Apixaban Superior to Warfarin for Atrial Fibrillation Stroke Prevention

By Jennifer L.W. Fink

  • Summary: The drug apixaban (Eliquis) was shown to be superior to warfarin for atrial fibrillation stroke prevention in a large study that was published in the New England Journal of Medicine. FDA approval of the drug is expected by March 28, 2012.
  • Approximate reading time: 3–5 minutes

November 30, 2011 — A recent New England Journal of Medicine article, Apixaban versus Warfarin in Patients with Atrial Fibrillation, reported on ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), an international multicenter trial that compared the effectiveness of apixaban and warfarin.

Apixaban is a “direct factor Xa (pronounced 10a) inhibitor”, which means that it prevents clotting by a different method than Vitamin K antagonists such as warfarin. Apixaban is a third warfarin alternative. Dabigatran (Pradaxa) was approved by the FDA for stroke prevention in patients with afib one year ago on the strength of the RE-LY trial, a study demonstrating that patients taking dabigatran suffered fewer strokes than those taking warfarin. See FDA Approves Pradaxa as Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation for more information about dabigatran.

The FDA also recently approved rivaroxaban (Xarelto), another direct factor Xa inhibitor and the second warfarin alternative. During the approval process, FDA officials expressed concerns about the drug’s dosing schedule and lack of a standardized plan to bridge patients from rivaroxaban to warfarin should it become necessary to discontinue rivaroxaban. See Xarelto Approved by the FDA for Atrial Fibrillation Stroke Prevention for more information about rivaroxaban and how the FDA’s concerns were addressed.

ARISTOTLE Study Results

The ARISTOTLE study was a large international study that was designed to see which drug — apixaban or warfarin — was better at preventing strokes (while minimizing bleeding) in patients with atrial fibrillation. The four-year study enrolled 18,201 patients from 39 countries. The median age (midpoint) of participants was 70 years, and 35.5% of the patients were female. All patients had atrial fibrillation or flutter and at least one other stroke risk factor (age greater than 75 years, previous stroke, heart failure, diabetes or high blood pressure). The mean (average) CHADS2 score of study participants was 2.1. (For comparison, patients in the ROCKET-AF study of rivaroxaban had a mean CHADS2 score of 3.5, indicating a higher risk for stroke.)

While 43% of study participants had never taken a vitamin K antagonist such as warfarin, 57% had previously used it. Investigators wanted to include patients who’d never used warfarin because previous studies have estimated that only about half of patients who could benefit from warfarin take the drug. Some doctors and patients shy away from the drug due to potential drug or food interactions, or because patients may lack the transportation necessary to return to the lab for the follow-up blood work necessary with warfarin.

Patients in the ARISTOTLE study were randomly assigned to either apixaban or warfarin, and neither the patients nor the investigators knew which patients were getting which drug. This is officially known as a “double blind double dummy” trial in that each patient takes two pills — one study drug and one placebo — and neither the doctors nor the patients know which patient got what drug until after the study ends. Most patients who received apixaban got 5 mg twice daily. Patients with two or more of the following criteria — age 80+ years, low body weight, or kidney (renal) issues — received a 2.5 mg dose of apixaban twice daily. Approximately a quarter of all patients in the study discontinued their drug (either study drug or placebo) before the end of the study, which includes the four percent that dropped out of the study due to death.

Patients were followed for an average of 1.8 years. The patients who were on warfarin were managed to achieve an INR (International Normalized Ratio) between 2.0 and 3.0. They achieved these target INR levels an average of 62.2% of the time, a level that meets the 60–70% time in therapeutic range (TTR) described as “skillfully-managed” warfarin by FDA advisory committee members in the rivaroxaban hearing. Researchers excluded the first seven days of treatment and interruptions in study drug treatment when calculating time in therapeutic range.

Study participants who took apixaban suffered fewer strokes or blood clots than those on warfarin (1.27% per year in the apixaban group vs. 1.60% in the warfarin group). The rate of hemorrhagic stroke (bleed) in the apixaban group was half that of the warfarin group, and the rate of ischemic (clot) or uncertain type of stroke was 8% lower in the apixaban group.

Fewer patients on apixaban died; the rate of death from any cause was 3.52% per year in the apixaban group vs. 3.94% in the warfarin group. Patients in the apixaban group also suffered fewer heart attacks, although the difference was not statistically significant.

