Reed Miller

July 11, 2011

July 8, 2011 (Updated July 12, 2011) (Madrid, Spain) — The European Society of Cardiology (ESC) is considering issuing an update of its September 2010 guidelines on the treatment of atrial fibrillation to reflect the latest clinical-trial data on new anticoagulant drugs, although one of the authors of that section points out that the current guidelines were written to anticipate some of these new drugs.

Dr Gregory Lip (University of Birmingham, UK) told heartwire that the ESC may revise the guidelines to reflect new research, but that "the 2010 guideline already contains most of the elements in the text, but an update would deal with the additional published data and the potential use of the new drugs as an alternative--or preference--to warfarin."

"Do we need an update? Possibly," Lip said in a presentation on the 2010 guidelines here at EUROPACE 2011 explaining the part of the new guidelines on anticoagulation. "The task force recognized that we would have the imminent arrival of new anticoagulant drugs and that we are getting better at monitoring warfarin, and therefore we started changing the emphasis to look for low-risk patients and to be better able to categorize patients who needed anticoagulation therapy."

The 2010 guidelines broke from previous guidelines in proposing a greater degree of individualization of anticoagulation therapy based on more comprehensive assessment of stroke and bleeding risk, Lip explained. "The bottom line is that oral anticoagulants should be considered in patients with one or more stroke risk factors," Lip said at the conference.

"The new ESC guidelines caused a little stir [by] by deemphasizing the artificial categorization by low risk, moderate risk, and high risk, which was certainly artificial [and designed] so that we could pick up the high-risk patients and could give them a terribly inconvenient drug called warfarin," he said at the meeting. The guidelines incorporate the new HAS-BLED system for assessing bleeding risk and the CHA2DS2-VASc system, a risk-factor–based approach that recognizes that any "risk factor for stroke is a risk factor, and if you have atrial fibrillation plus a risk factor, you'll stroke."

In the older CHADS2 score system, congestive heart failure, hypertension, age over 75, diabetes, and previous stroke were all weighted the same, and prior stroke was worth twice as much as any of the others. In CHA2DS2-VASc, the major risk factors of prior stroke or transient ischemic attack (TIA), thromboembolism, age over 75 years, and some types of valvular heart disease are weighted more than the "clinically relevant nonmajor risk factors" of heart failure, hypertension, diabetes, female gender, age 65 to 75, and vascular disease.

The latest guidelines state that AF patients with at least one major risk factor or two or more nonmajor risk factors should be on oral anticoagulant therapy such as a vitamin-K antagonist like warfarin adjusted to an intensity range of an INR 2.0–3.0 (target 2.5). The guidelines also predict that "new oral anticoagulant drugs, which may be viable alternatives to a vitamin-K antagonist, may ultimately be considered. For example, should both doses of dabigatran etexilate [Pradaxa, Boehringer Ingelheim] receive regulatory approval for stroke prevention in AF, the recommendations for thromboprophylaxis could evolve."

The guidelines state that patients with just one nonmajor risk factor (ie, CHA2DS2-VASc score=1) should be on aspirin or oral anticoagulants, but preferably the latter, and patients with no risk factors (ie, CHA2DS2-VASc score=0) should be on aspirin or no antithrombotic therapy, preferably the latter.

The guidelines also prepare for the newer anticoagulant drugs by citing a recent statistical analysis by Dr Mark Eckman (University of Cincinnati, OH) and colleagues that calculated the "tipping point" above which the risk of ischemic stroke outweighs the risk of major hemorrhage. The study showed that warfarin is the preferred therapy if the patient's predicted stroke risk is at least 1.7% per year, whereas aspirin is preferred at lower rates of stroke [1]. Eckman et al calculate, based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), that the threshold for anticoagulation with dabigatran is a stroke rate of 0.9% per year.

Asked at the conference about how to treat patients who are warfarin-resistant, Lip said "Despite all the trials, we'll still have some patients who will flatly refuse any kind oral anticoagulant therapy, and in those patients . . . it has to be reemphasized that a combination of aspirin and clopidogrel [Plavix, Bristol-Myers Squibb/Sanofi-Aventis] has some incremental benefit over aspirin alone, and the risk of bleeding is similar to what we've seen with anticoagulant therapy."

Lip says that the guidelines may need to be updated once the results of ROCKET AF and ARISTOTLE are published. ROCKET AF, presented at the AHA 2010 meeting, showed that rivaroxaban (Xarelto, Bayer/Johnson & Johnson) was noninferior to warfarin for the composite primary end point of stroke or non–central nervous system embolism in the intention-to-treat analysis and superior to warfarin in an "as-treated" analysis. ARISTOTLE results, which have not yet been formally presented (the company has released only top-line findings), showed that apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) was noninferior to warfarin for the primary end point of prevention of stroke and systemic embolism in subjects with atrial fibrillation and risk factors for stroke; the trial also met the secondary end points showing that apixaban was superior to warfarin for efficacy and major bleeding. ARISTOTLE results will be released at the upcoming ESC 2011 meeting in Paris.

He told heartwire , "Compliance will be an even greater issue with the new drugs, because if patients miss a few doses, they would be left unanticoagulated, [but] there is potential for optimizing therapy, as many patients do not take oral anticoagulation due to the inconvenience of warfarin."

An earlier version of this story incorrectly stated that rivaroxaban was noninferior to warfarin in the as-treated ROCKET AF analysis.


Lip has research contracts with AstraZeneca, Astellas, and Bayer and consulting agreements with AstraZeneca, Astellas, Bayer, Cardiome, Biotronic, Daiichi Sankyo, Sanofi-Aventis, Pfizer, Bristol-Myers Squibb, and Servier.