures, the drug resulted in a statistically significant increase in the risk of death, stroke, hypotension, and bradycardia. The risks versus the benefits of perioperative metoprolol must be taken into consideration in patients undergoing non-cardiac procedures.

Kaafarani and colleagues conducted a retrospective cohort study to test the hypothesis of no difference in the use of perioperative beta blockers in non-cardiac surgeries in patients at all stages of cardiac risk.2 Prior to surgery, 1238 patients were classified into high, intermediate, low, or negligible cardiac risk categories based on the American College of Cardiology/American Heart Association (ACC/AHA) classification. The primary outcome was stroke, cardiac arrest, MI, and mortality at 30 days. Mortality was also evaluated after 1 year. The results of this study were consistent in the beta blocker group despite the ACC/AHA risk classification. Patients who received beta blockers had a statistically significant difference in pre-operative heart rate (70 vs. 74 bpm; p=0.001), mean heart rate (71 vs. 78 bpm; p<0.001), minimum heart rate (60 vs. 63 bpm; p=0.02), and maximum heart rate (86 vs. 91 bpm; p<0.001). The results of the primary outcome measure at 30 days showed that patients in the beta blocker group had statistically higher incidences of non-fatal MI (2.94% vs. 0.74%; p=0.03), cardiovascular morbidity (5.04% vs. 1.47%, p=0.003), and all cause mortality (2.52% vs. 0.25%; p=0.007). The mortality rates at 1 year were similar between the groups. The results of this study suggested that beta blockers do not offer a cardio-protective effect in patients undergoing non-cardiac procedures, despite their ACC/AHA risk classification.

Bangalore and colleagues conducted a meta-analysis to assess the use of perioperative beta blockers in patients having non-cardiac surgery.4 A total of 12,306 patients were included from 33 trials. The primary outcome measures were 30-day all cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, heart failure, myocardial ischemia, and safety including bradycardia, hypotension, and bronchospasm. There was no significant reduction in the risk of all cause mortality, cardiovascular mortality, or heart failure. Beta blockers were associated with a decrease in non-fatal MI [odds ratio (OR) 2.01, 95% CI 1.27 to 3.68] and myocardial ischemia (OR 0.36, 95% CI 0.26 to 0.5). However, beta blockers were associated with an increase in non-fatal strokes (OR 2.01, 95% CI 1.27 to 3.68). Patients who received beta blockers had a greater risk for bradycardia and hypotension. The authors concluded that the current evidence in the published medical literature does not support the use of perioperative beta blockers in patients undergoing non-cardiac surgery.

The controversy

The 3 studies summarized above show that perioperative beta blockers increase the risk of stroke, mortality, hypotension, and bradycardia. The study by Kaafarani and colleagues showed that beta blockers were associated with an increased risk for non-fatal MI, whereas the other studies showed a reduction in non-fatal MI.2-4 Some experts have questioned the high dose (100 to 200 mg daily) of metoprolol used in the POISE trial.5 In a non-surgical patient, metoprolol is typically initiated at doses of 12.5 to 25 mg daily for heart failure and 25 to 100 mg daily for hypertension. These doses are titrated at weekly intervals based on patient tolerance. In the POISE trial, the starting dose of metoprolol was 2 to 8 times the recommended starting dose for these indications. The other trials did not report the agents and doses used.

Guidelines

The 2007 ACC/AHA guidelines on perioperative cardiovascular evaluation for non-cardiac surgery recommend the use of perioperative beta blockers for some patients undergoing non-cardiac surgery.6 The recommendations are as follows:

Class I (intervention is useful/effective)

  • Beta blockers should be continued in surgical patients that are currently receiving these agents for the treatment of angina, arrhythmias, hypertension, or other indications supported by the ACC/AHA guidelines (i.e. post MI).
  • Beta blockers should be given to patients who are at high cardiac risk based on the finding of ischemia on preoperative testing.

Class IIa (conflicting data, favors use)

  • Beta blockers are probably recommended for patients undergoing non-cardiac surgery in which preoperative testing indicates 1 high cardiac risk factor or evidence of CAD.
  • Beta blockers are probably recommended for patients undergoing immediate-risk, non-cardiac surgery in which preoperative testing indicates 1 high cardiac risk factor or evidence of CAD.

Class IIb (efficacy is less well established)

  • The usefulness of beta blockers is not known for patients undergoing intermediate-risk procedures or non-cardiac procedures in which preoperative testing identifies 1 risk factor.
  • The effectiveness of beta blockers in non-cardiac surgery in patients with low to no clinical risk factors has not been established.

At this time, the ACC/AHA has not provided a statement to change the current guidelines based on the results of these trials.

Conclusion

Recent literature on the use of perioperative beta blockers has sparked controversy. Beta blockers have been shown to increase the risk of stroke, mortality, hypotension, and bradycardia in patients undergoing non-cardiac surgery. Questions surround the use of the most appropriate agent and dose. The ACC/AHA guidelines recommend the use of beta blockers in high risk patient populations. Until the evidence of perioperative beta blockers is more conclusive, the use of these agents should be limited to patients who are at high cardiac risk.

References

  1. Ryder DL. The use of ß-blockers to decrease adverse perioperative cardiac events. Dimens Crit Care Nurs. 2008;27(2):47-53.
  2. Kaafarani H, Atluri PV, Thornby J, Itani K. ß-blockade in noncardiac surgery: outcome at all levels of cardiac risk. Arch Surg. 2008;143(10):940-944.
  3. POISE Study Group, Devereaux PJ, Yang H, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomized controlled trial. Lancet. 2008;371(9627):1839-1847.
  4. Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative ß blockers in patients having non-cardiac surgery: a meta-analysis. Lancet. 2008; doi:10.1016/S0140-6736(08)61560-3. [epub ahead of print].
  5. Fleisher LA, Poldermans D. Perioperative ß blockade: where do we go from here? Lancet. 2008;371( 9627):1813-1814.
  6. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation. 2007;116(17):1971-1996.