FDA Panel Rejects ACS Indication for Rivaroxaban

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on May 23 voted 6 to 4, with 1 abstention, against approving the oral anticoagulant rivaroxaban as a treatment for acute coronary syndrome, for reasons that included a large amount of missing data in the pivotal study and safety concerns.

At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee considered the proposed indication for rivaroxaban, at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine." If approved, it would be the third approved indication for rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals.

Rivaroxaban was initially approved in July 2011, at a dosage of 10 mg once daily, for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. It was then approved in November 2011 at a dosage of 30 mg or 15 mg once daily for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In an international study of 15,526 people with recent ACS, patients (mean age 62 years, about two-thirds were male and about two-thirds were white) were randomized to treatment with 2.5 mg or 5 mg of rivaroxaban twice a day or placebo, plus standard care (dual antiplatelet therapy with low-dose aspirin plus a thienopyridine in most patients, and in about 7% of patients, low-dose aspirin only). The company proposed the 2.5-mg dose for approval because of its more favorable safety profile.

Among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine – the patient group the FDA said most closely reflected the U.S. population – the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was statistically significant (P = .039).

As expected, treatment with rivaroxaban was associated with increased rates of bleeding events compared with placebo: Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%), a statistically significant difference. Intracranial hemorrhage (ICH) and hemorrhagic stroke rates were also higher among those on rivaroxaban compared with those on placebo, but the incidence of fatal ICH was similar between those on the 2.5-mg dose of rivaroxaban (five cases) and those on placebo (four cases).

A major issue discussed during the meeting was the possible impact of missing data for almost 1,300 study patients on the final results, which several panelists voting against approval pointed out was a particular concern because the primary efficacy end point for the 2.5-mg dose was only marginally significant.

"The incomplete data are very worrisome," said one of the panelists voting against approval, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, Washington, D.C. One of the implications of approving another drug for ACS is that it then becomes the standard of treatment for everyone who has one of the three components of ACS, "and this seems like a major, major leap forward given the fragility of the data."

The other reasons cited by panelists voting against approval included the significance of intracranial hemorrhages from the patient perspective.

If approved for the ACS indication, rivaroxaban would be the first factor Xa inhibitor approved for reducing the risk of thrombotic CV events in patients with ACS. Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for this indication.

The results of the ATLAS trial were published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

The FDA is expected to make its decision by June 29.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on May 23 voted 6 to 4, with 1 abstention, against approving the oral anticoagulant rivaroxaban as a treatment for acute coronary syndrome, for reasons that included a large amount of missing data in the pivotal study and safety concerns.

At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee considered the proposed indication for rivaroxaban, at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine." If approved, it would be the third approved indication for rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals.

Rivaroxaban was initially approved in July 2011, at a dosage of 10 mg once daily, for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. It was then approved in November 2011 at a dosage of 30 mg or 15 mg once daily for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In an international study of 15,526 people with recent ACS, patients (mean age 62 years, about two-thirds were male and about two-thirds were white) were randomized to treatment with 2.5 mg or 5 mg of rivaroxaban twice a day or placebo, plus standard care (dual antiplatelet therapy with low-dose aspirin plus a thienopyridine in most patients, and in about 7% of patients, low-dose aspirin only). The company proposed the 2.5-mg dose for approval because of its more favorable safety profile.

Among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine – the patient group the FDA said most closely reflected the U.S. population – the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was statistically significant (P = .039).

As expected, treatment with rivaroxaban was associated with increased rates of bleeding events compared with placebo: Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%), a statistically significant difference. Intracranial hemorrhage (ICH) and hemorrhagic stroke rates were also higher among those on rivaroxaban compared with those on placebo, but the incidence of fatal ICH was similar between those on the 2.5-mg dose of rivaroxaban (five cases) and those on placebo (four cases).

A major issue discussed during the meeting was the possible impact of missing data for almost 1,300 study patients on the final results, which several panelists voting against approval pointed out was a particular concern because the primary efficacy end point for the 2.5-mg dose was only marginally significant.

"The incomplete data are very worrisome," said one of the panelists voting against approval, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, Washington, D.C. One of the implications of approving another drug for ACS is that it then becomes the standard of treatment for everyone who has one of the three components of ACS, "and this seems like a major, major leap forward given the fragility of the data."

The other reasons cited by panelists voting against approval included the significance of intracranial hemorrhages from the patient perspective.

If approved for the ACS indication, rivaroxaban would be the first factor Xa inhibitor approved for reducing the risk of thrombotic CV events in patients with ACS. Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for this indication.

The results of the ATLAS trial were published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

The FDA is expected to make its decision by June 29.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on May 23 voted 6 to 4, with 1 abstention, against approving the oral anticoagulant rivaroxaban as a treatment for acute coronary syndrome, for reasons that included a large amount of missing data in the pivotal study and safety concerns.

At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee considered the proposed indication for rivaroxaban, at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine." If approved, it would be the third approved indication for rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals.

Rivaroxaban was initially approved in July 2011, at a dosage of 10 mg once daily, for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. It was then approved in November 2011 at a dosage of 30 mg or 15 mg once daily for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In an international study of 15,526 people with recent ACS, patients (mean age 62 years, about two-thirds were male and about two-thirds were white) were randomized to treatment with 2.5 mg or 5 mg of rivaroxaban twice a day or placebo, plus standard care (dual antiplatelet therapy with low-dose aspirin plus a thienopyridine in most patients, and in about 7% of patients, low-dose aspirin only). The company proposed the 2.5-mg dose for approval because of its more favorable safety profile.

Among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine – the patient group the FDA said most closely reflected the U.S. population – the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was statistically significant (P = .039).

As expected, treatment with rivaroxaban was associated with increased rates of bleeding events compared with placebo: Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%), a statistically significant difference. Intracranial hemorrhage (ICH) and hemorrhagic stroke rates were also higher among those on rivaroxaban compared with those on placebo, but the incidence of fatal ICH was similar between those on the 2.5-mg dose of rivaroxaban (five cases) and those on placebo (four cases).

A major issue discussed during the meeting was the possible impact of missing data for almost 1,300 study patients on the final results, which several panelists voting against approval pointed out was a particular concern because the primary efficacy end point for the 2.5-mg dose was only marginally significant.

"The incomplete data are very worrisome," said one of the panelists voting against approval, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, Washington, D.C. One of the implications of approving another drug for ACS is that it then becomes the standard of treatment for everyone who has one of the three components of ACS, "and this seems like a major, major leap forward given the fragility of the data."

The other reasons cited by panelists voting against approval included the significance of intracranial hemorrhages from the patient perspective.

If approved for the ACS indication, rivaroxaban would be the first factor Xa inhibitor approved for reducing the risk of thrombotic CV events in patients with ACS. Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for this indication.

The results of the ATLAS trial were published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

The FDA is expected to make its decision by June 29.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.