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| Dr Stuart J Connolly |
Although warfarin and vitamin-K antagonists are the treatment of choice for AF patients at high risk for stroke, up to 50% are not treated with either because they are judged as unsuitable candidates by their physician, and for these patients who are treated only with aspirin, "there is a major unmet medical need," lead author Dr Stuart J Connolly (McMaster University, Hamilton, ON) told the meeting here.
"The results of ACTIVE-A, which is the largest trial ever performed of an antithrombotic therapy in atrial fibrillation, with more than three times as many strokes as any other trial, have clearly shown that clopidogrel reduces major vascular events, primarily due to a reduction in stroke," Connolly concluded. "This occurs at a cost that is acceptable in terms of major bleeding. Overall, clopidogrel provides an important benefit to a majority of patients at an acceptable risk."
He presented a risk/benefit analysis suggesting that in 1000 AF patients treated for three years, 28 strokes would be prevented, 17 of which would be fatal or disabling, and six MIs, at the cost of 20 nonstroke major bleeds, three of which would be fatal. Total days in the hospital would also be reduced, from about 34,000 to just over 30,000 total days, he noted.
The results are published online March 31, 2009 in the New England Journal of Medicine to coincide with their presentation here at the American College of Cardiology 58th Annual Scientific Session. They will appear in the May 14 issue.
ACTIVE-A
In atrial fibrillation, vitamin-K antagonists have been shown to reduce the risk for stroke by 38% over aspirin therapy and so are recommended for stroke prevention by all guidelines, Connolly said. However, a substantial proportion of these patients do not receive warfarin because they are considered unsuitable for one of a number of reasons; among these, that they have poor INR [international normalized ratio] control, concern about bleeding, drug interactions, or the preference of the patient, many of whom find the need for monitoring of this therapy onerous.
Suppression of antiplatelet activity in AF with aspirin reduces stroke by about 22%; the addition of clopidogrel to aspirin reduces platelet activity further and has been shown to reduce vascular events in the setting of acute coronary syndromes with an "acceptable bleeding risk," Connolly said.
In the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trial program, patients with atrial fibrillation and one or more additional risk factors for stroke were enrolled in one of two trials. If they were considered suitable candidates for warfarin therapy, they were enrolled in ACTIVE-W, a comparison of warfarin with the combination of clopidogrel and aspirin. The results of ACTIVE-W were reported previously and showed that use of a vitamin-K antagonist reduced the risk for stroke by 42% over clopidogrel and aspirin [2].
Those considered unsuitable for warfarin therapy were enrolled in ACTIVE-A and randomized to receive clopidogrel (75 mg/day) or placebo on a background of aspirin therapy. The reasons patients were not considered suitable for vitamin-K-antagonist therapy and enrollment in ACTIVE-W included the presence of a specific risk factor for bleeding in 23%, a physician assessment that the patient was inappropriate in 50%, and in 26%, he said, "the only reason given for enrollment in ACTIVE-A was a patient preference not to receive a vitamin-K antagonist."
The primary outcome was a composite of major vascular events, including stroke, myocardial infarction (MI), noncentral-nervous-system (CNS) systemic embolism, or death from vascular causes. A total of 7554 patients were enrolled from 580 centers in 33 countries. Median follow-up was 3.6 years.
The primary outcome was reduced by 11% with the combination of clopidogrel and aspirin, a highly statistically significant reduction, Connolly reported. "This reduction was in large part due to a substantial reduction in the outcome of stroke, which was reduced by 28%, a result that is also highly statistically significant."
There was a trend to a reduction in MI, but this was not statistically significant. There was no reduction in vascular death and no reduction in non-CNS systemic embolism.
ACTIVE-A: Cardiovascular End Points by Treatment Group
| End point | Clopidogrel, n (%/y) | Placebo, n (%/y) | Relative risk (95% CI) | p |
|---|---|---|---|---|
| Major vascular events | 832 (6.8) | 924 (7.6) | 0.89 (0.81-0.98) | .01 |
| Stroke | 296 (2.4) | 408 (3.3) | 0.72 (0.62-0.83) | <.001 |
| MI | 90 (0.7) | 115 (0.9) | 0.78 (0.59-1.03) | .08 |
Strokes of ischemic or unknown origin were reduced significantly, and hemorrhagic stroke was increased, although not significantly.
ACTIVE-A: Strokes by Treatment Group
| End point | Clopidogrel, n (%/y) | Placebo, n (%/y) | Relative risk (95% CI) | p |
|---|---|---|---|---|
| All strokes | 296 (2.4) | 408 (3.3) | 0.72 (0.62-0.84) | <.001 |
| Ischemic stroke | 235 (1.9) | 343 (2.8) | 0.68 (0.57-0.80) | <.001 |
| Hemorrhagic stroke | 30 (0.2) | 22 (0.2) | 1.37 (0.79-2.37) | NS |
When they looked at stroke severity by treatment, there was a similar effect on both disabling and fatal vs nondisabling strokes with clopidogrel; disabling strokes accounted for about 65% of all strokes in ACTIVE-A.
