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Two new trials launched to examine Pradaxa
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DALLAS — Boehringer Ingelheim has announced the launch of two new global clinical trials of dabigatran. One will evaluate the oral anticoagulant in patients with nonvalvular atrial fibrillation who have undergone PCI and the other will evaluate the drug in patients with an embolic stroke of undetermined source.
The trials, RE-DUAL PCI and RE-SPECT ESUS, are part of the RE-VOLUTION clinical trial program for dabigatran (Pradaxa, Boehringer Ingelheim). To date, the program has evaluated more than 40,000 patients in 44 countries during the course of 10 completed phase 3 trials.
RE-DUAL PCI
Christopher P. Cannon
RE-DUAL PCI, to be conducted with the Harvard Clinical Research Institute and launched in 2014, will evaluate dabigatran plus single antiplatelet therapy vs. the current standard of care, warfarin plus two antiplatelet agents, in patients with nonvalvular AF who have undergone PCI. The population is understudied, principal investigator Christopher P. Cannon, MD, director of cardiometabolic trials for Harvard Clinical Research Institute, said at AHA 2013.
“We have a lot of large registry studies, but there aren’t prospective trials, in part because this is such a difficult management issue,” Cannon told Cardiology Today. “It is difficult to work out dosing strategies in patients with two problems at the same time, but now we’re ready, thanks in part to the WOEST study, which changed the antiplatelet-dosing strategy.”
Between 5% and 10% of patients who have undergone PCI also have AF, he said.
Because patients who are on anticoagulants and antiplatelets at the same time are at high risk for bleeding, “this is a balance that is one of the toughest things that all of us face each day,” Cannon said. “We wonder what is the right balance to optimally prevent stroke but also prevent clots from forming in the stent, which lead to heart attacks and other cardiovascular events. The study will try to identify the effects of two new strategies; two different doses [of dabigatran] with single antiplatelet therapy.”
Clinical outcomes evaluated will include death, MI, stroke and bleeding, he said.
RE-SPECT ESUS
Christopher B. Granger
RE-SPECT ESUS will evaluate two doses of dabigatran compared with the standard of care, acetylsalicylic acid 100 mg daily, for secondary stroke prevention in patients who had an embolic stroke of undetermined source within 3 months prior to enrollment, according to Christopher B. Granger, MD, professor of medicine at Duke University Medical Center. The trial is expected to launch in 2015.
In the group randomly assigned to dabigatran, patients aged 75 years or younger who have normal kidney function will receive 150 mg twice daily, and patients older than 75 years or those who have reduced kidney function will receive 110 mg twice daily, Granger said.
“This is an important program to address an unmet clinical need,” he said. “This addresses a large proportion of the 800,000 strokes that occur per year in the United States. When these strokes occur, the chance of another stroke occurring within the next year is substantial. Many of these subsequent strokes are likely caused by thromboembolism that could be prevented with anticoagulation, including dabigatran. This is especially the case when the original stroke fits into the category of ‘embolic stroke of undetermined cause’ in which non-embolic causes of stroke have been excluded. There hasn’t been effective development of an anticoagulation strategy for this purpose.”
Long-term data released
Boehringer Ingelheim also announced that analysis of combined results from the RE-LY and RELY-ABLE trials of dabigatran for stroke prevention in patients with nonvalvular AF showed that dabigatran continued to be associated with low rates of mortality, stroke and major hemorrhage through a median follow-up period of 4.6 years (maximum, 6.7 years).
According to a company press release, event rates associated with dabigatran during that follow-up period were as follows:
- Stroke or systemic embolism: 1.25% per year for the 150-mg twice-daily dose and 1.54% per year for the 110-mg twice-daily dose.
- Mortality: 3.43% per year for the 150-mg dose; 3.55% per year for the 110-mg dose (HR=0.97; 95% CI, 0.87-1.08).
- Ischemic stroke: 1.03% per year for the 150-mg dose; 1.29% per year for the 110-mg dose. Rates of hemorrhagic stroke associated with dabigatran observed during RE-LY, approximately one case per 1,000 patients per year, remained the same during the follow-up period.
- Major hemorrhage: 3.34% per year for the 150-mg dose; 2.76% per year for the 110-mg dose.
Antidote for dabigatran
Boehringer Ingelheim also released data from a phase 1 study in 145 healthy male volunteers that demonstrated an investigational fully humanized antibody fragment led to an immediate, complete and sustained reversal of the anticoagulation effect of dabigatran.
No serious adverse events were observed. Of participants whose response was measured by thrombin time, the most sensitive indicator of dabigatran’s anticoagulant effect, reversal of dabigatran’s anticoagulant effect was complete and sustained in all participants who received the 4-g dose and in seven of nine participants who received the 2-g dose. Reversal was not sustained in those who received the 1-g dose. – by Erik Swain
Disclosure: Cannon is a clinical adviser for and holds equity in Automedics Medical Systems and receives research grants or support from Accumetrix, AstraZeneca, CSL Behring, Essentials, GlaxoSmithKline, Merck, Regeneron, Sanofi and Takeda. He serves on advisory boards for Alnylam, Bristol-Myers Squibb, Lipimedix and Pfizer, but donates those funds to charity. Granger reports financial ties with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Medtronic Foundation, Merck, Pfizer, Ross Medical Corp., Sanofi-Aventis, Takeda and The Medicines Company.