How strong is the evidence for the use of perioperative blockers in n
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《英国医生杂志》
1 Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada, 2 Department of Surgery and Clinical Epidemiology and Biostatistics, McMaster University, 3 Department of Medicine and Population Health Research Institute, McMaster University, 4 Department of Anesthesia, University of Toronto, Toronto, ON, Canada, 5 Vancouver Coastal Health Research Institute and Department of Anesthesia, University of British Columbia, Vancouver, BC, Canada, 6 Departments of Anesthesiology and Perioperative Medicine, University of Western Ontario, London, ON, Canada, 7 Grupo de Cardiología Preventiva, Universidad Autonoma de Bucaramanga, Colombia, 8 Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia, 9 Departments of Anesthesiology and Critical Care, University of Alberta, Edmonton, AB, Canada, 10 Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA, 11 Dante Pazzanese Institute of Cardiology and the Albert Einstein Hospital, S?o Paulo, Brazil, 12 Nuffield Department of Anaesthetics, University of Oxford, 13 Department of Anesthesia, McGill University, Montreal, QC, Canada, 14 Department of Anesthesia, University of Ottawa, Ottawa, ON, Canada, 15 Department of Anaesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark
Correspondence to: P J Devereaux philipj@mcmaster.ca
Objective To determine the effect of perioperative blocker treatment in patients having non-cardiac surgery.
Design Systematic review and meta-analysis.
Data sources Seven search strategies, including searching two bibliographic databases and hand searching seven medical journals.
Study selection and outcomes We included randomised controlled trials that evaluated blocker treatment in patients having non-cardiac surgery. Perioperative outcomes within 30 days of surgery included total mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal cardiac arrest, non-fatal stroke, congestive heart failure, hypotension needing treatment, bradycardia needing treatment, and bronchospasm.
Results Twenty two trials that randomised a total of 2437 patients met the eligibility criteria. Perioperative blockers did not show any statistically significant beneficial effects on any of the individual outcomes and the only nominally statistically significant beneficial relative risk was 0.44 (95% confidence interval 0.20 to 0.97, 99% confidence interval 0.16 to 1.24) for the composite outcome of cardiovascular mortality, non-fatal myocardial infarction, and non-fatal cardiac arrest. Methods adapted from formal interim monitoring boundaries applied to cumulative meta-analysis showed that the evidence failed, by a considerable degree, to meet standards for forgoing additional studies. The individual safety outcomes in patients treated with perioperative blockers showed a relative risk for bradycardia needing treatment of 2.27 (95% CI 1.53 to 3.36, 99% CI 1.36 to 3.80) and a nominally statistically significant relative risk for hypotension needing treatment of 1.27 (95% CI 1.04 to 1.56, 99% CI 0.97 to 1.66).
Conclusion The evidence that perioperative blockers reduce major cardiovascular events is encouraging but too unreliable to allow definitive conclusions to be drawn.
Non-cardiac surgery is associated with an increase in catecholamines,1 which results in an increase in blood pressure, heart rate, and free fatty acid concentrations.2-4 blockers suppress the effects of increased catecholamines and as a result may prevent perioperative cardiovascular events.
Several authors and guideline committees have advocated the use of blockers for patients having non-cardiac surgery.5-8 The two authors of the American College of Physicians' non-cardiac surgery perioperative guidelines inserted an addendum, after the college had approved the guidelines, advocating the use of perioperative atenolol in patients with coronary artery disease.7 More recently, the American College of Cardiology/American Heart Association task force on guidelines for non-cardiac surgery recommended perioperative blockers for patients with preoperative stress test ischaemia having vascular surgery (class I recommendation) and for patients with established coronary artery disease, risk factors for coronary artery disease, or untreated hypertension having non-cardiac surgery (class IIa recommendation).8 Other authors have questioned the robustness of the evidence for perioperative blockers and have advocated the need for a large definitive randomised controlled trial.9 10
Accurate understanding of the strength of the evidence for perioperative blockers requires a systematic, comprehensive, and unbiased accumulation of the available evidence and methods adapted from formal interim monitoring boundaries applied to cumulative meta-analysis.11 We therefore undertook a systematic review and meta-analysis to evaluate the effect of blockers on cardiovascular events in patients having non-cardiac surgery.
