A majority of patients who have experienced cryptogenic stroke and have nonvalvular atrial fibrillation (NVAF), including the elderly and those with mild dementia, should be receiving newer oral anticoagulants to reduce the risk of ischemic stroke, but treatment decisions should be based on clinical judgment and include discussion of possible risks with patients.
Since the AAN issued its 1998 practice parameter on the issue, there have been major strides in developing direct oral anticoagulants with less risk of intracranial bleeding than with warfarin. Moreover, multiple studies have examined different technologies to better identify NVAF patients.
The AAN NVAF Guideline Development Subcommittee convened a panel of experts on NVAF and stroke to systematically review all research papers on the topic published between 1998 and March 2013. The search included MEDLINE, EMBASE, Cochrane, and Web of Science publications, and was limited to peer-reviewed papers written in English.
The panel classified the evidence on the basis of the quality of the study design, and assigned one of four levels to the evidence: Level A: “Must”; Level B: “Should”; Level C: “Might”; and Level U: No recommendation supported.
The guideline, which is published in the Feb. 25 edition of Neurology, was endorsed by the World Stroke Organization in 2012.
Neurology Today asked committee member and chair of AAN's Stroke and Vascular Neurology Section Antonio Culebras, MD, professor of neurology at the State University of New York Upstate Medical University in Syracuse, to discuss the new guideline.
WHAT ARE THE MAJOR CHANGES IN THE NEW GUIDELINE?
Clinicians should routinely offer anticoagulation to patients with NVAF and a history of transient ischemic attack or stroke, including elderly patients (those over 75 years of age) if there is no history of recent unprovoked bleeding or intracranial hemorrhage. Also, clinicians should use a risk stratification scheme when making decisions as to which patients with NVAF might benefit more from anticoagulation, as well as to help identify those who have a higher risk — or no clinically significant risk — for stroke.
That said, we want to emphasize that clinicians should not rigidly interpret anticoagulation thresholds as being definitive indicators of which patients require anticoagulation.
WHAT ABOUT THOSE WITH DEMENTIA OR A HISTORY OF FALLS?
That is another big change in this guideline. We have recommended continuing treatment in older patients with mild dementia and those who have experienced a fall. Currently, such patients are generally deemed no longer candidates for such therapy because of the risk of brain bleeds.
I believe that many elderly patients with NVAF, or those over 75 years of age, are currently undertreated because there is a fear of cerebral hemorrhage. But the evidence does not bear this out. In fact, studies show that some patients who have fallen as many as 200 times in one year are at no greater risk, so a single fall or occasional falls do not appear to negate the benefits of continued anticoagulant therapy. The same is true for those with mild dementia. But again, clinical judgment in these cases is paramount.
WHAT ABOUT TECHNOLOGICAL ADVANCES FOR DIAGNOSING AND/OR MONITORING NVAF IN CRYPTOGENIC STROKE PATIENTS?
We were unable to make any Level A or Level B recommendations on diagnostic approaches because there was no major evidence that monitoring patients over long periods yields a higher level of diagnosis. However, I am not saying that this may not be the case. The point is that the evidence is still lacking, and I suspect that longer monitoring could be the way to go. In patients with recent cryptogenic stroke, we determined that cardiac rhythm monitoring probably detects occult NVAF.
Our Level C recommendations include the use of outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify those with occult NVAF. In these patients, cardiac rhythm studies for prolonged periods — one or more weeks — instead of shorter periods, such as 24-hour studies, might be more useful in identifying occult NVAF.
BEFORE WE DISCUSS THE PANEL'S RECOMMENDATION ON THE NEWER ORAL ANTICOAGULANTS, WHAT DO THE GUIDELINES RECOMMEND REGARDING THE USE OF WARFARIN?
We know that warfarin is associated with an increased risk of intracerebral hemorrhage — more so than with the newer agents. However, we recommend that clinicians with patients who are currently taking warfarin, and whose condition is well controlled, continue treatment rather than switching to a new oral anticoagulant.
