Published ATLAS ACS-TIMI 46 Results for Rivaroxaban Pave the Way for Phase 3 Trial

Shelley Wood

June 18, 2009

June 18, 2009 (Boston, Massachusetts) — Results of the phase 2 ATLAS ACS-TIMI 46 trial, which paved the way for the phase 3 ACS trial of rivaroxaban (Xarelto, Johnson & Johnson) now enrolling patients, have now been published online June 17, 2009 in the Lancet [1]. First presented at the AHA 2008 meeting (and reported by heartwire at the time), the ATLAS-ACS-TIMI 46 demonstrated that while rivaroxaban, an oral direct factor Xa inhibitor, increased the risk of bleeding in a dose-dependent manner in stabilized ACS patients, it showed promise in reducing major ischemic outcomes, particular in the lower doses studied.

According to first author on the study, Dr Jessica Mega (Brigham and Women's Hospital, Boston, MA), the phase 3 trial, dubbed ATLAS ACS 2-TIMI 51, is already up and running with a target enrollment of up to 16 000 patients.

"[ATLAS-ACS-TIMI 46] was a phase 2 study, and the goal was to select an appropriate dose to be carried forward into the phase 3 study," Mega told heartwire . "We are pleased that we were able to achieve this goal, and the phase 3 study is evaluating 2.5 mg twice a day and 5 mg twice a day--a total daily dose of 5 mg and 10 mg." The point of the phase 2 trial, she emphasized, was to establish this dose for going forward, and the trial was not powered for efficacy. That said, "We observed that lower doses of rivaroxaban tended to reduce major atherothrombotic events."

Rivaroxaban is just one of several potential new oral anticoagulants in development that many hope will pan out as a substitute for warfarin in the setting of venous thromboembolism, in the prevention of stroke in atrial fibrillation patients, and, as in this study, for the treatment of ACS. Warfarin has generally not been used in clinical practice in the setting of ACS, because of the difficulty of keeping patients in the target bleeding range, except for patients in whom warfarin is indicated for other reasons. Rivaroxaban recently won a recommendation for approval from an FDA advisory panel evaluating the agent in the setting of deep vein thrombosis and pulmonary embolism prophylaxis, although the FDA has since asked the drug-maker for more information (although no additional studies) to support this indication.

Phase 2 Results for Rivaroxaban in ACS

Mega et al's Lancet paper is nearly identical to the results presented at the AHA meeting last year. For the study, 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 safety end point was "clinically significant bleeding" (TIMI major or minor bleeding or any other bleeding requiring medical attention); this end point was increased significantly in the rivaroxaban groups vs placebo in a dose-dependent manner. The primary efficacy end point, a composite of death, MI, stroke, or severe recurrent ischemia requiring revascularization during six months, was numerically lower for the rivaroxaban-treated patients vs placebo, but not statistically different (5.6% vs 7.0%, p=0.10), while a secondary end point of death, MI, and stroke was significantly reduced with rivaroxaban (3.9% vs 5.5%, p=0.027).

A key question that will need to be answered in the phase 3 trial will be the added value, if any, of using rivaroxaban on top of single and dual antiplatelet therapy. "For the primary end point [in the phase 2 trial], it appeared that there was a larger efficacy signal in subjects treated with single antiplatelet therapy," Mega said.

In the aspirin-only–treated patients (stratum one) rivaroxaban was associated with a hazard ratio (HR) of 0.53 (95% CI 0.33–0.84) for the primary efficacy end point, whereas no such reduced risk was seen in the dual-antiplatelet-therapy–treated patients (stratum two: HR 0.99; 95% CI 0.69–1.42).

"This observation may be related to being on single antiplatelet therapy or to the different baseline characteristics in subjects in stratum one and stratum two," Mega said. But whether this differential was a result of the different antiplatelet therapies per se or whether it reflected the different patient populations selected for treatment with one vs two antiplatelet drugs remains to be seen. "We're excited to be conducting a large phase 3 study, where these subgroups can be further evaluated," she said.

In an editorial [2] accompanying the study, Drs Hitinder S Gurm and Kim Eagle (University of Michigan Cardiovascular Center, Ann Arbor) call the future of rivaroxaban in ACS "difficult to predict," noting "there was no suggestion of benefit in patients receiving dual antiplatelet therapy; robust clinical benefits without major increase in bleeding risk would need to be shown in the ongoing trials before this drug could be integrated into practice." Moreover, rivaroxaban was linked to a two- to fourfold increase in bleeding, particularly in the elderly and patients with renal disease, they observe. "However," they continue, "we should not be completely pessimistic about the future role of this drug in treating patients with acute coronary syndromes. Although estimation of the drug's benefit in secondary prevention on the basis of the results of a dose-finding study would be premature, rivaroxaban could potentially displace parenteral anticoagulants for early management of these syndromes"--an indication that has "not yet been pursued," they note.

Commenting on the study for heartwire , Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) emphasized that the buzz over ATLAS ACS-TIMI 46 (in spite of missing its primary efficacy end point) stems in part from the promising results for the secondary efficacy end points and even more so from the promise of new anticoagulants generally. "There is this general excitement in the cardiovascular community about finally being able to replace warfarin, with all its challenges, with another orally available anticoagulant that seems to inhibit thrombosis in an effective manner," he said. On top of this are hopes that using anticoagulants either in place of or on top of antiplatelet therapy could yield greater antithrombotic effects than the kinds of incremental benefits seen with new antiplatelet drugs, he added.

Whether the bleeding risks are amply offset by the clinical gains remains to be seen, Harrington added. "If they get the kind of clinical benefit they are anticipating, the incremental increased risk of bleeding they see here might well be worth the tradeoff, but obviously the only way you're going to know that is if you do all the studies and balance one against the other. "

Also commenting for heartwire , Dr Sanjay Kaul (Cedars Sinai Heart Institute, Los Angeles, CA) highlighted the discrepant results in terms of benefit/risk profile in the stratum-one and stratum-two patients. The stratum-two patients, in whom no efficacy benefit was seen, represent the most common antiplatelet regimen for most ACS patients, he noted.

"I would like to caution the authors from overinterpreting the secondary efficacy data (death, MI, or stroke), which appear to favor rivaroxaban," he said, particularly since the primary efficacy data did not reach statistical significance. He also expressed concerns about the twofold increased bleeding seen in the dose chosen for the phase 3 study, given the relatively low-risk group in whom this bleeding rate was seen.

On the positive side, Kaul praised the large number of patients studied in the phase 2 trial (which typically enroll much lower numbers of patients) and the choice of a bleeding end point that "captures clinically relevant bleeding." Perhaps most striking in ATLAS ACS-TIMI 46, given the dashed hopes following the removal of ximelagatran from the market due to hepatic toxicity, there were "no safety concerns with liver adverse events for at least six months, which is somewhat reassuring," Kaul said.

According to the published paper, the TIMI study group receives research grant support from Johnson & Johnson, Bayer Healthcare AG, and Daiichi Sankyo. Mega reports receiving research grant support from Johnson & Johnson and Schering-Plough. Harrington disclosed that Duke Clinical Research Institute is coordinating the large AF trial with rivaroxaban (although he is not directly involved) and that Duke Clinical Research Institute is coordinating/coordinated the AF and ACS trials with apixiban (another factor Xa inhibitor) and that he has served as study cochair for the ACS trials of this agent. Harrington's full disclosure statement is available online . Kaul has previously disclosed owning stock, stock options, or bonds in Eli Lilly and Johnson & Johnson. He has served as an advisor or consultant for Novo Nordisk and Hoffmann-La Roche.

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