Prior stroke/TIA patients also show benefit in RE-LY subanalysis
Prior stroke/TIA patients also show benefit in RE-LY subanalysis
San Antonio, TX - Results of a subanalysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy, Warfarin, Compared With Dabigatran (RE-LY), comparing dabigatran (Boehringer Ingelheim) with warfarin show that, consistent with the overall trial results, dabigatran was noninferior to warfarin, with less major hemorrhage, particularly intracranial hemorrhage (ICH), in patients with a prior stroke or transient ischemic attack (TIA).
Among the 3623 patients with these prior events, constituting about 20% of the overall study population in RE-LY, "cerebral hemorrhage on warfarin was higher than in patients without prior TIA or stroke, and this was not the case with dabigatran," Dr Hans-Christoph Diener (University Hospital Essen, Germany) told attendees here at the American Stroke Association International Stroke Conference 2010.
The substudy was not powered to show a difference in efficacy among those with prior events, he noted, "but the results with dabigatran in patients with prior stroke or TIA were consistent with the main study."
Main results of the RE-LY trial were first presented at the EuropeanSociety of Cardiology Congress in 2009 and published simultaneously in the New England Journal of Medicine.
Oral anticoagulants
Dabigatran is one of a number of oral anticoagulants being developed for the prevention of thromboembolism in the setting of AF and other conditions, for which warfarin has long been the only choice. The last great hope was ximelagatran, which made it all the way to a Food and Drug Administration (FDA) review panel before being derailed by liver toxicity. Dabigatran is already available for venous thromboembolism (VTE) prevention during hip- and knee-replacement surgery in the European Union as Pradaxa and in Canada as Pradax.
Unlike warfarin, dabigatran can be taken as a fixed dose regardless of age, sex, or body-mass index (BMI), Diener noted. Only for patients with renal failure does the dose need to be adapted.
The main results of RE-LY showed that dabigatran at the higher dose reduced the annualized risk of the primary end point of stroke and peripheral embolic events by 34% and the risk of hemorrhagic stroke by 74% vs warfarin. The higher dose, though, was associated with a small but statistically significant increase in MI risk, a secondary end point. A post hoc analysis of the RE-LY trial, presented in November 2009 at the American Heart Association 2009 Scientific Sessions, showed that dabigatran was noninferior in the lower dose and superior in the higher dose to warfarin, even at centers where international normalized ratio (INR) control of warfarin treatment was excellent.
In this most recent subanalysis, the RE-LY investigators looked at the differential effect of dabigatran vs warfarin in the subgroup of participants with AF who had already had a stroke or TIA.
"We wanted to see whether the results in this subgroup, which has a higher risk of recurrent stroke, were consistent with results of the main study," he said.
Primary results in the overall RE-LY population showed 34% and 9% relative risk reductions in the risk for stroke or systemic embolism with the 150-mg and 110-mg doses, respectively, vs warfarin. Likewise, hemorrhagic stroke was reduced statistically significantly by 74% and 69%, respectively, and ICH was reduced by 60% and 69%, both statistically significant reductions. A similar pattern was seen in the prior-stroke/TIA subgroup and was particularly strong for the secondary prevention of ICH.
RE-LY: Outcomes in secondary-prevention patients with AF by treatment assignment
The trend to increased MI in the main study with dabigatran, which was also seen in the earlier ximelagatran studies, he noted, was not apparent in the subpopulation with prior stroke or TIA; MI occurred in 15 patients on low-dose dabigatran, 20 patients in the high-dose group, and 15 patients in the warfarin group, Diener said, "and this, as you can imagine, was not statistically significant."
Hypothesis-generating?
Diener pointed to some limitations of their study, including the relatively short mean observation time of two years, and the prospective, randomized, open, blinded-end-point (PROBE) study design, in which those on warfarin were not blinded to treatment assignment, although he noted that rigorous adjudication of end points would compensate for this.
During discussion after the presentation, an audience member raised a further issue with the PROBE design. "You mentioned that the adjudication process compensated for the PROBE design, but if that were the case, we really wouldn't need to do double-blind studies anymore, [we could] just do PROBE studies, which would be mechanistically much simpler," he said.
"I wonder if an observation of your results is that [the study] should be taken as hypothesis-generating, rather than truth-confirming, and whether in fact the results of this trial shouldn't prompt an agency [such as the National Institute of Neurological Disorders and Stroke] to now do a double-blind trial to try to confirm these results."
