Hemostasis and Thrombosis Issues

OCTOBER 10, 2011
Charles H. Brown, MSPharm, RPh, CACP

Nonvalvular AF and Stroke

Nonvalvular atrial fibrillation (AF) is a strong, independent risk factor for stroke, increasing the stroke risk approximately 5-fold. An estimated 15% of all strokes in the United States are due to AF. It is the most common chronic cardiac arrhythmia, with an estimated 2.7 million Americans with the condition in 2010. The prevalence of AF is expected to increase significantly by 2050.

Stroke is one of the leading causes of morbidity and mortality in the United States and it ranks third among all causes of death. Brain infarcts in patients with AF typically are larger than those in non-AF stroke patients, producing more severe acute neurologic deficits, worse long-term functional outcomes, and higher mortality rates. The consequences of a stroke can leave a person partially or totally dependent on others for their activities of daily living (ADL) and some will require institutional care for weeks/ months and possibly the remainder of their lives.

The cost of medical care in the United States is about $8700 per year higher for a patient with AF compared with a patient without AF. In fact, caring for stroke patients often exhausts their savings and may bankrupt the family.

Antithrombotic treatment For Stroke Prevention in AF

AF therapy is complex, and often includes chronic rate and rhythm control measures along with antithrombotic therapy to prevent thromboembolism. The focus of this column is limited to antithrombotic therapy.

Warfarin is an oral vitamin K antagonist with once-daily dosing, and it is a time- proven therapeutic option for managing stroke risk. For more than 60 years, warfarin was the anticoagulation standard of care for chronic stroke prevention therapy for AF. Although warfarin prevents 64% of strokes, it has numerous limitations, including slow onset and offset of action, a narrow therapeutic window, and a metabolism that is affected by diet, multiple drug–drug interactions, and genetic polymorphisms.

Because of its unpredictable dose response, warfarin requires careful coagulation monitoring of international normalized ratios (INRs) to ensure that a therapeutic anticoagulant effect is achieved and maintained. Warfarin remains one of the most economical treatments, costing less than $100 per month including the drug and once-monthly INR monitoring. It has a recognized oral antidote (vitamin K) for elevated INRs.

Aspirin is an oral antiplatelet drug that is administered once daily. It is more effective than placebo, and easier to use but less effective than warfarin in preventing stroke. Aspirin (low dose) is often taken concurrently with warfarin and antiplatelet drugs.

Dabigatran (Pradaxa) is the first oral direct thrombin inhibitor and is administered twice daily. It prevents more strokes than warfarin with a similar bleeding risk. It does not require INR monitoring, and has no special dietary limitations.

Although it has no known antidote, because approximately 80% of the drug is eliminated renally, hemodialysis may be of benefit. Dosage adjustment may be needed in patients with moderate renal insufficiency. It costs approximately $240 per month. When switching a patient from warfarin to dabigatran, it is recommended to wait until the patient’s INR is 2 or below before starting dabigatran.

Rivaroxaban (Xarelto) is the first oral factor Xa inhibitor, and has fixed, once-daily dosing. Currently, it is only FDA approved for prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing knee or hip replacement surgery. It is currently being evaluated in clinical studies for the prevention of stroke in subjects with AF. No routine monitoring for therapeutic effects is required.

Activated charcoal may reduce absorption in the case of an overdose, and prothrombin complex concentrate is being studied currently in Amsterdam as a possible antidote. Because more than 60% of rivaroxaban is eliminated renally, hemodialysis may be of benefit. Its use is contraindicated in patients with hepatic disease, including Child-Pugh Classes B and C. Dosage adjustment may be needed in patients with moderate renal insufficiency. Its cost per day is reportedly about the same as dabigatran.

Apixaban (Eliquis) is another twice-daily oral direct factor Xa inhibitor that is currently approved in Europe and is scheduled to be submitted for FDA review later this year. In clinical trials, it seems to be more effective and cause less bleeding than warfarin. PT

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations. 

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