(Updated August 30, 2009) (Barcelona, Spain) — An oral anticoagulant that does not go by the name of warfarin prevented strokes and peripheral embolic events in patients with atrial fibrillation (AF) significantly better than that much older drug at a higher dose and just as well at a lower dose in a huge randomized trial . It was also just as safe as warfarin or better than it, respectively, with respect to major bleeding events, according to investigators reporting today at the European Society of Cardiology (ESC) Congress 2009 and in a simultaneous online release from the New England Journal of Medicine. Both dosages were associated with fewer intracerebral bleeds.
The potential new contender in AF, dabigatran etexilate (Boehringer Ingelheim), is one of several oral anticoagulants in clinical trials for the prevention of AF-related thromboembolism, venous thromboembolism (VTE), and other conditions for which warfarin had long been the only choice. A competitive thrombin inhibitor, dabigatran is currently available for VTE prevention during hip- and knee-replacement surgery in the European Union as Pradaxa and in Canada as Pradax.
In the new trial, the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY), dabigatran given at 150 mg twice a day reduced the annualized risk of the primary end point, stroke/peripheral embolic events, by 34% (p<0.001) and the risk of hemorrhagic stroke by 74% (p<0.001) compared with warfarin. The higher dabigatran dose was associated with a slightly but significantly (p=0.048) increased risk of MI, a secondary end point.
"I think this is a dramatic study with very definitive results," Dr Michael D Ezekowitz (Lankenau Institute for Medical Research, Wynnewood PA) told heartwire . "Both doses for different reasons were better than warfarin. So the results of the trial were unequivocal." Ezekowitz is one of the trial's lead investigators and a coauthor on the report.
Pointing out that it takes several days to achieve therapeutic warfarin levels and that its effects have to be monitored, Ezekowitz said dabigatran "has a rapid onset of action, there are very few drug-drug interactions and those that occur have proven not to be important, and the patients don't require any form of monitoring. Operationally, warfarin is a much more difficult drug to use, and dabigatran is obviously much more user friendly for both the patients and the physicians taking care of those patients."
The trial isn't necessarily conclusive, "but I think it's very promising," Dr Fausto Jose Pinto (Lisbon University Medical School, Portugal) told heartwire. "I don't want to call it a breakthrough, but the data were very relevant for clinical practice."
Long-term outcomes should be explored before embracing any new drug, especially one intended for long-term use, he said. "For RE-LY, we have a two-year follow-up, which is reasonable, but we still need long-term results." Pinto comoderated the session featuring Connolly's presentation.
In an editorial accompanying the published RE-LY report , Dr Brian F Gage (Washington University, St Louis, MO) writes, "Because of dabigatran's twice-daily dosing and greater risk of nonhemorrhagic side effects, patients already taking warfarin with excellent INR [international normalized ratio] control have little to gain by switching to dabigatran." Dabigatran was associated with more dyspepsia in the trial, and more patients went off the drug than those who went off warfarin.
"In contrast," he writes, "many other patients who have atrial fibrillation and at least one additional risk factor for stroke could benefit from dabigatran."
The report's first author, Dr Stuart J Connolly (McMaster University, Hamilton, ON), formally reported RE-LY to attendees at the meeting.
"This [dabigatran] looks like it's going to be a better anticoagulant than warfarin. We were looking for something that would be as good as warfarin and easier to use," Connolly told heartwire . "Well, we got the 'easy-to-use' part, and we saw no toxicity other than dyspepsia. And on top of that we got a drug that's actually significantly more effective and safer at the same time."
"We did not find evidence of hepatotoxicity" from dabigatran, according to the published report from Connolly et al. It was liver toxicity that had derailed the otherwise-promising oral thrombin inhibitor ximelagatran for the same clinical use, they observe.
Dr A John Camm (St George's University of London, UK), appointed discussant following Connolly's presentation, lauded the trial's results and said that "dabigatran seems not to be merely a superior therapy, but we must probably regard this drug as a stimulus to a paradigm change in the antithrombotic management of atrial fibrillation."
Still, he raised some cautions and questions about the trial. For example, "do the elderly fare as well with dabigatran as [patients] in the trial as a whole? Does it matter that there is no antidote to dabigatran? What should we do when we want to cardiovert a patient--do we change back to warfarin?"
He also took on what may be RE-LY's most obvious potential shortcoming, that it had a prospective, randomized, open-label, blinded-end-point (PROBE) design. Such a trial design can allow comparisons of very different therapies, he noted, but patient and physician knowledge of treatment allocation can influence any events that are not blindly adjudicated.
While such a design does raise questions, "we are used to open trials in cardiology. The rate-vs-rhythm trials, the implantable-defibrillator trials, many pacemaker trials, ASCOT, and CIBIS 3 were all PROBE designs."
Finally, Camm said, "dabigatran is likely to be expensive, but we clearly must afford it. Perhaps the number of reduced strokes and the unnecessary monitoring will allow the drug to be afforded."
Contacted by heartwire for comment, Dr Albert L Waldo (University Hospitals of Cleveland, OH) also pointed out that "cost will obviously be an issue, but the cost of stroke, both economically and on families and the individual, is high." Dabigatran, he said, "I think will be the new gold standard." Waldo, not a coauthor of the published report, said he had some limited involvement in the early planning of RE-LY but not thereafter.
