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Link to original content: https://pubmed.ncbi.nlm.nih.gov/31544227
Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing cardiac surgery - PubMed Skip to main page content
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. 2019 Sep 23;9(9):CD013435.
doi: 10.1002/14651858.CD013435.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing cardiac surgery

Hermann Blessberger  1 , Sharon R Lewis, Michael W Pritchard, Lizzy J Fawcett, Hans Domanovits, Oliver Schlager, Brigitte Wildner, Juergen Kammler, Clemens Steinwender
Affiliations

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing cardiac surgery

Hermann Blessberger et al. Cochrane Database Syst Rev. .

Abstract

Background: Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update and assesses the evidence in cardiac surgery only.

Objectives: To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing cardiac surgery.

Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles.

Selection criteria: We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing cardiac surgery. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes.

Data collection and analysis: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.

Main results: We included 63 studies with 7768 participants; six studies were quasi-randomized and the remaining were RCTs. All participants were undergoing cardiac surgery, and in most studies, at least some of the participants were previously taking beta-blockers. Types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. In twelve studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in nine studies this was before surgery, in 20 studies during surgery, and in the remaining studies beta-blockers were started postoperatively. Overall, we found that most studies did not report sufficient details for us to adequately assess risk of bias. In particular, few studies reported methods used to randomize participants to groups. In some studies, participants in the control group were given beta-blockers as rescue therapy during the study period, and all studies in which the control was standard care were at high risk of performance bias because of the open-label study design. No studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. We judged 68% studies to be at high risk of bias in at least one domain.Study authors reported few deaths (7 per 1000 in both the intervention and control groups), and we found low-certainty evidence that beta-blockers may make little or no difference to all-cause mortality at 30 days (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.47 to 1.90; 29 studies, 4099 participants). For myocardial infarctions, we found no evidence of a difference in events (RR 1.05, 95% CI 0.72 to 1.52; 25 studies, 3946 participants; low-certainty evidence). Few study authors reported cerebrovascular events, and the evidence was uncertain (RR 1.37, 95% CI 0.51 to 3.67; 5 studies, 1471 participants; very low-certainty evidence). Based on a control risk of 54 per 1000, we found low-certainty evidence that beta-blockers may reduce episodes of ventricular arrhythmias by 32 episodes per 1000 (RR 0.40, 95% CI 0.25 to 0.63; 12 studies, 2296 participants). For atrial fibrillation or flutter, there may be 163 fewer incidences with beta-blockers, based on a control risk of 327 incidences per 1000 (RR 0.50, 95% CI 0.42 to 0.59; 40 studies, 5650 participants; low-certainty evidence). However, the evidence for bradycardia and hypotension was less certain. We found that beta-blockers may make little or no difference to bradycardia (RR 1.63, 95% CI 0.92 to 2.91; 12 studies, 1640 participants; low-certainty evidence), or hypotension (RR 1.84, 95% CI 0.89 to 3.80; 10 studies, 1538 participants; low-certainty evidence).We used GRADE to downgrade the certainty of evidence. Owing to studies at high risk of bias in at least one domain, we downgraded each outcome for study limitations. Based on effect size calculations in the previous review, we found an insufficient number of participants in all outcomes (except atrial fibrillation) and, for some outcomes, we noted a wide confidence interval; therefore, we also downgraded outcomes owing to imprecision. The evidence for atrial fibrillation and length of hospital stay had a moderate level of statistical heterogeneity which we could not explain, and we, therefore, downgraded these outcomes for inconsistency.

Authors' conclusions: We found no evidence of a difference in early all-cause mortality, myocardial infarction, cerebrovascular events, hypotension and bradycardia. However, there may be a reduction in atrial fibrillation and ventricular arrhythmias when beta-blockers are used. A larger sample size is likely to increase the certainty of this evidence. Four studies awaiting classification may alter the conclusions of this review.