Methods
Eligibility criteria
We included randomised controlled trials that evaluated the effect of blocker treatment in patients having non-cardiac surgery. Randomised controlled trials were eligible regardless of their publication status, language, or primary objectives. We excluded trials in which no control group received a placebo or standard care and those in which no relevant events occurred in the treatment and control groups, as these trials provide no information on the magnitude of treatment effects.12
Study identification
Strategies to identify studies included an electronic search of two bibliographical databases (see appendix A on bmj.com); a hand search of seven anaesthesia journals (appendix A); consultation with experts; our own files; review of reference lists from eligible trials; use of the "see related articles" feature for key publications in PubMed (April 2003); and search of SciSearch (April 2003) for publications that cited key publications.
Assessment of study eligibility
Two researchers independently evaluated study eligibility ( = 0.96). The consensus process to resolve disagreements required researchers to discuss the reasoning for their decisions; in all cases, one person recognised an error.
Data collection and quality assessment
We ed descriptive data (such as type of surgery, patient population) and markers of validity (such as concealment, blinding) from all trials. We ed data on the following perioperative outcomes: total mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal cardiac arrest, non-fatal stroke, congestive heart failure, hypotension needing treatment, bradycardia needing treatment, bronchospasm, and the composite outcome of major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest). We defined perioperative outcomes as outcomes that occurred within 30 days of surgery.
The definitions of outcomes were those used in the original trials, except when a trial did not define or report one of our main outcomes. We anticipated that three of our main outcomes would not be defined or reported in all trials. We therefore defined, a priori, cardiovascular death, bradycardia needing treatment, and hypotension needing treatment (see appendix B on bmj.com).
Teams of two researchers independently ed data from all trials ( = 0.69-1.0). Disagreements were resolved by consensus according to the process described above.
Statistical analysis
For each trial we calculated the relative risks of the outcomes for patients receiving perioperative blocker treatment compared with patients receiving placebo or standard care. For each relative risk we determined the conventional 95% confidence limit and the 99% confidence limit. When (as with small trials with few or a moderate number of events) statistical significance depends on a difference of only a handful of events, the 99% confidence interval may better convey our confidence in the estimate of the treatment effect.
We did analyses on an intention to treat basis. We pooled relative risks by using the DerSimonian and Laird random effects model.13 We calculated an I2 value as a measure of heterogeneity for each outcome analysis. An I2 value represents the percentage of total variation across trials that is due to heterogeneity rather than to chance, and we considered I2 < 25% as low and I2 > 75% as high.14 Before the analyses we specified several hypotheses related to the markers of trial validity, treatment interventions, and duration of follow-up to explain potential heterogeneity (I2 > 25%). We entered data in duplicate and used RevMan 4.2 (Cochrane Collaboration, Oxford) for all analyses.
Because no reason exists why the standards for a meta-analysis should be less rigorous than those for a good single randomised controlled trial, we used methods adapted from formal interim monitoring boundaries applied to cumulative meta-analysis to assess the reliability and conclusiveness of the available evidence on perioperative blockers,15 focusing on the composite outcome of major perioperative cardiovascular events. The sample size needed for a reliable and conclusive meta-analysis is at least as large as that for a single optimally powered randomised controlled trial, so we calculated the sample size (optimal information size) requirement for our meta-analysis. We did formal interim monitoring for meta-analyses by using the optimal information size to help to construct a Lan DeMets sequential monitoring boundary for our meta-analysis,15 analogous to interim monitoring in a randomised controlled trial. We used this monitoring boundary as a way of determining whether the evidence in our meta-analysis was reliable and conclusive.
