Selected Perioperative Beta Blocker Abstracts 1. Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg 2005; 41(4):602-609. Abstract: OBJECTIVE: To assess whether a pragmatic policy of perioperative beta-blockade, with metoprolol, reduced the 30-day cardiovascular morbidity and mortality and reduced the length of hospital stay in average patients undergoing infrarenal vascular surgery. METHODS: This was a double-blind randomized placebo-controlled trial that occurred in vascular surgical units in four UK hospitals. Participants were 103 patients without previous myocardial infarction who had infrarenal vascular surgery between July 2001 and March 2004. Interventions were oral metoprolol (50 mg twice daily, supplemented by intravenous doses when necessary) or placebo from admission until 7 days after surgery. Holter monitors were kept in place for 72 hours after surgery. RESULTS: Eighty men and 23 women (median age, 73 years) were randomized, 55 to metoprolol and 48 to placebo, and 97 (94%) underwent surgery during the trial. The most common operations were aortic aneurysm repair (38%) and distal bypass (29%). Intraoperative inotropic support was required in 64% and 92% of patients in the placebo and metoprolol groups, respectively. Within 30 days, cardiovascular events occurred in 32 patients, including myocardial infarction (8%), unstable angina (9%), ventricular tachycardia (19%), and stroke (1%). Four (4%) deaths were reported. Cardiovascular events occurred in 15 (34%) and 17 (32%) patients in the placebo and metoprolol groups, respectively (unadjusted relative risk, 0.94; 95% confidence interval, 0.53-1.66; adjusted [for age, sex, statin use, and aortic cross-clamping] relative risk, 0.87; 95% confidence interval, 0.48-1.55). Time from operation to discharge was reduced from a median of 12 days (95% confidence interval, 9-19 days) in the placebo group to 10 days (95% confidence interval, 8-12 days) in the metoprolol group (adjusted hazard ratio, 1.71; 95% confidence interval, 1.09-2.66; P < .02). CONCLUSIONS: 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 2. Devereaux PJ, Yang H, Yusuf S et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008; 371(9627):1839-1847. Abstract: BACKGROUND: Trials of beta blockers in patients undergoing non-cardiac surgery have reported conflicting results. This randomised controlled trial, done in 190 hospitals in 23 countries, was designed to investigate the effects of perioperative beta blockers. METHODS: We randomly assigned 8351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177), by a computerised randomisation phone service. Study treatment was started 2-4 h before surgery and continued for 30 days. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00182039. FINDINGS: All 8351 patients were included in analyses; 8331 (99.8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5.8%] patients in the metoprolol group vs 290 [6.9%] in the placebo group; hazard ratio 0.84, 95% CI 0.70-0.99; p=0.0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4.2%] vs 239 [5.7%] patients; 0.73, 0.60-0.89; p=0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] vs 97 [2.3%] patients; 1.33, 1.03-1.74; p=0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] vs 19 [0.5%] patients; 2.17, 1.26-3.74; p=0.0053). INTERPRETATION: Our results highlight the risk in assuming a perioperative beta-blocker
regimen has benefit without substantial harm, and the importance and need for large randomised trials in the perioperative setting. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol 3. Dunkelgrun M, Boersma E, Schouten O et al. Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV). Ann Surg 2009; 249(6):921-926. Abstract: OBJECTIVE: This study evaluated the effectiveness and safety of beta-blockers and statins for the prevention of perioperative cardiovascular events in intermediate-risk patients undergoing noncardiovascular surgery. SUMMARY BACKGROUND DATA: Beta-blockers and statins reduce perioperative cardiac events in high-risk patients undergoing vascular surgery by restoring the myocardial oxygen supply/demand balance and/or stabilizing coronary plaques. However, their effects in intermediate-risk patients remained ill-defined. METHODS: In this randomized open-label 2 x 2 factorial design trial 1066 intermediate cardiac risk patients were assigned to bisoprolol, fluvastatin, combination treatment, or control therapy before surgery (median: 34 days). Intermediate risk was defined by an estimated risk of perioperative cardiac death and myocardial infarction (MI) of 1% to 6%, using clinical data and type of surgery. Starting dose of bisoprolol was 2.5 mg daily, titrated to a perioperative heart rate of 50 to 70 beats per minute. Fluvastatin was prescribed in a fixed dose of 80 mg. The primary end point was the composite of 30-day cardiac death and MI. This study is registered in the ISRCTN registry and has the ID number ISRCTN47637497. RESULTS: Patients randomized to bisoprolol (N = 533) had a lower incidence of perioperative cardiac death and nonfatal MI than those randomized to bisoprolol-control (2.1% vs. 6.0% events; hazard ratios: 0.34; 95% confidence intervals: 0.17-0.67; P = 0.002). Patients randomized to fluvastatin experienced a lower incidence of the end point than those randomized to fluvastatin-control therapy (3.2% vs. 4.9% events; hazard ratios: 0.65; 95% confidence intervals: 0.35-1.10), but statistical significance was not reached (P = 0.17). CONCLUSION: Bisoprolol was associated with a significant reduction of 30-day cardiac death and nonfatal MI, while fluvastatin showed a trend for improved outcome 4. Juul AB, Wetterslev J, Gluud C et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMJ 2006; 332(7556):1482. Abstract: OBJECTIVES: To evaluate the long term effects of perioperative beta blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. DESIGN: Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. SETTING: University anaesthesia and surgical centres and one coordinating centre. PARTICIPANTS: 921 patients aged > 39 scheduled for major non-cardiac surgery. INTERVENTIONS: 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days. MAIN OUTCOME MEASURES: The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity. RESULTS: Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (- 0.8% to 5.6%). CONCLUSIONS: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes.