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Conflict of interest statement

Hermann Blessberger: none known

Sharon Lewis: none known

Michael Pritchard: none known

Lizzy Fawcett: none known

Hans Domanovits: none known

Oliver Schlager: none known

Brigitte Wildner: none known

Juergen Kammler: none known

Clemens Steinwender: I have received speaker's honoraria from MSD, Sanofi‐Aventis, Boehringer‐Ingelheim, Bayer, Medtronic, Biotronic, Abbott, St. Jude Medical and Boston Scientific. Sanofi‐Aventis, Boehringer‐Ingelheim Europe, Medtronic, Biotronik, Bayer Austria, Abbott Vascular, St. Jude Medical and Boston Scientific do not produce, market or distribute any of the studied drug entities. MSD have one beta‐blocker (timolol) in their portfolio.

Figures

1
1
Study flow diagram for updated search on 28 June 2019
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
4
4
Forest plot of comparison 1. Beta‐blocker vs control for cardiac surgery, outcome: 1.1 All‐cause mortality (30 days)
5
5
Forest plot of comparison 1. Beta‐blocker vs control for cardiac surgery, outcome: 1.7 Atrial fibrillation or flutter, or both
1.1
1.1. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 1 All‐cause mortality (30 days).
1.2
1.2. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 2 Long‐term mortality.
1.3
1.3. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 3 Death due to cardiac causes.
1.4
1.4. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 4 Acute myocardial infarction.
1.5
1.5. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 5 Cerebrovascular events.
1.6
1.6. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 6 Ventricular arrhythmias.
1.7
1.7. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 7 Atrial fibrillation or flutter, or both.
1.8
1.8. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 8 Bradycardia.
1.9
1.9. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 9 Hypotension.
1.10
1.10. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 10 Congestive heart failure.
1.11
1.11. Analysis
Comparison 1 Beta‐blocker vs control for cardiac surgery, Outcome 11 Length of hospital stay (in days).
2.1
2.1. Analysis
Comparison 2 Beta‐blocker vs control for cardiac surgery: subgroup by type of beta‐blocker, Outcome 1 All‐cause mortality (30 days).
2.2
2.2. Analysis
Comparison 2 Beta‐blocker vs control for cardiac surgery: subgroup by type of beta‐blocker, Outcome 2 Acute myocardial infarction.
2.3
2.3. Analysis
Comparison 2 Beta‐blocker vs control for cardiac surgery: subgroup by type of beta‐blocker, Outcome 3 Ventricular arrhythmias.
2.4
2.4. Analysis
Comparison 2 Beta‐blocker vs control for cardiac surgery: subgroup by type of beta‐blocker, Outcome 4 Atrial fibrillation and flutter.
2.5
2.5. Analysis
Comparison 2 Beta‐blocker vs control for cardiac surgery: subgroup by type of beta‐blocker, Outcome 5 Bradycardia.
2.6
2.6. Analysis
Comparison 2 Beta‐blocker vs control for cardiac surgery: subgroup by type of beta‐blocker, Outcome 6 Hypotension.
3.1
3.1. Analysis
Comparison 3 Beta‐blocker vs control for cardiac surgery: subgroup by start of beta‐blocker therapy, Outcome 1 All‐cause mortality (30 days).
3.2
3.2. Analysis
Comparison 3 Beta‐blocker vs control for cardiac surgery: subgroup by start of beta‐blocker therapy, Outcome 2 Acute myocardial infarction.
3.3
3.3. Analysis
Comparison 3 Beta‐blocker vs control for cardiac surgery: subgroup by start of beta‐blocker therapy, Outcome 3 Ventricular arrhythmias.
3.4
3.4. Analysis
Comparison 3 Beta‐blocker vs control for cardiac surgery: subgroup by start of beta‐blocker therapy, Outcome 4 Atrial fibrillation and flutter.
3.5
3.5. Analysis
Comparison 3 Beta‐blocker vs control for cardiac surgery: subgroup by start of beta‐blocker therapy, Outcome 5 Bradycardia.
3.6
3.6. Analysis
Comparison 3 Beta‐blocker vs control for cardiac surgery: subgroup by start of beta‐blocker therapy, Outcome 6 Hypotension.
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    1. Vecht RJ, Nicolaides EP, Ikeuke JK, Liassides C, Cleary J, Cooper WB. Incidence and prevention of supraventricular tachyarrhythmias after coronary bypass surgery. International Journal of Cardiology 1986;13(2):125‐34. [PUBMED: 3539826] - PubMed
Wenke 1999 {published data only}
    1. Wenke K, Parsa MH, Imhof M, Kemkes BM. Efficacy of metoprolol in prevention of supraventricular arrhythmias after coronary artery bypass grafting. Zeitschrift für Kardiologie 1999;88(9):647‐52. [PUBMED: 10525926] - PubMed
White 1984 {published data only}
    1. White HD, Antman EM, Glynn MA, Collins JJ, Cohn LH, Shemin RJ, et al. Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery. Circulation 1984;70(3):479‐84. [PUBMED: 6378423] - PubMed
Williams 1982 {published data only}
    1. Williams JB, Stephenson LW, Holford FD, Langer T, Dunkman WB, Josephson ME. Arrhythmia prophylaxis using propranolol after coronary artery surgery. Annals of Throacic Surgery 1982;34(4):435‐8. [PUBMED: 6982689 ] - PubMed
Yazicioglu 2002 {published data only}
    1. Yazicioglu L, Eryilmaz S, Sirlak M, Inan MB, Aral A, Tasoz R, et al. The effect of preoperative digitalis and atenolol combination on postoperative atrial fibrillation incidence. European Journal of Cardio‐Thoracic Surgery 2002;22(3):397‐401. [PUBMED: 12204730] - PubMed

