AHA 2008: New Factor Xa Inhibitor Rivaroxaban Moves Into Phase 3 for ACS

November 10, 2008

November 10, 2008 (New Orleans, LA) — A phase 2 trial with a novel oral factor Xa inhibitor rivaroxaban (Johnson & Johnson/Bayer) has demonstrated the feasibility of triple therapy for patients with acute coronary syndromes, showing a trend toward improved efficacy with the drug in addition to aspirin and clopidogrel. But there was a dose-dependent increase in bleeding using this approach, acknowledged Dr C Michael Gibson (Beth Israel Deaconess Medical Center, Boston), who reported the findings of the ATLAS ACS-TIMI 46 trial at a late-breaking clinical-trials session here at American Heart Association 2008 Scientific Sessions today.

Dr C Michael Gibson

In a press conference, discussant of the study, Dr Elaine M Hylek (Boston University Medical Center, MA), called the trial "terrific, ambitious, and responsible," and she applauded the researchers' efforts in trying "to come up with the best balance of risk and benefit as we move forward into this era of triple therapy."

Dr Elaine M Hylek

The ATLAS ACS-TIMI 46 trial identified two doses of rivaroxaban--2.5 mg and 5 mg twice daily--that will be taken forward into a phase 3 trial, Gibson said. This study is slated to begin next month, will enroll up to 16 000 patients, and is estimated to last around 33 months.

Dr Raymond Gibbons (Mayo Clinic, Rochester, MN) told heartwire : "Ultimately, [the success of rivaroxaban in this indication] will depend on the trade-off of benefit vs risk, and we don't know that from this small phase 2 trial. We will have to await the phase 3 data."

Rivaroxaban is one of several potential new oral anticoagulants in development that are set to become the long-awaited replacements for warfarin. First indications will be in preventing venous thromboembolism after surgery, but these agents are also being developed for the prevention of stroke in atrial fibrillation patients and, as in this study, for the treatment of ACS. Warfarin has not been used in clinical practice in the setting of ACS, because of the difficulty of keeping patients in the target bleeding range.

Number Needed to Treat With Rivaroxaban=63

Gibson described the phase 2 ATLAS ACS-TIMI 46 trial, in which 3491 recent ACS patients (who were stabilized one to seven days after the index event) were treated with aspirin alone (n=761) or aspirin plus clopidogrel (n=2730), depending on the preferences of the treating physician. Patients were then further randomized to placebo or rivaroxaban in a number of dosing regimens and treated for six months: 5 mg, 10 mg, or 20 mg of rivaroxaban once daily or 2.5 mg, 5 mg, or 10 mg twice daily.

The primary goal, said Gibson, was to identify tolerable doses of rivaroxaban in the treatment of ACS for evaluation in a large phase 3 trial. He noted that as well as TIMI major and minor bleeding, a more sensitive metric of bleeding, termed "bleeding that requires medical attention," was included, which, he said, could be as small as a nosebleed.

Reassuringly, there was no evidence of any drug-induced liver injury with rivaroxaban, Gibson noted.

Although the study was not powered to look at efficacy, this was reported. Death/MI/stroke/severe ischemia requiring revascularization was 7.0% in the placebo group at six months compared with 5.6% in the rivaroxaban groups combined, a nonsignificant difference (HR 0.79, p=0.10).

But the secondary efficacy end point of death/MI/stroke was 5.5% in placebo patients compared with 3.9% in those on rivaroxaban, which was significant (HR 0.69, p=0.028). This gives an absolute risk reduction of 1.6% and a number needed to treat of 63, Gibson noted.

Would Prasugrel Abrogate Benefit of Rivaroxaban?

Gibson explained that the two separate strata of the trials--those including patients just taking aspirin and those on aspirin plus clopidogrel--contained quite different patient populations. Those on aspirin alone were older, much more likely to have diabetes and/or a prior MI, and much less likely to have had PCI than those who got dual therapy.

For those reasons, they looked at the two groups separately. In those taking aspirin alone plus the 2.5-mg or 5-mg twice-daily doses of rivaroxaban that have been chosen to be taken forward into phase 3, the end point of death/MI/stroke was 11.9% in placebo patients compared with 6.6% in the rivaroxaban group (HR 0.54, p=0.08). This was offset by a TIMI major bleed rate of 1.2% in those taking the new factor Xa inhibitor compared with 0% for placebo patients (p=0.17).

Looking at the same end point with the same doses of rivaroxaban, but this time in those taking aspirin plus clopidogrel, the end point of death/MI/stroke occurred in 3.8% of those on placebo compared with 2.0% of those taking rivaroxaban (HR 0.55, p=0.09).

TIMI major bleeding was 1.2% in those taking rivaroxaban, compared with 0.2% in those who got placebo (p=0.03) in this dual therapy group. The absolute risk reduction was 1.8% with the new drug in this patient stratum, Gibson noted.

A panel member commented that the event rates were much lower in this second stratum--those receiving aspirin plus clopidogrel--and he asked Gibson whether he thought that more potent thienopyridines, such as the newer agent prasugrel (which is awaiting approval), might abrogate the benefit of the newer agent rivaroxaban.

"When you add clopidogrel to aspirin [in this setting] you get a 20% reduction in events," Gibson commented. "Obviously, prasugrel was not studied here," he noted, adding that only the phase 3 trial results will give a better idea of the magnitude of risk reduction in ACS with rivaroxaban.

Triple Therapy is Needed

Discussant Hylek said that triple therapy is needed in ACS, because in-hospital death and reinfarction affect 5% to 10% of patients and death or recurrent MI occur in another 5% to 10% of patients within a month of an acute episode.

Also, death/MI "remains high at one year despite PCI and dual therapy [with aspirin and clopidogrel]," she noted, adding that other trials, such as WARIS-2 with warfarin and ESTEEM with ximelagatran have already demonstrated proof of concept of triple therapy.

Triple therapy comes at a cost: it is difficult.

"The bulk of evidence is that there is a role for these agents in ACS. But triple therapy comes at a cost: it is difficult," she noted.

Applauding the efforts of the ATLAS ACS-TIMI 46 team, she nevertheless took issue with some aspects of the trial. "Patients 'with an increased bleeding risk' were excluded, which tends to enroll lower-risk patients from a bleeding perspective," she pointed out. Also, the renal function of the patients included "was pretty good," and the ACS patients in this trial are about 10 years younger, on average, than an AF population.

She had most to say about the bleeding criteria used. "TIMI minor and major bleeding tends to underestimate bleeding," she explained, adding that a better definition, to her mind, is the International Society of Thrombosis and Hemostasis (ISTH) bleeding classification.

In conclusion, she said the trial showed "a trend toward improved efficacy with rivaroxaban, but a dose-dependent increase in bleeding," and she pleaded for better documentation of bleeding. "It's incredibly important that we adopt universal reporting across trials and indications worldwide. This will facilitate a more informed assessment of the benefits and risks [of such agents] for patients and providers."

ATLAS ACS-TIMI 46 was funded by a grant from Johnson & Johnson/Bayer. Gibson has received honoraria and consulting fees from Johnson & Johnson and Bayer. Hylek has received research grants from AstraZeneca and Bristol-Myers Squibb, has served as a consultant for Bristol-Myers Squibb and Sanofi-Aventis, and has received honoraria from Bayer.

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