UPPSALA, SWEDEN. Although there is no evidence that otherwise healthy lone afibbers have an increased risk of ischemic stroke, it is clear that atrial fibrillation (AF) patients with heart failure, diabetes or hypertension have a significantly increased risk and this risk is further magnified if the patient has already suffered a heart attack or stroke. Oral anticoagulation with vitamin K antagonists such as warfarin (Coumadin) is still considered to be the best preventive therapy for patients at risk for stroke. Unfortunately, warfarin interacts with many foods and drugs and treatment requires constant, costly monitoring. Its use also substantially increases the risk of hemorrhagic stroke and major internal bleeding, particularly in older people, a group that, ironically, is also most at risk for an ischemic stroke. Effective warfarin therapy is based on maintaining an INR (international normalized ratio) between 2.0 and 3.0. Too low a ratio increases the risk of ischemic stroke, while too high a ratio increases the risk of hemorrhagic stroke and major bleeding. Warfarin acts by inhibiting the activation of the vitamin K-dependent coagulation factors V, VII, and X in the extrinsic and common pathways of the coagulation cascade. Research aimed at replacing warfarin has focused on developing new pharmaceutical drugs which will inhibit specific coagulation factors. A recent entry to the field is apixaban (Eliquis) a direct inhibitor of factor Xa, the first member of the common pathway in the coagulation cascade.

A very large study (ARISTOTLE) compared apixaban to warfarin. It involved 18,200 patients with AF and at least one additional risk factor for ischemic stroke. The average (median) age of the patients was 70 years and 35% were female. Most of the participants (85%) had persistent or permanent AF and had a CHADS2 score of at least 1 (mean score of 2.1). All in all, the trial involved a group of very sick people, in no way comparable to a group of otherwise healthy afibbers. Almost 90% were being treated for hypertension, 35% had heart failure or abnormally low left ventricular ejection fraction, over 30% had experienced a prior heart attack, stroke, TIA (transient ischemic attack) or systemic embolism, and 25% had diabetes. None of the study participants had a CHADS2 score of 0.

The participants were randomized to receive standard therapy with oral warfarin (INR range of 2.0 to 3.0) or 5 mg twice daily of apixaban (2.5 mg twice daily for elderly or frail persons and those with impaired kidney function). The warfarin-treated patients were within INR target range 66% of the time (median value). During an average (median) follow-up of 1.8 years, 212 patients (1.3%/year) in the apixaban group experienced a stroke, TIA or systemic embolism as compared to 265 patients (1.6%/year) in the warfarin group. The rate of major bleeding was 2.13%/year in the apixaban group compared to 3.09%/year in the warfarin group. The incidence of hemorrhagic stroke (intracranial bleeding) was 0.24%/year in the apixaban group compared to 0.47%/year in the warfarin group. The incidence of major gastrointestinal bleeding was 0.76%/year in the apixaban group and 0.86%/year in the warfarin group. Overall, 1009 patients (6.13%/year) in the apixaban group and 1168 patients (7.20%/year) in the warfarin group died (from any cause) or suffered a stroke, systemic embolism or major bleeding during follow-up.

The ARISTOTLE AF investigators concluded that apixaban is superior to warfarin in regard to preventing stroke and systemic embolism and non-inferior in all other aspects where a comparison was made.

Now the same investigators have re-analyzed the ARISTOTLE data to determine if the superiority of apixaban is related to the quality of INR control in warfarin-treated patients. In other words, "would apixaban still be superior if INR control was optimal?" INR control is measured by the percentage of INR measurements for a given patient or treatment center that are within the therapeutic range of 2.0 to 3.0. This percentage is known as time in therapeutic range or TTR.

The ARISTOTLE trial included centers in 40 countries. Average TTR was highest in Sweden (83.2%) followed by Norway, Australia, Denmark, and Finland. Canada was #8 and the USA #9 (TTR 74%) and India was last at 49%. Not surprisingly, the rate of stroke (including systemic embolism) was lower in centers with a high TTR. However, the incidence of major bleeding was higher in centers with high TTR, although the difference noted was not statistically significant.

It is clear that apixaban is superior to warfarin in all centers, but the advantage would appear to be most pronounced in centers with poor TTR.

In an accompanying editorial British and Spanish researchers point out that INR control (TTR) with warfarin depends on numerous factors and that it actually is possible to predict with reasonable accuracy how a patient will respond. The recently developed Apostolakis score assigns 1 point each for being female, over the age of 60 years, having a medical history of two or more of the following conditions – hypertension, diabetes, coronary artery disease, heart attack, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, or liver or kidney dysfunction. Therapy with interacting drugs such as amiodarone also warrants 1 point, while smoking and non-white race warrants 2 points. Thus the score gives a total value between 0 and 8. The Apostolakis score correlates well with actually measured TTR and a score of 2 or more requires more regular INR monitoring and other interventions to achieve appropriate anticoagulation control. NOTE: The conflict of interest disclosures for the authors of the study takes up over 100 lines of fine print.
Wallentin, L, et al. Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation, Vol. 127, June 4, 2013, pp. 2166-76
Gallego, P, et al. Apixaban compared with warfarin for stroke prevention in atrial fibrillation. Circulation, Vol. 127, June 4, 2013, pp. 2163-65

Editor's comment: The above study confirms the superiority of apixaban over warfarin in the prevention of ischemic stroke, especially in centers and countries with less than optimum INR control. Apixaban (Eliquis) would appear to be the best overall choice for anticoagulation and will likely be the leading medication for this purpose once a reliable antidote to apixaban-induced bleeding becomes routinely available.