Appendix 6

Perioperative Beta Blockade in Noncardiac Surgery Studies: Summary Table (NEW)

StudyYear of PublicationTrial TypeNo. of PatientsPatient PopulationPrimary End PointAnalysis: HR, RR, OR, NNT95% CI and/or pResults
Mangano et al. (87)1996RCT200Patients with or at risk for CAD undergoing noncardiac surgery“Overall mortality after discharge from the hospital was significantly lower among the atenolol-treated patients than among those who were given placebo over the 6 months following hospital discharge.”0% versus 8%p<0.001The authors concluded, “The principal effect was a reduction in deaths from cardiac causes during the first 6 to 8 months. Combined cardiovascular outcomes were similarly reduced among the atenolol-treated patients; event-free survival throughout the 2-year study period was 68% in the placebo group and 83% in the atenolol group; p=0.008.”
Over the first year3% versus 14%p=0.005
Over 2 years10% versus 21%p=0.019
Wallace et al. (381)1998RCT200Patients with, or at risk for, CAD“The incidence of myocardial ischemia on days 0–2 was significantly reduced in the atenolol group (atenolol, 17 of 99 patients; placebo, 34 of 101 patients).”p=0.008The authors concluded, “Perioperative administration of atenolol for 1 week to patients at high risk for CAD significantly reduces the incidence of postoperative myocardial ischemia. Reductions in perioperative myocardial ischemia are associated with reductions in the risk for death at 2 years.”
“The incidence of myocardial ischemia on Days 0–7 was significantly reduced in the atenolol group (atenolol, 24 of 99 patients; placebo, 39 of 101 patients).”p=0.029
“Patients with episodes of myocardial ischemia were more likely to die in the next 2 years.”p=0.025
Poldermans et al. (88)1999Randomized multicenter trial112Major vascular surgery“The primary study end point of death due to cardiac causes or nonfatal MI occurred in 2 patients in the bisoprolol group (3.4%) and 18 in the standard-care group (34%).”p<0.001The authors concluded, “Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal MI in high-risk patients who are undergoing major vascular surgery.”
“Two patients in the bisoprolol group died of cardiac causes (3.4%) compared with 9 in the standard-care group (17%).”p=0.02
“Nonfatal MI occurred in 9 patients given standard care only (17%) and in none of those given standard care plus bisoprolol.”p<0.001
Zaugg et al. (377)1999RCT63Elderly, noncardiac surgery patients. Group I, no atenolol; Group II, preoperative and postoperative atenolol; Group III, intraoperative atenolol.“Hormonal markers of the stress response (neuropeptide Y, epinephrine, norepinephrine, cortisol, and adrenocorticotropic hormone) were evaluated preoperatively and for 72 hours after surgery.”Perioperative beta blockade did not significantly alter the hormonal stress response.The authors concluded, “Beta-blockade does not reduce the neuroendocrine stress response, suggesting that this mechanism is not responsible for the previously reported improved cardiovascular outcome. However, it confers several advantages, including decreased analgesic requirements, faster recovery from anesthesia, and improved hemodynamic stability. The release of cardiac troponin I suggests the occurrence of perioperative myocardial damage in this elderly population, which appears to be independent of the neuroendocrine stress response.”
The beta-blocked patients “received less fentanyl intraoperatively (27.7%, p<0.0001), experienced faster early recovery, had lower pain scores, and required less analgesia in the postanesthesia care unit. Cardiac troponin I release was detected in 8 of 19, 4 of 20, and 5 of 20 patients in Groups I, II, and III, respectively (p=not significant).”p<0.0001
“Three patients in Group I had cardiac troponin I levels consistent with MI.”
Raby et al. (376)1999RCT26High-risk vascular surgery patients“Ischemia persisted in the postoperative period in 8 (73%) of 11 placebo patients but only 5 (33%) of 15 esmolol patients.”p<0.05The authors' data suggest that “patient-specific, strict heart rate control aiming for a predefined target based on individual preoperative ischemic threshold was associated with a significant reduction and frequent elimination of postoperative myocardial ischemia among high-risk patients and provides a rationale for a larger trial to examine this strategy's effect on cardiac risk.”
