Perioperative beta-blockers in noncardiac surgery: Evolution of the evidence
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.
DOES PERIOPERATIVE BETA-BLOCKER USE CAUSE HARM?
The published data on whether perioperative beta-blocker use harms patients are conflicting and up to now have been limited.
Stone et al39 reported a substantial incidence of bradycardia requiring atropine in patients treated with a single dose of a beta-blocker preoperatively, but the complications were not clearly characterized.
The Perioperative Beta-Blockade trial.35 Significantly more patients given short-acting metoprolol had intraoperative falls in blood pressure and heart rate, and more required inotropic support during surgery, although the treating anesthesiologists refused to be blinded in that study. (Short-acting metoprolol is available in the United States as Lopressor and generically.)
Devereaux et al,33 in their meta-analysis, found a higher risk of bradycardia requiring treatment (but not a higher risk of hypotension) in beta-blocker users in nine studies, including the study by Stone et al and the Perioperative Beta-Blockade trial (relative risk 2.27, 95% confidence interval 1.36–3.80).
Conversely, at least three other studies found no difference in rates of intraoperative events.36,40,41 There are few data on the incidence of other complications such as perioperative pulmonary edema and bronchospasm.
POISE: THE FIRST LARGE RANDOMIZED TRIAL
In May 2008, results were published from POISE, the first large randomized controlled trial of perioperative beta-blockade.1 An impressive 8,351 patients—most of them at intermediate risk—were randomized to receive extended-release metoprolol succinate or placebo starting just before surgery and continuing for 30 days afterward.
Although the incidence of the primary composite end point (cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest) was lower at 30 days in the metoprolol group than in the placebo group (5.8% vs 6.9%, hazard ratio 0.83, P = .04), other findings were worrisome: more metoprolol recipients died of any cause (3.1% vs 2.3%, P = .03) or had a stroke (1.0% vs 0.5%, P = .005). The major contributor to the higher mortality rate in this group appears to have been sepsis.
How beta-blockers might promote death by sepsis is unclear. The authors offered two possible explanations: perhaps beta-blocker-induced hypotension predisposes patients to infection and sepsis, or perhaps the slower heart rate and lower force of contraction induced by beta-blockers could mask normal responses to systemic infection, which in turn could delay recognition and treatment or impede the normal immune response. These mechanisms, like others, are speculative.
The risks of other adverse outcomes such as bradycardia and hypotension were substantially higher in the metoprolol group. The authors also pointed out that most of the patients who suffered nonfatal strokes were subsequently disabled or incapacitated, while most of those who suffered nonfatal cardiac events did not progress to further cardiac problems.
This new study has not yet been rigorously debated, but it will likely come under scrutiny for its dosing regimen (extended-release metoprolol succinate 100 mg or placebo 2–4 hours before surgery; another 100 mg or placebo 6 hours after surgery or sooner if the heart rate was 80 beats per minute or more and the systolic blood pressure 100 mm Hg or higher; and then 200 mg or placebo 12 hours after the second dose and every 24 hours thereafter for 30 days). This was fairly aggressive, especially for patients who have never received a beta-blocker before. In contrast, the protocol for the Perioperative Beta-Blockade trial called for only 25 to 50 mg of short-acting metoprolol twice a day. Another criticism is that the medication was started only a few hours before surgery, although there is no current standard practice for either the dose or when the treatment should be started. The population had a fairly high rate of cerebrovascular disease (perhaps predisposing to stroke whenever blood pressure dropped), and 10% of patients were undergoing urgent or emergency surgery, which carries a higher risk of morbidity.
