Efficacy and Safety of Dabigatran vs. Warfarin for Stroke After more than five decades as the preferred anticoagulant worldwide, warfarin is being challenged by a new rival that doesn't require careful dosage monitoring. Pradaxa (dabigatran) was unanimously approved by the FDA on October 19, 2010 for treating atrial fibrillation (AF) patients, who are at an increased risk for suffering stroke and systemic embolisms (U.S. Food and Drug Administration). Dabigatran acts by binding directly to thrombin. Warfarin (Coumadin) is an anticoagulant that functions by inhibiting the synthesis of vitamin K-dependent clotting factors (Lemos et al., 770-771). Variations in the levels of vitamin K in the diet can influence how effective a given dose of warfarin is for a patient, so appropriate therapeutic dosages are determined on an individual basis periodically through a standardized clotting test (international normalized ratio [INR]). Even though warfarin can reduce the risk of stroke in AF patients by as much as 68%, patient compliance with treatment (time in therapeutic range [TTR]) is a significant problem because of the requisite periodic monitoring of dose effectiveness and the risk of major bleeding events (Ezekowitz, 2007). Because dabigatran doesn't require the labor and time intensive monitoring that warfarin does, the expectation is that patient compliance should increase.

Atrial fibrillation increases the risk of stroke and systemic embolisms because the upper chambers of the heart begin to beat irregularly, thus impairing blood flow efficiency. Slowed blood flow can result in blood pooling in the heart chambers and clots can form. If these clots enter the brain they could cause a stroke. For this reason AF patients are often prescribed anticoagulants to help prevent clot formation. The prevalence of AF in the United States increases from less than 1% for persons under the age of 60, to over 10% for persons over 80 (Centers for Disease Control and Prevention [CDC], 2003). Deaths linked to AF affect about 1 in 4000 people each year, but 84% occur in people over the age of 75.

Atrial fibrillation patients often suffer from coronary artery disease, so the focus of a dabigatran phase 2 clinical trial was to determine the safety of combining this anticoagulant with aspirin (Ezekowitz et al., 2007). Three dabigatran doses were administered (50, 150, and 300 mg twice daily) to patients for 12 weeks, alone or in combination with 81 or 325 mg aspirin, thus creating nine experimental groups. The patients treated with warfarin (INR = 2.0-3.0) were used as a control. The primary outcome of concern was bleeding events and the results indicated major (6% increase, p < 0.02) or all types of bleeding events (26% increase, p = 0.0003) occurred more often in patients treated with 300 mg dabigatran twice a day plus aspirin. On the other end of the dosage spectrum, 50 mg dabigatran was less likely to cause bleeding than all other conditions (15% increase vs. 300 mg p = 0.0002; 11% increase vs. 150 mg p = 0.01; 11% increase vs. warfarin, p = 0.044), but the two embolisms that occurred during the study happened in patients taking 50 mg dabigatran twice daily, alone or with 81 mg of aspirin. The last result indicates 50 mg dabigatran, with or without 81 mg of aspirin, doesn't provide effective protection against stroke or systemic embolisms. This possibility was supported by finding plasma D-dimer levels were inversely correlated with dabigatran dose (13% increase at 50 mg, p = 0.0008; 3% increase at 150 mg, p = 0.027; 300 mg p =0.267) when compared to warfarin. The results of this study suggest 150 mg dabigatran twice daily is a relatively safe and effective dose for coronary artery patients taking aspirin. This conclusion is limited by the small sample size (502), consisting mostly of men (411), which precludes making stronger statements about safety and efficacy for the general population.

A direct head-to-head comparison between 150 mg dabigatran twice daily and warfarin (INR = 2.0-3.0) was conducted using patients beginning anticoagulation therapy at 228 clinics in 29 countries (Schulman et al., 2009). The efficacy outcomes of concern were embolism and associated deaths. The safety outcomes were all types of bleeding, acute coronary symptoms, and several other adverse events. During the 6-month treatment period no difference in the rate of embolism or related deaths were observed between the two anticoagulants (noninferiority, p < 0.001). There was no difference in the number of major bleeding events between the two drugs, but when both major and clinically-relevant bleeding events were combined, patients...

