Rivaroxaban Not Approved for ACS Indication

The Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban as a treatment for patients with acute coronary syndrome, according to a statement issued by Johnson & Johnson.

The agency has issued a complete response letter regarding the supplemental indication for rivaroxaban for use in reducing the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS) that has been under review at the agency, the statement said.

The FDA issues complete response letters for a drug when there are outstanding issues that need to be resolved before approval; the FDA does not make these letters public, and the company statement did not provide any details about the issues that were raised in the FDA letter.

Rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals, a Johnson & Johnson subsidiary, was initially approved in July 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery; and in November 2011 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In December of last year, Janssen submitted the ACS application for rivaroxaban at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with 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."

But at a meeting in May, the majority of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval for this indication, with those voting no citing a large amount of missing data in ATLAS ACS, the pivotal study, as well as safety concerns, among the reasons for their votes (6 to 4 with one abstention).

In the study of 15,526 people with recent ACS, 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% among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths).

This was a statistically significant difference but with a marginal P value of .039. Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%). Intracranial hemorrhage and hemorrhagic stroke rates were also higher in those on rivaroxaban than in those on placebo (N. Engl. J. Med. 2012;366:9-19).

In an interview, Dr. Sanjay Kaul, one of the panel members who voted against approval, referred to the degree of missing data and the lack of robust data in favor of rivaroxaban in this study, pointing out that fewer than 10 excess events in the treatment arm would have negated the statistically significant treatment advantage.

He also referred to the lack of a dose response (there was a greater benefit with the lower dose), a differential impact of the two doses on cardiovascular mortality and MI that was difficult to explain, and the lack of external evidence supporting an incremental advantage of anticoagulant therapy over antiplatelet therapy.

Although the contents of the FDA’s letter are not made public, "I suspect some, if not all, of these issues likely contributed to the unfavorable verdict," said Dr. Kaul, who is the director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles.

"I hope that with proper due diligence, which might involve additional trials, the sponsor will be able to respond satisfactorily to the FDA’s concerns," he added.

In the Johnson & Johnson statement, Dr. Paul Burton, vice president and cardiovascular franchise medical leader at Janssen R&D, said that the company "will continue to work with the FDA to fully address their questions as quickly as possible."

Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for reducing the risk of thrombotic CV events in patients with ACS.

Dr. Kaul holds stock in Johnson & Johnson, but less than the amount for which a waiver to be on an FDA panel is required.

The Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban as a treatment for patients with acute coronary syndrome, according to a statement issued by Johnson & Johnson.

The agency has issued a complete response letter regarding the supplemental indication for rivaroxaban for use in reducing the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS) that has been under review at the agency, the statement said.

The FDA issues complete response letters for a drug when there are outstanding issues that need to be resolved before approval; the FDA does not make these letters public, and the company statement did not provide any details about the issues that were raised in the FDA letter.

Rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals, a Johnson & Johnson subsidiary, was initially approved in July 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery; and in November 2011 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In December of last year, Janssen submitted the ACS application for rivaroxaban at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with 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."

But at a meeting in May, the majority of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval for this indication, with those voting no citing a large amount of missing data in ATLAS ACS, the pivotal study, as well as safety concerns, among the reasons for their votes (6 to 4 with one abstention).

In the study of 15,526 people with recent ACS, 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% among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths).

This was a statistically significant difference but with a marginal P value of .039. Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%). Intracranial hemorrhage and hemorrhagic stroke rates were also higher in those on rivaroxaban than in those on placebo (N. Engl. J. Med. 2012;366:9-19).

In an interview, Dr. Sanjay Kaul, one of the panel members who voted against approval, referred to the degree of missing data and the lack of robust data in favor of rivaroxaban in this study, pointing out that fewer than 10 excess events in the treatment arm would have negated the statistically significant treatment advantage.

He also referred to the lack of a dose response (there was a greater benefit with the lower dose), a differential impact of the two doses on cardiovascular mortality and MI that was difficult to explain, and the lack of external evidence supporting an incremental advantage of anticoagulant therapy over antiplatelet therapy.

Although the contents of the FDA’s letter are not made public, "I suspect some, if not all, of these issues likely contributed to the unfavorable verdict," said Dr. Kaul, who is the director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles.

"I hope that with proper due diligence, which might involve additional trials, the sponsor will be able to respond satisfactorily to the FDA’s concerns," he added.

In the Johnson & Johnson statement, Dr. Paul Burton, vice president and cardiovascular franchise medical leader at Janssen R&D, said that the company "will continue to work with the FDA to fully address their questions as quickly as possible."

Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for reducing the risk of thrombotic CV events in patients with ACS.

Dr. Kaul holds stock in Johnson & Johnson, but less than the amount for which a waiver to be on an FDA panel is required.

The Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban as a treatment for patients with acute coronary syndrome, according to a statement issued by Johnson & Johnson.

The agency has issued a complete response letter regarding the supplemental indication for rivaroxaban for use in reducing the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS) that has been under review at the agency, the statement said.

The FDA issues complete response letters for a drug when there are outstanding issues that need to be resolved before approval; the FDA does not make these letters public, and the company statement did not provide any details about the issues that were raised in the FDA letter.

Rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals, a Johnson & Johnson subsidiary, was initially approved in July 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery; and in November 2011 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In December of last year, Janssen submitted the ACS application for rivaroxaban at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with 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."

But at a meeting in May, the majority of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval for this indication, with those voting no citing a large amount of missing data in ATLAS ACS, the pivotal study, as well as safety concerns, among the reasons for their votes (6 to 4 with one abstention).

In the study of 15,526 people with recent ACS, 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% among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths).

This was a statistically significant difference but with a marginal P value of .039. Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%). Intracranial hemorrhage and hemorrhagic stroke rates were also higher in those on rivaroxaban than in those on placebo (N. Engl. J. Med. 2012;366:9-19).

In an interview, Dr. Sanjay Kaul, one of the panel members who voted against approval, referred to the degree of missing data and the lack of robust data in favor of rivaroxaban in this study, pointing out that fewer than 10 excess events in the treatment arm would have negated the statistically significant treatment advantage.

He also referred to the lack of a dose response (there was a greater benefit with the lower dose), a differential impact of the two doses on cardiovascular mortality and MI that was difficult to explain, and the lack of external evidence supporting an incremental advantage of anticoagulant therapy over antiplatelet therapy.

Although the contents of the FDA’s letter are not made public, "I suspect some, if not all, of these issues likely contributed to the unfavorable verdict," said Dr. Kaul, who is the director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles.

"I hope that with proper due diligence, which might involve additional trials, the sponsor will be able to respond satisfactorily to the FDA’s concerns," he added.

In the Johnson & Johnson statement, Dr. Paul Burton, vice president and cardiovascular franchise medical leader at Janssen R&D, said that the company "will continue to work with the FDA to fully address their questions as quickly as possible."

Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for reducing the risk of thrombotic CV events in patients with ACS.

Dr. Kaul holds stock in Johnson & Johnson, but less than the amount for which a waiver to be on an FDA panel is required.