Results
Included trials
We identified 22 randomised controlled trials published between 1980 and 2004 that fulfilled our eligibility criteria (fig 1).16-37 We obtained data from or confirmed them with trialists from all included trials. Table 1 summarises the design characteristics of the included trials.16-37 The 22 trials randomised a total of 2437 patients, and the median sample size was 61 patients. The type of non-cardiac surgery was unrestricted in eight trials. Treatment interventions varied from brief intravenous blocker just before surgery to 30 day postoperative blocker use. The duration of follow-up was limited to the end of surgery in one trial and until discharge from the recovery room in five trials.
Fig 1 Flowchart of randomised controlled trials through the systematic review
Table 1 Design characteristics of randomised controlled trials included in systematic review
Quality assessment
Most randomised controlled trials fulfilled our quality measures (for example, all trials had complete patient follow-up). Table 2 reports the quality measures of the trials that failed to fulfil at least one of our markers of validity.19 22 33 35 36
Table 2 Quality measures of randomised controlled trials that failed to fulfil any one of the markers of validity
Effect of perioperative blockers
Table 3 presents the results of the meta-analyses. Overall only a moderate number of major perioperative cardiovascular events occurred (18 cardiovascular deaths, 58 non-fatal myocardial infarctions, and 7 non-fatal cardiac arrests).
Table 3 Effect of perioperative blockers within the first 30 days after non-cardiac surgery
Perioperative blockers did not show any statistically significant beneficial effects on any of the individual outcomes. Patients in four trials had fatal events.31-33 37 Nine deaths (five cardiovascular) occurred among the 453 patients randomised to blocker treatment, compared with 19 deaths (13 cardiovascular) among the 454 patients randomised to placebo or standard care (relative risk 0.56, 95% confidence interval 0.14 to 2.31, 99% confidence interval 0.09 to 3.60 for total mortality; 0.40, 0.14 to 1.15, 0.10 to 1.60 for cardiovascular mortality).
The individual safety outcomes in patients treated with perioperative blockers showed a relative risk of 2.27 (1.53 to 3.36, 1.36 to 3.80) for bradycardia needing treatment (fig 2) and 1.27 (1.04 to 1.56, 0.97 to 1.66) for hypotension needing treatment. Both these analyses showed low heterogeneity (I2 of 3% for bradycardia needing treatment and 6% for hypotension needing treatment).
Fig 2 Relative risks for bradycardia needing treatment
Eight trials had patients who had a major perioperative cardiovascular event (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest) (fig 3).30-37 Twenty eight major perioperative cardiovascular events occurred among the 589 patients randomised to blocker treatment, compared with 55 among the 563 patients randomised to placebo or standard care (relative risk 0.44, 0.20 to 0.97, 0.16 to 1.24). Moderate heterogeneity existed across the trial results (I2 = 42%).
Fig 3 Relative risks for major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest)
Exploring heterogeneity
Our a priori hypothesis related to trial validity helped to explain the heterogeneity. The three trials by Poldermans, Zaug, and Urban did not fulfil all our quality measures (these trials were stopped early after an interim analysis suggested a much larger than predicted treatment effect or there was no blinding of patients, healthcare providers, or data collectors) and their pooled relative risk for major perioperative cardiovascular events was 0.13 (0.04 to 0.38, 0.03 to 0.54) with I2 = 0%.33 35 36 The remaining five high quality trials had a pooled relative risk for major perioperative cardiovascular events of 0.82 (0.49 to 1.36, 0.42 to 1.59) with I2 = 0%.30-32 34 37
Reliability and conclusiveness of composite outcome result
To determine the optimal information size we assumed a 10% control event rate (the control event rate in our meta-analysis for the composite outcome) and a 25% relative risk reduction (the average relative risk reduction among the blocker myocardial infarction trials38) with 80% power and a 0.01 two sided . Our calculations indicated that the optimal information size needed to reliably detect a plausible treatment effect, for the composite outcome of major perioperative cardiovascular events, is 6124 patients. Currently, 1152 patients have been randomised in the blocker randomised controlled trials with patients who have had a major perioperative cardiovascular event. We used the optimal information size to help to construct the Lan-DeMets sequential monitoring boundary (fig 4). The sequential monitoring boundary has not been crossed, indicating that the cumulative evidence is unreliable and inconclusive.
