BMJ  2005;331:919-920 (22 October), doi:10.1136/bmj.331.7522.919

Editorial

blockers for patients at risk of cardiac events during non-cardiac surgery

Anaesthetists should wait for better evidence of benefit

More than a million patients each year develop cardiovascular complications arising from non-cardiac surgery in the United States alone, and effective strategies and interventions to reduce perioperative cardiac morbidity are badly needed.^{1 2} The best perioperative outcomes for patients at such risk depend partly, as always, on taking a good history, completing a relevant clinical examination, and ordering appropriate investigations.³ But the best strategies for protecting high risk patients from cardiac ischaemia during surgery are still not clear.

One issue—the use of perioperative blockers—is particularly controversial, and a systematic review and meta-analysis by Devereaux et al published recently in the BMJ sheds further doubt on previous evidence.⁴ Unlike many previous studies, which have found that perioperative blockers reduce the risk of major cardiovascular events, this meta-analysis concludes that the evidence is encouraging but too unreliable to allow definitive conclusions to be drawn.⁴

This analysis by Devereaux et al includes 22 clinical trials, all published, in which 2437 patients were randomised.⁴ Thus it is considerably more comprehensive than previous reviews by Auerbach and Goldman⁵ and Stevens et al,⁶ which included five and 11 trials, respectively. These authors have reported, albeit with some caveats, that perioperative blockade reduces mortality, with numbers needed to treat of 3-8⁵ and 32.⁶ These reviews, and treatment recommendations based on them, may have been inadvertently biased.^6-11 Studies that seemed to confirm conclusively the benefit of perioperative blockade may have coloured our reasoning^{1 10} and led to earlier studies being left out of systematic reviews. Furthermore, one study¹ was a long term follow-up of patients already included in another trial¹⁰ and did not include an analysis by intention to treat. Although the new meta-analysis by Devereaux et al raises uncertainty about the benefits of perioperative blockers, it endorses the drugs' overall safety.⁴

The drugs used in the 22 trials included eight different blockers administered by different routes and methods (oral, oral slow release, intravenous bolus, and infusion). Drugs were started up to two weeks before surgery and as late as the start of anaesthesia. The duration of treatment varied from a single dose of a short acting agent to several weeks.⁴ But this heterogeneity in treatment does not explain the disparity between the findings of this meta-analysis and those of previous systematic reviews and clinical practice guidelines.

The observational study by Redelmeier et al in this week's BMJ confirms, however, the extra benefit conferred by the use of a long acting blocker (atenolol) over a shorter acting one (metoprolol).¹² The study is not randomised and would not have been included in the meta-analysis by Devereaux et al.⁴ It examines the effect on cardiac outcomes of different blockers in the perioperative period for patients older than 65 having inpatient, non-cardiac surgery. This paper's findings are important for two reasons.

Firstly, the paper identifies the increased ability of perioperative atenolol over metoprolol to reduce the risk of perioperative myocardial infarction and death in these patients.¹² This finding should inform the development of new guidelines on perioperative blockade for non-cardiac surgery if the forthcoming POISE (PeriOperative ISchaemic Evaluation) trial, which is already under way, confirms a beneficial effect.^w1 Secondly, the paper by Redelmeier et al¹² raises the possibility that the mechanism for the increased myocardial infarction and mortality in the patients who had metoprolol is related to acute withdrawal of the short acting blocker owing to missed doses.

This explanation of the observed difference between the two drugs in this context requires us to accept two theories of causation. These are that acute withdrawal of blockade increases the risk of cardiac events and death in elderly patients having non-cardiac, inpatient surgery. The other theory is that such withdrawal arises from lapses in health care and omission of short acting blockers in the perioperative period, hence the reported differences in the rates of cardiac events and death between patients who had metoprolol and atenolol. This explanation is very plausible and has been identified before.^{w2 w3} The contribution of medication errors to excess deaths underscores the need to improve the safety and quality of care delivery in all complex healthcare systems.^w4 A question not posed in the paper but posed by the results is: "Should long acting drugs be used whenever possible in complex healthcare environments simply to reduce the occurrence of errors of omission?" The answer may well be yes.

