Clinical Review & Education
JAMA Clinical Evidence Synopsis
PerioperativeUseofβ-BlockersinCardiacandNoncardiacSurgery Hermann Blessberger, MD; Juergen Kammler, MD; Clemens Steinwender, MD
CLINICAL QUESTION Are β-blockers associated with lower rates of mortality and morbidity after cardiac or noncardiac surgery? BOTTOM LINE In cardiac surgery, β-blockers are associated with a lower incidence of supraventricular tachycardias (SVTs) and ventricular arrhythmias. In noncardiac surgery, β-blockers are associated with a possible increase in mortality and strokes, a lower incidence of acute myocardial infarctions (AMIs) and SVTs, and an increase in bradycardia and hypotension. If tolerated, long-term β-blocker treatment should be continued perioperatively, whereas the decision to start a β-blocker should be individualized, weighing risks and benefits.
In the perioperative setting, β-blockers may prevent untoward events in high-risk patients by protecting against catecholamine surges. However, randomized clinical trials have yielded conflicting results. This JAMA Clinical Evidence Synopsis summarizes a Cochrane review1 of randomized clinical trials regarding associations of β-blockers and rates of mortality and morbidity after cardiac or noncardiac surgery.
Summary of Findings In cardiac surgery (53 trials), there was no association between β-blocker use and all-cause mortality (risk ratio [RR], 0.73 [95% CI, 0.35 to 1.52]; 9/1939 for β-blocker vs 13/1844 for control) or the incidence of acute myocardial infarction (AMI), cerebrovascular events, hypotension, bradycardia, or congestive heart failure. However, β-blockers were associated with a lower incidence of supraventricular tachycardias (SVTs; RR, 0.44 [95% CI, 0.36 to 0.53]; 572/3260 for β-blocker vs 1089/3160 for control, number needed to treat [NNT], 6 [95% CI, 5 to 6]) and ventricular arrhythmias (RR, 0.37 [95%
Evidence Profile Number of randomized clinical trials: Cardiac surgery, 53; noncardiac surgery, 36 Study years: Published, 1979-2013 Date of most recent literature search: June 30, 2013 No. of patients: Cardiac, 6486 ; noncardiac, 12 725
Discussion
Women: 32.9% (not specified, 14 trials)
Our findings for noncardiac surgery were heavily influenced by the POISE trial. 2 When this study was omitted from analysis of placebo-controlled trials, the association between β-blockers and all-cause mortality or strokes lost statistical significance (RR, 1.07 [95% CI, 0.66-1.72] for all-cause mortality and RR, 3.52 [95% CI, 0.59-20.95] for strokes). One reason may be that patients in the POISE trial received a relatively high β-blocker dose 2 to 4 hours prior to surgery. Lack of preoperative up-titration may have contributed to a higher rate of hypotension, resulting in additional strokes and deaths in POISE. Significant associations between β-blockers and a reduction of SVTs and an increase of hypotension and bradycardia were preserved, even when POISE was excluded from analyses.