Brady et al. (379)2005Double-blind RCT103Patients without previous MI who had infrarenal vascular surgery“Cardiovascular events occurred in 15 (34%) and 17 (32%) patients in the placebo and metoprolol groups, respectively.”Unadjusted RR 0.940.53 to 1.66The authors concluded, “Myocardial ischemia was evident in a high proportion (one-third) of the patients after surgery. A pragmatic regimen of perioperative beta-blockade with metoprolol did not seem to reduce 30-day cardiovascular events, but it did decrease the time from surgery to discharge.”
Adjusted RR 0.870.48 to 1.55
“Time from operation to discharge was reduced from a median of 12 days (95% CI 9–19 days) in the placebo group to 10 days (95% CI 8–12 days) in the metoprolol group.”Adjusted HR 1.711.09 to 2.66; p<0.02
Juul et al. (372)2006RCT921Patients who have diabetes >39 years of age scheduled for major noncardiac surgery“The composite primary outcome measure was time to all-cause mortality, acute MI, unstable angina, or CHF.”The authors concluded, “Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. CI, however, were wide, and the issue needs reassessment.”
“The primary outcome occurred in 99 (21%) of 462 patients in the metoprolol group and 93 (20%) of 459 patients in the placebo group during a median follow-up of 18 months (range 6–30 months).”HR 1.060.80 to 1.41
“All-cause mortality was 16% (74 of 462 patients) in the metoprolol group and 16% (72 of 459 patients) in the placebo group.”HR 1.030.74 to 1.42
Poldermans et al. (59)2006RCT1476Patients undergoing elective open abdominal aortic or infrainguinal arterial reconstruction“Patients assigned to no testing had a similar incidence of the primary end point as those assigned to testing (1.8% versus 2.3%).”OR 0.780.28 to 2.1; p=0.62The authors concluded, “Cardiac testing can safely be omitted in intermediate-risk patients, provided that beta blockers aiming at tight [heart rate] control are prescribed.”
“Regardless of allocated strategy, patients with a heart rate <65 bpm had lower risk than the remaining patients (1.3% versus 5.2%).”OR 0.240.09 to 0.66; p=0.003
Yang et al. (373)2006RCT496Abdominal aortic surgery and infrainguinal or axillofemoral revascularizationsPrimary outcome was postoperative 30-day composite incidence of nonfatal MI, unstable angina, new CHF, new atrial or ventricular dysrhythmia requiring treatment, or cardiac death.The authors concluded, “Metoprolol was not effective in reducing the 30-day and 6-month postoperative cardiac event rates. Prophylactic use of perioperative beta blockers in all vascular patients is not indicated.”
“Primary outcome events at 30 days occurred in 25 patients (10.2%) versus 30 (12.0%) in the metoprolol and placebo groups, respectively.”RR reduction 15.3%
  • −38.3% to 48.2%; p=0.57

Observed effects at 6 months were not significantly different.RR reduction 6.2%
  • −58.4% to 43.8%; p=0.81

Intraoperative bradycardia requiring treatment was more frequent in the metoprolol group (53 of 246 patients versus 19 of 250 patients).p=0.00001
Intraoperative hypotension requiring treatment was more frequent in the metoprolol group (114 of 246 patients versus 84 of 250 patients).p=0.0045
Zaugg et al. (378)2007Double-blind, placebo-controlled, multicenter trial219Patients undergoing surgery with spinal block“One-year composite outcome included cardiovascular mortality, nonfatal MI, unstable angina, CHF, and cerebrovascular insult.”The authors concluded, “Perioperative bisoprolol therapy did not affect cardiovascular outcome in these elderly at-risk patients undergoing surgery with spinal block.”
