This article is a collaboration between MedPage Today® and:
Neither aspirin nor clonidine helped prevent heart attacks as a complication of non-cardiac surgery, a randomized trial showed.
The rate of death or nonfatal myocardial infarction at 30 days came out at 7% whether it was aspirin or placebo loaded preoperatively and continued after surgery (P=0.92), PJ Devereaux, MD, PhD, of the Population Health Research Institute in Hamilton, Ontario, and colleagues found.
The same was true for low-dose clonidine (P=0.29) in the Perioperative Ischemic Evaluation 2 (POISE-2) trial, both portions of which appeared online in the New England Journal of Medicine.
"More broadly, I think it's back to the drawing board to try to reduce risk of MI in non-cardiac surgery," commented John Jarcho, MD, of Brigham and Women's Hospital in Boston.
The immediate impact, though, will be to settle differences of opinion between the cardiology community and other surgeons, suggested Michael Rinaldi, MD, of Carolinas HealthCare System's Sanger Heart & Vascular Institute in Charlotte, N.C.
"The findings will confirm the suspicions of the noncardiac surgery physicians," he told MedPage Today. "No surgeon really wants to operate on aspirin, in general."
And with definitive proof it was at least as safe to withhold aspirin in these higher-risk patients as to give it, he added, "It will quell concerns from the cardiology provider population and we'll feel much more comfortable about stopping aspirin in patients at risk for events."
In the trial, major bleeding was a relative 23% more common with aspirin (4.6% versus 3.8% on placebo, P=0.04) and independently predicted an 82% higher risk of having an MI (P<0.001) when analyzed in composite with life-threatening bleeding.
Thus, aspirin likely prevented some perioperative MIs by inhibiting thrombus but caused others as bleeding led to mismatch between the supply of and demand for oxygen, explained an accompanying editorial in NEJM.
The trial's elevated risk population was over age 45 and had a history of coronary artery or peripheral vascular disease, stroke, or prior vascular surgery or some combination of at least three risk factors.
But because it excluded people with a recent bare metal stent or drug eluting stent in the prior year, Rinaldi noted that it's still an open question how to treat that group at risk for stent thrombosis if they go off aspirin.
The trial randomized 10,010 patients at risk for vascular complications of an upcoming noncardiac surgery to aspirin or placebo and clonidine or placebo in a two-by-two factorial design.
In the aspirin arm, patients were stratified by whether they were already on aspirin (4,382 patients). All got 200 mg of aspirin just before surgery. They stayed on it at 100 mg for 30 days, or for 7 days before going back to their pre-existing aspirin regimen.
However, there was no net advantage to aspirin in either group, Devereaux noted in the results he presented at a late-breaking clinical trial session at the American College of Cardiology meeting.
The original POISE trial had shown that perioperative doses of the beta-blocker metoprolol cut MI in noncardiac surgery but at the expense of more deaths and severe strokes.
So it made sense to try clonidine, a blood pressure drug that acts centrally against the same sympathetic activation target, Prashant Vaishnava, MD, and Kim A. Eagle, MD, both of the University of Michigan Health System in Ann Arbor, noted in the editorial.
But clonidine not only didn't reduce overall death or MI risk but also was associated with more clinically important hypotension (47.6% versus 37.1% on placebo, P<0.001).
The drug also was associated with a relative threefold higher risk of nonfatal cardiac arrest, but the number of events was small and this may have been a spurious finding, Devereaux cautioned (0.3% [16 patients] versus 0.1% [5 patients], P=0.02).
As with aspirin, the hypotensive events caused by clonidine appeared to undermine any impact on heart attacks. These events independently predicted a 37% elevated risk of MI (P<0.001).
"We need something that provides great control without hypotension," co-author Daniel Sessler, MD, of the Cleveland Clinic suggested.
An ideal way to do so might be to use clonidine under careful control for hypotension in the ICU, Thoralf Sundt, III, MD, of Massachusetts General Hospital in Boston.
For now, guidelines should be updated to recommend against clonidine as they do for beta-blockers after the initial POISE trial, argued Freek W. A. Verheugt, MD, of the University Medical Centre of Nijmegen, the Netherlands.
Devereaux cautioned against going too far in tossing out aspirin as a preventive measure based on the results.
"In the nonperioperative setting, the risk of bleeding is much lower and we have clear evidence of efficacy of aspirin," he said, adding that the findings don't rule out secondary prevention in patients after surgery either.
"If you're a few days post-surgery, your risk of bleeding has dropped substantially, so if you have a patient that suffers an MI or suffers a stroke that you think is thrombotic, it's a very reasonable thing to consider initiating aspirin at that time, weighing the risks and benefits."