Patients With AF, Intermediate Stroke Risk Should Receive Anticoagulation, Says Group

February 18, 2015

TAIPEI, TAIWAN — For men with atrial fibrillation (AF) who tick at least one box on the CHA2DS2-VASc risk-factor score sheet, the risk of ischemic stroke ranges from 1.96% per year to as high as 3.50%, depending on the specific risk factor composing the score, according to the results of a new analysis[1]. For women with AF and at least one additional risk factor, the risk of stroke ranges from 1.91% to 3.34% per year.

The data, say investigators, support the European recommendations that all AF patients with at least one additional risk factor—a CHA2DS 2-VASc score of 1 in men or 2 in women—should be prescribed an oral anticoagulant given their high risk for ischemic stroke.

"This analysis showed that the ischemic stroke rate can be as high as 2% to 3% per year," senior investigator Dr Gregory Lip (University of Birmingham, UK) told heartwire . "We should ask ourselves, 'Is it worth taking the risk of a fatal and devastating stroke?' These days now with the novel oral anticoagulants and with well-controlled anticoagulation—that being a [time in therapeutic range] TTR greater than 70%—the potential for serious bleeding is very low."

Lead investigator Dr Tze-Fan Chao (Taipei Veterans General Hospital, Taiwan) told heartwire he believes a stroke risk exceeding 1% annually is typically the threshold in which anticoagulation should be initiated in men and women with AF. At present, the clinical guidelines for recommending anticoagulant therapy differ among the major cardiology organizations.

The European Society of Cardiology (ESC), the Asia-Pacific Heart Rhythm Society, and the National Institute for Health Care Excellence (NICE) guidelines, for example, advise that male AF patients with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2 (female sex is a risk factor for stroke) receive oral anticoagulation for stroke prevention. In contrast, the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines state that that "no antithrombotic therapy, aspirin, or oral anticoagulant" should be considered for AF patients with a CHA2DS2-VASc score of 1.

Based on the annual stroke risks observed among their AF patients, Chao agrees with the European, Asian-Pacific, and NICE guidelines and would recommend oral anticoagulation in these "intermediate-risk" patients.

The new study is published in the February 24, 2015 issue of the Journal of the American College of Cardiology.

AF Plus One Additional Risk Factor

In their retrospective data from the National Health Insurance Database in Taiwan, which contains detailed information on enrollees in the mandatory universal health insurance program, the researchers identified 12 935 men with a CHA2DS2-VASc score of 1 and 7900 women with a CHA2DS2-VASc score of 2 who were not taking an oral anticoagulant or antiplatelet medication.

After 5.2 years of follow-up, 14.4% of male patients experienced an ischemic stroke. The annual stroke rate was 2.75%. For men, the risk of ischemic stroke varied depending on the risk factor. For example, men with AF and vascular disease had an annual stroke rate of 1.96%, while those with AF and hypertension had a stroke rate of 2.18% per year. For those with AF and congestive heart failure or AF and diabetes, the stroke rates were 2.37% and 2.96%, respectively. Individuals with AF aged 65 to 74 years had the highest risk of stroke, with an annual rate of 3.5%.

Among the women, 14.9% experienced an ischemic stroke for an annual event rate of 2.55%. As in the men, the risk varied depending on the risk factor. For example, the risk of ischemic stroke varied from 1.91% annually for women with hypertension to 3.34% for those aged 65 to 74 years old. For women with AF and diabetes, the annual risk of ischemic stroke was 2.88%.

"For both males and females, the most important driver for the risk of ischemic stroke is age followed by diabetes," said Chao. "These findings are similar to what was observed in the Danish registry, where it was also shown that age and diabetes were the most important risk factors for ischemic stroke."

Trading Stroke Prevention for Bleeding Risks

In the Danish registry analysis, which was published in 2011 in the BMJ[2], the rate of thromboembolic events was 2.01 per 100 patient-years of follow-up among AF patients with a CHA2DS2-VASc score of 1. As with the Taiwanese patients, age was associated with the highest risk of ischemic stroke.

