August 28, 2011

(Updated August 28, 2011) (Paris, France) — The full results of the ARISTOTLE trial have certainly lived up to expectations, showing convincing benefits of the new oral factor Xa inhibitor apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) over warfarin in atrial fibrillation (AF) patients [1].

In the trial, presented today at the European Society of Cardiology (ESC) 2011 Congress and simultaneously published online in the New England Journal of Medicine, apixaban was superior to warfarin in preventing stroke or systolic embolism (the primary end point) and was also associated with less bleeding and lower mortality than warfarin.

The results have been positioned as the most positive yet for one of the new oral anticoagulants in AF and appear to give apixaban the edge over its two major competitors, dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson). Both dabigatran and rivaroxaban have also shown benefits over warfarin in the RE-LY and ROCKET-AF trials respectively, but apixaban is the first of these three agents to have shown definite reductions in each of the major outcomes of stroke, bleeding, and mortality.

Lead ARISTOTLE investigator Dr Christopher Granger (Duke University, Durham, US) commented to heartwire : "We are delighted with the results. It is very exciting to see large significant reductions in both stroke and bleeding simultaneously. We seem to have hit the sweet spot on the dose of apixaban, which produced both great efficacy and safety."

No Significant Reduction in Ischemic Stroke

However, RE-LY investigator Dr Salim Yusuf (McMaster University, Hamilton, ON) pointed out to heartwire that although the ARISTOTLE results were very good, apixaban did not show a reduction in ischemic stroke, whereas the 150-mg dabigatran dose in RE-LY did. He said he would position the ARISTOTLE result "somewhere in between the two doses of dabigatran in RE-LY."

The ARISTOTLE trial randomized 18 201 AF patients to apixaban (5 mg orally twice daily) or warfarin (target INR of 2.0 to 3.0). After a median follow-up of 1.8 years, results showed that apixaban was associated with a 21% reduction in the risk of stroke or systemic embolism, a 31% reduction in bleeding, and an 11% reduction in all-cause mortality.

ARISTOTLE Major Results

End point Apixaban

(%/year)

Warfarin (%/year) HR (95% CI) p
Stroke or systemic embolism* 1.27 1.60 0.79 (0.66–0.95) 0.01
Major bleeding 2.13 3.09 0.69 (0.60–0.80) <0.001
All-cause mortality 3.52 3.94 0.89 (0.80–0.99) 0.047
Hemorrhagic stroke 0.24 0.47 0.51 (0.35–0.75) <0.001
Ischemic/uncertain stroke 0.97 1.05 0.92 (0.74–1.13) 0.42

*Primary end point

Combining the Advantages of Both Dabigatran Doses

Noting that the 150-mg twice-daily dose of dabigatran showed a reduction in stroke but a similar rate of bleeding (and an increase in GI bleeding) vs warfarin in the RE-LY trial, whereas the 110-mg twice-daily dose of dabigatran showed a similar stroke rate to warfarin with reduced bleeding, Granger commented to heartwire : "Apixaban appears to combine the advantages of both doses of dabigatran, with greater reductions in both stroke and bleeding (including GI bleeding) than warfarin."

We seem to have hit the sweet spot on the dose of apixaban, which produced both great efficacy and safety.

The MI data are also reassuring in ARISTOTLE. There was some concern raised about a possible increase in MI rate with dabigatran vs warfarin in RE-LY, but this was not seen in ARISTOTLE. Granger said: "The MI issue with dabigatran was never a particular concern for me, as warfarin is very effective at reducing MI, but we were pleased to see a lower numerical rate with apixaban than with warfarin in ARISTOTLE."

Yusuf, however, said he still believed the higher dabigatran dose gave the best results, because of the reduction in ischemic stroke. "With this, we are trading a reduction in ischemic stroke for an increase in GI bleeding, so it would probably depend on the profile of the patient which drug I would choose," he told heartwire .

But Dr Lars Wallentin (Uppsala Clinical Research Centre, Sweden), who copresented the ARISTOTLE data and was also involved in RE-LY, countered: "When using a prophylactic drug, the first rule must be not to cause harm. Using a safe agent is of utmost importance."

Yusuf added that trying to tease out differences between the three drugs was like "splitting hairs" and that the key message should be that all three are major advances.

What About Rivaroxaban?

Meanwhile, rivaroxaban was shown to be noninferior to warfarin in preventing stroke, but the superiority analysis drew questions when, in the intention-to-treat group, the drug failed to demonstrate superiority, statistically, over warfarin, although rivaroxaban was statistically superior in an "as-treated" analysis. Moreover, in ROCKET AF, intracranial and fatal bleeding was lower with rivaroxaban, while other major bleeding was similar to warfarin.

Once- vs Twice-Daily Dosing

Rivaroxaban does, however, have the advantage over the other two drugs of being the only one with a once-daily dosing regimen, a factor that is considered important in boosting compliance. On this issue, Granger commented: "The once-daily dosing of rivaroxaban is definitely an advantage, but many drugs with a twice-daily dosing are used successfully in clinical practice. I would say it is only a modest disadvantage."