Age, mean (SD): 58.3 years (9.8) (not specified, 8 trials) Race/ethnicity: White (19.7%), Asian (6.6%), South American (1.0%), not specified (72.7%) Settings: Cardiac and noncardiac surgery Countries: Global Comparison: β-Blocker vs control (standard care or placebo) Primary outcome: All-cause mortality within 30 days after surgery Secondary outcomes: Acute myocardial infarction, supraventricular tachycardias, ventricular arrhythmias, hypotension, bradycardia, cerebrovascular events, congestive heart failure, length of hospital stay
2070
CI, 0.24 to 0.58]; 22/1143 for β-blocker vs 62/1149 for control, NNT, 29 [95% CI, 24 to 44]). β-Blocker use was associated with a shorter length of hospital stay (mean difference for β-blocker vs control, −0.54 days [95% CI, −0.90 to −0.19], P = .003). In noncardiac surgery (36 trials), there was no association between β-blockers and all-cause mortality (RR, 1.24 [95% CI, 0.99-1.54]; 168/5830 for β-blocker vs 136/5633 for control) or strokes when all trials were combined (ie, with a placebo or a standard care control group). However, if only placebo-controlled trials were analyzed, β-blockers were associated with a significant increase in all-cause mortality (RR, 1.27 [95% CI, 1.01-1.59]; 161/ 5524 for β-blocker vs 127/5321 for control, number needed to harm [NNH], 189 [95% CI, 71-4190]) (Figure) and cerebrovascular events (RR, 2.09 [95% CI, 1.14-3.82]; 32/4326 for β-blocker vs 15/4322 for control, NNH, 255 [95% CI, 102-2058]). Among all trials combined, β-blockers were associated with a significant reduction in AMIs (RR, 0.73 [95% CI, 0.61-0.87]; 194/5522 for β-blocker vs 266/5436 for control, NNT, 72 [95% CI, 52-157]) and SVTs (RR, 0.72 [95% CI, 0.56-0.92]; 109/4405 for β-blocker vs 148/4389 for control, NNT, 111 [95% CI, 67-371]). Conversely, the use of β-blockers was associated with an increase in episodes of hypotension (RR, 1.50 [95% CI, 1.38-1.64]; NNH, 15 [95% CI, 13-21]) and bradycardia (RR, 2.24 [95% CI, 1.49-3.35]; NNH, 18 [95% CI, 11-52]). There was no association between β-blockers and ventricular arrhythmias, congestive heart failure, or length of stay.
JAMA May 26, 2015 Volume 313, Number 20 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Eastern Kentucky University User on 05/26/2015
jama.com
JAMA Clinical Evidence Synopsis Clinical Review & Education
Figure. Association of β-Blocker Treatment and Type of Control Group With All-Cause Mortality in Noncardiac Surgery β-Blocker Study or Subgroup
No. of Events
Control Total Participants
No. of Events
Total Participants
Favors β-Blocker
Risk Ratio (95% CI)
Favors Control
Trials with a placebo control group Miller, 1990
0
30
0
15
Not estimable
Miller, 1991
0
368
0
180
Not estimable
Mangano, 1996
4
99
2
101
2.04 (0.38-10.89)
Bayliff, 1999
2
49
1
50
2.04 (0.19-21.79)
POBBLE, 2005
3
53
1
44
2.49 (0.27-23.11)
20
462
15
459
1.32 (0.69-2.55)
DIPOM-Juul, 2006 Neary, 2006
3
18
5
20
0.67 (0.19-2.40)
Yang, 2006
0
246
4
250
0.11 (0.01-2.09)
129
4174
97
4177
1.33 (1.03-1.73)
0
25
2
25
0.20 (0.01-3.97)
161
5524
127
5321
1.27 (1.01-1.59)
POISE, 2008 Suttner, 2009 Subtotal
Trials with a standard care control group Lai, 2006
0
30
0
30
Not estimable
Yang, 2008
0
51
1
51
0.33 (0.01-8.00)
Marwick, 2009
6
197
5
203
1.24 (0.38-3.99)
Kawaguchi, 2010
1
28
3
28
0.33 (0.04-3.01)
Subtotal
7
306
9
312
0.81 (0.31-2.06)
168
5830
136
5633
1.24 (0.99-1.54)
Total
0.01
0.1
1.0
10
100
Risk Ratio (95% CI)
Source: Data have been adapted with permission from Wiley.1 Size of the square markers indicate number of randomized patients for each trial. The 3 diamond markers with their respective lateral dimensions depict summary estimates and corresponding 95% CIs. Although no evidence of an association was found
when all trials were combined, a statistically significant increase in all-cause mortality with the use of β-blockers was detected, if only placebo-controlled trials were analyzed.1
Limitations
Guidelines from US and European societies on noncardiac surgery support continuing β-blockers if patients already receive longterm treatment before surgery.4,5 Initiation may be considered in individuals with more than 3 cardiovascular risk factors or evidence of ischemia on preoperative testing.4 β-Blockers should be started well in advance of surgery (about 2-7 days)4 and dose titration may be beneficial (target resting heart rate, 60-70/min).5
Statistical power was sufficient only for the reduction of SVTs and length of stay in cardiac surgery, and the reduction of SVTs and AMI as well as the increase in hypotension in noncardiac surgery. Definitive conclusions are not possible for the remaining outcomes, most notably for all-cause mortality. Comparison of Findings With Current Guidelines
For cardiac surgery, current guidelines recommend β-blocker therapy inpatientswithanejectionfractiongreaterthan30%undergoingcoronary artery bypass grafting to improve survival and prevent postoperative atrial fibrillation.3 ARTICLE INFORMATION Author Affiliations: Department of Internal Medicine 1—Cardiology, Linz General Hospital, Johannes Kepler University Linz School of Medicine, Austria. Corresponding Author: Hermann Blessberger, MD, Department of Internal Medicine 1—Cardiology, Linz General Hospital, Johannes Kepler University Linz School of Medicine, Krankenhausstrasse 9, A-4020 Linz, Austria ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Blessberger reports receiving consultancy honoraria from EVER Neuro Pharma. Dr Steinwender reports receiving lecture honoraria from Merck Sharp & Dohme, sanofi-aventis, Boehringer-Ingelheim, Bayer Austria, Medtronic,
jama.com
Areas in Need of Further Study
The exact timing, titration, and type of β-blocker, as well as the ideal patient subset that benefits from β-blockers perioperatively, need further investigation.