Overall, there were 26 fewer fatal ischemic strokes and three more fatal hemorrhagic strokes with clopidogrel, "for a net reduction of fatal strokes of 23," Connolly said.
However, the rate of major bleeding was significantly increased, from 1.3% to 2.0% per year, with treatment, and there was a trend to increased fatal bleeding that did not reach statistical significance. There were also significant increases in intracranial and extracranial bleeding.
ACTIVE-A: Major Bleeding by Treatment Group
| End point | Clopidogrel, n (%/y) | Placebo, n (%/y) | Relative risk (95% CI) | p |
|---|---|---|---|---|
| Major bleeding | 251 (2.0) | 162 (1.3) | 1.57 (1.29-1.92) | <.001 |
| Fatal hemorrhage | 42 (0.3) | 27 (0.2) | 1.56 (0.96-2.53) | .07 |
In the paper, the researchers point out that in ACTIVE-W, vitamin-K-antagonist therapy reduced stroke by 42% over clopidogrel and aspirin, very similar to a 38% reduction from a meta-analysis of trials of warfarin vs aspirin alone. This point came up during a press conference here as well.
"So how do we square those results with the results of ACTIVE-A, which clearly show that clopidogrel plus aspirin reduces the risk of stroke by 28%?" Connolly said. He speculated that the difference may lie in the fact that in ACTIVE-W, most of the patients had already been on warfarin for more than two years.
"We were comparing clopidogrel plus aspirin with people who were already on warfarin, who were used to taking warfarin, and in fact excluding patients who had problems with warfarin, most likely," he said.
"If you look in the ACTIVE-W trial at the patients who were not on warfarin at the start of the study, the effects of clopidogrel plus aspirin vs warfarin are more in line with the results of ACTIVE-A, so we think that in part the results of ACTIVE-W overestimate the benefits of warfarin compared with clopidogrel plus aspirin."
Too Ready to Switch?
During the discussion, panelist Dr Albert L Waldo (University Hospitals of Cleveland, OH) raised some concern about how patients were selected for ACTIVE-A. "If the patient said 'I don't want to take rat poison,' is that enough? I'm worried that since warfarin is so much better, that people might be taking this medication too readily."
Connolly agreed that warfarin is excellent drug for those who can take it and pointed out that for these patients, entry into the ACTIVE-W trial was an option. "Physicians were clearly judging based on their understanding, their knowledge, of an individual patient, that the patient was not a good candidate for warfarin. Furthermore, this was consistent with their previous decision, because we saw that very, very, few of patients who went into ACTIVE-A were on a vitamin-K antagonist at baseline."
Waldo also pointed out that there is evidence that, of patients legitimately judged not to be candidates for warfarin therapy, a year later only 3% to 5% still have the same relative contraindication to warfarin. "So I'm glad to see the data from this study because they're helpful, but I think it doesn't mean once on clopidogrel/aspirin, always on clopidogrel/aspirin; I think you have to really consider that the patient in six months to a year might have resolved the issue that prevented initial use of warfarin."
Dr Aaron Kugelmass (Heart and Vascular Center, Baystate Medical Center, Springfield, MA) moderated the press conference where the ACTIVE-A trial was presented. He pointed out that although this combination-treatment alternative is not recommended yet in guidelines, this and other trials "will probably help put it in the guidelines."
Again, almost half of patients with atrial fibrillation, particularly the elderly, "are very poor or completely not candidates for warfarin therapy," Kugelmass said. "Yes, there was excess bleeding, but this was basically done in a population such as that, and the benefit's still there, so I think you will see either clopidogrel or other clopidogrel-like agents become an alternative therapy used in conjunction with aspirin, as opposed to vitamin-K antagonists."
For others still judged at too high risk for bleeding, "we would probably leave those patients on aspirin alone."
Risk/Benefit Neutral?
Asked for comment on the ACTIVE-A findings, Dr Philip B Gorelick (University of Illinois College of Medicine, Chicago, IL) said that the trial provides data to answer an important clinical question relating to patients who are unsuitable for vitamin-K-antagonist therapy.
"If one takes the absolute difference for the reduction of major vascular events between the two study treatment groups, which is about 0.8% per year, and compares it with the major bleeding rate, which is 0.7% per year, one may conclude that the risk/benefit profile is neutral," Gorelick pointed out. Overall, compared with aspirin alone, the combination of clopidogrel and aspirin in these AF patients unsuitable for vitamin-K antagonists reduces the risk of major vascular events but does so at an increased risk for major bleeding.
"Therefore, if one chooses to use clopidogrel plus aspirin therapy in AF patients unsuitable for warfarin treatment, for example, careful attention should be paid to major bleeding risk, especially gastrointestinal bleeding, and minimizing it," Gorelick said. "Furthermore, it will be interesting to see whether direct-thrombin-inhibitor or anti-factor Xa drugs that are being studied in AF patients in randomized controlled trials will be safe and effective and offer an additional alternative therapy."
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