|Methods||Study type: Double-blind randomised controlled trial|
Study aim: To test the hypothesis that, at 30 days and 6 months after vascular surgery, the perioperative administration of metoprolol reduces the incidence of cardiac complications defined as cardiac death, nonfatal MI, CHF, unstable angina, and dysrhythmias requiring treatment.
Setting: 3 tertiary care centres: General Campus, Hamilton Health Sciences; Victoria Campus, London Health Sciences; and Kingston General Hospital between 1999 and 2002.
Recruitment: all patients undergoing vascular surgery were screened for eligibility. Elective vascular surgical patients are evaluated by internists, cardiologists, or anaesthesiologists in preoperative clinics. Screening was also undertaken on the wards when applicable
|Participants||Inclusion criteria: Patients with American Society of Anesthesiology class 3 or less and undergoing abdominal aortic surgery and infrainguinal or axillofemoral revascularisation|
Exclusion criteria: current or recent β-blocker use, current amiodarone use, airflow obstruction requiring treatment, history of CHF, history of atrioventricular block, previous adverse drug reactions to β-blockers, and previous participation in the MaVS study
Gender: Placebo group 184 M/66 F; Metoprolol group 193 M/53 F
Age: Placebo patients mean 65.9 ± 10.0 years; Metoprolol patients mean 66.4± 10.0 years
Prior MI: 30 placebo, 37 metoprolol
Angina: 25 placebo, 18 metoprolol
Diabetes mellitus (DM) on treatment: 37 placebo, 54 metoprolol
Permanent pacemaker: 1 placebo, 0 metoprolol
AAA subgroup: 116 placebo, 111 metoprolol
|Interventions||Treatment: Metoprolol administered orally or intravenously. Patients weighing ≥ 75 kg received metoprolol 100 mg; patients weighing between 40 and 75 kg received metoprolol 50 mg; and patients weighing ≤ 40 kg received metoprolol 25 mg OR intravenously at 1 mg/mL for 15 minutes. IV treatment was converted to oral as soon as oral intake was tolerated|
Control: Placebo administered orally as tablet or given intravenously as saline 0.2 mL/kg (to a maximum of 15 mL), diluted with 20 mL of saline for 15 minutes
Duration: Metoprolol or placebo given orally 2 hours preoperatively. Within 2 hours of surgery, metoprolol or placebo were give intravenously or orally. IV drug administered over 15 minutes every 6 hours. Oral administration was twice daily. Treatment lasted for 5 days or until hospital discharge, whichever occurred sooner
Co-interventions: Short-acting vasoactive medications including phenylephrine, ephedrine, nitroglycerine, and low-dose dopamine were allowed. Open-label β-blocker use was strongly discouraged except when deemed absolutely necessary by the attending physician. Circumstances for open-label use were generally for rapid heart rate control. Intraoperatively, esmolol, if deemed absolutely necessary, was allowed
|Outcomes||Primary outcome: Composite of cardiac complications at 30 days post operation including; cardiac death1, nonfatal MI2, CHF3, unstable angina4, and dysrhythmia requiring treatment defined as atrial fibrillation or ventricular dysrhythmias5|
1 Cardiac death was defined as either the ultimate cause of death traceable to an initiating cardiac complication or death in which the cause was not clearly identifiable or was insufficient to account for the demise in a patient who was not expected to succumb at the time of death.
2 Nonfatal MI within 3 postoperative deaths diagnosed if ≥ 1 of the following present: chemical evidence of MI or new Q waves > 0.04 s on 2 contiguous leads. Beyond 3 days, nonfatal MI was determined by attending physicians with supporting documentation of hospital chart, troponins, and pre- and postoperative electrocardiograms.
3 Unstable angina diagnosed by attending physician when anginal symptoms necessitated a change in medications, coronary revascularisation, or intensive care admission.
4 Congestive heart failure was diagnosed clinically with the requisite radiographic evidence.
5 Dysrhythmia requiring treatment was defined as one of the following: ventricular fibrillation requiring counter shock, ventricular tachycardia requiring counter shock or medication, or atrial fibrillation > 15 minutes in duration requiring counter shock or medication.
1. Study drug discontinuation due to bronchospasm, advanced heart blocks, hypotension (systolic BP < 90 mmHg) or bradycardia (50 beats/min)
2. Reoperation or amputation
3. Intraoperative hypotension and bradycardia requiring treatment by the attending anaesthesiologists
|Risk of bias|
|Bias||Authors' judgement||Support for judgement|
|Random sequence generation (selection bias)||Low risk||Quote: "Randomization was constructed in blocks of 4 by the study statistician"|
|Allocation concealment (selection bias)||Unclear risk||Comment: Methods of concealment of allocation are not stated. Insufficient information to permit judgement of low or high risk of selection bias|
|Blinding of participants and personnel (performance bias) |
|Low risk||Quote: "The patients, investigators, and all caretakers were blinded to the study randomisation. Blinding of randomisation was maintained throughout clinical decisions on reducing or discontinuing the study medication"|
|Blinding of outcome assessment (detection bias) |
|Low risk||Quote: "All data were collected by the participating centres and evaluated by the adjudication committee in a blinded fashion"|
|Incomplete outcome data (attrition bias) |
|Low risk||Quote: "Completion of the study protocol was similar in the placebo (77.6%) and treatment groups (75.2%). Discontinuation of the study protocol was also similar in the placebo and treatment groups; primary outcome event (30 and 25,respectively); patient/family/physician preference (27 and 14, respectively); open-label β-blockers (24 and 14, respectively); patient death (3 and 0, respectively), atrioventricular block (2 and 3, respectively), bronchospasm (1 and 4, respectively); and other reason (11 and 13, respectively)." |
Comment: All missing data accounted for and similarly balanced across the two treatment groups. Low risk of attrition bias
|Selective reporting (reporting bias)||Low risk||Quote: "Our results show that the RRR achieved with perioperative metoprolol in the vascular population is smaller than previously reported and is not significant" |
Comment: Authors commented on study results in relation to expected outcomes from other published reports. Furthermore, all of the primary and secondary pre-specified outcomes were reported.
|Other bias||Low risk||The study appears to be free from other sources of bias|