Perioperative beta-blockers in noncardiac surgery: The evidence continues to evolve
ABSTRACTThe effectiveness and safety of giving beta-blockers to patients undergoing noncardiac surgery remain controversial. The use of these drugs in this clinical scenario increased after the publication of two positive trials in the late 1990s and was encouraged by national organizations and clinical guidelines. However, when several subsequent studies failed to show a benefit, recommendations became more limited and use decreased. This paper reviews recent evidence for and against the perioperative use of beta-blockers.
KEY POINTS
- If patients have other indications for beta-blocker therapy, such as a history of heart failure, myocardial infarction in the past 3 years, or atrial fibrillation, they should be started on a beta-blocker before surgery if time permits.
- Of the various beta-blockers, the cardioselective ones appear to be preferable in the perioperative setting.
- Beta-blockers may need to be started at least 1 week before surgery, titrated to control the heart rate, and used only in patients at high risk (Revised Cardiac Risk Index score > 2 or 3) undergoing high-risk surgery.
- Further clinical trials are necessary to clarify the ongoing controversy, particularly regarding the risk of stroke, which was increased in the large Perioperative Ischemic Evaluation (POISE) trial.
ARE ALL BETA-BLOCKERS EQUIVALENT?
In various studies evaluating specific beta-blockers, the more cardioselective agents bisoprolol and atenolol were associated with better outcomes than metoprolol. The affinity ratios for beta-1/beta-2 receptors range from 13.5 for bisoprolol to 4.7 for atenolol and 2.3 for metoprolol.32 Blocking beta-1 receptors blunts tachycardia, whereas blocking beta-2 receptors may block systemic or cerebral vasodilation.
In patients with anemia, beta-blockade in general may be harmful, but beta-2 blockade may be even worse. Beta-blockers were associated with an increased risk of MACE (6.5% vs 3.0%)33 in patients with acute surgical anemia if the hemoglobin concentration decreased to less than 35% of baseline, and increased risks of hospital death (OR 6.65) and multiorgan dysfunction syndrome (OR 4.18) with severe bleeding during aortic surgery.34
In addition, the pathway by which the beta-blocker is metabolized may also affect outcome, with less benefit from beta-blockers metabolized by the CYP2D6 isoenzyme of the cytochrome P450 system. Individual variations in CYP2D6 activity related to genetics or drug interactions may result in insufficient or excessive beta-blockade. Because metoprolol is the most dependent on this system, patients using it may be more susceptible to bradycardia.35
Studies comparing atenolol and metoprolol found that the atenolol groups had fewer myocardial infarctions and deaths36 and lower 30-day and 1-year mortality rates37 than the groups on metoprolol. Studies comparing the three beta-blockers found better outcomes with atenolol and bisoprolol than with metoprolol—fewer strokes,38,39 a lower mortality rate,31 and a better composite outcome39 (Table 3 and Table 4).
START THE BETA-BLOCKER EARLY, TITRATE TO CONTROL THE HEART RATE
A number of studies suggest that how long the beta-blocker is given before surgery may influence the outcome (Table 5). The best results were achieved when beta-blockers were started approximately 1 month before surgery and titrated to control the heart rate.
Because this long lead-in time is not always practical, it is important to determine the shortest time before surgery in which starting beta-blockers may be beneficial and yet safe. Some evidence suggests that results are better when the beta-blocker is started more than 1 week preoperatively compared with less than 1 week, but it is unknown what the minimum or optimal time period should be.
If a beta-blocker is started well in advance of the scheduled surgery, there is adequate time for dose titration and tighter heart rate control. Most of the studies demonstrating beneficial effects of perioperative beta-blockers used dose titration and achieved lower heart rates in the treatment group than in the control group. A criticism of the MaVs,19 POBBLE,20 and DIPOM21 trials was that the patients did not receive adequate beta-blockade. The POISE trial1 used a much higher dose of metoprolol in an attempt to assure beta-blockade without dose titration, and although the regimen decreased nonfatal myocardial infarctions, it increased strokes and the overall mortality rate, probably related to excess bradycardia and hypotension. The target heart rate should probably be between 55 and 70 beats per minute.
RISK OF STROKE
POISE1 was the first trial to note a clinically and statistically significant increase in strokes with perioperative beta-blocker use. Although no other study has shown a similar increased risk, almost all reported a higher number of strokes in the beta-blocker groups, although the absolute numbers and differences were small and not statistically significant. This risk may also vary from one beta-blocker to another (Table 4).
The usual incidence rate of postoperative stroke after noncardiac, noncarotid surgery is well under 1% in patients with no prior history of stroke but increases to approximately 3% in patients with a previous stroke.40 An observational study from the Dutch group reported a very low incidence of stroke overall (0.02%) in 186,779 patients undergoing noncardiac surgery with no significant difference in those on chronic beta-blocker therapy.41 The DECREASE trials, with a total of 3,884 patients, also found no statistically significant increase in stroke with beta-blocker use (0.46% overall vs 0.5% with a beta-blocker),42 which in this case was bisoprolol started well in advance of surgery and titrated to control the heart rate. Although the DECREASE data are under suspicion, they seem reasonable and consistent with those of observational studies.
Proposed mechanisms by which beta-blockers may increase stroke risk include the side effects of hypotension and bradycardia, particularly in the setting of anemia. They may also cause cerebral ischemia by blocking cerebral vasodilation. This effect on cerebral blood flow may be more pronounced with the less cardioselective beta-blockers, which may explain the apparent increased stroke risk associated with metoprolol.
WHAT SHOULD WE DO NOW?
The evidence for the safety and efficacy of beta-blockers in the perioperative setting continues to evolve, and new clinical trials are needed to clarify the ongoing controversy, particularly regarding the risk of stroke.
If patients have other indications for beta-blocker therapy, such as history of heart failure, myocardial infarction in the past 3 years, or atrial fibrillation for rate control, they should be receiving them if time permits.
If prophylactic beta-blockers are to be effective in minimizing perioperative complications, it appears that they may need to be more cardioselective, started at least 1 week before surgery, titrated to control heart rate, and used in high-risk patients (Revised Cardiac Risk Index score > 2 or 3) undergoing high-risk surgery.
Ideally, a large randomized controlled trial using a cardioselective beta-blocker started in advance of surgery in patients with a Revised Cardiac Risk Index score greater than 2, undergoing intermediate or high-risk procedures, is needed to fully answer the questions raised by the current data.