“The primary outcome occurred in 25 patients (22.7%) in the bisoprolol group and 24 (22.0%) in the placebo group during the 1-year follow-up.”HR 0.970.55 to 1.69; p=0.90
“Carriers of at least 1 Gly allele of the beta-1-adrenergic receptor polymorphism Arg389Glyshowed a higher number of adverse events than Arg-homozygous subjects (32.4% versus 18.7%).”HR 1.871.04 to 3.35; p=0.04
Devereaux et al. (371)2008RCT8331Patients undergoing noncardiac surgery“The primary end point was a composite of cardiovascular death, nonfatal MI, and nonfatal cardiac arrest. Fewer patients in the metoprolol group than in the placebo group reached the primary end point (244 [5.8%] patients in the metoprolol group versus 290 [6.9%] in the placebo group).”HR 0.840.70 to 0.99; p=0.0399The authors concluded their “results highlight the risk in assuming a perioperative beta blocker regimen has benefit without substantial harm, and the importance and need for large randomized trials in the perioperative setting. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.”
“Fewer patients in the metoprolol group than in the placebo group had an MI (176 [4.2%] versus 239 [5.7%] patients).”HR 0.730.60 to 0.89; p=0.0017
“More deaths occurred in the metoprolol group than in the placebo group (129 [3.1%] versus 97 [2.3%] patients).”HR 1.331.03 to 1.74; p=0.0317
“More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] versus 19 [0.5%] patients).”HR 2.171.26 to 3.74; p=0.0053
Dunkelgrun et al. (369)2009RCT1066Intermediate-risk patients undergoing noncardiovascular surgeryThe primary end point was the composite of perioperative cardiac death and nonfatal MI.The authors concluded, “In intermediate-risk surgical patients, bisoprolol was associated with a significant reduction of 30-day cardiac complications, while fluvastatin showed a trend for improved outcome.”
“Patients randomized to bisoprolol (n=533) had a lower incidence of the primary end point than those randomized to bisoprolol-control therapy (2.1% versus 6.0% events).”HR 0.340.17 to 0.67; p=0.002
“The beneficial effects of bisoprolol were not modified by fluvastatin. Patients randomized to fluvastatin experienced a lower incidence of the primary efficacy end point than those randomized to fluvastatin-control therapy (3.2% versus 4.9% events).”HR 0.650.35 to 1.10; p=0.17
Nonrandomized Studies
Pasternack et al. (374)198783Patients scheduled for abdominal aortic aneurysm surgeryGroup 1 was treated with oral metoprolol immediately before surgery and with intravenous metoprolol during the postoperative period. Group 2, who did not receive metoprolol, served as a control.The authors concluded that their “data demonstrate that beta blockade with metoprolol is effective in controlling systolic blood pressure and heart rate both intraoperatively and postoperatively in patients undergoing repair of AAA and can significantly reduce the incidence of perioperative MI and arrhythmias.”
“In Group 1, only 1 patient (3%) had an acute MI. In contrast, 9 Group 2 patients (18%) had perioperative MI.p<0.05
Only 4 Group 1 patients (12.5%) developed significant cardiac arrhythmias as opposed to 29 Group 2 patients (56.9%).”p<0.001
Pasternack et al. (78)1989Clinical trial48Peripheral vascular surgery patients“Patients treated with oral metoprolol had significantly less intraoperative silent ischemia with respect to relative duration and frequency of episodes, a significantly lower intraoperative heart rate, and less intraoperative silent myocardial ischemia in terms of total absolute duration.”The authors concluded, “These results suggest that beta-adrenergic activation may play a major role in the pathogenesis of silent myocardial ischemia during peripheral vascular surgery.”
Yeager et al. (375)1995Case-control study159Vascular surgery“Beta blockers were used less frequently in patients with perioperative MI than in control patients without perioperative MI (30% versus 50%).”p=0.01The authors concluded, “Beta blockade is associated with a decreased incidence of perioperative MI in patients undergoing vascular surgery. Prophylactic perioperative use of beta-blockers may decrease perioperative MI in patients requiring major vascular surgery.”
