Arrhythmias and conduction disturbance
Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study)

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This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 502) were randomized to receive blinded doses of 50-, 150-, or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, d-dimer, urinary 11-dehydrothromboxane B2 (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p = 0.0002 and p = 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p = 0.02, p = 0.03, and p = 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress d-dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution.

Section snippets

Methods

This study was conducted in 53 centers in Denmark, the Netherlands, Sweden, and the United States. The protocol was developed by the Steering Committee of the Prevention of Embolic and Thrombotic Events in Patients with Persistent AF (PETRO) study group. An independent adjudication committee blinded to treatment evaluated all bleeding events. An independent data and safety monitoring board monitored the study for safety. Boehringer Ingelheim (Biberach, Germany) sponsored the study and was

Results

Of 502 patients randomized, 411 (81.9%) were men, with 192 (38.2%) having permanent AF, 195 (38.8%) persistent AF, and 115 (22.9%) paroxysmal AF. The median duration of AF was 4 years (range 0.05 to 30). Mean ages were 70.9 ± 7.9 years in patients with CAD (n = 306) and 68.0 ± 8.8 years in those without CAD. The baseline characteristics were balanced among the 10 randomized treatment groups (Table 1). Patients had a median of 3 risk factors for stroke.

The mean rate of compliance with dabigatran

Discussion

This phase 2 trial of several fixed doses of a direct thrombin inhibitor with and without aspirin compared with warfarin alone in AF established a dose response for bleeding and an upper limit of tolerability (300 mg twice daily plus aspirin) based on the frequency of major and clinically significant bleeding events. As anticipated, the frequency of thromboembolic events was too low to reach conclusions, but the only 2 strokes in this 12-week trial occurred in patients receiving the lowest dose

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Boehringer Ingelheim Pharmaceuticals, Biberach, Germany, is the sponsor of this study and has provided a research grant. The members and structure of the PETRO study group are given in the Appendix at the end of this article.

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