Cardiovascular complications continue to be a major cause of morbidity and mortality in the perioperative period. Although progress has been made in terms of risk stratification, an effective invasive or pharmacologic intervention that decreases this risk remains elusive. Well designed studies have shown that prophylactic invasive measures are not effective in decreasing this risk, leaving clinicians uncertain as to the best way to maximize the physiology of the patient in the perioperative period.
Enthusiasm for perioperative ß-blockade is based on two landmark studies. About twelve years ago Mangano (1) randomized 200 patients with or at risk for cardiac disease undergoing general noncardiac surgery to atenolol or placebo in the immediate perioperative period and demonstrated a significant reduction in mortality at 6 months (0% vs. 8%), 1 year (3% vs. 14%) and 2 years (10% vs. 21%) favoring atenolol. Subsequently, in the DECREASE trial (2), Poldermans randomized 112 patients with an abnormal dobutamine stress echo undergoing major vascular surgery to bisoprolol or placebo and showed a remarkable decrease in cardiovascular death (3.4% vs. 17%) favoring the ß-blocker group. Both trials were limited by small sample sizes and methodological flaws and these impressive results have not been reproduced in subsequent studies.
Additional trials supporting ß-blockade in the perioperative period have generally been limited to observational and retrospective reviews. Lindenauer (3) analyzed a multicenter administrative database of patients undergoing noncardiac surgery, stratified by the RCRI score, and found an increased risk of death in patients receiving ß-blockers in the lowest risk group with a stepwise decrease in risk actually favoring ß-blockers in patients with an RCRI score of 3 or greater. In DECREASE II (4), Poldermans studied intermediate-risk patients undergoing intermediate-risk surgeries, giving all patients ß-blockers with HR titration, to determine if routine stress testing improved outcomes. While not demonstrating a benefit to routine stress testing, patients with heart rates less than 65 bpm had lower risk than the remaining patients.
A comprehensive systematic review and meta-analysis of published RCT’s of ß-blockers published in the BMJ in 2005 concluded that while ß-blocker use may decrease the incidence of perioperative cardiac events, it did so at the expense of an increased incidence of hypotension and bradycardia requiring treatment(5).
More recently, three randomized trials of patients undergoing vascular surgery (MaVS6 and POBBLE7) and diabetics undergoing noncardiac surgery (DIPOM8) have all shown no benefit to the addition of ß-blockers in the perioperative period.
In October, 2007, the American College of Cardiology/American Heart Association updated its recommendations for perioperative care of patients requiring non-cardiac surgery (9). While acknowledging the lack of robust data, the committee considered the following recommendations to be reasonable for perioperative ß-blockade:
1. Use the RCRI score to determine the patient’s pre-operative risk category.
2. Low risk patients: do not use ß-blockers perioperatively, unless the patient is already taking them.
3. Intermediate risk patients: unclear if ß-blockers are harmful or beneficial.
4. High risk patients facing vascular procedures, especially those with inducible ischemia on pre-operative testing: the perioperative use of ß-blockers is probably beneficial (Class I B).
5. High risk cardiac patients facing intermediate risk surgery: ß-blockers are probably recommended (Class IIa B)
6. Low, intermediate, and high risk patients: continue ß-blockers in the perioperative period if the patient was already on them. (Class I C)
7. Begin ß-blockers several days to weeks before surgery, if possible. Aim for a HR in the low 60’s, and continue for at least one week post-op.
8. Overall, ß-blockers may decrease perioperative cardiac events, but they increase hypotension and bradycardia, which often may need treatment.
9. The use of cardioselective ß-blockers (currently metoprolol or atenolol) in patients with COPD or hyper-reactive airway disease is probably safe.
10. ß-blockers should be started with caution in patients with HF and not at all in patients with second or third degree HB.
Shortly following these recommendations, the results of the much anticipated POISE trial became available (10). In an attempt to further assess the impact of perioperative ß-blockade, the PeriOperative ISchemic Evaluation (POISE) trial randomly assigned 8351 patients undergoing noncardiac surgery to receive long acting metoprolol succinate or placebo starting preoperatively and continued for the next 30 days. This study, the results of which were presented at the American Heart Association meeting in October, 2007, and published online in May in the electronic version of the Lancet, is the largest randomized controlled study to date on the use of perioperative ß-blockers. The results confirmed that the primary endpoint of non-fatal myocardial infarction, cardiac arrest, or death from a cardiovascular cause was decreased in the group treated with metoprolol compared to placebo (5.8% vs. 6.9%, P=0.040). This “benefit,” however, was driven by non-fatal myocardial infarction and was offset by an increase in 30 day overall mortality (3.1 % vs. 2.3%, P=0.032) and increased number of strokes (1% vs. 0.5%, P = 0.005) in the group receiving metoprolol. Hypotension (15% vs. 9.7%, P = 0.0001) and clinically significant bradycardia (6.6% vs. 2.4%, P = 0.03) were also more common in the treatment group. Unexpectedly and somewhat strangely, there appeared to be a statistically significant increase in the number of patients who died from sepsis (27.9% vs. 18.6% of deaths in each group, P = 0.016) in the group receiving metoprolol.
Although the study was well designed and executed (centers in Colombia and Iran were excluded due to concerns of fraudulent data), it is important to note areas of potential bias. Many of the patients included in the study were at relatively low risk for cardiovascular complications and would not be given ß-blockers based on the current ACC/AHA guidelines. Furthermore, the dose of metoprolol was rather high (metoprolol 100 mg extended release tablets were given twice daily or 15 mg intravenously Q6H for those unable able to tolerate oral medication), and were most often started immediately prior to surgery (between 2-4 hours). Patients who were thought to require ß-blockers (and thus may have been most likely to benefit and tolerate the drug) by their doctor were excluded from the study, and patients with a relatively low HR (above 50 bpm) were included in the study. Finally, by pre-specifying ten secondary outcomes and accepting p<=0.05 as statistically significant, the likelihood of a Type I error is substantial.
Will this study change management of the patient in the perioperative period? We think not. The patient population, the dose and the timing of the ß-blockers given in POISE are significantly different than current practice thus making generalization of its results and conclusions problematic. Although POISE does not directly address the issue, it is reasonable to continue ß-blockers throughout the perioperative period in those patients who are already tolerating this type of therapy. The initiation of ß-blockers in the perioperative period should be limited to those with relatively high cardiovascular risk, should be initiated early, if possible, and with the intent to titrate the dose for a goal HR around 60 BPM.
POISE is now being “fast tracked” for publication in Lancet and our expectation is that we have not heard the last about it. The final chapter on the perioperative use of ß-blockade has yet to be written.
1. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. Dec 5 1996;335(23):1713-1720.
2. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. Dec 9 1999;341(24):1789-1794.
3. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. Jul 28 2005;353(4):349-361.
4. Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol. Sep 5 2006;48(5):964-969.
5. Devereaux PJ, Beattie WS, Choi PT, et al. How strong is the evidence for the use of perioperative beta blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ. Aug 6 2005;331(7512):313-321.
6. Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J. Nov 2006;152(5):983-990.
7. Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg. Apr 2005;41(4):602-609.
8. Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMJ. Jun 24 2006;332(7556):1482.
9. 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 (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol. Oct 23 2007;50(17):1707-1732.
10. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. May 31 2008;371(9627):1839-1847.
Image of the surgeon’s consultation room, a painting by Balthasar van den Bossche, courtesy of Wikipedia.