Wallentin believes the key to the success of ARISTOTLE was the dose of apixaban. Interestingly, he noted that apixaban and rivaroxaban have very similar half-lives, but rivaroxaban was developed with a once-daily dose, perhaps for marketing reasons, whereas apixaban went with a twice-daily dose.

"Maybe we were lucky, but we chose the twice-daily dose to keep the smooth profile of plasma concentration. The science seemed to suggest that a twice-daily dose would be better, and we went with that decision, and it seems to have paid off."

Commenting on differences between the trials for heartwire , ROCKET-AF investigator Dr Ken Mahaffey (Duke University, Durham, NC) said: "There are now potentially three new drugs and five well-done clinical trials. The totality of the data is strikingly consistent across the trials, with reductions in stroke and non-[central nervous system] CNS embolism and significant reductions in intracranial hemorrhage and fatal bleeding. While indirect comparisons will be made across the three agents, until we have direct comparisons with randomized trials, the decision about which specific agent to use will need to be made by individual physicians and patients based on applicability of the specific trial findings and preferences."

Mortality Reduction

Apixaban is the first of the three new oral anticoagulants to show a clearly significant reduction in all-cause mortality compared with warfarin. Granger noted that the mortality results were in line with those from RE-LY and ROCKET but were clearer in ARISTOTLE. "In RE-LY, the mortality reduction with dabigatran approached significance, and there was also a strong trend in ROCKET, but in ARISTOTLE the mortality reduction is clearer from a clinical perspective and much clearer from a regulatory view."

In the paper, the ARISTOTLE authors write that for every 1000 patients treated for 1.8 years, apixaban, as compared with warfarin, prevented a stroke in six patients (four hemorrhagic strokes and two ischemic strokes), major bleeding in 15 patients, and death in eight patients.

Noting that all three new oral anticoagulants have shown a large reduction in intracranial hemorrhage compared with warfarin, the authors say this suggests a specific risk of such events with warfarin, possibly related to its inhibition of multiple coagulation factors or an interaction with specific clotting factors in the brain.

Wallentin said the ARISTOTLE results still looked good when considering the time in therapeutic range for the warfarin patients, which was around 62%, compared with 64% in the RE-LY trial and 54% in ROCKET.

ARISTOTLE: Primary End Point in Relation to Time In Warfarin Therapeutic Range

Time in therapeutic range (%) (by center) Apixaban (rate per 100 person-years) Warfarin (rate per 100 person-years) HR (95% CI)
<58.0 1.75 2.28 0.77 (0.56–1.06)
58–65 1.30 1.61 0.80 (0.56–1.15)
65–72 1.21 1.55 0.79 (0.54–1.13)
>72 0.83 1.02 0.81 (0.52–1.26)

Yusuf pointed out that it was curious that both groups did better as INR levels improved. "This is understandable for the warfarin group, but how can this be explained for the apixaban group?" he asked.

Wallentin replied that this was probably due to other factors. "INRs are normally better in higher-income countries. There will be many other factors that will affect outcome that will be better in higher-income countries, and that is probably what we are seeing."

Differences Between the Trial Designs

In an accompanying editorial [2], Dr Jessica Mega (Brigham and Women's Hospital, Boston, MA) points out that there are many differences between the three trials that make it difficult to compare the agents directly. These include differences in blinding (ROCKET and ARISTOTLE were blinded, whereas RE-LY was open label) and in risk of patients included (with ROCKET enrolling higher-risk patients than the other two studies).

Another difference that seems to have put rivaroxaban at a disadvantage is that the primary end point was set at a point after rivaroxaban was stopped in ROCKET, with many events occurring when patients were crossed over back onto warfarin; in ARISTOTLE, the primary-end-point data were collected on a specific date, when 75% of patients were still taking the study drug.

Granger commented to heartwire : "We have done some analyses at 30 days after the study drug was stopped and patients were put back on warfarin, and we have seen equally robust findings." He added that they had "learned from the ROCKET experience" and issued very specific instructions regarding crossing patients over to avoid a period of underanticoagulation.

Replacing Warfarin

Addressing the question of whether these new oral agents will completely replace warfarin, Mega points out that that they overcome the need for monitoring with warfarin and have shown encouraging results in many different subgroups, but "switching to a newer agent may not be necessary for the individual patient in whom the INR has been well controlled with warfarin for years."

Wallentin, however, believes the superior data for these new drugs presents a challenge for anyone to continue on warfarin. "The one issue that might prevent people from switching is cost. These new drugs will be much more expensive. And I think if we have to make decisions on whom to give these new drugs to, we will start first with new patients and switch over those not managing well on warfarin.”

So far, dabigatran is the only one of the new oral agents to be approved for the AF indication, but its uptake has been slower than expected, with one estimate that it has only 6% of market share. Wallentin says he is putting his new AF patients onto dabigatran now and will switch to apixaban when that becomes available.

ARISTOTLE was supported by Bristol-Myers Squibb and Pfizer. Granger reports receiving grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck, Sanofi-Aventis, Astellas, and the Medicines Company; consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman-La Roche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, and the Medicines Company; and support from the Medtronic Foundation and Merck for travel, accommodations, or expenses. Disclosures for the coauthors are listed in the paper. Mega reports consulting for AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, and Sanofi-Aventis and receiving grants or pending grants from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, and Sanofi-Aventis.

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