Because anaesthesia encompasses preoperative assessment, perioperative treatment, and postoperative management, anaesthetists should, perhaps, be renamed perioperative physicians. But the science of perioperative medicine still has much to do to achieve practical benefits in the practice of anaesthesia. Several important lessons for perioperative physicians arise from the evolution of this knowledge on blockers.

Firstly, anaesthetists should wait for conclusive evidence from the POISE trial of benefit in defined groups of patients before recommending blockade at the time of non-cardiac surgery. Further research evidence is needed on optimal regimens of blockers, along with dosing schedules, duration, and timing of treatment to achieve the best outcomes for patients and to develop practical strategies for using such regimens.² Lastly, systematic reviews and meta-analyses should drive the design of similar studies on the effects of statins, adrenergic receptor agonists, and combinations of drugs that are thought to protect the heart during the perioperative phase for patients having non-cardiac surgery.^w5-w7

(steveb{at}barwonhealth.org.au)
Division of Perioperative Medicine, Anaesthesia and Pain Management, Geelong Hospital, Geelong, Victoria 3220, Australia

Division of Perioperative Medicine, Anaesthesia and Pain Management, Geelong Hospital, Geelong, Victoria 3220, Australia

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Papers p 932

Additional references w1-w7 are on bmj.com

Competing interests: None declared.

References

1. Mangano DT, Layug EL, Wallace E, Tateo I, Multicenter Study of Perioperative Ischemia Research Group. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996;335: 1713-21.[Abstract/Free Full Text]
2. Fleisher LA, Corbett W, Berry C, Poldermans D. Cost-effectiveness of differing perioperative beta-blockade strategies in vascular surgery patients. J Cardiothorac Vasc Anesth 2004;18: 7-13.[CrossRef][ISI][Medline]
3. Bolsin SN, Seal P. Adult cardiac disease. In: Vickers M, Power I, eds. Medicine for anaesthetists. London: Blackwell Science, 1998: 1-44.
4. Devereaux PJ, Scott Beattie W, Choi PTL, Badner NH, Guyatt GH, Villar JC, et al. How strong is the evidence for the use of perioperative -blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ 2005;331: 313-21.[Abstract/Free Full Text]
5. Auerbach AD, Goldman L. -blockers and reduction of cardiac events in noncardiac surgery: scientific review. JAMA 2002;287: 1435-44.[Abstract/Free Full Text]
6. Stevens RD, Burri H, Tramer MR. Pharmacologic myocardial protection in patients undergoing noncardiac surgery: a quantitative systematic review. Anesth Analg 2003;97: 623-3.[Abstract/Free Full Text]
7. Auerbach AD, Goldman L. -blockers and reduction of cardiac events in noncardiac surgery: clinical applications. JAMA 2002;287: 1445-7.[Abstract/Free Full Text]
8. Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to update the 1996 guidelines on perioperative cardiovascular evaluation for noncardiac surgery). Anesth Analg 2002;94: 1052-64.[Free Full Text]
9. Palda VA, Detsky AS. Perioperative assessment and management of risk from coronary artery disease. Ann Intern Med 1997;127: 313-28.[Abstract/Free Full Text]
10. Wallace A, Layug E, Tateo I, Li J, Hollenberg M, Browner W, et al. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998;88: 7-17.[CrossRef][ISI][Medline]
11. Stevens RD, Fleisher LA. Strategies in the high-risk cardiac patient undergoing non-cardiac surgery. Best Pract Res Clin Anaesthesiol 2004;18: 549-63.[Medline]
12. Redelmeier D, Scales DC, Kopp A. blockers for elective surgery in elderly patients: population based, retrospective cohort study. BMJ 2005;331: 932-4.[Abstract/Free Full Text]

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