POISE-2: Aspirin, Clonidine Don't Protect in Noncardiac Surgery

April 08, 2014

WASHINGTON, DC — Neither aspirin nor clonidine reduced the risk of death or nonfatal MI when given in conjunction with noncardiac surgery, a large trial demonstrated using separate double-blind randomizations for each drug[1,2].

On the other hand, both drugs had downsides in the Perioperative Ischemic Evaluation 2 (POISE-2) trial of about 10 000 noncardiac-surgery candidates at risk for coronary complications. Aspirin given preoperatively and for 30 days after the procedure significantly increased the risk of major bleeding, regardless of whether patients had been on long-term aspirin before the trial. And with clonidine, there were significant increases in clinically important hypotension and bradycardia and in nonfatal cardiac arrest.

The aspirin and clonidine parts of the trial were separately published March 31, 2014 in the New England Journal of Medicine, with principal investigator Dr Philip J Devereaux (Population Health Research Institute, McMaster University, Hamilton, ON) as first author on both reports. They were presented the same day here at the American College of Cardiology 2014 Scientific Sessions . Devereaux presented the aspirin results, and the clonidine outcomes were presented by coauthor Dr Daniel I Sessler (Cleveland Clinic, OH).

Dr John A Jarcho (Brigham and Women's Hospital, Boston, MA), speaking at a briefing on POISE-2 for the media, pointed out that clonidine blocks the sympathetic nervous system and that beta-blockers do the same thing but by a difference mechanism. As beta-blockers have previously been shown to lower the risk of MI from noncardiac surgery, the current study "suggests that if you are going to go and block the sympathetic nervous system in this setting, it matters how you do it. It's more complicated than we might have thought originally."

Regarding the POISE-2 results as a whole, "It's really back to the drawing board in terms of trying to find ways to reduce the risk of myocardial infarction in noncardiac surgery," said Jarcho, who is a deputy editor for the journal.

The trial separately randomized 10 010 patients at 135 centers in 23 countries to receive low-dose clonidine (n=5009) vs placebo (n=5001) and low-dose aspirin (n=4998) vs placebo (n=5012). The primary end point was death or nonfatal MI at 30 days for both randomizations.

Clonidine was given as 0.2 mg/day two to four hours before surgery and continued for 72 hours after surgery. Aspirin was given as 200 mg before surgery; postoperative aspirin consisted of 100 mg/day for 30 days for patients who had not been on long-term aspirin before the trial, and 100 mg/day for seven days for patients on previous long-term aspirin. After seven days, the latter group returned to their pretrial dosage.

For aspirin vs placebo, the 30-day hazard ratios (95% CI) for outcomes included:

  • 0.99 (0.86–1.15) for death or nonfatal MI.

  • 0.98 (0.84–1.15) for MI.

  • 1.23 (1.01–1.49; p=0.04) for major bleeding.

  • 0.84 (0.43–1.64) for stroke.

Outcomes were about the same whether or not patients had been on long-term aspirin prior to the study. The most common forms of bleeding were at the surgical site at 78.3% and gastrointestinal at 9.3%.

For clonidine vs placebo, 30-day hazard ratios (95% CI) included:

  • 1.08 (0.93–1.26) for death or nonfatal MI.

  • 1.11 (0.95–1.30) for MI.

  • 3.20 (1.17–8.73; p=0.02) for nonfatal cardiac arrest.

  • 1.32 (1.24–1.40; p<0.001) for clinically important hypotension.

  • 1.49 (1.32–1.69; p<0.001) for clinically important bradycardia.

In a post hoc analysis, significant predictors of MI included age at least 75; histories of CAD, peripheral vascular disease, heart failure, preoperative renal dysfunction (each separately); major bleeding; and clinically important hypotension.

In an editorial accompanying both papers[3], Drs Prashant Vaishnava and Kim A Eagle (University of Michigan Health System and Medical School, Ann Arbor) write, "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. Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension."

They conclude, "Future progress in perioperative medicine may depend on the implementation of strategies that successfully address one pathophysiological mechanism of perioperative myocardial infarction without being limited by another."

"POISE-2 was supported by the Canadian Institutes of Health Research, the Commonwealth Government of Australia's National Health and Medical Research Council, the Spanish Ministry of Health and Social Policy, and Boehringer Ingelheim. Bayer Pharma provided the aspirin study drug, and Boehringer Ingelheim the clonidine study drug." Devereaux discloses receiving research grants from Abbott Diagnostics, Stryker, Bayer, Covidien, Boehringer Ingelheim, and Roche Diagnostics. Sessler had no disclosures. Disclosures for the coauthors are listed on www.nejm.org. Vaishnava and Eagle stated that they have no conflicts of interest.


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