Therapeutics

Review: In noncardiac surgery, β-blockers started before surgery increase 30-day mortality

Bouri S, Shun-Shin MJ, Cole GD, Mayet J, Francis DP. Meta-analysis of secure randomised controlled trials of β-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2013; Jul 31 [Epub ahead of print].

Clinical impact ratings: h ★★★★★★✩ C ★★★★★★✩ Question

Conclusion

Does starting a course of β-blockers before surgery prevent perioperative mortality in adults having noncardiac surgery?

In well-done randomized controlled trials, β-blockers started before surgery and continued after surgery increase 30-day all-cause mortality in patients having noncardiac surgery.

Review scope Included studies evaluated a course of β-blockers, started before surgery and continued after surgery, in adults having noncardiac surgery. Exclusion criteria were comparison of β-blockers with another treatment or lack of intention-to-treat data. The primary outcome was all-cause mortality at 30 days or at hospital discharge. Other outcomes were perioperative nonfatal myocardial infarction (MI), nonfatal stroke, and hypotension.

Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Central Register of Controlled Trials, CINAHL, and World Health Organization International Clinical Trials Registry Platform (on 23 Mar 2013); and reference lists were searched for published randomized controlled trials (RCTs). 11 RCTs met the selection criteria; results from 9 placebo-controlled RCTs (n = 10 529, range = 38 to 8351) are reported in this abstract. 2 RCTs (n = 1178) from the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) program were reported separately in the article because data from some DECREASE trials have been discredited; they are not reported here. Of the 9 RCTs, 5 evaluated metoprolol, with doses ranging from 50 to 200 mg/d; 2 evaluated atenolol; 1 bisoprolol; and 1 propranolol. β-blockers were started ≤ 1 day before surgery, and duration varied from 5 to 30 days after surgery. 2 RCTs involved patients having vascular surgery, and 7 involved various types of surgery, including abdominal, emergency general, gastrointestinal, gynecologic, lung or esophageal, neurologic, orthopedic, plastic, urologic, vascular, or other. 8 RCTs were described as double-blind.

Main results Meta-analysis showed that β-blockers increased all-cause mortality compared with placebo at 30 days. Although β-blockers reduced nonfatal MI compared with placebo, they increased hypotension; groups did not differ for nonfatal stroke (Table). β-blockers started before surgery vs placebo in patients having noncardiac surgery* Outcomes

Number of trials (n)

All-cause mortality at 30 d or hospital discharge

9 (10 529)

Nonfatal stroke

6 (10 186)

Hypotension

6 (10 286)

Nonfatal MI

6 (10 189)

Weighted During perioperative period event rates β-blockers Placebo RRI (95% CI) NNH (CI) 3.2%

0.67% 15% 3.5%

2.5%

0.39% 10% 4.8%

27% (1 to 60)

149 (67 to 4000)

73% (0 to 199)

Not significant

51% (37 to 67)

20 (15 to 28)

RRR (CI)

NNT (CI)

27% (12 to 39)

78 (54 to 174)

*MI = myocardial infarction; other abbreviations defined in Glossary. RRI, RRR, NNH, NNT, and CI calculated from risk ratios and control event rates in article using a random-effects model.

JC2

© 2013 American College of Physicians

Source of funding: No external funding. For correspondence: Dr. S. Bouri, National Heart and Lung Institute, London, England, UK. E-mail [email protected]

Commentary Practice recommendations for perioperative β-blockade are most compelling for continuation of preexisting therapy (1); however, perioperative β-blockade is controversial, particularly amid recent allegations of scientific misconduct in the perioperative community (2). Recognizing the potential impact of such allegations, Bouri and colleagues performed a meta-analysis of RCTs of initiation of β-blockers before noncardiac surgery, excluding trials from the discredited DECREASE program. Meta-analysis of the 9 “secure” trials showed that β-blockade initiated before surgery resulted in a 27% increase in mortality. 79% of patients in the meta-analysis were from the POISE trial, which administered extended-release metoprolol, 100 mg, 2 to 4 hours before surgery; this is rarely done in the perioperative setting. More commonly, β-blockade is initiated and appropriately titrated weeks in advance of surgery. Bouri and colleagues concluded that “guideline bodies should retract their recommendations based on fictitious data without further delay.” Although the meta-analysis is a step forward in presenting secure data, a recent retrospective cohort analysis by London and colleagues, which included almost 140 000 patients treated at 104 US Veterans Affairs medical centers, found that use of β-blockers through the perioperative period was associated with a reduction in 30-day mortality (relative risk [RR] 0.73, 95% CI 0.65 to 0.83) and nonfatal Q-wave MI or nonfatal cardiac arrest at 30 days (RR 0.67, CI 0.57 to 0.79) (3). These findings should not be overlooked. However, the study design could not evaluate the acute start (within 7 d of surgery) of β-blockers because of lack of data. It is premature to suggest that guidelines be retracted. Although it may be reasonable to emphasize the findings from POISE that β-blockade started too late or too aggressively in the perioperative period is unsafe, we should turn our attention to settling controversies about β-blockade. There are important questions about patient selection, dosing and titration, and ideal timing of perioperative treatment. These questions would be best answered in a secure trial that would avoid the risks for β-blocker withdrawal. Stay tuned. Prashant Vaishnava, MD Kim Eagle, MD, MACC University of Michigan Medical School Ann Arbor, Michigan, USA References 1. Fleisher LA, Beckman JA, Brown KA, et al. Circulation. 2009;120:e169e276. 2. Chopra V, Eagle KA. Am J Med. 2012;125:953-5. 3. London MJ, Hur K, Schwartz GG, Henderson WG. JAMA. 2013;309: 1704-13. 17 December 2013 | ACP Journal Club | Volume 159 • Number 12

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ACP Journal Club. Review: In noncardiac surgery, β-blockers started before surgery increase 30-day mortality.

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