Diener thought it unlikely anyone would be willing to invest the same amount of money spent on this trial to recruit another 18 000 patients. Further, he pointed out that in the SPORTIF program investigating ximelagatran, bleeding rates were actually higher in the double-blind trial than in the open trial. "I have my doubts whether it's safe that we do double-blind trials with anticoagulation, so I'm really promoting the PROBE design."
He added, however, that there are two other double-blind trials of dabigatran ongoing, "so we will learn at the end what the truth is."
Another open question is what the best dose of dabigatran may be for these higher-risk patients, Diener added.
The company has submitted an application to the FDA for approval of dabigatran for stroke prevention in AF, he noted.
Warfarin a "substantial competitor"
Asked for comment on these findings, Dr Philip B Gorelick (University of Illinois, Chicago) pointed out that despite the problems associated with warfarin treatment—the food-drug and drug-drug interactions, the need for monitoring, and the narrow therapeutic window—"it's a very substantial competitor," reducing stroke risk in atrial fibrillation "conservatively" by about 60% and up to 80% in some trials.
Now, RE-LY findings show that dabigatran is not only similar to warfarin but is superior and safer. "So you've got a real potential game-changer," which has no known interactions and limited drug-drug interactions, he said, although renal function must be monitored, because the drug is eliminated by the kidney.
It may also help with the major problem associated with anticoagulation—that many high-risk patients aren't taking warfarin at all. "In clinical practice, the problem we face is up to half or more of patients who need warfarin aren't on it," he said. "Hopefully with dabigatran, we're going to be able to close that gap, get more patients on the drug, and get better outcomes in terms of stroke reduction."
This may be particularly true in older patients, who have higher risks, but in whom the efficacy of aspirin appears to drop off, he added.
San Antonio, TX - Results of a subanalysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy, Warfarin, Compared With Dabigatran (RE-LY), comparing dabigatran (Boehringer Ingelheim) with warfarin show that, consistent with the overall trial results, dabigatran was noninferior to warfarin, with less major hemorrhage, particularly intracranial hemorrhage (ICH), in patients with a prior stroke or transient ischemic attack (TIA).
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Dr Hans-Christoph Diener |
Among the 3623 patients with these prior events, constituting about 20% of the overall study population in RE-LY, "cerebral hemorrhage on warfarin was higher than in patients without prior TIA or stroke, and this was not the case with dabigatran," Dr Hans-Christoph Diener (University Hospital Essen, Germany) told attendees here at the American Stroke Association International Stroke Conference 2010.
The substudy was not powered to show a difference in efficacy among those with prior events, he noted, "but the results with dabigatran in patients with prior stroke or TIA were consistent with the main study."
Main results of the RE-LY trial were first presented at the EuropeanSociety of Cardiology Congress in 2009 and published simultaneously in the New England Journal of Medicine.
Oral anticoagulants
Dabigatran is one of a number of oral anticoagulants being developed for the prevention of thromboembolism in the setting of AF and other conditions, for which warfarin has long been the only choice. The last great hope was ximelagatran, which made it all the way to a Food and Drug Administration (FDA) review panel before being derailed by liver toxicity. Dabigatran is already available for venous thromboembolism (VTE) prevention during hip- and knee-replacement surgery in the European Union as Pradaxa and in Canada as Pradax.
Unlike warfarin, dabigatran can be taken as a fixed dose regardless of age, sex, or body-mass index (BMI), Diener noted. Only for patients with renal failure does the dose need to be adapted.
The main results of RE-LY showed that dabigatran at the higher dose reduced the annualized risk of the primary end point of stroke and peripheral embolic events by 34% and the risk of hemorrhagic stroke by 74% vs warfarin. The higher dose, though, was associated with a small but statistically significant increase in MI risk, a secondary end point. A post hoc analysis of the RE-LY trial, presented in November 2009 at the American Heart Association 2009 Scientific Sessions, showed that dabigatran was noninferior in the lower dose and superior in the higher dose to warfarin, even at centers where international normalized ratio (INR) control of warfarin treatment was excellent.
In this most recent subanalysis, the RE-LY investigators looked at the differential effect of dabigatran vs warfarin in the subgroup of participants with AF who had already had a stroke or TIA.
"We wanted to see whether the results in this subgroup, which has a higher risk of recurrent stroke, were consistent with results of the main study," he said.
Primary results in the overall RE-LY population showed 34% and 9% relative risk reductions in the risk for stroke or systemic embolism with the 150-mg and 110-mg doses, respectively, vs warfarin. Likewise, hemorrhagic stroke was reduced statistically significantly by 74% and 69%, respectively, and ICH was reduced by 60% and 69%, both statistically significant reductions. A similar pattern was seen in the prior-stroke/TIA subgroup and was particularly strong for the secondary prevention of ICH.
