FDA Panel: Approve Rivaroxaban for Stroke Prevention

COLLEGE PARK, MD. – The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee advisory panel on Sept. 8 voted 9-2, with 1 abstention, that the anticoagulant rivaroxaban is effective for prevention of stroke in nonvalvular atrial fibrillation.

But the panelists were generally in agreement that the drug, to be marketed as Xarelto by Johnson & Johnson and Bayer Healthcare, should only be offered as a third-line therapy. The committee members expressed concern that although the drug was no less effective than warfarin, it presented safety concerns. In particular, there was an excess of bleeding events when the drug was discontinued.

The FDA generally follows the advice of its advisory panels.

That is even more likely in this case, said Dr. Norman Stockbridge, director of the FDA’s Division of Cardiovascular and Renal Products. "I would characterize our internal discussions so far as being fairly ambivalent," said Dr. Stockbridge at the outset of the meeting. "So what the committee does today is likely to have considerable influence on us," he said.

The committee members made much of the fact that in trials, the already-available anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) had a more impressive number of patients who reached the primary end point of time in therapeutic range (TTR). Some 64% of patients hit that marker in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study, compared with only 55% of patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study (N. Engl. J. Med. 2011;365:883-91).

Even so, nine of the FDA advisers said that rivaroxaban should be approved. Dr. Sanjay Kaul, director of the Cardiology Fellowship Training Program and the Cardiology Consult Service at Cedars-Sinai Medical Center, Los Angeles, was skeptical throughout the day, but in the end voted yes. He said he would support use of the drug in patients who had failed other anticoagulants. But, he added, "I am concerned about one major issue – when you stop the treatment, what happens?"

That was a key reason that led Dr. Steven Nissen to vote against approval. "I still think the agency should not approve this drug without having the data on what to do when you stop the drug," said Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation, Cleveland.

Both he and Dr. Kaul, among other FDA advisers, also questioned why Johnson & Johnson had not given more specific instructions to investigators on how to manage warfarin. The company said that it had decided to leave management up to local investigators’ discretion.

ROCKET AF was conducted at 1,187 sites in 45 countries, but the TTR for warfarin patients was consistently better at the North American sites. Dr. Robert M. Califf, director of the Duke Translational Medicine Institute and a principal investigator on ROCKET AF, said the differences in TTR were primarily due to geography and culture.

In addition, TTR is not a surrogate for risk and benefit. Rivaroxaban patients had less disabling stroke and a decreased occurrence of hemorrhagic strokes and intracranial and fatal bleeding, he said. "If you go according to what is most valued by those who will be prescribing and those contemplating the treatment, rivaroxaban has a favorable risk-benefit balance," said Dr. Califf, who spoke to the efficacy of rivaroxaban on behalf of Johnson & Johnson at the meeting.

However, Dr. Nissen said, "It would have been more prudent to make sure the course of warfarin met the highest contemporary standards," he said, "and that didn’t happen." Since the TTR "was well below other studies," it introduced a "level of uncertainty as to the efficacy."

The seed of doubt had already been planted by the FDA’s own reviewers. Dr. Martin Rose, from the FDA’s Cardiovascular and Renal Drug Products Division, said that rivaroxaban had not met the standard applied to dabigatran. In ROCKET AF, the drug did not prove a "robust noninferiority."

Most of the FDA advisers, however, were satisfied that rivaroxaban would offer a reasonable alternative to patients who could not tolerate warfarin or dabigatran.

Rivaroxaban is already on the market, having been approved by the FDA in July for the prevention of deep vein thrombosis (DVT) in knee or hip replacement surgery.

The company is looking forward to the second approval. "We are pleased with the committee’s recommendation and look forward to working with the FDA to help make this important therapy available in the U.S.," said Dr. Peter M. DiBattiste, Global Therapeutic Area Head of Cardiovascular and Metabolism at Johnson & Johnson/Bayer in a statement issued after the meeting.

COLLEGE PARK, MD. – The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee advisory panel on Sept. 8 voted 9-2, with 1 abstention, that the anticoagulant rivaroxaban is effective for prevention of stroke in nonvalvular atrial fibrillation.

But the panelists were generally in agreement that the drug, to be marketed as Xarelto by Johnson & Johnson and Bayer Healthcare, should only be offered as a third-line therapy. The committee members expressed concern that although the drug was no less effective than warfarin, it presented safety concerns. In particular, there was an excess of bleeding events when the drug was discontinued.

The FDA generally follows the advice of its advisory panels.

That is even more likely in this case, said Dr. Norman Stockbridge, director of the FDA’s Division of Cardiovascular and Renal Products. "I would characterize our internal discussions so far as being fairly ambivalent," said Dr. Stockbridge at the outset of the meeting. "So what the committee does today is likely to have considerable influence on us," he said.

The committee members made much of the fact that in trials, the already-available anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) had a more impressive number of patients who reached the primary end point of time in therapeutic range (TTR). Some 64% of patients hit that marker in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study, compared with only 55% of patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study (N. Engl. J. Med. 2011;365:883-91).

