Journal of Cardiothoracic and Vascular Anesthesia
Volume 24, Issue 2 , Pages 217-218, April 2010

Can Meta-analysis of the Current Literature Help Determine if Perioperative β-Blockers Improve Outcome of High-Risk Patients Undergoing Noncardiac Surgery?

Department of Anesthesiology, Mount Sinai School of Medicine, New York, NY

Article Outline

 

THE EFFECT OF ROUTINE β-blocker administration on patients undergoing noncardiac surgery is one of the most prominent and controversial issues in perioperative medicine. In brief summary, the main trials that are most widely quoted and form the basis for almost every systematic review and meta-analysis are the following:


1.In 1996, Mangano et al,1 in a single-center Veterans Administration trial (n = 200, atenolol), showed long-term benefit from, remarkably, just 1 week of perioperative β-blocker administration. There was no in-hospital benefit in this trial.

2.In 1999 and then 2001, Poldermans et al2, 3 in the DECREASE study (n = 112, bisoprolol) reported a dramatic reduction in short-term and long-term morbidity and mortality using a regimen that consisted of more than 1 week of preoperative β-blockade followed by prolonged postoperative administration, unlike the regimen used in Mangano's investigation, in a very high-risk population who all had a preoperative positive stress test.

3.In 2005, the POBBLE trial4 of patients (n = 103, metoprolol) undergoing infrarenal vascular surgery revealed no improvement in outcome.

4.In 2006, the DIPOM trial5 (n = 921, metoprolol) revealed no difference in outcome in diabetic patients undergoing surgeries lasting more than 1 hour.

5.In 2006, the MAVS trial6 (n = 496, metoprolol) revealed no difference in outcome in patients undergoing vascular surgery.

6.In 2008, the penultimate POISE trial7 (n = 8,351, metoprolol) showed improved cardiac morbidity, but an increase in strokes and a greater mortality in patients randomized to β-blocker administration. Because this was the largest and most ambitious study to date and received an enormous amount of press, it is worthwhile to review these results in more exacting detail. Specifically, fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4.2%] v 239 [5.7%], hazard ratio = 0.73, 0.60-0.89; p = 0.0017), but mortality in the metoprolol group was greater than in the placebo group (129 [3.1%] v 97 [2.3%], hazard ratio = 1.33, 1.03-1.74; p = 0.0317); more patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] v 19 [0.5%], hazard ratio = 2.17, 1.26-3.74; p = 0.0053). A relatively large dose of metoprolol given immediately before and after surgery has received most of the “blame” regarding these negative outcomes.

7.In 2009, the DECREASE-IV trial8 of β-blockers and statin in a 2 × 2 factorial design (n = 1,066, bisoprolol) showed improved outcomes in the β-blocker group of patients.

Simplistically summarized, these 7 relatively large prospective trials resulted in 3 “for” β-blockers, 1 “against,” and 3 “no difference.” The author would be remiss not to mention the retrospective database review by Lindenauer et al9 of 782,969 patients that showed increasingly improved outcomes when β-blockers were administered to patients at some time during their perioperative course and who had a greater number of revised cardiac risk factors (ie, high-risk surgery, coronary artery disease, congestive heart failure, neurovascular disease, insulin requiring diabetes, and creatinine >2 mg/dL). Outcomes were possibly worse if 0 or 1 factor was present, whereas among the patients with 2, 3, or 4 or more factors, the adjusted odds ratios for death in the hospital were 0.88 (95% confidence interval, 0.80-0.98), 0.71 (95% confidence interval, 0.63-0.80), and 0.58 (95% confidence interval, 0.50-0.67), respectively.

Several meta-analyses have tried to discern the proper course of action, but they are intuitively flawed because different drugs (eg, bisoprolol, atenolol, and metoprolol) in different potencies were administered at different points in the course of care for different lengths of time in grossly different patient populations. In this issue of the Journal, the paper titled “Esmolol Reduces Perioperative Ischemia in Noncardiac Surgery: A Meta-analysis of Randomized Controlled Trials”10 does little to quell the author's negativism toward meta-analysis.

