Depending on a patient’s comorbidities and history of prior cerebrovascular events, the rate of stroke among adults with atrial fibrillation (AF) varies widely, ranging between 1% and 20% annually. It is important to stratify the risk of stroke to determine whether prophylactic treatment with an anticoagulant is warranted because the medications used to lower the incidence of AF-related stroke are associated with bleeding. “Aspirin and warfarin have been the primary medications used to prevent stroke in patients with nonvalvular AF (NVAF),” says Larry B. Goldstein, MD, FAAN, FAHA. “Aspirin is indicated primarily for lower-risk patients, while warfarin is reserved for those at greater thromboembolic risk.”

Until recently, the American Heart Association and the American Stroke Association (AHA/ASA) have centered their recommendations on preventing stroke in patients with NVAF around using aspirin or warfarin. There are also some data reflecting the use of clopidogrel plus aspirin as compared to warfarin or aspirin alone.

The Role of Newer Antithrombotic Agents

The new antithrombotics are alternatives to warfarin and aspirin for patients with NVAF. In the August 2, 2012 online issue of Stroke, the AHA/ ASA released a science advisory for healthcare professionals reviewing these new oral antithrombotic agents and providing revised management recommendations. The AHA/ASA scientific advisory updates its existing guidelines based on clinical trial data for three new antithrombotic drugs that have been evaluated in patients with NVAF.

“When selecting specific agent for stroke prevention in AF, clinicians must individualize treatment decisions based on risk factors, cost, and tolerability.”

—Larry B. Goldstein, MD, FAAN, FAHA

“We reviewed recent trials that tested the safety and efficacy of dabigatran—a direct thrombin inhibitor—and rivaroxaban and apixaban—two factor Xa inhibitors—in preventing stroke in patients with AF,” says Dr. Goldstein, who was co-chair of the writing committee that created the guidelines. Dabigatran and rivaroxaban have been approved by the FDA, but apixaban is still awaiting approval. Prior to the current science advisory, rivaroxaban and apixaban were not included in any AHA guidelines. Clinical trial data on apixaban were considered strong enough that the ASA/ AHA writing group included it in the new recommendations, pending FDA approval.

Indications for Preventing First & Recurrent Stroke

According to the ASA/AHA science advisory, warfarin, dabigatran, apixaban, and rivaroxaban are all indicated for the prevention of first and recurrent stroke in patients with NVAF (Table). “When selecting a specific agent for stroke prevention in AF, clinicians must individualize treatment decisions based on risk factors, cost, and tolerability,” Dr. Goldstein says. “Patient preference, potential for drug interactions, and other clinical characteristics— including time in international normalized ratio therapeutic range if the patient has been taking warfarin—must also be factored into the equation.”

The advisory also contains more specific recommendations regarding the dosing of dabigatran, apixaban, and rivaroxaban based on pharmacologic issues in patients with renal impairment. “Before selecting any of these newer antithrombotic agents, it’s important to assess renal function with creatinine clearance tests, among other factors,” says Dr. Goldstein. “These agents may be attractive because they don’t require patient monitoring, but we have less experience with them. Warfarin, on the other hand, requires close monitoring, has more extensive potential drug interactions, and dietary restrictions.”

More Data Needed On New Antithrombotics

Dr. Goldstein notes that there are unresolved issues relating to the clinical use of dabigatran, rivaroxaban, and apixaban. “We currently don’t have published data from clinical trials that directly compare dabigatran, rivaroxaban, and apixaban to one another. The current body of evidence compares these therapies only with warfarin. The durations of the pivotal clinical trials evaluating each agent were limited. Plus, there are no approved antidotes available to reverse the effects of these drugs in case of an emergency, and at present, no test to readily assess the drugs’ anticoagulant effects.”

In addition, it is unknown which factors will be related to long-term adherence to the newer drugs in a real-world setting and how cost will affect compliance. The ASA/AHA notes that patients who are noncompliant and miss medication doses might be at risk for thromboembolism because of the short half-life of newer antithrombotic agents. “Treatment decisions need to account for differences in costs to patients, which could also affect compliance,” adds Dr. Goldstein.

Clinical effectiveness data are only beginning to emerge for dabigatran and are unavailable for rivaroxaban and apixaban, the latter of which still awaits FDA approval. In future research, clinical trials need to further elucidate the balance of benefits and risks of the newer agents when they are used in real-world settings, Dr. Goldstein says. “It’s also unknown if patients receiving newer agents but are also eligible for thrombolysis can be treated safely with a thrombolytic agent for an acute ischemic stroke. Furthermore, the safety and efficacy of combining any of the three newer agents with an antiplatelet drug have not been established. As these data emerge, we’ll hopefully further enhance our ability to reduce risks for stroke in patients with AF even further. In the interim, having alternatives to aspirin and warfarin offers new options for patients.”

References

Furie KL, Goldstein LB, Albers GW, et al; on behalf of the American Heart Association Stroke Council, Council on Quality of Care and Outcomes Research, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012 Aug 2. [Epub ahead of print]. Available at: http://stroke.ahajournals.org/content/early/2012/08/02/STR.0b013e318266722a.full.pdf+html.

Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69:546-554.

Loewen P, Dahri K. Risk of bleeding with oral anticoagulants: an updated systematic review and performance analysis of clinical prediction rules. Ann Hematol. 2011;90:1191-1200.

Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2011;42:e26]. Stroke. 2011;42:517-584.

Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:227-276.

Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110: 2287-2292.

Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA. 2003;290:2685-2692.