A dangerous cocktail: Aspirin and anticoagulants

Dr John Mandrola


March 06, 2013

Brain surgeons and heart doctors may never see eye to eye about atrial fibrillation. It's always the same: we think about preventing stroke, and they see the worst-case scenarios. A recent "encounter" I had with a neurosurgeon got me thinking about an important clinical scenario. First the story of the encounter, then the clinical stuff.

Immediately after presenting a grand-rounds talk on atrial fibrillation at my home hospital, a neurosurgeon stood up to ask a question. My talk included a survey of recent data on novel anticoagulants, so I knew what was coming. He didn't ask a question; rather, he took the opportunity to tell the large gathering of doctors of the bleeding danger of these drugs, including the lack of an antidote. His take-home message: if your patient has an intracranial bleed while taking a novel anticoagulant, they are a goner. Brain surgeons have influence. Heads nodded in agreement.

You would have been proud of me. I engaged respectfully, offering my standard response about parallax:  the phenomenon where the same image looks different depending on the viewpoint of the observer. Clearly, electrophysiologists see AF differently from neurosurgeons. The truth is, though, my colleague raised an important point—namely, that the risk of catastrophic bleeding deserves attention. It gets to the harm issue.

Later that week (as if on cue), I received a related question from a reader:

When should aspirin be used in combination with an oral anticoagulant (OAC)?

It's a great question. I see lots of patients on the combination of an antiplatelet drug and an anticoagulant. You probably do, too. My experience mirrors this 2007 estimate, which had 40% of patients with a warfarin indication also taking aspirin. On a population scale, even a small absolute increase in bleeding risk could have major public-health implications.

Intuitively, the combination makes sense. The OAC takes care of "red clot" (cardioembolic) that occurs in low-flow states like atrial fibrillation and venous thromboembolism, and the antiplatelet drug treats the "white clot" associated with atherosclerosis. Cover the bases. Protect the patient.

Intuition still holds strong; combining aspirin and anticoagulants is common practice. It stands to reason, then, the evidence in support of such a (more-is-better) strategy would be strong. But that's not what I discovered. In the following paragraphs, I would like to share some of what I have learned. It was quite a surprise.

[A disclaimer: This is not a review article. I am not an anticoagulant expert; I am just a clinician who uses these drugs on a daily basis. If you have useful input or references, please chime in in the comments.]

General studies on OAC plus ASA

In 2007, Canadian researchers performed a meta-analysis of 10 studies (and 4180 patients) that looked at the comparison of OAC alone vs OAC+ASA in patients at risk for heart disease. Benefit was seen only in patients with a mechanical heart valve. In patients with coronary disease or atrial fibrillation, there were no differences in embolic events or overall mortality. Bleeding risk was 43% higher in patients on the combination. The researchers concluded: "Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding." This study is available (for free) at the Archives of Internal Medicine .

This 2004 meta-analysis found similar results. Dartmouth researchers asked the relevant question of whether to continue aspirin when starting patients on warfarin. In patients with mechanical heart valves, the combination of OAC+ASA reduced the risk of embolic events by 66%, increased bleeding risk by 42%, and lowered overall mortality by 57% compared with those on warfarin alone. They found insufficient data on the combination in patients with recent MI or AF.

Even though ximelagatran did not gain market approval (liver toxicity), a post hoc analysis of the SPORTIF trial adds to our knowledge base about combination therapy. In patients with atrial fibrillation, warfarin+ASA compared with warfarin alone increased the risk of bleeding without reducing embolic events. A nice review of this analysis is available here in the journal Stroke .

After coronary stents

Patients with atrial fibrillation who undergo coronary stent procedures face a tough situation. Antiplatelet drugs are required to prevent stent thrombosis, and anticoagulation lowers the risk of stroke. What's clear from the literature is that such triple therapy markedly increases bleeding risk. This makes sense.

