ACCEL: American College of Cardiology Extended Learning
Interviews and topical summaries of cardiology’s most interesting research areas

Aspirin Is No ‘Soft Option’ for Stroke Prevention in AF
Atrial fibrillation is a major cause of stroke and thromboembolism, resulting in substantial morbidity and mortality. At the end of 2015, the European Heart Rhythm Society published a consensus document, “A Roadmap to Improve the Quality of Atrial Fibrillation (AF) Management.”1 The paper’s discussion on aspirin is reproduced here in its entirety: Aspirin is not effective in preventing strokes in AF.

Well, the topic did come up a second time in this 14-page report. Aspirin was addressed in general in a table discussing individual risk assessment, which recommended assessing bleeding risk and minimizing bleeding risk factors in all patients, including, “Discontinue treatment with non-essential antiplatelet(s)/NSAIDs (nonsteroidal anti-inflammatory drugs).”

By that measure, a paper by Gregory Y. H. Lip, MD, FACC, professor of cardiovascular medicine, University of Birmingham, United Kingdom, on “The Role of Aspirin for Stroke Prevention in Atrial Fibrillation” must be one of the shortest papers published.2 Not really: knowing that aspirin is still used for this purpose, Dr. Lip did his best to explain in detail just why aspirin is a really poor choice for stroke prevention in patients with AF. He wrote: “For the majority of patients with AF, aspirin has a limited role in stroke prevention, being an inferior strategy and not necessarily safer than the anticoagulant warfarin, especially in the elderly.” Compared with warfarin, for example, aspirin has only a marginal effect on reducing stroke but carries a similar bleeding risk.

Having said that, Dr. Lip added, “Aspirin use should continue in the early stages following presentation of a patient with AF and acute coronary syndrome, and after stenting, in combination with oral anticoagulant drugs and clopidogrel, as appropriate.” (For more on the topic of aspirin in patients with AF and one or more drug-eluting stents, please see the article that follows.) However, Dr. Lip noted that aspirin combined with clopidogrel shows only modest benefit in stroke prevention compared with aspirin monotherapy in patients with AF who refuse oral anticoagulant drugs (including warfarin).

Blame Marketing
Recently, Dr. Lip coauthored a paper with S. Ben Freedman, MBBS, FACC, professor of cardiology, University of Sydney, Concord Hospital, Australia.3 They noted that people have been conditioned over many years to accept aspirin as an effective, safe, and inexpensive remedy for MI and for primary and secondary prevention of cardiovascular events.

Indeed, the marketing of aspirin for this very purpose has been so wildly successful that a recent advertising campaign focused on the fact that aspirin can still be used as a pain reliever. (When offered an aspirin for pain, a man responds, “I’m not having a heart attack.”)

The current ACC/AHA Guideline for the Management of Patients With Atrial Fibrillation states, that for patients with nonvalvular AF and a CHA2DS2-VASc score of 1, “No antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered.”4 However, in previous guidelines, aspirin was recommended as thromboprophylaxis for those not considered at high risk (e.g., CHADS2 score < 2).

Why the change? According to the writing committee’s chair, Craig T. January, MD, PhD, “Data showing that aspirin decreases stroke risk are weak.”

However, the previous guidelines set a pattern that remains today in a lot of practices. Overall, a little more than one-third of AF patients on oral anticoagulation (OAC) also receive ASA.5 While aspirin is no longer recommended, Dr. Freedman and colleagues note, “Unfortunately, the implied benefit of guideline approbation probably led to widespread use of aspirin as the ‘easy’ or ‘soft’ option in those at higher stroke risk with either real or perceived contraindications to vitamin K antagonist (VKA; e.g., warfarin).”

This could be the result of differences in perception among physicians and patients regarding the risk of stroke versus bleeding and also the misperception that aspirin is somewhat effective in stroke prevention in this setting and has a lower bleeding risk. Another possible contributory factor may be an exaggerated estimate of VKA-associated bleeding, feared by physicians who do not see the strokes prevented but do see the bleeds.