He observed that the drug's potential contribution to patient care, for those who can avoid warfarin, wasn't fully evaluated in RE-LY. "With warfarin, if you stay in the therapeutic range, it's very effective. The problem is, it has enormous effects on quality of life. As patients will tell you, they have to go in for an [INR] check once a month, and if they're a little up or low they have to go back in a week or so. It interferes with everything," Waldo said about warfarin, a vitamin-K antagonist. "You have to change your diet. It seems like half the food in the world has vitamin K, and the other half increases the potency of warfarin."
Conducted at 951 centers in 44 countries, the trial had randomized 18 113 patients with AF (mean age 71) and at least one other risk factor for stroke to receive blinded treatment with dabigatran at either 110 mg or 150 mg two times per day or unblinded prophylaxis with warfarin adjusted to an INR of 2.0 to 3.0; INR was measured at least once per month. Concomitant aspirin at <100 mg/day "or other antiplatelet agents were permitted," according to RE-LY investigators. As it turned out, aspirin was taken throughout the trial by about one-fifth of patients on dabigatran and about 17% of those on warfarin.
The AF had to have been ECG-documented at screening for the trial or within the prior six months, and eligibility required that patients have at least one non-AF stroke risk factor, which could include prior stroke or transient ischemic attack (TIA), LVEF <40, NYHA class 2 to 4 heart failure within the prior six months, or either age >75 or age 65 to 74 with diabetes, hypertension, or coronary disease.
Over a median two-year follow-up, the annualized rates of the primary end point were 1.53% for low-dose dabigatran, 1.11% for the high-dose drug, and 1.69% for those on warfarin.
The relative risks vs warfarin were 0.91 (95% CI 0.74–1.11) for the low-dose (p<0.001 for noninferiority) and 0.66 (95% CI 0.53–0.82) for the high-dose group (p<0.001 for superiority).
Annualized mortality was 3.75% and 3.64% for the low- and high-dose groups, respectively, compared with 4.13% for warfarin. The relative risk was 0.91 (95% CI 0.80–1.03) for the low dose (p=0.13) and 0.88 (95% CI 0.77–1.00) for the high dose (p=0.051).
The annualized MI rates were 0.72%, 0.74%, and 0.53%, respectively, for low-dose dabigatran, high-dose dabigatran, and warfarin. The risk trended higher for low-dose dabigatran at 1.35 (95% CI 0.98-1.87; p=0.07) and was significantly higher for in the high-dose group at 1.38 (95% CI 1.00-1.91; p=0.048).
"This was an unexpected finding," Connolly said to heartwire . "The working hypothesis now is, we know that warfarin is effective in reducing myocardial infarction, and it may well be that warfarin is more potent than dabigatran at this particular aspect of antithrombotic therapy."
The absolute rates of MI were quite low, Ezekowitz observed. And "the effect of dabigatran in reducing stroke and intracerebral bleeds far outweighed the small increase in MI rate, but this is a question we will be looking into in much more detail."
Hemorrhagic stroke rates were 0.12%/year (p<0.001) and 0.10%/year (p<0.001) for the low- and high-dose groups respectively, and 0.38% for warfarin.
The rates for major bleeding were 2.71 (p=0.003 vs warfarin) for the low dose, 3.11 (NS vs warfarin) for the high dose, and 3.36 for warfarin.
Significantly more patients taking dabigatran went off the drug, which Ezekowitz attributes largely to the severe dyspepsia, the main side effect that occurred more often with dabigatran than with warfarin.
Also, Connolly proposed, "In an open-label trial, where physicians and patients both knew whether or not they were getting the new drug or the old drug, there may be a tendency for people to get a little bit scared when they're on an experimental agent; that may explain part of it."
Ezekowitz said his group can't currently make a recommendation for one dabigatran dose over the other. They'll be looking at this issue further by exploring whether there were outcomes differences between the 110-mg twice daily and 150-mg twice-daily dosages in any subgroups.
Still, Connolly said, "It's our expectation that both of the doses will offer advantages to patients and will allow physicians to tailor therapy according to individual patient characteristics such as the risk of hemorrhage and the risk of stroke."
"This drug is going to get approved, no doubt about it," Connolly predicted for heartwire . "Regulators are going to have questions about the unblinded nature of the warfarin therapy, they're going to have questions about it being a single trial, obviously. But in the end, they'll have no choice but to approve this drug, the results are so outstanding," he said. "An anticoagulant that actually is more effective than warfarin and doesn't have the side effect of increased bleeding? It's almost never happened before, it's remarkable."
RE-LY author disclosures are in the report, which further states that RE-LY is a collaboration between Boehringer-Ingelheim, McMaster University and Hamilton Health Sciences, the Uppsala Clinical Research Centre, Sweden, and Lankenau Institute for Medical Research. Camm reports having no direct involvement in the trial but discloses having been an advisor or speaker for Sanofi-Aventis, AstraZeneca, Cardiome, Astellas, Gilead, Menarini, Xention, ARYx, Prism, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, St Jude Medical, Boston Scientific, Boehringer-Ingelheim, Merck, and Bayer. Waldo says he has consulted for Boehringer-Ingelheim and had briefly been on the trial's steering committee at its outset.
Heartwire from Medscape © 2009 Medscape, LLC
Cite this: RE-LY: Oral Antithrombin Dabigatran Outshines Warfarin in Atrial Fib - Medscape - Aug 30, 2009.