RE-LY: Outcomes in secondary-prevention patients with AF by treatment assignment
| End point | Warfarin | Dabigatran 110 mg twice daily | RR (95% CI) vs warfarin | p | Dabigatran 150 mg twice daily | RR (95% CI) vs warfarin | p |
| Stroke/systemic embolism (%/year) | 2.74 | 2.32 | 0.85 (0.59-1.22) | 0.37 | 2.07 | 0.76 (0.53-1.10) | 0.14 |
| Hemorrhagic stroke (n) | 18 | 2 | 0.11 (0.03-0.47) | 0.003 | 5 | 0.27 (0.10-0.72) | 0.009 |
| ICH (n) | 30 | 6 | 0.20 (0.08-0.47) | 0.001 | 13 | 0.41 (0.21-0.79) | 0.007 |
The trend to increased MI in the main study with dabigatran, which was also seen in the earlier ximelagatran studies, he noted, was not apparent in the subpopulation with prior stroke or TIA; MI occurred in 15 patients on low-dose dabigatran, 20 patients in the high-dose group, and 15 patients in the warfarin group, Diener said, "and this, as you can imagine, was not statistically significant."
Hypothesis-generating?
Diener pointed to some limitations of their study, including the relatively short mean observation time of two years, and the prospective, randomized, open, blinded-end-point (PROBE) study design, in which those on warfarin were not blinded to treatment assignment, although he noted that rigorous adjudication of end points would compensate for this.
During discussion after the presentation, an audience member raised a further issue with the PROBE design. "You mentioned that the adjudication process compensated for the PROBE design, but if that were the case, we really wouldn't need to do double-blind studies anymore, [we could] just do PROBE studies, which would be mechanistically much simpler," he said.
"I wonder if an observation of your results is that [the study] should be taken as hypothesis-generating, rather than truth-confirming, and whether in fact the results of this trial shouldn't prompt an agency [such as the National Institute of Neurological Disorders and Stroke] to now do a double-blind trial to try to confirm these results."
Diener thought it unlikely anyone would be willing to invest the same amount of money spent on this trial to recruit another 18 000 patients. Further, he pointed out that in the SPORTIF program investigating ximelagatran, bleeding rates were actually higher in the double-blind trial than in the open trial. "I have my doubts whether it's safe that we do double-blind trials with anticoagulation, so I'm really promoting the PROBE design."
He added, however, that there are two other double-blind trials of dabigatran ongoing, "so we will learn at the end what the truth is."
Another open question is what the best dose of dabigatran may be for these higher-risk patients, Diener added.
The company has submitted an application to the FDA for approval of dabigatran for stroke prevention in AF, he noted.
Warfarin a "substantial competitor"
Asked for comment on these findings, Dr Philip B Gorelick (University of Illinois, Chicago) pointed out that despite the problems associated with warfarin treatment—the food-drug and drug-drug interactions, the need for monitoring, and the narrow therapeutic window—"it's a very substantial competitor," reducing stroke risk in atrial fibrillation "conservatively" by about 60% and up to 80% in some trials.
Now, RE-LY findings show that dabigatran is not only similar to warfarin but is superior and safer. "So you've got a real potential game-changer," which has no known interactions and limited drug-drug interactions, he said, although renal function must be monitored, because the drug is eliminated by the kidney.
It may also help with the major problem associated with anticoagulation—that many high-risk patients aren't taking warfarin at all. "In clinical practice, the problem we face is up to half or more of patients who need warfarin aren't on it," he said. "Hopefully with dabigatran, we're going to be able to close that gap, get more patients on the drug, and get better outcomes in terms of stroke reduction."
This may be particularly true in older patients, who have higher risks, but in whom the efficacy of aspirin appears to drop off, he added.
| The RE-LY trial was funded by Boehringer Ingelheim. Diener reports he has received consulting and lecture fees from Boehringer Ingelheim, Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, CoAxia, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme, MindFrame, Neurobiological Technologies, Novartis, Novo Nordisk, Paion, Parke Davis, Pfizer, Sanofi-Aventis, Sankyo, Servier, Solvay, Thrombogenics, Wyeth, and Yamaguchi. He has also received grant support from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Novartis, Janssen Cilag, Sanofi-Aventis, theGerman Research Council, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Gorelick reports he has been an advisor to Boehringer Ingelheim. |
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