Coupled with this is the issue that VKA therapy is hard to manage, and appears to be universally disliked by physicians, patients, the media, and industry.

Disservice to Patients
Dr. Freedman argues that the consequences of the underutilization of OAC are documented in the neurology literature reviewing incident strokes. The Adelaide Stroke Study reported in 2013 that AF accounted for 36% of all ischemic strokes, of which 85% were inadequately anticoagulated despite the fact that all of them had a CHADS2 score ≥ 2.6 Specifically, only 27% of those with known AF prior to stroke were taking warfarin, while most of the remaining two-thirds were on aspirin.

In previous studies of AF-related strokes in which the patient was known to have AF prior to stroke, aspirin was being taken by half of those not on warfarin. This suggests that, rather than improving over time, the situation may have actually gotten worse.

And forget the idea that aspirin is some sort of ‘soft’ option: in BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged Study), aspirin was associated with a similar risk of major bleeding and intracranial hemorrhage as warfarin.7 As Dr. Freedman puts it, “If you are trading the same amount of bleeding for less efficacy, that’s a bad tradeoff.”

Bottom line: Aspirin is neither effective nor safe for thromboprophylaxis for stroke.


  1. Kirchhof P, Breithardt G, Bax J, et al. Europace. 2015 Oct 18. [Epub ahead of print]
  2. Lip GY. Nat Rev Cardiol. 2011;8:602-6.
  3. Ben Freedman S, Gersh BJ, Lip GY. Eur Heart J. 2015;36:653-6.
  4. January CT, Wann LS, Alpert JS, et al. J Am Coll Cardiol. 2014;64:e1-76.
  5. Steinberg BA, Kim S, Piccini JP, et al. Circulation. 2013;128:721-8.
  6. Leyden JM, Kleinig TJ, Newbury J, et al. Stroke. 2013;44:1226-31.
  7. Mant J, Hobbs FD, Fletcher K, et al. Lancet. 2007;370:493-503.

Updated ‘Practical Guide’ to the NOACs
What’s New (and Industry Can’t Tell You)

Current guidelines for managing patients with nonvalvular AF mainly discuss the indications for anticoagulation in general (e.g., based on the CHA2DS2-VASc score and bleeding risk). They broadly cover vitamin K antagonists (VKAs) as well as the use of the non-vitamin K antagonist oral anticoagulants, but these documents offer less guidance on how to deal with new oral anticoagulants (NOACs) in specific clinical situations. Recently, the European Society of Cardiology (ESC) and European Heart Rhythm Association (EHRA) published a practical guide on the use of the NOACs.1

The document was thought to be necessary in order to better summarize existing information on different drugs, to answer clinical questions that fall outside of what drug companies can legally answer, and to make distinctions between the different drugs.

This is the second time the EHRA has been involved in the development of such a document.2 The first document was featured in the June 2013 CardioSource WorldNews: “ESC Guide to New Oral Anticoagulants When industry can’t legally tell you, it’s up to societies to offer clinical guidance.”

According to Hein Heidbuchel, MD, PhD, a professor at the University of Leuven, Belgium, secretary of the EHRA, and first author of both of the guides, “I felt a tremendous need among colleagues on how to deal with practical situations in patients treated with NOACs.” Moreover, he said, the numerous new drugs on the market make it challenging. Given the different package inserts, which he noted are largely analogous but differ in some important aspects, “there was a risk of a chaos of information.”

The new guide was co-authored by A. John Camm, MD, FACC, (St. George’s University, London, UK), first author of the ESC AF guidelines.3 Dr. Heidbuchel explained the importance of the NOACs guide by distinguishing between guidelines (“when to use a drug or intervention”) and guidance (“how to use them properly”).