WHAT CONSENSUS WAS REACHED REGARDING THE NEWER ANTICOAGULANTS?
The evidence indicates that dabigatran, rivaroxaban, and apixaban are probably at least as effective as warfarin in preventing stroke but with a lower risk of intracranial hemorrhage. We also found that triflusal, an antiplatelet drug structurally related to aspirin that is used in Europe, Latin America, Africa, and Southeast Asia, plus acenocoumarol and moderate-intensity anticoagulation, is likely more effective than acenocoumarol alone in reducing moderate stroke risk. Clopidogrel plus aspirin is probably less effective than warfarin in preventing stroke but has a lower risk of intracranial bleeding, while clopidogrel plus aspirin versus aspirin alone probably reduces stroke risk but increases the risk of major hemorrhage. [See “Recommended Dosages for the Anticoagulants.”]
Our goal is to address this issue not only in the United States, but also in the rest of the world. We estimate that new oral anticoagulants are not available in about 80 percent of other countries, especially in the developing world.
WHAT ARE THE RECOMMENDATIONS FOR MONITORING PATIENS TAKING NEW ANTICOAGULANT MEDICATIONS?
Patients do not need to be monitored regularly. Unfortunately, unlike warfarin, we do not have any tests to determine the excess or lack of anticoagulation in the blood, so there is no way currently to determine if there is toxicity or undertreatment. Nor do we have antidotes that can immediately address bleeding problems, like we do with warfarin and vitamin K. Fortunately, though, these newer agents have a short half-life of around 12 hours.
IN SUMMARY, WHAT IS THE TAKE-HOME MESSAGE FOR CLINICIANS READING THE NEW GUIDELINE?
We now have new potent oral anticoagulants that are at least as effective as warfarin, if not more, and also have a reduced intracranial bleeding risk — which is the deal-maker. I would emphasize again that this guideline is intended to reduce therapeutic uncertainty, but that clinical judgment should always prevail. Equally important is that patients should be part of treatment decisions after being made aware of all risks and benefits.
RECOMMENDED DOSAGES FOR THE ANTICOAGULANTS
- Dabigatran:150 mg twice daily if creatinine clearance (CrCl) is greater than 30 mL/min;
- Rivaroxaban: 15 mg/day (if CrCl is 30–49 mL/min) or 20 mg/day;
- Apixaban: 5 mg twice daily (if serum creatinine < 1.5 mg/dL) or 2.5 mg twice daily (if serum creatinine > 1.5 and < 2.5 mg/dL, and body weight < 60 kg or age at least 80 years [or both]);
- Triflusal: 600 mg plus acenocoumarol, with a target INR of 1.25–2.0, but this is primarily for patients in developing countries where access to oral anticoagulants is often very limited.
Clinicians also should offer dabigatran, rivaroxaban, or apixaban to patients unwilling or unable to submit to frequent periodic testing of INR levels; and apixaban for patients unsuitable for being treated, or unwilling to be treated, with warfarin. For patients with NVAF and gastrointestinal bleeding risk, apixaban might be considered.
Also, where triflusal is available and patients are unable or unwilling to take new oral anticoagulants — again, mostly in developing countries — clinicians should offer acenocoumarol (target INR 1.25–2.0) and triflusal to patients with NVAF who are at moderate stroke risk and higher bleeding risk.
STROKE EXPERTS COMMENT ON THE NEW GUIDELINE
Neurology: Clinical Practice is publishing in its online Feb. 24 edition a commentary on the updated guideline on nonvalvular atrial fibrillation. The editorialists — Robert G. Hart, MD, professor of medicine (neurology) at McMaster University in Hamilton, Ontario, Canada, and John W. Eikelboom, MBBS, professor of medicine (thrombosis) at McMaster University — acknowledged the challenges of developing evidence-based guidelines, but noted that they disagreed with the panel's recommendations in three areas. To read their commentary, see “Stroke prevention in atrial fibrillation: Commentary regarding the AAN's evidence-based guideline update” in Neurology: Clinical Practice.