POISE-2 Trials: Evaluation of Low-Dose Clonidine and Aspirin in Patients at Risk For ASCVD

Low-dose clonidine increased rates of "clinically important hypotension" and non-fatal cardiac arrest after non-cardiac surgery, according to data from the POISE-2 trial. A separate POISE-2 trial found that patients given aspirin after non-cardiac surgery had a higher risk of major bleeding than the patients who did not receive aspirin. At the same time, aspirin did not reduce incidence of post-operative MI or mortality. Both trials were presented March 31 as part of ACC.14 in Washington, DC, and simultaneously published in the New England Journal of Medicine.

POISE-2: Impact of acetyl-salicylic acid on major arterial and venous complications in noncardiac surgery
POISE-2: Clonidine Effects on Major Arterial Events in Patients Having Noncardiac Surgery

POISE-2 is the largest clinical trial focused on major cardiovascular complications in non-cardiac surgery. The trial looked at the efficacy and safety of low-dose clonidine vs. placebo and also low-dose aspirin vs. placebo in 10,010 patients at 135 centers in 23 countries with, or at risk for, atherosclerotic cardiovascular disease.

Evaluating clonidine, patients at cardiovascular risk with a systolic blood pressure of at least 105 mm Hg and a heart rate of at least 55 beats per minute were randomly assigned to clonidine or placebo before inpatient surgery. The clonidine group (n=5009) was given 0.2 mg oral clonidine just before surgery and a transdermal patch that delivered the same dose daily for 72 hours after surgery. The placebo group (n=5001) was given matching tablets and patches. Patients were followed for one year.

Results showed clonidine compared with placebo failed to improve the primary outcome of mortality and non-fatal MI at 30 days (367 and 339 respectively; 95 percent CI, 0.93 to 1.26; P=0.29). The clonidine group had a non-significant increase in MI (329 clonidine vs. 295 placebo; 95 percent CI, 0.95 to1.30; P=0.18). Two secondary measures were significant: clinically important hypotension was seen in 48 percent of clonidine patients (n=2385) vs. 37 percent of placebo patients (n=1854; 95 percent CI, 1.24 to 1.40; P<0.001); and 16 clonidine patients had non-fatal cardiac arrest vs. five in the placebo group (95 percent CI, 1.17 to 8.73; P=2).

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"Clonidine should not be given to patients having non-cardiac surgery in an attempt to reduce perioperative mortality or heart attack," said Daniel I. Sessler, MD, Michael Cudahy professor and chair of the Outcomes Research Department at the Cleveland Clinic and a study investigator. "If anything, it worsens the outcome, probably by reducing blood pressure." He speculated that clonidine didn’t perform as expected because it caused hypotension out of proportion to its protective effect on heart rate.

In the separate trial looking at aspirin, patients were stratified according to whether they had been taking any dose daily for four of the six weeks before surgery (continuation stratum, n=4382) or had not (initiation stratum, n=5628). For the continuation stratum, aspirin use was stopped at least 72 hours before surgery. All patients received placebo or 200 mg aspirin just before surgery. The initiation stratum continued 100 mg aspirin or placebo daily for 30 days. The continuation stratum received 100 mg aspirin or placebo for seven days and then resumed their previous aspirin regimen.

The primary outcome of death or non-fatal MI at 30 days was no different between the two groups, at 7 percent in the aspirin group and 7.1 percent in the placebo group (95 percent CI, 0.86 to 1.15; P= 0.92); however, major bleeding was significantly higher in aspirin-treated patients than in the placebo group, at 4.6 percent vs. 3.8 percent (95 percent CI, 1.01 to 1.49; P=0.04). The primary and secondary outcomes were similar in the two aspirin strata.

"On balance, the authors provide cogent evidence against the use of aspirin perioperatively in patients with and those without preexisting vascular disease," wrote Prashant Vaishnava, MD, and Kim Eagle, MD, in an NEJM editorial accompanying the studies. Addressing both sets of results, the editorial stated that "It is not surprising that medical therapies directed at favorably modifying one mechanism causing perioperative myocardial infarction have the potential to increase risk through augmentation of a different pathway. Important questions linger."

Keywords: Outcome Assessment, Health Care, Myocardial Infarction, Atherosclerosis, Hypotension, Blood Pressure, Clonidine, Risk Factors, Heart Arrest, Heart Rate, Transdermal Patch, Cardiovascular Diseases, Cardiac Surgical Procedures, Hemorrhage

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