Addressing Important Issues
The practical guide covers 15 topics of concrete clinical scenarios for which practical answers have been formulated, based on available evidence. Topics covered include:

  • how to initiate and monitor the NOACs
  • how to measure their anticoagulant effect (if needed) in specific situations
  • switching between anticoagulants
  • managing patients who require surgical intervention or ablation
  • patients with chronic kidney disease
  • management of bleeding complications.

The guide also addresses adherence-related issues. While the new drugs remove the need for regular monitoring of anticoagulation level necessary with the VKAs, Dr. Heidbuchel said, “Compliance is very important for the novel anticoagulant drugs because they have a very short half-life. That means that if you don’t take them you will not be protected by anticoagulation and are at greater risk of thromboembolic events.”

In an effort to improve adherence, the document includes a universal patient education card. The issue is also addressed with a pre-specified follow up scheme.

Addressing drug-drug interactions, the document shows the effect (if any) of 14 specific drugs or drug classes on anticoagulant plasma levels (per area under the curve or AUC) for each new agent. The drug-drug interactions and recommendations for new oral anticoagulant dosing include atorvastatin, verapamil, antacids, the azole antifungals, and HIV protease inhibitors. For example:

In the case of atorvastatin, dabigatran AUC increased by 18%, with no data yet for apixaban, and no effect seen when used with edoxaban or rivaroxaban.

The effect of verapamil on AUC of the new agents varies: for dabigatran, the increase reported ranged from 12%–180%, with the ESC/EHRA guide suggesting a reduced dose of dabigatran and that the drugs be taken simultaneously. For edoxaban, a 53% increase in AUC lead to the recommendation to reduce the new oral anticoagulant dose by 50% when used in patients on verapamil. Limited data demonstrate only a minor interaction of verapamil and rivaroxaban thus far, although the guide recommends using the combination with caution if creatinine clearance is 15–50 ml/min. Because detailed information is not available yet for apixaban or rivaroxaban, the authors state it is prudent to abstain from using these two agents in combination with verapamil until more information is available.

The guide also summarizes key data on the use of NOACs in the setting of ACS, PCI, or stable CAD plus atrial fibrillation. The document urges that measures to reduce bleeding risk in patients with ACS should be retained: low doses of aspirin (75–100 mg), especially when combined with a P2Y12 inhibitor; new-generation DES or bare-metal stents (BMSs) to minimize the duration of triple therapy; and a radial approach for interventional procedures (reducing at least the risk of access site bleeding).

For patients who have had elective PCI, the authors propose a default time of triple therapy of 1 month (for a BMS or newer DES), thereafter stepping down to dual therapy (with OAC and either aspirin or clopidogrel) until 1 year, then monotherapy thereafter.

In patients after an ACS, treated medically or with PCI, the practical guide suggests a default strategy of 6 months of triple therapy before stepping down to double therapy. In those with a high (uncorrectable) bleeding risk, the duration of triple therapy can be shortened from 6 months to 1 month, or even to immediate double therapy (with either aspirin or clopidogrel) in highly selected cases. Conversely, longer triple therapy (up to 12 months) may be considered in individual patients who received a first-generation DES or those with a combination of very high atherothrombotic risk and low bleeding risk.

Finally, while the data are especially limited on the use of NOACs in patients with malignancy, there are practical suggestions on their use in this setting, too.

Professor Stefan Hohnloser, MD (Frankfurt, Germany), a reviewer of the EHRA guide and a member of the ESC AF guidelines task force, said: “Physicians who follow the practical advice in this guide will dramatically improve the safety of their patients.”


  1. Heidbuchel H, Verhamme P, Alings M, et al. Europace. 2015;17:1467-507.
  2. Heidbuchel H, Verhamme P, Alings M, et al. Europace. 2013;15:625-51,
  3. Camm AJ, Lip GY, De Caterina R, et al. Eur Heart J. 2012;33:2719-47.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: CardioSource WorldNews, Anticoagulants, Aspirin, Atrial Fibrillation, Consensus, Hemorrhage, Stroke, Thromboembolism, Vitamin K

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