Fig 4 Cumulative meta-analysis assessing the effect of perioperative blockers on the 30 day risk of major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest) in patients having non-cardiac surgery. The Lan-DeMets sequential monitoring boundary, which assumes a 10% control event rate and a 25% relative risk reduction with 80% power and a two sided =0.01, has not been crossed, indicating that the cumulative evidence is inconclusive
Discussion
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Coleman AJ, Jordan C. Cardiovascular responses to anaesthesia: influence of beta-adrenoreceptor blockade with metoprolol. Anaesthesia 1980;35: 972-8.
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Liu PL, Gatt S, Gugino LD, Mallampati SR, Covino BG. Esmolol for control of increases in heart rate and blood pressure during tracheal intubation after thiopentone and succinylcholine. Can Anaesth Soc J 1986;33: 556-62.
Magnusson J, Thulin T, Werner O, Jarhult J, Thomson D. Haemodynamic effects of pretreatment with metoprolol in hypertensive patients undergoing surgery. Br J Anaesth 1986;58: 251-60.
Gibson BE, Black S, Maass L, Cucchiara RF. Esmolol for the control of hypertension after neurologic surgery. Clin Pharmacol Ther 1988;44: 650-3.
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: 495-500.
Mackenzie JW, Bird J. Timolol: a non-sedative anxiolytic premedicant for day cases. BMJ 1989;298: 363-4.
Inada E, Cullen DJ, Nemeskal AR, Teplick R. Effect of labetalol or lidocaine on the hemodynamic response to intubation: a controlled randomized double-blind study. J Clin Anesth 1989;1: 207-13.
Leslie JB, Kalayjian RW, McLoughlin TM, Plachetka JR. Attenuation of the hemodynamic responses to endotracheal intubation with preinduction intravenous labetalol. J Clin Anesth 1989;1: 194-200.
Jakobsen CJ, Blom L, Brondbjerg M, Lenler-Petersen P. Effect of metoprolol and diazepam on pre-operative anxiety. Anaesthesia 1990;45: 40-3.
Miller D, Martineau R, Hull K, Hill J. Bolus administration of esmolol for controlling the hemodynamic response to laryngoscopy and intubation: efficacy and effects on myocardial performance. J Cardiothorac Anesth 1990;4: 31-6.
Miller DR, Martineau RJ, Wynands JE, Hill J. Bolus administration of esmolol for controlling the haemodynamic response to tracheal intubation: the Canadian multicentre trial. Can J Anaesth 1991;38: 849-58.
Davies MJ, Dysart RH, Silbert BS, Scott DA, Cook RJ. Prevention of tachycardia with atenolol pretreatment for carotid endarterectomy under cervical plexus blockade. Anaesth Intensive Care 1992;20: 161-4.
Jakobsen CJ, Bille S, Ahlburg P, Rybro L, Pedersen KD, Rasmussen B. Preoperative metoprolol improves cardiovascular stability and reduces oxygen consumption after thoracotomy. Acta Anaesthesiol Scand 1997;41: 1324-30.
Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W, et al. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998;88: 7-17.
Bayliff CD, Massel DR, Inculet RI, Malthaner RA, Quinton SD, Powell FS, et al. Propranolol for the prevention of postoperative arrhythmias in general thoracic surgery. Ann Thorac Surg 1999;67: 182-6.
Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999;341: 1789-94.
Raby KE, Brull SJ, Timimi F, Akhtar S, Rosenbaum S, Naimi C, et al. The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg 1999;88: 477-82.