This summer, however, at the European Society of Cardiology Meeting in Munich, I learned that the WOEST trial might be changing our thinking about triple therapy after coronary stenting. Recently published in the Lancet, the WOEST trial found that clopidogrel plus warfarin was superior to clopidogrel plus ASA plus warfarin. It's also interesting to note (paradoxical even) that triple therapy may actually worsen ischemic outcomes. In WOEST, triple vs double therapy increased overall mortality, and in this Danish registry, a combination of warfarin and aspirin increased the risk of ischemic stroke by 27%.

The treatment of patients with AF and coronary stents is complex and, as we say, "dynamic." Stent technology and its accompanying antiplatelet therapy move forward rapidly. We have no obvious template, and there is a lot of learning to be had. For now, clinical judgment reigns supreme, as does close collaboration between EP docs and interventionalists.

In coronary artery disease and after acute coronary syndrome

In patients with coronary artery disease or post-MI, two trials (ASPECT-2 and WARIS-II) looked at a warfarin+aspirin combination. Both studies are now more than a decade old. Combined therapy offered only modest benefits, and in ASPECT-2 a slight signal for increased bleeding was noted.

It's clear that antiplatelet drugs confer a benefit when given to patients who suffer acute coronary syndrome (ACS). ACC/AHA guidelines recommend aspirin use after ACS even when patients are on warfarin. The problem is deciding on the duration of combination therapy. Practice guidelines from the ACC/AHA offer little assistance: "These strategies have not been evaluated and may increase the risk of bleeding." The level of evidence is class IIb.

ASA plus novel anticoagulants

RE-LY investigators recently published a subgroup analysis looking at the interaction of dabigatran and antiplatelet drugs. Nearly 40% of the RE-LY cohort (6952 patients) received an anticoagulant-antiplatelet combination, although only 27% stayed on both agents throughout the entire trial. Triple therapy with aspirin, clopidogrel, and an OAC was used in 4.3%.

Quoting from the authors: "Our results showed that, whether or not patients were on antiplatelet agents, dabigatran given at 150 mg bid reduced stroke and systemic embolism to a greater extent than warfarin, with no increase in the rate of major bleeding. In contrast, dabigatran given at 110 mg bid reduced stroke and systemic embolism to the same extent as warfarin, but with substantially lower rates of major bleeds, irrespective of whether patients were on other antiplatelet drugs or not."

The overall story in this RE-LY analysis is consistent with the warfarin/aspirin story. The relative risk of a major bleed was 60% higher on double therapy and 2.3-fold higher on triple therapy, yet no signal of additional benefit was seen for embolic prevention. The authors, and an accompanying editorial, raise the consideration of using the lower dose of dabigatran when antiplatelet therapy is needed over the long term. (Of course, dabigatran 110 mg is not available in the US.)

My take home

Combining warfarin and aspirin increases the risk of bleeding. A review of the evidence reveals scant few groups of patients that enjoy a net clinical benefit from the combination. In patients with mechanical valves, acute coronary syndrome and recent coronary stents, the benefit (embolic prevention) seems to outweigh the burden (bleeding).

What I have learned from this eye-opening look at the evidence base is to be much more cautious about combining these drugs.

Again, could less be more?


See also:

Can we omit aspirin when anticoagulated patients undergo PCI?


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Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin–oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: A meta-analysis of randomized trials. Arch Intern Med 2007; 167:117-124. Available here.

Larson RJ, Fisher ES. Should aspirin be continued in patients started on warfarin? A systematic review and meta-analysis J Gen Intern Med 2004; 19: 879–886. Available here.

Gorelick PB. Combining aspirin with oral anticoagulant therapy: Is this a safe and effective practice in patients with atrial fibrillation? Stroke 2007; 38:1652-1654. Available here.

Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170:1433-1441. Available here.

Mandrola J. Not the worst, the WOEST trial is my pick for most influential at ESC 2012. Available here.

Dewilde WJM, Oirbans T, Verheugt FWA, et al.Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; abstract.

Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634-640. Available here. 


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