Biotronik, Abbott Vascular, St Jude Medical, and Boston Scientific. No other disclosures were reported. EVER Neuro Pharma, 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. Merck Sharp & Dohme (timolol) has a β-blocker its portfolio. Additional Contributions: We thank the Cochrane Anaesthesia Review Group for their support in publishing the Cochrane Review. REFERENCES 1. Blessberger H, Kammler J, Domanovits H, et al. Perioperative β-blockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst Rev. 2014;9:CD004476.
2. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing noncardiac surgery (POISE trial). Lancet. 2008;371(9627):1839-1847. 3. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. Circulation. 2011;124(23):e652-e735. 4. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation. 2014;130(24):e278-e333. 5. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on noncardiac surgery. Eur Heart J. 2014;35(35):2383-2431.
(Reprinted) JAMA May 26, 2015 Volume 313, Number 20
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Eastern Kentucky University User on 05/26/2015
2071
JAMA Clinical Evidence Synopsis
PerioperativeUseofβ-BlockersinCardiacandNoncardiacSurgery Hermann Blessberger, MD; Juergen Kammler, MD; Clemens Steinwender, MD
CLINICAL QUESTION Are β-blockers associated with lower rates of mortality and morbidity after cardiac or noncardiac surgery? BOTTOM LINE In cardiac surgery, β-blockers are associated with a lower incidence of supraventricular tachycardias (SVTs) and ventricular arrhythmias. In noncardiac surgery, β-blockers are associated with a possible increase in mortality and strokes, a lower incidence of acute myocardial infarctions (AMIs) and SVTs, and an increase in bradycardia and hypotension. If tolerated, long-term β-blocker treatment should be continued perioperatively, whereas the decision to start a β-blocker should be individualized, weighing risks and benefits.
In the perioperative setting, β-blockers may prevent untoward events in high-risk patients by protecting against catecholamine surges. However, randomized clinical trials have yielded conflicting results. This JAMA Clinical Evidence Synopsis summarizes a Cochrane review1 of randomized clinical trials regarding associations of β-blockers and rates of mortality and morbidity after cardiac or noncardiac surgery.