Importantly, patients taking apixaban had fewer bleeding episodes than patients on warfarin. The rate of any bleeding was 18.1% per year in the apixaban group vs. 25.8% per year in the warfarin group. An intention-to-treat analysis, which looked at all patients who received even one dose of a study drug, revealed a consistent 27% reduction in the rate of major bleeding in the apixaban group, as compared to the warfarin group.

In summary, apixaban reduced strokes and blood clots by 21%, major bleeds by 31%, and death by 11%. So for every 1,000 patients treated for 1.8 years, apixaban prevented a stroke in 6 patients, major bleeding in 15 patients and death in 8 patients. The investigators conclude that “in patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.” They further state that “The lower risk of hemorrhagic stroke associated with all three novel anticoagulants suggests that there is a specific risk associated with warfarin.”

Comments:  If apixaban is approved by the FDA early next year, which is expected as the FDA has just announced an expedited review to be completed by March 28, 2012, patients with atrial fibrillation will have three alternatives to warfarin for stroke prevention. The new drugs, though, will all cost more than warfarin, and none has been studied as long as warfarin has. You’ll have to talk with your doctor, of course, to find out which option is best for you. Here are some things to consider:

  • Is warfarin working for you? If you have no contraindications or drug/food interactions with warfarin, and can effectively maintain your INR within the desired range, warfarin may be the best drug for you. Warfarin is just pennies per dose, compared to dollars per dose for the newer drugs.
  • What’s your risk for stroke? All three alternatives have been shown to reduce stroke risk when compared to warfarin, though only rivaroxaban (Xarelto) was tested in a high-risk population.
  • Are you comfortable that these new drugs do not yet have antidotes? Vitamin K reverses the effects of warfarin, but researchers are still working on ways to reverse the action of the newer drugs. However, warfarin lasts for several days in the body whereas dabigatran (Pradaxa) and apixaban (Eliquis) have just a 12-hour half-life and thus clear out of the body much more quickly.
  • How good are you at remembering to take your meds? Dabigatran and apixaban require twice-per-day dosing, and rivaroxaban (Xarelto) is just once-per-day. However, since all three have a shorter half-life than warfarin, you must adhere very strictly to your dosing schedule.
  • Do you have a previous history of digestive tract bleeding? Both dabigatran and rivaroxaban appear to increase the likelihood of digestive bleeds when compared with warfarin, whereas apixaban does not.
  • Are you comfortable taking a relatively new medication? Or do you prefer to take a medication that’s been used for decades?
  • Will your insurance cover the more expensive new drugs, or are you able to afford them?

Also be sure to ask your doctor why he or she is recommending a specific drug for you. Given the fact that none of the newer drugs have gone head-to-head, it’s difficult to compare their effectiveness and side effects.

For more information, see:

Jennifer L.W. Fink is a freelance writer and Registered Nurse who writes frequently about health and wellness.

Comments from Mellanie:  The publication of this ARISTOTLE study has recently come under fire from former New England Journal of Medicine editor, Arnold Relman, because a number of the investigators and authors received payments from drug companies. Relman claims that the study should not have been published because it failed to note that there was little difference in outcomes between warfarin and apixaban in Europe. But it has been pointed out that the trial was designed to measure statistically important data in a worldwide population, but was not large enough to capture small differences by region. It is likely that the apparent similarity in outcomes in Europe was simply due to a statistical anomaly.

Relman also complained that the time in therapeutic range for warfarin patients was only 62.2 percent, and thus that the difference in outcomes between warfarin and apixaban might be erased if warfarin had been better managed. The same argument was made by the FDA panel regarding rivaroxaban and warfarin. However, it is not unusual for only 60 percent of patients on warfarin to be within the desired INR range in real-world clinical practice.

On his personal Cardiobrief blog, Larry Husten (who also works for the NEJM) explains all this controversy, including what the former NEJM editor said and why he was simply wrong in this case. And while Larry and I don’t see eye-to-eye on a lot of things [he simply doesn’t understand why I’m so adamant about wiping out afib strokes, but if he had had multiple close calls with stroke, like I did, or had experienced the devastating effects of stroke, like I have on my family, he might be less critical of my efforts to raise afib stroke awareness], in this case, he got the story right.

Afib is a very complex and challenging condition, and preventing afib strokes is sometimes as much luck as science. New options that are as effective as warfarin (or more so), require less day-to-day intervention, and cause less bleeding, are a huge step forward for many of us who have struggled with warfarin. We, and our families, know that strokes often prove to be “a fate worse than death.”

Disclaimer: Companies mentioned on this site may or may not be donors to StopAfib.org but no one receives favored treatment in coverage as atrial fibrillation patients are our first priority.