Myocardial infarction is the most common major vascular complication of surgery and is associated with substantial mortality.1 During and after noncardiac surgery, there is marked activation of the sympathetic nervous system, which can lead to a mismatch between the supply of and demand for myocardial oxygen and to subsequent myocardial infarction.2-4
We previously reported that perioperative administration of a high-dose, long-acting beta-blocker (initiated 2 to 4 hours before surgery and continued after surgery) reduced the risk of myocardial infarction but increased the risk of death, stroke, and clinically important hypotension.5 Clonidine, an α2-adrenergic agonist, blunts central sympathetic outflow and has analgesic, anxiolytic, antishivering, and antiinflammatory effects, all of which may prevent perioperative myocardial infarction.6-9 The results of small, randomized trials have suggested that perioperative administration of low-dose clonidine reduces the risk of myocardial ischemia without inducing hemodynamic instability and may prevent myocardial infarction and death.6,10,11
To further evaluate the effects of perioperative clonidine, we conducted the Perioperative Ischemic Evaluation 2 (POISE-2) trial. We tested the hypothesis that perioperative administration of low-dose clonidine, as compared with placebo, reduces the 30-day risk of a composite of death or nonfatal myocardial infarction in at-risk patients undergoing noncardiac surgery.
We performed a blinded, randomized trial with a 2-by-2 factorial design to allow separate evaluation of low-dose clonidine versus placebo and low-dose aspirin versus placebo in patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. A total of 10,010 patients at 135 centers in 23 countries were enrolled. For the comparison of clonidine with placebo, patients were randomly assigned to receive clonidine (0.2 mg per day) or placebo just before surgery, with the study drug continued until 72 hours after surgery. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days.
After providing written informed consent, patients were randomly assigned, in a 1:1:1:1 ratio, to receive clonidine and aspirin, clonidine and aspirin placebo, clonidine placebo and aspirin, or clonidine placebo and aspirin placebo. Randomization was performed in fixed blocks with the use of a computerized interactive Web-based randomization system, with stratification according to center and status with respect to long-term aspirin therapy. Patients, health care providers, data collectors, and outcome adjudicators were unaware of the study-group assignments.
The study centers were encouraged to instruct patients not to take their usual antihypertensive medications, including beta-blockers, on the morning of surgery and to have study personnel review patients' vital signs in the presurgical area, report the results to the anesthesiologist, and ask the anesthesiologist whether the patients should receive their antihypertensive medications and, if they should, what dose they should receive.
At 2 to 4 hours before surgery, patients who met the hemodynamic criteria (i.e., systolic blood pressure ≥105 mm Hg and heart rate ≥55 beats per minute) received 0.2 mg of oral clonidine or placebo and had a transdermal clonidine patch (which releases 0.2 mg per day and has physiological effects within 24 hours)14 or a placebo patch applied to their upper arm or chest; the patch remained there until 72 hours after surgery. Patients also received aspirin or placebo just before surgery and continued receiving it daily throughout the postoperative period.
Blood pressure and heart rate were measured 1 hour after the first dose of the study drug was administered and every 4 hours for the first 96 hours after surgery. If clinically important hypotension or bradycardia developed in a patient and did not respond to initial treatment (e.g., a fluid bolus), study personnel encouraged removal of the patient's clonidine patch. Attending physicians made all medical decisions, including decisions about discontinuing either study drug.
Blood was obtained for measurement of the troponin level (or the MB fraction of creatine kinase [CK-MB] if troponin was not measured) 6 to 12 hours after surgery and daily for the next 3 days. Electrocardiography was performed if the troponin level or CK-MB level was elevated. Research personnel at participating centers followed patients until 30 days after randomization, collected the data, and submitted the case-report forms and supporting documentation of events directly to the data management system (iDataFax). Data monitoring consisted of central checks for data consistency, statistical monitoring, and on-site monitoring.
Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02).