The trade-off with anticoagulation is the potential for bleeding, but Chao said the risk of intracranial hemorrhage is low with the newer oral anticoagulants. In the randomized clinical trials testing the novel agents, the risk of intracranial hemorrhage ranged from 0.23% with edoxaban (Lixiana, Daiichi-Sankyo) to 0.50% with rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals).

"Considering the risk of stroke in patients left untreated and the low risk of intracranial hemorrhage, I think we should try to start oral anticoagulation for these kinds of patients," said Chao.

To heartwire , Lip agreed, noting that while physicians tend to worry about bleeding risks, the patients are more concerned about preventing strokes. That said, when treating an AF patient, Lip first eliminates the patients at low risk for stroke, that being men and women with AF but no additional factors. For those at "intermediate risk," the men with a CHA2DS2-VASc of 1 and women with a CHA2DS 2-VASc score of 2, the goal is to have a conversation about the absolute and relative risks of bleeding if anticoagulation is started vs the risks of ischemic stroke if it is not.

"I've yet to find a patient who doesn't give a high priority to stroke prevention," said Lip. "They are desperate to avoid strokes."

Dr Hugh Calkins (Johns Hopkins Hospital, Baltimore, MD), who wrote an editorial accompanying the study[3], told heartwire there is a "gray area" in the management of men and women with AF and one additional risk factor and that the guidelines give very little direction on how to treat them.

"It's an area that needs more research," said Calkins. "And I think the reason the guidelines landed here is that guidelines these days are all evidence-based. There haven't been randomized studies of anticoagulation in these patients. It is a gray area, but I think a lot of people in the field will err on the side of anticoagulating CHA2DS2-VASc-1 patients (CHA2DS2-VASc-2 for females)."

He added that the field is also transitioning from the older CHADS2 score to the newer CHA2DS2-VASc score, and this is one of the reasons for the lack of clinical studies looking specifically at the benefits and risks of prescribing anticoagulation to the intermediate-risk patients. "It's sort of a new population, and we don't have hard data," said Calkins in reference to the male CHA2DS2-VASc-1 and female CHA2DS2-VASc-2 patients. "Until we do, I think the studies from Taiwan support my general belief that a lot of these patients should get anticoagulation."

That said, there are multiple factors to consider when making such a decision, said Calkins. For example, patients in continuous AF, those with a larger atria, or those who also have mitral-valve calcification will be at a higher risk of stroke and this will influence his decision. A patient with one reading indicating hypertension does not have the same level of risk as a patient with uncontrolled hypertension, he notes in the editorial.

The study by Chao and colleagues also raises an important question, that being whether or not there is something unique about Asian patients that might put them at higher risk for stroke. At present, "the answer is unknown," said Calkins.

The Data Elsewhere

Recently, Dr Leif Friberg (Karolinska Institute, Stockholm, Sweden) and colleagues published a study in the Journal of the American College of Cardiology suggesting the estimates of the risk of ischemic stroke in AF patients with one risk factor might have been too high[4]. For their analysis, the group excluded patients with transient ischemic attack (TIA), pulmonary embolism, or "unspecified" stroke as well as any patient with exposure to warfarin.

In that retrospective analysis of 140 420 Swedish patients with AF, the risk of ischemic stroke among CHA2DS2-VASc-1 patients was just 0.3% per year.

To heartwire , Lip questioned the methodology of the Swedish analysis, noting that the group excluded patients exposed to warfarin. In doing so, this creates a "conditioning-for-the-future" selection bias where the patients left untreated are inherently lower risk, said Lip. "Essentially, the people who are started on anticoagulation are not considered," he said. "This impacts the event rates over the course of time. Therefore, it [the risk of ischemic stroke] will be lower."

While removing TIA from the end point is reasonable, Lip added that patients with AF who have a TIA are predisposed to a higher risk of ischemic stroke in the future. "I don't think they should have been so dismissive of TIAs, because at the end of the day all of us are in the business of preventing devastating strokes."

Lip has served as a consultant for Bayer, Astellas, Merck, Sanofi, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola, and Boehringer Ingelheim; and has been on the speaker's bureau for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, and Sanofi . Chao and the other coauthors have reported they have no relevant financial relationships. Calkins has consulted for Boehringer Ingelheim, AtriCure, and Daiichi-Sankyo.


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