Rivaroxaban's ACS Claim Faces Data Quality Hurdle


The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.


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