A dangerous cocktail: Aspirin and anticoagulants

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?

JMM

See also:

Can we omit aspirin when anticoagulated patients undergo PCI?

References

Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007; 131:1500-1507. Available here.

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. 

Your comments

	A dangerous cocktail: Aspirin and anticoagulants
	# 1 of 13	March 7, 2013 12:21 (EST)
	Sok-Ja Janket	Amen, to Dr. JMM's last comment I am very concerned about more! more! anticoagulants! when the benefits are only minor. Why? The benefits are in logarithmic curve and if you add so many drugs after a while the benefits do not match the risks. Author's disclosure (Mar 7, 2013) I have no relevant disclosures to make in connection with this topic.
	# 2 of 13	March 7, 2013 12:27 (EST)
	Thomas Edwards	What about novel OAC and ASA in Factor V Leiden? Another excellent article. Thank you for that. Although outside the normal scope of your articles here, I have a found that there is little study of Factor V Leiden patients who have no other risk factors (besides a history of DVTs, of which I have two). I understand, there is just no money in it. Most patients don't know that they carry the gene, therefore, it cannot be used as a markeitng tool. Your article suggests that I reconsider taking ASA with rivaroxiban. Author's disclosure (Mar 7, 2013) I am an employee of Boston Scientific.
	# 3 of 13	March 7, 2013 03:39 (EST)
	Marla Heller	Thank you. The bleeding risk is highly overlooked, even for ASA-only therapy. I suffered a fall, where I landed nose-first. I asked the ER doc, my PCP, and my neurologist if I should discontinue my ASA due to my concern about developing a subdural hematoma. All said no, there was little risk for me (at age 61). Two-and-a-half weeks later, I was diagnosed with a significant subdural hematoma, and needed platelet therapy before surgery could be done. And the hematoma recurred 1 week later necessitating a second surgery. Significant bleeding risk is real. Author's disclosure (Mar 7, 2013) I have no relevant disclosures to make in connection with this topic.
	# 4 of 13	March 7, 2013 06:39 (EST)
	Daniel Yeo	Novel OAC I agree we have to be careful especially with the novel OAC. It seemed like intuitively dabigatran should work for anticoagulation for prosthetic valves as well, but the recent trial results show the opposite. Maybe it was because they could not find the "optimum" dose. Nevertheless, it is still not usable in this group. It is one of the recurring themes in modern medicine - "hold your horses!" Author's disclosure (Mar 7, 2013) I have no relevant disclosures to make in connection with this topic.
	# 5 of 13	March 7, 2013 10:30 (EST)
	John Mandrola	Not medical advice A word of caution about this post. A (my) survey of the database concerning the combination of anticoagulants and anti-platelet drugs should not be construed as medical advice. Each patient presents a different set of circumstances. As an example, recently I saw a patient on aspirin and warfarin. I thought about what I recently learned, and the risks of double therapy. I discussed it with the patient, and though there isn't specific data on this one situation, we made a shared judgment to continue with double therapy. The point of the piece is to shed light on a scantly-researched but commonly-encountered topic. I aim only to inform and stimulate discussion. Thanks for the comments. Author's disclosure (Mar 7, 2013) I have no relevant disclosures to make in connection with this topic.
	# 6 of 13	March 7, 2013 10:42 (EST)
	abhijit Valanju	more data required with the introduction of newer anticoagulants such as Apixaban, rivoroxaban and Debigatran more studies even post marketing studies are required in patients already taking antiplatelet agents so as to get some guideline for the prevention of stroke and risk of bleeding Author's disclosure (Mar 7, 2013) I have no relevant disclosures to make in connection with this topic.
	# 7 of 13	March 7, 2013 11:25 (EST)
	SUKHVINDER  SINGH	A REAL ISSUE Dear Sir we combine two agents(ASA+WARF)for PHV patients only and never for other patients of AF, especially never in population similar to RELY. Recent DES implantation with AF is rare in our practice and we do tend to switch to clopidogrel with warf at 6 weeks or so. one of our patients with a DES on DAPT only had a roadside accident and we lost him because of IC bleed, so it a real issue, no doubts. and must be evaluated honestly and carefully before being put into practice. Author's disclosure (Mar 7, 2013) I have no relevant disclosures to make in connection with this topic.
	# 8 of 13	March 8, 2013 08:29 (EST)
	Jo Yaldren	Thank you It is perhaps helpful to consider the use of risk stratification for individual risk. The HASBLED tool might help identify the patients at higher risk of bleeds. Link to paper: Author's disclosure (Mar 8, 2013) I have no relevant disclosures to make in connection with this topic.
	# 9 of 13	March 8, 2013 09:54 (EST)
	Thomas Samson	CYP 450 Profile Has a CYP 450 analysis of the patient's genetic profile been considered? Author's disclosure (Mar 8, 2013) I am an employee of AutoGenomics, Inc.
	# 10 of 13	March 8, 2013 10:51 (EST)
	Jonas Millgard	WARIS-II Thank you for a very interesting article! Spot on clinical every day situations with increasing numbers of AF patients with an indication for PCI. I recently read the same papers trying to get a grip of the evidence, an eye opener was that according to the WARIS-II study warfarin is even more effective (compared to ASA) as secondary prevention after myocardioal infarction. Author's disclosure (Mar 8, 2013) I have no relevant disclosures to make in connection with this topic.
	# 11 of 13	March 8, 2013 01:16 (EST)
	Thomas Pelz	Warfarin and Aspirin work, provided you teach the patient Interesting presentation. However, I prefer to treat patients rather then studies. I have also learned that things work better if I negotiate my patient’s care with the patient, rather than the opinion of a study. Therefore, when I initiate someone on Warfarin, I sit down and discuss with the patient why they are going to be taking the Warfarin. I also discuss the complications. I then tell the patient that they are to ignore the recommendations that they avoid leafy green vegetables. I explain to the patient why they are told to avoid the vegetables. I tell the patient that not eating vegetables can lead to malnutrition. I emphasize that the patient eat a balanced diet, as they know they should. We then discuss pain medication. I ask them how many anti-inflammatory pills they take daily. We then discuss the complications of taking these pills when they are taking Warfarin. We then negotiate. Usually we agree that the patient will take “N” number of anti-inflammatory pills daily. No more and no less. Then, all I have to do is regulate the Warfarin dose to achieve the desired INR. I do this as a consultant, not as the patient’s primary physician. Doing this for over 12 years has not produced any complications. Author's disclosure (Mar 8, 2013) I have no relevant disclosures to make in connection with this topic.
	# 12 of 13	March 8, 2013 10:35 (EST)
	clive halliday	CA -- Another variable? When considering the risk of combining OACs and aspirin, should the recent findings that long-term aspirin use possibly significantly reduces the incidence of cancer be taken into consideration. Is it bleeding versus cancer? Author's disclosure (Mar 8, 2013) I have no relevant disclosures to make in connection with this topic.
	# 13 of 13	March 10, 2013 01:30 (EDT)
	Melvin Taylor	ASA Dose AS a retired pharmacist and patient with chronic AF, on warfarin, digoxin, lisinopril and carvediol, I wanted to add ASA and started with 40mg (1/2 baby asa) but got funny feelings in my head, slight headache and stopped ASA...Could adverse effects be dose related ?? What dose of ASA is regularly used? Also on 1200mg Fish Oil, hate to miss the benefits of Fish Oil and ASA....MRT I enjoy Blog... Author's disclosure (Mar 10, 2013) I have no relevant disclosures to make in connection with this topic.

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