Stop Aspirin in Stable CAD/AF Patients on Warfarin? More Evidence from CORONOR

Shelley Wood

October 08, 2014

CAEN, FRANCE — Another study is cautioning against aspirin use, this time in the secondary prevention of cardiovascular events among stable CAD patients also taking oral anticoagulation[1]. The analysis from the multicenter CORONOR registry is the latest to suggest that the bleeding risk related to aspirin, in this specific setting, exceeds any benefits related to prevention of ischemic events.

Importantly, in CORONOR, the window of interest was one year after the index MI or coronary revascularization. As such, it offers insights that complement and extend those of WOEST , the randomized trial that demonstrated that, in the first year after stenting, clopidogrel alone was superior to aspirin and clopidogrel together in patients also on oral anticoagulation.

Dr Martial Hamon (Centre Hospitalier Universitaire de Caen, France) and colleagues published their CORONOR analysis in the October 7, 2014 issue of the Journal of the American College of Cardiology.

Between February 2010 and April 2011, CORONOR enrolled 4184 patients with stable coronary artery disease who had been free of MI or coronary revascularization at the time of their inclusion in the study.

Over the course of the two-year follow-up, 51 major bleeds occurred, yielding a rate of less than 1% per year, the largest proportion of them (55%) gastrointestinal. That's an important point, Dr Harold Dauerman (University of Vermont College of Medicine, Burlington) writes in an accompanying editorial[2], since it shows that major bleeds (BARC 3-5) are less common in outpatients than in the inpatient setting.

But of note, major bleeds were an independent predictor of death, with an adjusted hazard ratio of 2.89 (95% CI 1.73–4.83), a finding that the authors say should prompt physicians to pay "special attention to the determinants of bleeding."

In multivariate analyses, increasing age, diabetes, use of a vitamin-K antagonist (VKA; eg, warfarin) were the key predictors of bleeding, but strikingly, the risk associated with warfarin use was statistically significant only in patients also taking aspirin. Indeed, the hazard ratio for the cumulative risk of bleeding was 7.30 (95% CI 3.91–13.64) among patients taking both aspirin and a VKA, but 1.69 (95% CI 0.39–7.30) among patients taking warfarin alone.

Few Studies of Bleeding in Stable CAD

There have been very few studies analyzing bleeding rates among stable CAD patients, senior author on the study Dr Christophe Bauters told heartwire . "In this population, the incidence of bleeding is relatively low, and its origin is mainly gastrointestinal; however, it is an independent predictor of death. We also observed that in patients who need oral anticoagulation, aspirin is frequently combined, and this is a major determinant of the risk of bleeding."

Of note, the addition of aspirin did not help prevent cardiovascular events. Rates of the composite ischemic end point—CV death, MI, or nonhemorrhagic stroke—were no different among patients taking aspirin plus VKA and patients taking VKA alone.

Dual Therapy Not Recommended by Guidelines

What's interesting, note the authors, is that patients in CORONOR were enrolled in the period immediately after the publication of the European Society of Cardiology guidelines that suggested that VKA monotherapy "may be considered" in secondary prevention for patients who also have atrial fibrillation and that in the absence of a new CV event, concomitant aspirin should not be prescribed. US guidelines subsequently took a similar view.

Yet, in CORONOR, one in 10 patients were also taking oral anticoagulation, and of these, three-quarters were also taking aspirin.

Asked about this, Bauters pointed out that other study cohorts have found similar rates of dual therapy as well. "Recruitment in our study was performed at the time the guidelines were released, so maybe we need time to document changes in practice," he speculated. As well, guidelines are largely based on expert consensus rather than evidence from controlled trials, and this may have played a role.

When to Withhold Aspirin

Bauters stressed that CORONOR was an observational study, not a randomized controlled trial, providing a snapshot of physician practice and bleeding outcomes between 2010 and 2011. But he believes, "Our results should be an incentive to analyze carefully the risk/benefit for each stable CAD patient receiving aspirin and anticoagulation. In a number of patients, anticoagulation alone will be a valid option, although we agree that in some cases, such as patients with first-generation [drug-eluting stents] DES and low bleeding risk, for example, the combination may be justified."

Dauerman, in his editorial, took a more cautious view, saying, "The absence of clear data does not provide any relief from clinical decision making."

That said, he continued, registry studies provide "some actionable messages."

CORONOR highlighted the risk of gastrointestinal bleeding among patients taking both an oral anticoagulant and aspirin and no benefit in terms of reduced ischemic events. "If a patient with atrial fibrillation and stable CAD is at high risk for gastrointestinal bleeding, aspirin cessation rather than warfarin cessation may be recommended.

"Tomorrow in clinic," Dauerman concludes, "I will continue to give a platelet-activation inhibitor, aspirin 81 mg/day, to many of my patients in stable condition with CAD and atrial fibrillation; this will be especially true for those patients who have first-generation drug-eluting stents, who had platelet activation leading to very late stent thrombosis, which is a rare but devastating risk."

In selected stable CAD patients with atrial fibrillation "identified by CORONOR as at high risk for bleeding, these registry observations will be heeded: stop the aspirin, continue the warfarin, and use the art of clinical medicine to guide decisions where clear information remains wanting."

The study authors had no conflicts of interest. Dauerman disclosed being a consultant for Medtronic and the Medicines Company and receiving research grants from Abbott Vascular and Medtronic.

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