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Confidence intervals, however, were wide, and the issue needs reassessment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58485613 5. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335(23):1713-1720. Abstract: BACKGROUND: Perioperative myocardial ischemia is the single most important potentially reversible risk factor for mortality and cardiovascular complications after noncardiac surgery. Although more than 1 million patients have such complications annually, there is no effective preventive therapy. METHODS: We performed a randomized, double-blind, placebo-controlled trial to compare the effect of atenolol with that of a placebo on overall survival and cardiovascular morbidity in patients with or at risk for coronary artery disease who were undergoing noncardiac surgery. Atenolol was given intravenously before and immediately after surgery and orally thereafter for the duration of hospitalization. Patients were followed over the subsequent two years. RESULTS: A total of 200 patients were enrolled. Ninety-nine were assigned to the atenolol group, and 101 to the placebo group. One hundred ninety-four patients survived to be discharged from the hospital, and 192 of these were followed for two years. Overall mortality after discharge from the hospital was significantly lower among the atenolol-treated patients than among those who were given placebo over the six months following hospital discharge (0 vs. 8 percent, P<0.001), over the first year (3 percent vs. 14 percent, P=0.005), and over two years (10 percent vs. 21 percent, P=0.019). The principal effect was a reduction in deaths from cardiac causes during the first six to eight months. Combined cardiovascular outcomes were similarly reduced among the atenolol-treated patients; event-free survival throughout the two-year study period was 68 percent in the placebo group and 83 percent in the atenolol group (P=0.008). CONCLUSIONS: In patients who have or are at risk for coronary artery disease who must undergo noncardiac surgery, treatment with atenolol during hospitalization can reduce mortality and the incidence of cardiovascular complications for as long as two years after surgery 6. Pasternack PF, Imparato AM, Baumann FG et al. The hemodynamics of beta-blockade in patients undergoing abdominal aortic aneurysm repair. Circulation 1987; 76(3 Pt 2):III1-III7. Abstract: To assess the intraoperative and postoperative hemodynamic effects of beta-blockade and its benefits in limiting myocardial ischemia and infarction, a group of 32 patients scheduled for abdominal aortic aneurysm (AAA) surgery (group 1) was treated with oral metoprolol immediately before surgery and with intravenous metoprolol during the postoperative period. Mean age was 71 years, and mean ejection fraction was 56% (range 36% to 83%). Eight patients had a preoperative history of angina, 13 had a history of myocardial infarction, and five had electrocardiographic evidence of prior myocardial infarction. A group of 51 closely matched patients with AAA who did not receive metoprolol served as controls (group 2). In group 1, overall hemodynamic tolerance of metoprolol intraoperatively and postoperatively was good, and there was no incidence of congestive heart failure, hypotension, or asthma. Furthermore, in group 1 significant reduction of systolic blood pressure and heart rate was consistently noted at frequent intraoperative intervals and for 48 hr after surgery, with only a transient reduction of cardiac index. In group 1, only one patient (3%) suffered an acute myocardial infarction. In contrast, nine group 2 patients (18%; p less than .05) suffered perioperative myocardial infarction. Furthermore, only four (12.5%) group 1 patients developed significant cardiac arrhythmias as opposed to 29 group 2 patients (56.9%; p less than .001). These 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 myocardial infarction and arrhythmias 7. Pasternack PF, Grossi EA, Baumann FG et al. Beta blockade to decrease silent myocardial ischemia during peripheral vascular surgery. Am J Surg 1989; 158(2):113-116. Abstract: The incidence and duration of intraoperative silent myocardial ischemia have
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been shown to be significantly correlated with the incidence of perioperative myocardial infarction in patients undergoing peripheral vascular surgery. To assess the effectiveness of intraoperative beta blockade in limiting such silent myocardial ischemia, a group of 48 patients was treated with oral metoprolol immediately prior to peripheral vascular surgery. The total duration of intraoperative silent myocardial ischemia, the percentage of intraoperative time silent myocardial ischemia was present, the number of intraoperative episodes of silent myocardial ischemia, and the intraoperative heart rate in the treated patients were compared with those in 152 similar but untreated peripheral vascular surgery patients. The 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. These results suggest that beta-adrenergic activation may play a major role in the pathogenesis of