Zaugg M, Tagliente T, Lucchinetti E, Jacobs E, Krol M, Bodian C, et al. Beneficial effects from beta-adrenergic blockade in elderly patients undergoing noncardiac surgery. Anesthesiology 1999;91: 1674-86.
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: 1257-61.
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Correspondence to: P J Devereaux philipj@mcmaster.ca
Objective To determine the effect of perioperative blocker treatment in patients having non-cardiac surgery.
Design Systematic review and meta-analysis.
Data sources Seven search strategies, including searching two bibliographic databases and hand searching seven medical journals.
Study selection and outcomes We included randomised controlled trials that evaluated blocker treatment in patients having non-cardiac surgery. Perioperative outcomes within 30 days of surgery included total mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal cardiac arrest, non-fatal stroke, congestive heart failure, hypotension needing treatment, bradycardia needing treatment, and bronchospasm.
Results Twenty two trials that randomised a total of 2437 patients met the eligibility criteria. Perioperative blockers did not show any statistically significant beneficial effects on any of the individual outcomes and the only nominally statistically significant beneficial relative risk was 0.44 (95% confidence interval 0.20 to 0.97, 99% confidence interval 0.16 to 1.24) for the composite outcome of cardiovascular mortality, non-fatal myocardial infarction, and non-fatal cardiac arrest. Methods adapted from formal interim monitoring boundaries applied to cumulative meta-analysis showed that the evidence failed, by a considerable degree, to meet standards for forgoing additional studies. The individual safety outcomes in patients treated with perioperative blockers showed a relative risk for bradycardia needing treatment of 2.27 (95% CI 1.53 to 3.36, 99% CI 1.36 to 3.80) and a nominally statistically significant relative risk for hypotension needing treatment of 1.27 (95% CI 1.04 to 1.56, 99% CI 0.97 to 1.66).
Conclusion The evidence that perioperative blockers reduce major cardiovascular events is encouraging but too unreliable to allow definitive conclusions to be drawn.
Non-cardiac surgery is associated with an increase in catecholamines,1 which results in an increase in blood pressure, heart rate, and free fatty acid concentrations.2-4 blockers suppress the effects of increased catecholamines and as a result may prevent perioperative cardiovascular events.
Several authors and guideline committees have advocated the use of blockers for patients having non-cardiac surgery.5-8 The two authors of the American College of Physicians' non-cardiac surgery perioperative guidelines inserted an addendum, after the college had approved the guidelines, advocating the use of perioperative atenolol in patients with coronary artery disease.7 More recently, the American College of Cardiology/American Heart Association task force on guidelines for non-cardiac surgery recommended perioperative blockers for patients with preoperative stress test ischaemia having vascular surgery (class I recommendation) and for patients with established coronary artery disease, risk factors for coronary artery disease, or untreated hypertension having non-cardiac surgery (class IIa recommendation).8 Other authors have questioned the robustness of the evidence for perioperative blockers and have advocated the need for a large definitive randomised controlled trial.9 10
Accurate understanding of the strength of the evidence for perioperative blockers requires a systematic, comprehensive, and unbiased accumulation of the available evidence and methods adapted from formal interim monitoring boundaries applied to cumulative meta-analysis.11 We therefore undertook a systematic review and meta-analysis to evaluate the effect of blockers on cardiovascular events in patients having non-cardiac surgery.
Methods
Eligibility criteria
We included randomised controlled trials that evaluated the effect of blocker treatment in patients having non-cardiac surgery. Randomised controlled trials were eligible regardless of their publication status, language, or primary objectives. We excluded trials in which no control group received a placebo or standard care and those in which no relevant events occurred in the treatment and control groups, as these trials provide no information on the magnitude of treatment effects.12
Study identification
Strategies to identify studies included an electronic search of two bibliographical databases (see appendix A on bmj.com); a hand search of seven anaesthesia journals (appendix A); consultation with experts; our own files; review of reference lists from eligible trials; use of the "see related articles" feature for key publications in PubMed (April 2003); and search of SciSearch (April 2003) for publications that cited key publications.