Summary of Findings In cardiac surgery (53 trials), there was no association between β-blocker use and all-cause mortality (risk ratio [RR], 0.73 [95% CI, 0.35 to 1.52]; 9/1939 for β-blocker vs 13/1844 for control) or the incidence of acute myocardial infarction (AMI), cerebrovascular events, hypotension, bradycardia, or congestive heart failure. However, β-blockers were associated with a lower incidence of supraventricular tachycardias (SVTs; RR, 0.44 [95% CI, 0.36 to 0.53]; 572/3260 for β-blocker vs 1089/3160 for control, number needed to treat [NNT], 6 [95% CI, 5 to 6]) and ventricular arrhythmias (RR, 0.37 [95%
Evidence Profile Number of randomized clinical trials: Cardiac surgery, 53; noncardiac surgery, 36 Study years: Published, 1979-2013 Date of most recent literature search: June 30, 2013 No. of patients: Cardiac, 6486 ; noncardiac, 12 725
Discussion
Women: 32.9% (not specified, 14 trials)
Our findings for noncardiac surgery were heavily influenced by the POISE trial. 2 When this study was omitted from analysis of placebo-controlled trials, the association between β-blockers and all-cause mortality or strokes lost statistical significance (RR, 1.07 [95% CI, 0.66-1.72] for all-cause mortality and RR, 3.52 [95% CI, 0.59-20.95] for strokes). One reason may be that patients in the POISE trial received a relatively high β-blocker dose 2 to 4 hours prior to surgery. Lack of preoperative up-titration may have contributed to a higher rate of hypotension, resulting in additional strokes and deaths in POISE. Significant associations between β-blockers and a reduction of SVTs and an increase of hypotension and bradycardia were preserved, even when POISE was excluded from analyses.
Age, mean (SD): 58.3 years (9.8) (not specified, 8 trials) Race/ethnicity: White (19.7%), Asian (6.6%), South American (1.0%), not specified (72.7%) Settings: Cardiac and noncardiac surgery Countries: Global Comparison: β-Blocker vs control (standard care or placebo) Primary outcome: All-cause mortality within 30 days after surgery Secondary outcomes: Acute myocardial infarction, supraventricular tachycardias, ventricular arrhythmias, hypotension, bradycardia, cerebrovascular events, congestive heart failure, length of hospital stay
2070
CI, 0.24 to 0.58]; 22/1143 for β-blocker vs 62/1149 for control, NNT, 29 [95% CI, 24 to 44]). β-Blocker use was associated with a shorter length of hospital stay (mean difference for β-blocker vs control, −0.54 days [95% CI, −0.90 to −0.19], P = .003). In noncardiac surgery (36 trials), there was no association between β-blockers and all-cause mortality (RR, 1.24 [95% CI, 0.99-1.54]; 168/5830 for β-blocker vs 136/5633 for control) or strokes when all trials were combined (ie, with a placebo or a standard care control group). However, if only placebo-controlled trials were analyzed, β-blockers were associated with a significant increase in all-cause mortality (RR, 1.27 [95% CI, 1.01-1.59]; 161/ 5524 for β-blocker vs 127/5321 for control, number needed to harm [NNH], 189 [95% CI, 71-4190]) (Figure) and cerebrovascular events (RR, 2.09 [95% CI, 1.14-3.82]; 32/4326 for β-blocker vs 15/4322 for control, NNH, 255 [95% CI, 102-2058]). Among all trials combined, β-blockers were associated with a significant reduction in AMIs (RR, 0.73 [95% CI, 0.61-0.87]; 194/5522 for β-blocker vs 266/5436 for control, NNT, 72 [95% CI, 52-157]) and SVTs (RR, 0.72 [95% CI, 0.56-0.92]; 109/4405 for β-blocker vs 148/4389 for control, NNT, 111 [95% CI, 67-371]). Conversely, the use of β-blockers was associated with an increase in episodes of hypotension (RR, 1.50 [95% CI, 1.38-1.64]; NNH, 15 [95% CI, 13-21]) and bradycardia (RR, 2.24 [95% CI, 1.49-3.35]; NNH, 18 [95% CI, 11-52]). There was no association between β-blockers and ventricular arrhythmias, congestive heart failure, or length of stay.