References to studies excluded from this review

De Bruijn 1987 {published data only}
    1. Bruijn NP, Croughwell N, Reves JG. Hemodynamic effects of esmolol in chronically beta‐blocked patients undergoing aortocoronary bypass surgery. Anesthesia and Analgesia 1987;66(2):137‐41. [PUBMED: 2880530] - PubMed
Deng 2002 {published data only}
    1. Deng YK, Wei F, Li ZL, Zhang DG, Yang SY. Esmolol protects the myocardium and facilitates direct version intracardiac operation with a beating heart. Circulation Journal 2002;66(8):715‐7. [PUBMED: 12197593] - PubMed
Efe 2014 {published data only}
    1. Efe EM, Bilgin BA, Alanoglu Z, Akbaba M, Denker C. Comparison of bolus and continuous infusion of esmolol on hemodynamic response to laryngoscopy, endotracheal intubation and sternotomy in coronary artery bypass graft. Brazilian Journal of Anesthesiology 2014;64(4):247‐52. [PUBMED: 24998108] - PubMed
Fujii 2012 {published data only}
    1. Fujii M, Bessho R, Ochi M, Shimizu K, Terajima K, Takeda S. Effect of postoperative landiolol administration for atrial fibrillation after off pump coronary artery bypass surgery. Journal of Cardiovascular Surgery 2012;53(3):369‐74. [CN‐00881488; PUBMED: 22249647] - PubMed
Hamaguchi 2014 {published data only}
    1. Hamaguchi S, Nagao M, Takahashi Y, Ikeda T, Yamaguchi S. Low dose landiolol combined with catecholamine can decrease heart rate without suppression of cardiac contraction after cardiopulmonary bypass. Dokkyo Journal of Medical Sciences 2014;41(1):27‐33. [373250136]
Imren 2007 {published data only}
    1. Imren Y, Benson AA, Zor H, Tasoglu I, Ereren E, Sinci V. Preoperative beta‐blocker use reduces atrial fibrillation in off‐pump coronary bypass surgery. Australian and New Zealand Journal of Surgery 2007;77(6):429‐32. [CN‐00866547; PUBMED: 17501880] - PubMed
Newsome 1986 {published data only}
    1. Newsome LR, Roth JV, Hug CC, Nagle D. Esmolol attenuates hemodynamic responses during fentanyl‐pancuronium anesthesia for aortocoronary bypass surgery. Anesthesia and Analgesia 1986;65(5):451‐6. [PUBMED: 3485937] - PubMed
O'Dwyer 1993 {published data only}
    1. O'Dwyer JP, Yorukoglu D, Harris MN. The use of esmolol to attenuate the haemodynamic response when extubating patients following cardiac surgery ‐ a double‐blind controlled study. European Heart Journal 1993;14(5):701‐4. [PUBMED: 8099549] - PubMed
Rees 2015 {published data only}
    1. Rees C, Sultani Z, Theologou T, Poon S, Field LM, Kuduvalli M, et al. Prophylactic treatment of atrial fibrillation post coronary artery bypass grafting. A randomised controlled trial of sotalol and magnesium versus placebo. European Surgical Research 2015;1:89. [71958303]
Sezai 2015 {published data only}
    1. Sezai A, Osaka S, Yaoita H, Ishii Y, Arimoto M, Hata H, et al. Safety and efficacy of landiolol hydrochloride for prevention of atrial fibrillation after cardiac surgery in patients with left ventricular dysfunction: prevention of atrial fibrillation after cardiac surgery with landiolol hydrochloride for left ventricular dysfunction (PLATON) trial. Journal of Thoracic and Cardiovascular Surgery 2015;150(4):957‐64. [PUBMED: 26254752] - PubMed
Tempe 1999 {published data only}
    1. Tempe DK, Mulchandani P, Tandon MS, Mehta N, Tomar AS, Banerjee A, et al. Control of tachycardia and hypertension following coronary artery bypass graft surgery: efficacy and haemodynamic effects of esmolol. Indian Heart Journal 1999;51(3):294‐300. [PUBMED: 10624069] - PubMed
Yazicioglu 2012 {published data only}
    1. Yazicioglu H, Ozgok A, Balaban F, Doganay B, Unver S. Single dose esmolol attenuates bispectral index scale response to intubation during fentanyl‐midazolam anesthesia for cardiac surgery. Turkish Journal of Thoracic and Cardiovascular Surgery 2012;20(1):72‐8. [DOI: 10.5606/tgkdc.dergisi.2012.012; WOS:000299866900012] - DOI