“Overall, beta blockade was associated with a 50% reduction in perioperative MI.”p=0.03
Boersma et al. (246)2001Cohort study1351Of patients undergoing major vascular surgery, 611 patients (45%) had a Lee risk index of 1; 509 (38%) had an index of 2; and 231 (17%) had an index of ≥3 points (all patients underwent high-risk surgery and thus had a risk index ≥1 point).Cardiac death or nonfatal MI within 30 days after surgery was the main outcome measure, compared by clinical characteristics, DSE results, and beta-blocker use.The authors concluded the “additional predictive value of DSE is limited in clinically low-risk patients receiving beta blockers. In clinical practice, DSE may be avoided in a large number of patients who can proceed safely for surgery without delay. In clinically intermediate- and high-risk patients receiving beta blockers, DSE may help identify those in whom surgery can still be performed and those in whom cardiac revascularization should be considered.”
Among the 83% of patients with <3 clinical risk factors, patients receiving beta blockers had a lower risk of cardiac complications (0.8% [2 of 263]) than those not receiving beta blockers (2.3% [20 of 855]), and DSE had minimal additional prognostic value. In patients with ≥3 risk factors (17%), DSE provided additional prognostic information; patients without stress-induced ischemia had a much lower risk of events than those with stress-induced ischemia (among those receiving beta blockers, 2.0% [1 of 50] versus 10.6% [5 of 47]). Patients with limited stress-induced ischemia (1–4 segments) experienced fewer cardiac events (2.8% [1 of 36]) than those with more extensive ischemia (≥5 segments, 36% [4 of 11]).”
“Patients who did not undergo DSE (i.e., patients without clinical cardiac risk factors) and those without NWMAs during DSE had a significantly lower cardiac death or MI rate than patients with NWMAs during DSE (0.4% and 1.6% versus 13.5%, respectively).”p<0.001
“In the 222 patients with NWMAs, 67% received beta blockers, with 4.7% having a perioperative cardiac event versus 31.5% of those not receiving beta blockers.”Mantel-Haenszel test 0.10.1 to 0.3
222Univariable relation between DSE results and perioperative cardiac death or MI: NWMA (DSE summary).OR 39.55.3 to 292; p<0.001
“Multivariable model: After correction for differences in clinical characteristics, patients receiving beta blockers were still at significantly lower risk for the composite end point than those who were not.”Adjusted OR 0.30.1 to 0.7
“DSE results (especially the presence or absence of NWMAs) were the most important determinants of perioperative cardiac outcome. In connection with both clinical data and DSE results, beta-blocker therapy was again associated with a significantly reduced risk of the composite end point. The protective effect of beta-blocker therapy was observed in long-term users and in patients who received bisoprolol as part of the DECREASE study (OR 0.1, 95% CI 0.0 to 0.4).”OR 0.10.0 to 0.3
“The incidence of the composite end point in patients with a Lee index of 1, 2, or ≥3 points was 1.3%, 3.1%, and 9.1%, respectively.”p<0.001
Shammash et al. (403)2001140Major vascular surgical procedures“Mortality in the 8 patients who had beta blockers discontinued postoperatively (50%) was significantly greater than mortality (1.5%) in 132 patients who continued taking beta blockers.”OR 65.0p<0.001The authors concluded, “Discontinuing beta blockers immediately after vascular surgery may increase the risk of postoperative cardiovascular morbidity and mortality.”
“Beta-blocker discontinuation also was associated with increased cardiovascular mortality (0% versus 29%).”p=0.005
“Beta-blocker discontinuation also was associated with increased postoperative MI.”OR 17.7p=0.003
Lindenauer et al. (370)2005Retrospective cohort study663 635Patients ≥18 years of age who underwent major noncardiac surgery“Among the 580 665 patients with an RCRI score of 0 or 1, treatment was associated with no benefit and possible harm.”Adjusted OR 1.091.01 to 1.19The authors concluded, “Perioperative beta-blocker therapy is associated with a reduced risk of in-hospital death among high-risk, but not low-risk, patients undergoing major noncardiac surgery. Patient safety may be enhanced by increasing the use of beta-blockers in high-risk patients.”