JAMA May 26, 2015 Volume 313, Number 20 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Eastern Kentucky University User on 05/26/2015
jama.com
JAMA Clinical Evidence Synopsis Clinical Review & Education
Figure. Association of β-Blocker Treatment and Type of Control Group With All-Cause Mortality in Noncardiac Surgery β-Blocker Study or Subgroup
No. of Events
Control Total Participants
No. of Events
Total Participants
Favors β-Blocker
Risk Ratio (95% CI)
Favors Control
Trials with a placebo control group Miller, 1990
0
30
0
15
Not estimable
Miller, 1991
0
368
0
180
Not estimable
Mangano, 1996
4
99
2
101
2.04 (0.38-10.89)
Bayliff, 1999
2
49
1
50
2.04 (0.19-21.79)
POBBLE, 2005
3
53
1
44
2.49 (0.27-23.11)
20
462
15
459
1.32 (0.69-2.55)
DIPOM-Juul, 2006 Neary, 2006
3
18
5
20
0.67 (0.19-2.40)
Yang, 2006
0
246
4
250
0.11 (0.01-2.09)
129
4174
97
4177
1.33 (1.03-1.73)
0
25
2
25
0.20 (0.01-3.97)
161
5524
127
5321
1.27 (1.01-1.59)
POISE, 2008 Suttner, 2009 Subtotal
Trials with a standard care control group Lai, 2006
0
30
0
30
Not estimable
Yang, 2008
0
51
1
51
0.33 (0.01-8.00)
Marwick, 2009
6
197
5
203
1.24 (0.38-3.99)
Kawaguchi, 2010
1
28
3
28
0.33 (0.04-3.01)
Subtotal
7
306
9
312
0.81 (0.31-2.06)
168
5830
136
5633
1.24 (0.99-1.54)
Total
0.01
0.1
1.0
10
100
Risk Ratio (95% CI)
Source: Data have been adapted with permission from Wiley.1 Size of the square markers indicate number of randomized patients for each trial. The 3 diamond markers with their respective lateral dimensions depict summary estimates and corresponding 95% CIs. Although no evidence of an association was found
when all trials were combined, a statistically significant increase in all-cause mortality with the use of β-blockers was detected, if only placebo-controlled trials were analyzed.1
Limitations
Guidelines from US and European societies on noncardiac surgery support continuing β-blockers if patients already receive longterm treatment before surgery.4,5 Initiation may be considered in individuals with more than 3 cardiovascular risk factors or evidence of ischemia on preoperative testing.4 β-Blockers should be started well in advance of surgery (about 2-7 days)4 and dose titration may be beneficial (target resting heart rate, 60-70/min).5
Statistical power was sufficient only for the reduction of SVTs and length of stay in cardiac surgery, and the reduction of SVTs and AMI as well as the increase in hypotension in noncardiac surgery. Definitive conclusions are not possible for the remaining outcomes, most notably for all-cause mortality. Comparison of Findings With Current Guidelines
For cardiac surgery, current guidelines recommend β-blocker therapy inpatientswithanejectionfractiongreaterthan30%undergoingcoronary artery bypass grafting to improve survival and prevent postoperative atrial fibrillation.3 ARTICLE INFORMATION Author Affiliations: Department of Internal Medicine 1—Cardiology, Linz General Hospital, Johannes Kepler University Linz School of Medicine, Austria. Corresponding Author: Hermann Blessberger, MD, Department of Internal Medicine 1—Cardiology, Linz General Hospital, Johannes Kepler University Linz School of Medicine, Krankenhausstrasse 9, A-4020 Linz, Austria ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Blessberger reports receiving consultancy honoraria from EVER Neuro Pharma. Dr Steinwender reports receiving lecture honoraria from Merck Sharp & Dohme, sanofi-aventis, Boehringer-Ingelheim, Bayer Austria, Medtronic,
jama.com
Areas in Need of Further Study
The exact timing, titration, and type of β-blocker, as well as the ideal patient subset that benefits from β-blockers perioperatively, need further investigation.
Biotronik, Abbott Vascular, St Jude Medical, and Boston Scientific. No other disclosures were reported. EVER Neuro Pharma, 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. Merck Sharp & Dohme (timolol) has a β-blocker its portfolio. Additional Contributions: We thank the Cochrane Anaesthesia Review Group for their support in publishing the Cochrane Review. REFERENCES 1. Blessberger H, Kammler J, Domanovits H, et al. Perioperative β-blockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst Rev. 2014;9:CD004476.
2. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing noncardiac surgery (POISE trial). Lancet. 2008;371(9627):1839-1847. 3. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. Circulation. 2011;124(23):e652-e735. 4. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation. 2014;130(24):e278-e333. 5. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on noncardiac surgery. Eur Heart J. 2014;35(35):2383-2431.
(Reprinted) JAMA May 26, 2015 Volume 313, Number 20
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Eastern Kentucky University User on 05/26/2015
2071
