Stockholm, Sweden - Patients with atrial fibrillation unable to take warfarin who are treated with apixaban (Pfizer/Bristol-Myers Squibb), an investigational oral factor Xa inhibitor, had a significantly lower risk of stroke and systemic embolic events compared with patients treated with aspirin.
Importantly, the benefits of apixaban did not come at a cost of increased bleeding, with no observed increases in the risk of major bleeding, minor bleeding, or intracranial hemorrhage, among other end points, in those treated with apixaban.
The results of the study, known as the Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, were presented today here at the European Society of Cardiology 2010 Congress by lead investigator Dr Stuart Connolly (McMaster University, Hamilton, ON). Asked his impression of the reduction in stroke risk, coupled with the safety of apixaban, in these difficult-to-treat patients, Connolly called the novel anticoagulant "superb."
"It's a very easy to use drug to give," Connolly told heartwire . "You take it twice a day, and it's well tolerated. It didn't have any liver toxicity, no particular adverse events that we saw. If anything, it's extremely safe. We consider aspirin to be a drug we can just about give any patient, but aspirin does cause bleeding. It's not completely benign."
AVERROES trial stopped early
Briefly, AVERROES included 5600 patients with atrial fibrillation from 36 countries who were unsuitable for or intolerant of warfarin. The study began in September 2007, with patients randomized to 5 mg of apixaban or 81 to 324 mg of aspirin for up to 36 months or until the end of the study.
As previously reported by heartwire , the AVERROES trial was stopped early when the data and safety monitoring board performed a prespecified interim analysis showing significant benefit with apixaban. The analysis was repeated three months later and the benefit confirmed, leading to the early termination of the trial.
Treatment with apixaban significantly reduced the risk of stroke or systemic embolic events 54%, a statistically significant reduction. The benefit of treatment, however, occurred without a corresponding increase in the risk of bleeding. Overall, the risk of major bleeding increased 14%, but this increase was statistically nonsignificant. Regarding specific types of bleeding, there was no increased risk of fatal or intracranial hemorrhage, two particular concerns with atrial-fibrillation patients who receive anticoagulation therapy.
AVERROES: Primary and secondary end points
|Outcomes||Apixaban (n= 2809)||Aspirin (n= 2791)||Relative r isk (95% CI)|
|Stroke or systemic embolic event||1.6||3.6||0.46 (0.33-0.64)|
|Stroke, embolic event, MI, or vascular death||4.1||6.2||0.66 (0.53-0.83)|
|Vascular death||2.5||2.9||0.86 (0.64-1.16)|
|Cardiovascular hospitalizations||11.8||14.9||0.79 (0.68-0.91)|
|Total death||3.4||4.4||0.79 (0.62-1.02)|
AVERROES: Bleeding events
|Outcomes||Apixaban (n=2809)||Aspirin (n=2791)||Relative r isk (95% CI)|
|Major bleeding||1.4||1.2||1.14 (0.74-1.75)|
|Clinical relevant nonmajor bleeding||3.0||2.6||1.18 (0.88-1.58)|
|Minor bleeding||5.2||4.1||1.27 (1.01-1.61)|
|Fatal bleeding||0.1||0.1||0.84 (0.26-2.75)|
Patients in AVERROES had all types of atrial fibrillation, as well as different risks for stroke based on their CHADS2 score. Patients were roughly divided into three groups, with 36% of patients at low risk, having a CHADS2 score of 0-1, while 37% had a CHADS2 score of 2 and 27% had a CHADS2 score of 3 or greater. According to Connolly, the patients included in AVERROES were similar to those included in the ACTIVE and RE-LY studies.
"The baseline risk of these patients is high," said Connolly. "On standard therapy, which is aspirin, these patients had a 3.6% annual risk of stroke, so that speaks for itself. With these patients, our first goal is to put them on warfarin. If they haven't been on it before, the physician has to make a decision about how well they'll do on warfarin. It's a difficult treatment, tricky to use, and a lot of patients have trouble with it. And for many patients, they're not candidates for warfarin, so they get put on aspirin, and with aspirin they have a higher risk of stroke."
What do the results mean?
Dr Harald Arnesen (Oslo University Hospital, Norway), the scheduled discussant during the late-breaking clinical-trials session, called AVERROES a "landmark study" and predicted the use of aspirin will drastically decrease once the drug becomes available. In addition, Dr Thomas L ü scher (University of Zurich, Switzerland), who commented on the results of the study for heart wire , said the findings were "impressive," particularly the equivalent risk in bleeding compared with aspirin.
"As a proof of principle, it's exciting, because these new drugs are so selective just on one factor, like factor Xa, whereas warfarin is much less selective, inhibiting around five factors, so it makes sense that bleeding tends to be lower in these new drugs," he said. "The fact that the [bleeding] risks are quite similar to aspirin is really quite exciting."
To heart wire , Dr Martin Jan Schalij (Leiden University Medical Center, the Netherlands) said that the present study is encouraging, but most doctors will be waiting for head-to-head comparisons between warfarin and apixaban in atrial-fibrillation patients. Patients at low risk, those with a CHADS2 score of 0-1, are not treated with warfarin and usually given aspirin alone. For those with a higher risk, it is already known that aspirin is insufficient to stave off the risk of stroke.
"Most patients are treated with warfarin, and I don't know how it is in other countries, but in Western Europe it's an effective therapy, and it's cheap," said Schalij. "The drugs cost only a few cents a day. On the other hand, we do have problems with respect to the therapeutic goals we need to reach, and it's a problem. Bleeding is not usually the major problem, but rather getting patients into the therapeutic range. It seems that with the new drugs this problem is more or less solved, but we still have to wait, because this study looked only at patients unsuitable for warfarin."
A number of experts questioned the definition of "unsuitable for warfarin," noting that the definition can change from one physician to the next. In AVERROES, 61% of the included patients were expected to be unsuited for warfarin, while 39% used the drug and discontinued it. Connolly said the decision about which patients are unsuitable for warfarin rests with the clinician. If they have not taken warfarin in the past, doctors typically question whether the patient will return for regular clinic visits to adjust or to maintain the international normalized ratio (INR). Patients with alcohol problems or those who take other medications that interact with warfarin are not candidates for the drug. He said that in most general-hospital clinics, roughly 25% of patients might not be candidates for warfarin, although this number is lower in specialized tertiary-care centers.
The next study, known as the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial, is a comparison of apixaban 5.0 mg twice daily vs warfarin adjusted to an INR of 2.5 in patients with atrial fibrillation. The trial is currently under way, and results are expected in April 2011.
|The study was sponsored by Bristol- Myers-Squibb and Pfizer. Connolly reports research support and lecture and consulting fees from the sponsor.|
Heartwire from Medscape © 2010
Cite this: AVERROES: Apixaban yields significant reductions in stroke, no increased bleeding - Medscape - Aug 31, 2010.