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Meeting Coverage
Published: Mar 31, 2014
By Todd Neale, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
Action Points
The administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of death or nonfatal myocardial infarction but increased the risk of hypotension in a blinded, randomized trial.
Similarly, in the same randomized trial, administration of aspirin before surgery and during the early postoperative period had no significant effect upon the rate of a composite of death or nonfatal myocardial infarction, but did increase the risk of major bleeding during the first postoperative week.
WASHINGTON -- The search must continue for a therapy that will lessen the risk of myocardial infarction (MI) following noncardiac surgery, following disappointing results from a large randomized trial.
In the POISE-2 trial, neither aspirin nor clonidine -- versus placebo -- administered just before surgery reduced the rate of death or nonfatal MI in patients who were already at risk for vascular complications, according to two presentations at the American College of Cardiology meeting here.
And both carried risks: major bleeding with aspirin and hypotension and bradycardia with clonidine.
The implication of the findings, also published in two separate papers in the New England Journal of Medicine, is that "there is going to be a lot less use of prophylactic aspirin in noncardiac surgery," Elliott Antman, MD, a cardiologist at Brigham and Women's Hospital in Boston and president-elect of the American Heart Association, told MedPage Today. "And that's why we do these trials, to understand whether what turns out to be a common practice is really something we should continue."
As for clonidine, it seemed logical to try a drug that blocks the sympathetic nervous system because of the association between sympathetic activation and increased cardiovascular risks, according to John Jarcho, MD, also of Brigham and Women's Hospital.
He also pointed out during a press briefing that beta-blockers -- which also act on the sympathetic nervous system -- were shown to reduce the risk of MI after surgery, albeit with accompanying prohibitive increases in the risks of death and stroke.
"Which suggests that if you are going to go in to block the sympathetic nervous system in this setting, it matters how you do it. It's more complicated than we might have thought originally," Jarcho said. "And more broadly ... I think 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."
POISE-2 randomized 10,010 patients at 135 centers in 23 countries to aspirin versus placebo and to clonidine versus placebo. The 2 x 2 factorial trial included patients 45 and older who were undergoing various types of noncardiac surgery and who were at risk for vascular complications, defined by a history of coronary disease, stroke, or peripheral arterial disease, being scheduled for vascular surgery, or having at least three of nine risk factors.
Aspirin Intervention
The trial included 4,382 patients who were taking aspirin chronically and 5,628 patients who were not. All were required to have not taken aspirin in the 3 days before surgery.
The average age of the patients was 69 and about one-third had known vascular disease. About two-thirds received prophylactic anticoagulants for venous thromboembolism.
The intervention consisted of 200 mg of aspirin -- or matching placebo -- given just before surgery, with 100 mg taken daily for the next 30 days for patients who were not on chronic therapy and for the next 7 days in patients who were on chronic therapy (after which they resumed their normal regimens).
The results, presented by P.J. Devereaux, MD, PhD, of McMaster University's Population Health Research Institute in Hamilton, Ontario, showed that aspirin did not have any benefits in this setting.
The primary outcome -- the rate of death or nonfatal MI at 30 days -- was not different between the aspirin and placebo groups (7% versus 7.1%; HR 0.99, 95% CI 0.86-1.15). The components of the endpoint, as well as various other clinical outcomes, occurred at similar rates in the two groups, and there was no interaction with clonidine.
Major bleeding occurred in significantly more patients who were taking aspirin (4.6% versus 3.7%; HR 1.23, 95% CI 1.01-1.49).
And having a life-threatening or major bleed was an independent predictor of MI (HR 1.82, 95% CI 1.40-2.36), which might explain why the well-known benefits of aspirin in a nonoperative setting -- where there is a lower risk of bleeding to start with -- were not seen in POISE-2, according to Devereaux.
Clonidine Intervention
In the trial, patients were randomized to receive low-dose clonidine administered at a dose of 0.2 mg/day starting right before surgery and continued for 3 days.
As in the aspirin part of the trial, the primary outcome was death or MI at 30 days, which occurred at similar rates in the clonidine and placebo arms (7.3% in clonidine and 6.8% in placebo; HR 1.08, 95% CI 0.93-1.26), reported Daniel Sessler, MD, of the Cleveland Clinic.
Multiple secondary and tertiary clinical outcomes failed to show differences between the two groups. An exception was nonfatal cardiac arrest, which was slightly more frequent in the clonidine arm (0.3% versus 0.1%, P=0.02). Because that was based on only 21 events, however, it was likely a spurious finding, Sessler said.
That lack of benefit was accompanied by increased risks of clinically important hypotension (48% versus 37%; HR 1.32, 95% CI 1.24-1.40) and clinically important bradycardia (12% verus 8%; HR 1.49, 95% CI 1.32-1.69) in the clonidine arm.
Clinically important hypotension, in particular, was a strong predictor of MI (HR 1.37, 95% CI 1.16-1.62).
"Low-dose clonidine should therefore not be given to surgical patients in an effort to reduce postoperative mortality or myocardial infarction," Sessler said. "A safe and effective way of preventing postoperative infarctions remains to be identified."
POISE-2 was supported by grants from 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 disclosed relevant relationships with 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, Bayer Pharma AG, Boehringer Ingelheim, Abbott Diagnostics, Covidien, Roche Diagnostics, and Stryker. Sessler disclosed a relevant relationship with the Population Health Research Institute. The other authors disclosed relevant relationships with the Spanish Ministry of Health and Social Policy, Hamilton Health Sciences, PHRI Canada, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, sanofi-aventis, Pfizer, and the Population Health Research Institute,
Primary source: New England Journal of Medicine
Source reference: Devereaux P, et al "Aspirin in patients undergoing noncardiac surgery" N Engl J Med 2014; DOI: 10.1056/NEJMoa1401105.
Additional source: New England Journal of Medicine
Source reference:Devereaux P, et al "Clonidine in patients undergoing noncardiac surgery" N Engl J Med 2014; DOI: 10.1056/NEJMoa1401106.
Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University.
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