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Perioperative beta-blockers in noncardiac surgery: Evolution of the evidence

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ABSTRACTAfter studies in the 1990s suggested that beta-blockers offer substantial benefits when given before surgery, several national organizations endorsed the perioperative use of these drugs as a best practice in certain patients. However, subsequent research has cast doubt on whether it is appropriate to use these drugs as widely as suggested by those early studies.

KEY POINTS

  • Beta-blockers reduce perioperative ischemia, but the benefit may be only in high-risk patients undergoing high-risk surgery. Currently, the best evidence supports their use in two groups: patients undergoing vascular surgery who have known ischemic heart disease or multiple risk factors for it, and patients who are already on beta-blockers.
  • The Perioperative Ischemic Evaluation (POISE) findings suggest that beta-blockers should be used in the immediate preoperative period only with great caution, after ensuring that the patient is clinically stable and without evidence of infection, hypovolemia, anemia, or other conditions that could make heart-rate titration misleading or use of the drug dangerous.
  • When feasible, beta-blockers should be started a month before surgery, titrated to a heart rate of 60 beats per minute, and continued for approximately a month. If the drug is then to be discontinued, it should be tapered slowly.


 

References

The pendulum of expert opinion is swinging away from routinely recommending beta-blockers to prevent cardiac events in non-cardiac surgery patients. We won’t be abandoning the perioperative use of beta-blockers altogether, but we will probably be using them more selectively than in the past.

The latest factor driving the trend is the online publication in May 2008 of the results of the Perioperative Ischemic Evaluation (POISE) trial,1 the largest placebo-controlled trial of perioperative beta-blocker use to date. In brief, in a cohort of patients with atherosclerotic disease or at risk for it who were undergoing noncardiac surgery, fewer patients who received extended-release metoprolol succinate had a myocardial infarction, but more of them died or had a stroke compared with those receiving placebo. (Extended-release metoprolol succinate is available in the United States as Toprol-XL and generically.)

Not so long ago, the pendulum was going the other way. After two small trials in the 1990s concluded that beta-blockers reduced the risk of perioperative cardiac events in selected patients with known or suspected coronary disease,2,3 their perioperative use was subsequently endorsed by the Leapfrog Group and the Agency for Healthcare Research and Quality. The National Quality Forum included perioperative beta-blockade in its “Safe Practices for Better Healthcare 2006 update,”4,5 and the Physician Consortium for Performance Improvement and the Surgical Care Improvement Project both listed it as a quality measure.

Since then, this practice has been closely studied, especially as concomitant research has failed to demonstrate that pre-operative coronary revascularization improves outcomes, even in the presence of ischemic disease. But evidence has been accumulating that routine use of beta-blockers may not benefit as many patients as was hoped, and may actually cause harm. The 2007 joint American College of Cardiology (ACC) and American Heart Association (AHA) guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery gives its strongest recommendation (class I: benefit clearly outweighs risk) for perioperative beta-blocker use only for patients at high risk: those with known ischemic heart disease undergoing vascular surgery and those who are already on these drugs before surgery.6

However, there are still gaps in our knowledge. Perhaps, with proper implementation, we may be able to use beta-blockers to improve outcomes in patients at intermediate risk as well. In this paper, we review the rationale and the evidence for and against perioperative use of beta-blockers and provide practical guidance for internists and hospitalists.

WHY CARDIAC EVENTS OCCUR AFTER SURGERY

Adverse cardiovascular events such as myocardial infarction and unstable angina are the leading causes of death after surgery.7 Such events occur in approximately 1% of patients older than 50 years undergoing elective inpatient surgery, but this number may be higher (approximately 5%) in those with known or suspected coronary disease.8,9 Perioperative cardiac events can also be harbingers of further complications, dramatically increasing hospital length of stay.10

Some ischemic events are caused by physiologic derangements involving the balance between inflammatory mediators, sympathetic tone, and oxygen supply and demand that occur under the stress of surgery. Others are more “traditional” in etiology, involving acute plaque rupture, thrombosis, and occlusion. Studies have consistently found a correlation between perioperative ischemia and cardiac events (both in-hospital and long-term) and death.11–17 Other studies suggest that most perioperative cardiac infarcts are non-Q-wave events,18 and most events occur within the first few days after surgery, particularly the first 48 hours, when the effects of anesthetics, pain, fluid shifts, and physiologic derangements are greatest.

Factors that may trigger acute occlusion in the perioperative period include abrupt changes in sympathetic tone, increased levels of cortisol and catecholamines, and tissue hypoxia. Other potential triggers activated or increased by the stress of surgery include coagulation factors such as alterations in platelet function; inflammatory factors such as tumor necrosis factor alpha, interleukin 1, interleukin 6, and C-reactive protein; and metabolism of free fatty acids (which contribute to increased oxygen demand as well as endothelial dysfunction).9,19,20

A 1996 autopsy study found that 38 (90%) of 42 patients who died of a perioperative infarct had evidence of acute plaque rupture or plaque hemorrhage on coronary sectioning, findings corroborated in another, similar study.21,22 These studies suggest that multiple causes contribute to perioperative myocardial infarction, and a single strategy may not suffice for prevention.

IF BETA-BLOCKERS PROTECT, HOW DO THEY DO IT?

Beta-blockers have several effects that should, in theory, protect against cardiac events during and after surgery.23 They reduce cardiac oxygen demand by reducing the force of contraction and the heart rate, and they increase the duration of diastole, when the heart muscle is perfused. They are also antiarrhythmic, and they may limit free radical production, metalloproteinase activity, and myocardial plaque inflammation.24

Some researchers have speculated that using beta-blockers long-term may alter intra-cellular signaling processes, for example decreasing the expression of receptors that receive signals for cell death, which in turn may affect the response to reperfusion cell injury and death. If this is true, there may be an advantage to starting beta-blockers well in advance of surgery.25

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