silent myocardial ischemia during peripheral vascular surgery 8. Poldermans D, Boersma E, Bax JJ et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341(24):1789-1794. Abstract: BACKGROUND: Cardiovascular complications are the most important causes of perioperative morbidity and mortality among patients undergoing major vascular surgery. METHODS: We performed a randomized, multicenter trial to assess the effect of perioperative blockade of beta-adrenergic receptors on the incidence of death from cardiac causes and nonfatal myocardial infarction within 30 days after major vascular surgery in patients at high risk for these events. High-risk patients were identified by the presence of both clinical risk factors and positive results on dobutamine echocardiography. Eligible patients were randomly assigned to receive standard perioperative care or standard care plus perioperative beta-blockade with bisoprolol. RESULTS: A total of 1351 patients were screened, and 846 were found to have one or more cardiac risk factors. Of these 846 patients, 173 had positive results on dobutamine echocardiography. Fifty-nine patients were randomly assigned to receive bisoprolol, and 53 to receive standard care. Fifty-three patients were excluded from randomization because they were already taking a beta-blocker, and eight were excluded because they had extensive wall-motion abnormalities either at rest or during stress testing. Two patients in the bisoprolol group died of cardiac causes (3.4 percent), as compared with nine patients in the standard-care group (17 percent, P=0.02). Nonfatal myocardial infarction occurred in nine patients given standard care only (17 percent) and in none of those given standard care plus bisoprolol (P<0.001). Thus, the primary study end point of death from cardiac causes or nonfatal myocardial infarction occurred in 2 patients in the bisoprolol group (3.4 percent) and 18 patients in the standard-care group (34 percent, P<0.001). CONCLUSIONS: Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction in high-risk patients who are undergoing major vascular surgery 9. Raby KE, Brull SJ, Timimi F et al. The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg 1999; 88(3):477-482. Abstract: Patients undergoing vascular surgery have a high risk of suffering major postoperative cardiac events. Preoperative myocardial ischemia as detected by Holter monitoring identifies a high-risk subgroup whose postoperative ischemia, similarly detected, seems to herald major cardiac events. In this study, we determined whether systematic, patient-specific postoperative heart rate control with beta-adrenergic blocker therapy decreases the incidence of postoperative ischemia among high-risk vascular surgery patients. A total of 26 of 150 patients who underwent elective vascular surgery and were monitored preoperatively by 24-h Holter were found to have significant myocardial ischemia as defined by ST-segment depression. The minimal heart rate at which this ST-segment depression occurred was identified (ischemic threshold), and these 26 patients were then randomized to receive continuous i.v. beta-blockade with esmolol or placebo plus usual medical therapy, aiming to reduce the postoperative heart rate to 20% below the ischemic
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threshold. All patients were monitored by Holter for 48 h postoperatively. Postoperative Holter readings were analyzed for the incidence of ischemia and for the number of hours during which heart rate was controlled below the ischemia threshold. Patients had a median of two episodes of preoperative ischemia lasting a median of 30 min (range 1-155 min). A total of 15 patients were randomized to receive esmolol, and 11 were randomized to receive placebo. The two groups were comparable with respect to clinical characteristics and incidence and duration of preoperative ischemia. Ischemia persisted in the postoperative period in 8 of 11 placebo patients (73%), but only 5 of 15 esmolol patients (33%) (P < 0.05). Of the 15 esmolol patients, 9 had mean heart rates below the ischemic threshold, and all 9 had no postoperative ischemia. A total of 4 of 11 placebo patients had mean heart rates below the ischemic threshold, and 3 of the 4 had no postoperative ischemia. There were two postoperative cardiac events among patients who had postoperative ischemia (one placebo, one esmolol) and whose mean heart rates exceeded the ischemic threshold. Our 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 provide a rationale for a larger trial to examine this strategy's effect on cardiac risk. IMPLICATIONS: Patients who undergo peripheral vascular surgery often experience transient cardiac complications and/or permanent heart damage just after surgery because of inadequate myocardial blood flow. In this study, we identified patients at high risk of cardiac complications after vascular surgery and showed that if their heart rate was carefully controlled for 48 h after surgery, myocardial ischemia, a common marker of heart injury, was markedly reduced 10. Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent. Anesthesiology 1988; 68(4):495-500. Abstract: In a non-double-blind, prospective, randomized study, the intra-operative electrocardiograms of 128 mildly hypertensive surgical patients were examined in order to determine the incidence of myocardial ischemia during anesthesia. No patient had been receiving chronic antihypertensive therapy prior to the study, but a single small oral dose of a beta-adrenergic blocking agent (labetalol, atenolol, or oxprenolol) was given to 89 of them along with premedication. Forty-four per cent of the untreated control patients and 61% of the patients pretreated with a beta-adrenergic blocking agent had normal preoperative electrocardiograms and no risk factors for coronary artery disease other than hypertension (this difference between groups was not statistically significant). During tracheal intubation and/or emergence from anesthesia, a brief, self-limited episode of myocardial ischemia was detected in 11 of 39 untreated control patients, and in two of 89 patients pretreated with a beta-adrenergic blocking agent (P less than 0.001). Tachycardia always accompanied the ischemic events, but a conspicuous increase in blood pressure did not. The authors conclude that mild hypertension, when untreated prior to the induction of anesthesia, is associated with a high incidence of myocardial ischemia; and that a single small oral dose of a beta-adrenergic blocking agent, given with pre-medication, can significantly reduce that risk 11. Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg 2000; 90(6):1257-1261. Abstract: Perioperative myocardial ischemia (MI) is associated with postoperative cardiac morbidity. Postoperative sympatholysis may reduce the incidence of MI. This study evaluated such a reduction postoperatively with the administration of prophylactic beta-blockers in patients undergoing elective total knee arthroplasty with epidural anesthesia and postoperative epidural analgesia. One hundred seven patients were preoperatively randomized into two groups, control and beta-blockers, who received postoperative esmolol infusions on the day of surgery and metoprolol for the next 48 h to maintain a heart rate less than 80 bpm. Patients were followed for ST segment depression
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by using a Holter monitor and adverse cardiac outcomes. Postoperative electrocardiographic ischemia was significantly more prevalent in the control group compared with the beta-blocker group during esmolol blockade (0 of 52 vs 4 of 55; P = 0.04) and tended to be more common in the control group the next two days (8 of 55 vs 3 of 52; P = 0.135). In addition, the number of ischemic events (control, 50; beta-blockers, 16) and total ischemic time (control, 709 min; beta-blocker, 236 min) were also significantly different from the control group. Myocardial infarctions and cardiac events were more common in the control group, but these differences were not significant. Our results suggest that the use of prophylactic beta-blocker therapy may reduce the incidence of postoperative MI. Implications: Prophylactic beta adrenergic blockade administered after elective total knee arthroplasty was associated with a reduced prevalence and duration of postoperative myocardial ischemia detected with Holter monitoring 12. Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J 2006; 152(5):983-990. Abstract: BACKGROUND: Patients undergoing vascular surgery comprise the highest risk group for perioperative cardiac mortality and morbidity after noncardiac procedures. Many current guidelines recommend the use of beta-blockers in all patients undergoing vascular surgery. We report a trial of the perioperative administration of metoprolol and its effects on the incidence of cardiac complications at 30 days and 6 months after vascular surgery. METHODS: Patients undergoing abdominal aortic surgery and infrainguinal or axillofemoral revascularizations were recruited to a double-blind randomized controlled trial of perioperative metoprolol versus placebo. Patients were randomized to receive study medication, starting 2 hours preoperatively until hospital discharge or maximum of 5 days postoperatively. Primary outcome were postoperative 30-day composite incidence of nonfatal myocardial infarction, unstable angina, new congestive heart failure, new atrial or ventricular dysrhythmia requiring treatment, or cardiac death. RESULTS: Patients were randomized to receive either metoprolol (n = 246) or placebo (n = 250). Primary outcome events at 30 days postoperative occurred in 25 (10.2%) versus 30 (12.0%) (P = .57) in metoprolol and placebo groups, respectively (relative risk reduction 15.3%, 95% CI -38.3% to 48.2%). Observed effects at 6 months were not significantly different (P = .81) (relative risk reduction 6.2%, 95% CI% -58.4% to 43.8%). Intraoperative bradycardia requiring treatment was more frequent in the metoprolol group (53/246 vs 19/250, P = .00001), as was intraoperative hypotension requiring treatment (114/246 vs 84/250, P = .0045). CONCLUSION: Our results showed 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
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