When all adverse events were combined, patients on dabigatran did worse (OR = 1.33, p = 0.05), but when adverse events were compared individually, only an increased occurrence of dyspepsia in dabigatran patients reached statistical significance (OR = 4.8, p < 0.001). The number of patients leaving the study due to adverse events was also higher for patients taking dabigatran (2.2% increase, p = 0.05). This study found that the anticoagulation efficacy of dabigatran and warfarin are equivalent, but the choice of which anticoagulant to use may depend on the primary safety concerns of the patient. Overall no difference was found in the efficacy or safety of the two drugs, which suggests dabigatran may become the drug of choice given that warfarin treatment is more labor intensive.
In a large phase III clinical trial (Connolly et al., 2009) that followed over 18,000 AF patients with a mean CHADS2 score of 2.1, for an average of two years, the relative efficacy and safety of 110 mg or 150 mg of dabigatran, or warfarin (INR 2.0-3.0) were determined. Only the warfarin treatment dosage was unblinded. The 150 mg dose of dabigatran was superior to warfarin in reducing the risk of stroke and systemic embolism (OR = 0.66, p < 0.001), and the 110 mg dose was as effective as warfarin (noninferiority, p < 0.001), the primary outcome for the study. The secondary outcome, death, trended towards significance in favor of the 150 mg dose of dabigatran (OR = 0.88, p = 0.051) when compared to warfarin. Major bleeding events were reduced for the 110 mg dabigatran dose (OR = 0.80, p = 0.003) compared to warfarin, and warfarin did worse when all other bleeding events were examined (p < 0.05). The net clinical benefit did not differ significantly between 110 and 150 mg dabigatran, but the 150 mg dose of dabigatran did slightly better than warfarin (OR = 0.91, p = 0.04). Warfarin did better that dabigatran in several ways, including major gastrointestinal bleeding (150 mg dabigatran, OR = 1.50, p < 0.001), dyspepsia (p < 0.001), and participant drop-out rates. Overall dabigatran is at least as effective as warfarin in preventing stroke and seems to have a similar safety profile. The one exception is major gastrointestinal bleeding and dyspepsia, but the authors mentioned that the dabigatran formulation included tartaric acid to lower the pH to aid in dabigatran absorption. This could be the cause of the increased major gastrointestinal bleeding and dyspepsia in dabigatran-treated patients. Should this issue be resolved then dabigatran could become the anticoagulant of choice for most AF patients.

Given reports of wide variations in the accuracy of INR determinations and TTR, from center to center and country to country, Wallentin et al. (2010) saw value in performing a retrospective study investigating the influence of quality of care on the data from a phase 3 clinical trial. Each center's TTR was estimated by averaging individual TTR values for that center. In addition, an assumption was made that a center's TTR score would be positively correlated with the center's accuracy of INR determination. Using this approach it was found that center TTR scores did not change the original studies conclusion that 150 mg dabigatran twice daily provides better protection against stroke, systemic embolism, non-hemorrhagic stroke, and intracranial bleeding in AF patients, but this did not hold true for a number of other adverse patient outcomes. The protective advantage against major bleeding (OR = 1.16, p = 0.03) that 150 mg dabigatran seemed to provide disappears at centers with higher TTR. Total death also trends towards increased risk with dabigatran treatment (OR = 1.08, p = 0.052). In addition, 150 mg dabigatran actually caused twice as much major gastrointestinal bleeding than warfarin at centers with higher TTR (OR = 2.00, p = 0.019). The same holds true if the outcomes for all cardiovascular events are combined, for both 110 mg (OR = 1.07, p = 0.036) and 150 mg (OR = 1.11, p = 0.0006) dosages. This retrospective study suggests quality of care does have a significant impact on several important safety concerns regarding anticoagulant treatment choices. The main limitation of this study is the assumption that warfarin INR accuracy and individual TTR values accurately reflects quality of care, since there are many confounding variables that impact quality of care, including possible regional differences in patient compliance.

The overall conclusion of these studies is that 150 mg dabigatran twice daily is at least as effective as warfarin in reducing…