References to studies awaiting assessment

Bozotlan 2013 {published data only}
    1. Bozotlan O, Gultekin Y, Mese B, Erdem K, Erotlu E, Yasim A. The effect of esmolol on prevention of postoperative atrial fibrillation after coronary artery bypass graft surgery. International Journal of Cardiology 2013;1:S142. [71039415]
Ishigaki 2012 {published data only}
    1. Ishigaki D, Arimoto T, Iwayama T, Yashiro Y, Kutsuzawa D, Tamura H, et al. Landiolol, an ultra‐short‐acting beta‐blocker, for prevention of atrial fibrillation after catheter ablation. European Heart Journal 2012;33(Suppl 1):352.
NCT00959569 {published data only}
    1. NCT00959569. Esmolol in cardiac surgery. clinicaltrials.gov/ct2/show/NCT00959569 (first received 14 August 2009).
PACTR201801003026226 {published data only}
    1. PACTR201801003026226. Cardiac recovery after single, low esmolol dose in patients undergoing valve replacement surgery. A randomized controlled double‐blind study. apps.who.int/trialsearch/Trial2.aspx?TrialID=PACTR201801003026226 (first received 28 January 2018).

References to ongoing studies

Chictr‐ior‐16009203 {published data only}
    1. Chictr‐ior‐16009203. Perioperative esmolol injection and acute kidney injury associated with CPB after cardiac surgery. www.chictr.org.cn/showproj.aspx?proj=15579 (first received 13 August 2016).
UMIN000004216 {published data only}
    1. UMIN000004216. Efficacy of beta‐blocker on the autonomic nervous activities and the onset of atrial fibrillation or flutter in patients after cardiac surgery. upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000005063 (first received 1 October 2010).

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References to other published versions of this review

Blessberger 2014
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