On May 24, the European Commission approved Bayer's novel oral anticoagulant rivaroxaban (Xarelto) for the secondary prevention of atherothrombotic events (cardiovascular death, myocardial infarction or stroke) after an acute coronary syndrome (ACS) in adult patients with elevated cardiac biomarkers. The indication for the 2.5 mg twice-daily (BID) dose in combination with standard antiplatelet therapy comes approximately 2 months after the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a favorable view regarding the extension of rivaroxaban's indication. In contrast to its smooth sailing experience in Europe, in the United States, we still await a response from Janssen to the second complete response letter (CRL) regarding their supplemental new drug application (sNDA) to market rivaroxaban for the reduction of the risk of cardiovascular events in ACS patients. The FDA's Cardiovascular and Renal Drugs Advisory Committee initially expressed concern about the increased risk of bleeding and doubts about whether missing data in the Phase III trial, as well as a high dropout rate, may have skewed results in rivaroxaban's favor.

In general, the ACS indication has proved challenging for the novel oral anticoagulants. Of the oral anticoagulants that were under investigation for the secondary prevention of cardiovascular events in ACS patients including BMS/Pfizer's apixaban (Eliquis), Astellas's darexaban, and Boehringer Ingelheim's dabigatran etexilate (Pradaxa) only rivaroxaban remains in development. This litany of failures underlines the difficulty involved in finding the optimal doses of oral anticoagulants for ACS when these agents are being added to dual antiplatelet therapy regimens (see Table 1).

Table 1

Drug Name

Company

Action

Status

Dabigatran etexilate

Boehringer Ingelheim

Direct thrombin inhibitor

Phase II RE-DEEM trial completed in 2009. No development reported in ACS since then.

Apixaban

BMS & Pfizer

Factor Xa inhibitor

APPRAISE-2 trial stopped early in November 2010 because of an increased bleeding risk that was not offset by reductions in ischemic events.

Letaxaban (TAK-442)

Takeda

Factor Xa inhibitor

Development discontinued for ACS in May 2011 following negative results from a Phase II study.

Darexaban (YM-150)

Astellas

Factor Xa inhibitor

Development discontinued in September 2011 following increased bleeding without an increase in efficacy in a Phase II study.

So how did rivaroxaban do it. It appears that clever dose selection and trial design were key:

  • The dose of rivaroxaban investigated in its Phase III ACS trial (2.5 mg BID) was much lower than the dose approved for atrial fibrillation patients (20 mg/day).
  • In the APPRAISE-2 trial, the apixaban dose approved for atrial fibrillation (5 mg BID) was also used in ACS patients and likely contributed to the higher risk of bleeding found in this study.
  • In addition, rivaroxaban's Phase III ACS study was designed to exclude patients who had a history of ischemic stroke or transient ischemic attack, a group that has not shown benefit from greater degrees of antithrombotic therapy in the past.

So, what does the future hold in store for the novel oral anticoagulant agents. Perhaps BMS/Pfizer and Boehringer Ingelheim will take another look at the ACS market, or they could, similar to Bayer and Janssen, look to other indications such as coronary artery disease, peripheral artery disease, and heart failure (see EXPLORER trial program in Table 2 below). One thing is for sure, when designing a trial in patients already treated with antithrombotic therapy, striking a balance between increased bleeding and efficacy is paramount.

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