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Dabigatran Etexilate Has Long-Term Safety and Efficacy in Patients With Atrial Fibrillation: Presented at ESC

By Chris Berrie

BRUSSELS, BELGIUM -- May 19, 2006 -- The novel orally bioavailable prodrug dabigatran etexilate shows acceptable safety and efficacy at 150 mg twice daily for the prevention of stroke and systemic embolism in high-risk patients with chronic atrial fibrillation (AF), according to the long-term continuation, open-label, Petro-ex study presented here at the 15^th European Stroke Conference (ESC).

Paul Reilly, MD, study coordinator and director, clinical research, Boehringer Ingelheim, Richfield, Connecticut, United States, presented the study findings on May 17^th on behalf of the Petro-ex Investigators. The study's principal investigator was Michael D. Ezekowitz, MD, PhD, vice president, Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States.

Vitamin K antagonists are the only effective oral agents for the prevention of stroke in high-risk patients with chronic AF. The original Petro trial was a randomised, 3-dose, 3-month comparison of dabigatran etexilate versus warfarin.

Etexilate is converted to the active reversible competitive inhibitor of thrombin, dabigatran.

Dr. Reilly indicated that dabigatran etexilate is converted into its active form -- dabigatran -- following oral administration, providing plasma concentrations of this competitive thrombin inhibitor that peak after 2 to 3 hours and have a terminal half-life of 14 to 17 hours.

In his study, patients in the dabigatran etexilate groups who completed the Petro trial (n = 432) were offered the option of continuing on long-term, open-label, dabigatran etexilate treatment. The 361 patients who continued had the following demographic characteristics: mean age, 69.7 years; female, 16.3%; median AF duration, 4.2 years; and median number of additional risk factors for stroke, 3.

Their maximum follow-up time was 26 months, with a minimum observation time of 16 months, and a total of 338 patient-years of exposure to dabigatran etexilate.

The 2 lowest doses of dabigatran etexilate (50 mg BID, n = 105; 150 mg QD, n = 103) were discontinued upon the recommendation of the Data Safety Monitoring Board (DSMB) due to nonefficacy. Stroke rates were 8.4%/year and 8.1%/year, respectively. The patients in these dosing arms were moved over into the higher dose groups.

Similarly, the DSMB later recommended discontinuation of 300 mg BID (n = 161) for patient safety reasons. Although this group had no strokes, transient ischaemic attacks (TIAs), or myocardial infarction (MI), it did have a high rate of major haemorrhage (7.1% per year). These patients also moved over to 1 of the 2 remaining dosing arms.

The remaining doses of 300 mg QD (n = 78) and 150 mg BID (n = 339) show annual stroke rates of 9.5%/year and 0.7%/year, respectively. The rates of TIA, MI, and major bleeds (respectively) were 0%/year, 2.2%/year; 0%/year, 2.2%/year; 0%/year, 2.9%/year. Dr. Reilly stressed that the major bleed rate of 2.9%/year compares favourably with what is normally seen with standard warfarin (1.0-1.5%/year).

Transaminase elevation to levels greater than 3 times the upper limit of normal (3x ULN) were also seen. Analysis of 408 patients who received at least 30 days of dabigatran etexilate treatment showed a 2% cumulative frequency after 12 months. Dr. Reilly indicated that this was acceptable, particularly when compared with a ximelagatran trial, where it reached some 8% to 9% cumulative frequency, with the warfarin and placebo comparator analysis in this last trial at around 1%.

These 3x ULN transaminase levels also showed rapid normalisation following early termination of dabigatran etexilate.

Dr. Reilly concluded that the dabigatran etexilate 150 mg BID dosing appeared to be efficacious and to have an acceptable safety profile. This is therefore an appropriate dose for their now-ongoing phase 3 controlled trial -- Randomized Evaluation of Long Term Anticoagulant Therapy -- that has a planned patient enrolment of 15,000.

Boehringer Ingelheim sponsored this study.


[Study title: Long-Term Safety and Efficacy of Dabigatran Etexilate: a Novel Direct Thrombin Inhibitor in Patients With Atrial Fibrillation. Abstract 5]

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