In this meta-analysis, data from 32 randomized trials totaling 1,765 patients were used. Trials ranged in size from grossly underpowered, including a study with just 20 total patients, to just plain underpowered, with the largest study enrolling only 152 patients but that was a trial of a single bolus dose of esmolol used for the induction of patients undergoing microlaryngoscopy and investigated only blood pressure and heart rate not ischemia. In fact, in the included studies, esmolol could have been administered as a 1-time bolus, a bolus and an infusion, an infusion, at the beginning, throughout, only at the time of extubation, or postoperatively. Among these trials examined to reach the conclusion trumpeted in the title that “perioperative ischemia is reduced with esmolol administration,” only 11 actually were designed to supposedly detect ischemia, and only 4 of them reported any ischemia in either group of patients. A brief review of these 4 references11, 12, 13, 14 revealed only 3 in which monitoring for ischemia was even a prominent feature of the investigation, 2 by the same group of authors12, 13 studying patients undergoing “laryngomicroscopy” and the other that only investigated postoperative administration.11 Maguire et al's study14 happened to note 1 brief ischemic-appearing electrocardiographic change, but the study was not designed for this purpose and only 2 leads were monitored. All in all, this is simply not a group of studies to draw any conclusion from let alone influence standard practice.

So, in answer to this editorial's title, the author does not know if perioperative β-blockers should be administered to high-risk patients undergoing noncardiac surgery, and yes, unfortunately, it does appear that the literature can get more confusing. However, it is crystal clear that meta-analysis of the current literature will certainly not provide any further meaningful guidance.

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References 

  1. Mangano DT, Layug EL, Wallace A, et al. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med. 1996;335:1713–1720
  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. N Engl J Med. 1999;341:1789–1794
  3. Poldermans D, Boersma E, Bax JJ, et al. Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J. 2001;22:1353–1358
  4. POBBLE Trial Investigators. Perioperative b-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: Results of a randomized double-blind controlled trial. J Vasc Surg. 2005;41:602–609
  5. Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative b blockade in patients with diabetes undergoing major non-cardiac surgery: Randomized placebo controlled blinded multicentre trial. BMJ. 2006;332:1482–1489
  6. Yang H, Raymer K, Butler R, et al. The effects of perioperative b-blockage: Results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J. 2006;152:983–990
  7. POISE Study Group. Effects of extended release metoprolol succinate in patients undergoing non-cardiac surgery (POISE TRIAL): A randomized controlled trial. Lancet. 2008;31:1839–1847
  8. Dunkelgrun M, Boersma E, Schouten O, et al. Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: A randomized controlled trial (DECREASE-IV). Ann Surg. 2009;249:921–926
  9. Lindenauer PK, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. 2005;353:349–361
  10. Landoni G, Turi S, Biondi-Zoccai G, et al. Esmolol reduces perioperative ischemia in non-cardiac surgery: A meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth. 2010;24:219–229
  11. Raby KE, Brull SJ, TImimi , et al. The effect of heart rate control on myocardial ischemia among high risk patients after vascular surgery. Anesth Analg. 1999;88:477–482
  12. Korpinen R, Simola M, Saarnivarra L. Effect of esmolol on the hemodynamic and electrocardiographic changes during laryngomicroscopy under propofol/alfentanil anesthesia. Acta Anaesthesiol Belg. 1998;49:123–132
  13. Korpinen R, Simola M, Saarnivarra L. Effect of esmolol on the heart rate, arterial pressure and electrocardiographic changes during laryngomicroscopy. Acta Anaesthesiol Scand. 1997;41:371–375
  14. Maguire A, Thompson JP, Guest C, et al. Comparison of the effects of intravenous alfentanil and esmolol on the cardiovascular response to double-lumen endobronchial intubation. Anaesthesia. 2001;56:319–325

PII: S1053-0770(10)00018-2

doi:10.1053/j.jvca.2010.01.014

Journal of Cardiothoracic and Vascular Anesthesia
Volume 24, Issue 2 , Pages 217-218, April 2010

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