RCRI score 2Adjusted OR 0.880.80 to 0.98
RCRI score 3Adjusted OR 0.710.63 to 0.80
RCRI score ≥4Adjusted OR 0.580.50 to 0.67
Redelmeier et al. (389)2005Retrospective cohort study37 151Patients >65 years of age who were admitted for elective surgery, without symptomatic coronary disease1038 patients experienced an MI or died, at a rate that was significantly lower for patients receiving atenolol than for those receiving metoprolol (2.5% versus 3.2%).p<0.001The authors concluded, “Patients receiving metoprolol do not have as low a perioperative cardiac risk as patients receiving atenolol, in accord with possible acute withdrawal after missed doses.”
Feringa et al. (396)2006Observational cohort study272Vascular surgery“In multivariate analysis, higher beta-blocker doses (per 10% increase) were significantly associated with a lower incidence of myocardial ischemia.”HR 0.620.51 to 0.75The authors concluded, “This study showed that higher doses of beta blockers and tight heart rate control are associated with reduced perioperative myocardial ischemia and troponin T release and improved long-term outcome in vascular surgery patients.”
Troponin T releaseHR 0.630.49 to 0.80
Long-term mortalityHR 0.860.76 to 0.97
“Higher heart rates during electrocardiographic monitoring (per 10-bpm increase) were significantly associated with an increased incidence of myocardial ischemia.”HR 2.491.79 to 3.48
Troponin T releaseHR 1.531.16 to 2.03
Long-term mortalityHR 1.421.14 to 1.76
Hoeks et al. (404)2006Prospective survey711Peripheral vascular surgery patients“After adjustment for potential confounders and the propensity of its use, continuous beta-blocker use remained significantly associated with a lower 1-year mortality compared with nonusers.”HR 0.40.2 to 0.7The authors concluded that this “study demonstrated an under-use of beta blockers in vascular surgery patients, even in high-risk patients. Perioperative beta blocker use was independently associated with a lower risk of 1-year mortality compared to non-use, while perioperative withdrawal of beta-blocker therapy was associated with a higher 1-year mortality.”
“In contrast, beta-blocker withdrawal was associated with an increased risk of 1-year mortality compared with nonusers.”HR 2.71.2 to 5.9
Kaafarani et al. (391)2008Retrospective cohort study646All patients who underwent various noncardiac surgical procedures“Patients at all levels of cardiac risk who received beta blockers had lower preoperative and intraoperative heart rates.”The authors concluded, “Among patients at all levels of cardiac risk undergoing noncardiac surgery, administration of beta blockers should achieve adequate heart rate control and should be carefully monitored in patients who are not at high cardiac risk.”
The beta-blocker group had higher rates of 30-day MI (2.94% versus 0.74%) than the control group.p=0.03
The beta-blocker group had higher 30-day mortality (2.52% versus 0.25%) than the control group.p=0.007
Patients in the beta-blocker group who died perioperatively had significantly higher preoperative heart rate (86 versus 70 bpm).p=0.03
Matyal et al. (392)2008Retrospective960Vascular surgery (primarily infrainguinal)“Adverse outcome was defined as MI, new-onset CHF, significant arrhythmias, renal failure, or death. The incidence of adverse outcomes was lower when beta blockers were administered in men (12.6% versus 18.9%).”p=0.04The authors concluded, “Women did not benefit from perioperative beta-blockade. Women at high risk appeared to have a worse outcome because of a higher incidence of CHF.”
“The incidence of adverse outcomes was not lower in women (17.8% versus 13.7%).”p=0.37
“Among beta-blocker–naïve subjects, men had significant reductions in MI and renal failure, whereas women did not have a reduction in the incidence of any outcome.”
“After risk stratification, the high-risk women who received beta blockade had a statistically worse outcome (36.8% versus 5.9%) because of an increased incidence of CHF.”p=0.02

AAA indicates abdominal aortic aneurysm; bpm, beats per minute; CAD, coronary artery disease; CHF, congestive heart failure; CI, confidence interval; DSE, dobutamine stress echocardiography; HR, hazard ratio; MI, myocardial infarction; n, number; NNT, number needed to treat; NWMA, new wall-motion abnormality; OR, odds ratio; RCRI, Revised Cardiac Risk Index; RCT, randomized controlled trial; and RR, relative risk.