Assessment of study eligibility
Two researchers independently evaluated study eligibility ( = 0.96). The consensus process to resolve disagreements required researchers to discuss the reasoning for their decisions; in all cases, one person recognised an error.
Data collection and quality assessment
We ed descriptive data (such as type of surgery, patient population) and markers of validity (such as concealment, blinding) from all trials. We ed data on the following perioperative outcomes: total mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal cardiac arrest, non-fatal stroke, congestive heart failure, hypotension needing treatment, bradycardia needing treatment, bronchospasm, and the composite outcome of major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest). We defined perioperative outcomes as outcomes that occurred within 30 days of surgery.
The definitions of outcomes were those used in the original trials, except when a trial did not define or report one of our main outcomes. We anticipated that three of our main outcomes would not be defined or reported in all trials. We therefore defined, a priori, cardiovascular death, bradycardia needing treatment, and hypotension needing treatment (see appendix B on bmj.com).
Teams of two researchers independently ed data from all trials ( = 0.69-1.0). Disagreements were resolved by consensus according to the process described above.
Statistical analysis
For each trial we calculated the relative risks of the outcomes for patients receiving perioperative blocker treatment compared with patients receiving placebo or standard care. For each relative risk we determined the conventional 95% confidence limit and the 99% confidence limit. When (as with small trials with few or a moderate number of events) statistical significance depends on a difference of only a handful of events, the 99% confidence interval may better convey our confidence in the estimate of the treatment effect.
We did analyses on an intention to treat basis. We pooled relative risks by using the DerSimonian and Laird random effects model.13 We calculated an I2 value as a measure of heterogeneity for each outcome analysis. An I2 value represents the percentage of total variation across trials that is due to heterogeneity rather than to chance, and we considered I2 < 25% as low and I2 > 75% as high.14 Before the analyses we specified several hypotheses related to the markers of trial validity, treatment interventions, and duration of follow-up to explain potential heterogeneity (I2 > 25%). We entered data in duplicate and used RevMan 4.2 (Cochrane Collaboration, Oxford) for all analyses.
Because no reason exists why the standards for a meta-analysis should be less rigorous than those for a good single randomised controlled trial, we used methods adapted from formal interim monitoring boundaries applied to cumulative meta-analysis to assess the reliability and conclusiveness of the available evidence on perioperative blockers,15 focusing on the composite outcome of major perioperative cardiovascular events. The sample size needed for a reliable and conclusive meta-analysis is at least as large as that for a single optimally powered randomised controlled trial, so we calculated the sample size (optimal information size) requirement for our meta-analysis. We did formal interim monitoring for meta-analyses by using the optimal information size to help to construct a Lan DeMets sequential monitoring boundary for our meta-analysis,15 analogous to interim monitoring in a randomised controlled trial. We used this monitoring boundary as a way of determining whether the evidence in our meta-analysis was reliable and conclusive.
Results
Included trials
We identified 22 randomised controlled trials published between 1980 and 2004 that fulfilled our eligibility criteria (fig 1).16-37 We obtained data from or confirmed them with trialists from all included trials. Table 1 summarises the design characteristics of the included trials.16-37 The 22 trials randomised a total of 2437 patients, and the median sample size was 61 patients. The type of non-cardiac surgery was unrestricted in eight trials. Treatment interventions varied from brief intravenous blocker just before surgery to 30 day postoperative blocker use. The duration of follow-up was limited to the end of surgery in one trial and until discharge from the recovery room in five trials.
