March 5th, 2013

FDA Again Rejects ACS Indication for Rivaroxaban

For the second time the FDA has turned down the supplemental new drug application (sNDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) to treat patients with acute coronary syndrome (ACS).

Despite early hopes, the ACS indication has proved tantalizingly elusive for the drug.  When the pivotal ATLAS ACS 2-TIMI 51 trial was unveiled in 2011 it was widely praised. Great expectations were enhanced when the FDA granted priority review for the ACS indication in February 2012. But a few months later the momentum ground to a halt when FDA reviewers raised questions about the ATLAS trial. Shortly afterwards, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against the ACS indication.

The FDA issued the first complete response letter rejecting the sNDA last June. In a press release issued at the time, a J&J company official said the company remains “confident in the robust results of the ATLAS ACS 2 TIMI 51 trial and the positive benefit-risk profile of rivaroxaban in patients with ACS.”

In a new press release issued on Monday afternoon the company restated its confidence “in the robustness and results” of the ATLAS  trial. Criticism of ATLAS from the FDA and the advisory panel members had focused on missing data from the ATLAS trial. In today’s press release J&J provided more information about its efforts to address this question:

On September 6, 2012, Janssen submitted to the FDA important data related to patients who had withdrawn from the ATLAS ACS 2 TIMI 51 trial… as part of its complete response.

To compile these data, the company undertook a global effort and was able to confirm the vital status information for 843, or 63%, of the 1,338 trial participants who previously had unknown vital status. The mortality benefit observed during the treatment phase of the study was maintained. These new events were distributed equally between the three treatment groups (2.5 mg, 5 mg and placebo) of patients who were alive (806) and those who had died (37). After these efforts, follow up data was not available on only 2.4% of patients.

4 Responses to “FDA Again Rejects ACS Indication for Rivaroxaban”

  1. William Edward Boden, MD says:


    I’m a little unclear on the numbers cited in the italicized quote, which I presume is from the J&J press release; if there were 1,338 subjects on whom vital status had not been ascertained, and subsequently through the global effort cited above there was vital status ascertained on 843 trial participants, then that leaves 37% (or 495 patients) on whom vital status is still unaccounted for. I’m trying to understand the very last sentence, which states that “follow-up data was not available on only 2.4% of patients”. In other words, the numbers don’t add up. Also, do we know if this is the only remaining barrier behind the FDA’s decision to reject the new ACS indication?

    • Dr. Boden– yes, this was a direct quote from the press release. I’m guessing the denominator here is the total number of patients randomized in the trial. I’m sure J&J or a study investigator could provide more detailed information.

  2. Carlos Cuneo, MD says:

    Dr Boden. The number of patients in ATLAS 2 TIMI 51 was more than 15.570. So 475 patients are less than 3%.
    Carlos Cuneo MD. Study Investigator ATLAS ACS2 TIMI 51

  3. Judith Andersen, AB, MD says:

    I think that the decision by the FDA to not approve rivaroxaban for secondary cardiac prevention was conditioned heavily by Eugene Braunwald — and largely related to the disconnect between our understanding of dose response issues. 2.5 mg was more effective than 5mg: why? — we don’t know– although many hypotheses are available. And although caution with regard to anomalous responses to a new drug that purports to abrogate risk in an inexplicable way is appropriate, not understanding the data is not. Safety is a paramount issue, but heavyhanded rejection from a weighty guru can be lethal — and the value of a small-dose, minimal side effect anti-Xa agent may be exactly what we need for secondary prophylaxis for folks who have had prior interventions, require dual antiplatelet therapy and are therefore at risk for bleeding with full-dose anticoagulation with warfarin.