Fig 1 Flowchart of randomised controlled trials through the systematic review
Table 1 Design characteristics of randomised controlled trials included in systematic review
Quality assessment
Most randomised controlled trials fulfilled our quality measures (for example, all trials had complete patient follow-up). Table 2 reports the quality measures of the trials that failed to fulfil at least one of our markers of validity.19 22 33 35 36
Table 2 Quality measures of randomised controlled trials that failed to fulfil any one of the markers of validity
Effect of perioperative blockers
Table 3 presents the results of the meta-analyses. Overall only a moderate number of major perioperative cardiovascular events occurred (18 cardiovascular deaths, 58 non-fatal myocardial infarctions, and 7 non-fatal cardiac arrests).
Table 3 Effect of perioperative blockers within the first 30 days after non-cardiac surgery
Perioperative blockers did not show any statistically significant beneficial effects on any of the individual outcomes. Patients in four trials had fatal events.31-33 37 Nine deaths (five cardiovascular) occurred among the 453 patients randomised to blocker treatment, compared with 19 deaths (13 cardiovascular) among the 454 patients randomised to placebo or standard care (relative risk 0.56, 95% confidence interval 0.14 to 2.31, 99% confidence interval 0.09 to 3.60 for total mortality; 0.40, 0.14 to 1.15, 0.10 to 1.60 for cardiovascular mortality).
The individual safety outcomes in patients treated with perioperative blockers showed a relative risk of 2.27 (1.53 to 3.36, 1.36 to 3.80) for bradycardia needing treatment (fig 2) and 1.27 (1.04 to 1.56, 0.97 to 1.66) for hypotension needing treatment. Both these analyses showed low heterogeneity (I2 of 3% for bradycardia needing treatment and 6% for hypotension needing treatment).
Fig 2 Relative risks for bradycardia needing treatment
Eight trials had patients who had a major perioperative cardiovascular event (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest) (fig 3).30-37 Twenty eight major perioperative cardiovascular events occurred among the 589 patients randomised to blocker treatment, compared with 55 among the 563 patients randomised to placebo or standard care (relative risk 0.44, 0.20 to 0.97, 0.16 to 1.24). Moderate heterogeneity existed across the trial results (I2 = 42%).
Fig 3 Relative risks for major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest)
Exploring heterogeneity
Our a priori hypothesis related to trial validity helped to explain the heterogeneity. The three trials by Poldermans, Zaug, and Urban did not fulfil all our quality measures (these trials were stopped early after an interim analysis suggested a much larger than predicted treatment effect or there was no blinding of patients, healthcare providers, or data collectors) and their pooled relative risk for major perioperative cardiovascular events was 0.13 (0.04 to 0.38, 0.03 to 0.54) with I2 = 0%.33 35 36 The remaining five high quality trials had a pooled relative risk for major perioperative cardiovascular events of 0.82 (0.49 to 1.36, 0.42 to 1.59) with I2 = 0%.30-32 34 37
Reliability and conclusiveness of composite outcome result
To determine the optimal information size we assumed a 10% control event rate (the control event rate in our meta-analysis for the composite outcome) and a 25% relative risk reduction (the average relative risk reduction among the blocker myocardial infarction trials38) with 80% power and a 0.01 two sided . Our calculations indicated that the optimal information size needed to reliably detect a plausible treatment effect, for the composite outcome of major perioperative cardiovascular events, is 6124 patients. Currently, 1152 patients have been randomised in the blocker randomised controlled trials with patients who have had a major perioperative cardiovascular event. We used the optimal information size to help to construct the Lan-DeMets sequential monitoring boundary (fig 4). The sequential monitoring boundary has not been crossed, indicating that the cumulative evidence is unreliable and inconclusive.
Fig 4 Cumulative meta-analysis assessing the effect of perioperative blockers on the 30 day risk of major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest) in patients having non-cardiac surgery. The Lan-DeMets sequential monitoring boundary, which assumes a 10% control event rate and a 25% relative risk reduction with 80% power and a two sided =0.01, has not been crossed, indicating that the cumulative evidence is inconclusive
Discussion
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