Even so, nine of the FDA advisers said that rivaroxaban should be approved. Dr. Sanjay Kaul, director of the Cardiology Fellowship Training Program and the Cardiology Consult Service at Cedars-Sinai Medical Center, Los Angeles, was skeptical throughout the day, but in the end voted yes. He said he would support use of the drug in patients who had failed other anticoagulants. But, he added, "I am concerned about one major issue – when you stop the treatment, what happens?"

That was a key reason that led Dr. Steven Nissen to vote against approval. "I still think the agency should not approve this drug without having the data on what to do when you stop the drug," said Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation, Cleveland.

Both he and Dr. Kaul, among other FDA advisers, also questioned why Johnson & Johnson had not given more specific instructions to investigators on how to manage warfarin. The company said that it had decided to leave management up to local investigators’ discretion.

ROCKET AF was conducted at 1,187 sites in 45 countries, but the TTR for warfarin patients was consistently better at the North American sites. Dr. Robert M. Califf, director of the Duke Translational Medicine Institute and a principal investigator on ROCKET AF, said the differences in TTR were primarily due to geography and culture.

In addition, TTR is not a surrogate for risk and benefit. Rivaroxaban patients had less disabling stroke and a decreased occurrence of hemorrhagic strokes and intracranial and fatal bleeding, he said. "If you go according to what is most valued by those who will be prescribing and those contemplating the treatment, rivaroxaban has a favorable risk-benefit balance," said Dr. Califf, who spoke to the efficacy of rivaroxaban on behalf of Johnson & Johnson at the meeting.

However, Dr. Nissen said, "It would have been more prudent to make sure the course of warfarin met the highest contemporary standards," he said, "and that didn’t happen." Since the TTR "was well below other studies," it introduced a "level of uncertainty as to the efficacy."

The seed of doubt had already been planted by the FDA’s own reviewers. Dr. Martin Rose, from the FDA’s Cardiovascular and Renal Drug Products Division, said that rivaroxaban had not met the standard applied to dabigatran. In ROCKET AF, the drug did not prove a "robust noninferiority."

Most of the FDA advisers, however, were satisfied that rivaroxaban would offer a reasonable alternative to patients who could not tolerate warfarin or dabigatran.

Rivaroxaban is already on the market, having been approved by the FDA in July for the prevention of deep vein thrombosis (DVT) in knee or hip replacement surgery.

The company is looking forward to the second approval. "We are pleased with the committee’s recommendation and look forward to working with the FDA to help make this important therapy available in the U.S.," said Dr. Peter M. DiBattiste, Global Therapeutic Area Head of Cardiovascular and Metabolism at Johnson & Johnson/Bayer in a statement issued after the meeting.

COLLEGE PARK, MD. – The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee advisory panel on Sept. 8 voted 9-2, with 1 abstention, that the anticoagulant rivaroxaban is effective for prevention of stroke in nonvalvular atrial fibrillation.

But the panelists were generally in agreement that the drug, to be marketed as Xarelto by Johnson & Johnson and Bayer Healthcare, should only be offered as a third-line therapy. The committee members expressed concern that although the drug was no less effective than warfarin, it presented safety concerns. In particular, there was an excess of bleeding events when the drug was discontinued.

The FDA generally follows the advice of its advisory panels.

That is even more likely in this case, said Dr. Norman Stockbridge, director of the FDA’s Division of Cardiovascular and Renal Products. "I would characterize our internal discussions so far as being fairly ambivalent," said Dr. Stockbridge at the outset of the meeting. "So what the committee does today is likely to have considerable influence on us," he said.

The committee members made much of the fact that in trials, the already-available anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) had a more impressive number of patients who reached the primary end point of time in therapeutic range (TTR). Some 64% of patients hit that marker in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study, compared with only 55% of patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study (N. Engl. J. Med. 2011;365:883-91).

Even so, nine of the FDA advisers said that rivaroxaban should be approved. Dr. Sanjay Kaul, director of the Cardiology Fellowship Training Program and the Cardiology Consult Service at Cedars-Sinai Medical Center, Los Angeles, was skeptical throughout the day, but in the end voted yes. He said he would support use of the drug in patients who had failed other anticoagulants. But, he added, "I am concerned about one major issue – when you stop the treatment, what happens?"

That was a key reason that led Dr. Steven Nissen to vote against approval. "I still think the agency should not approve this drug without having the data on what to do when you stop the drug," said Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation, Cleveland.

Both he and Dr. Kaul, among other FDA advisers, also questioned why Johnson & Johnson had not given more specific instructions to investigators on how to manage warfarin. The company said that it had decided to leave management up to local investigators’ discretion.

ROCKET AF was conducted at 1,187 sites in 45 countries, but the TTR for warfarin patients was consistently better at the North American sites. Dr. Robert M. Califf, director of the Duke Translational Medicine Institute and a principal investigator on ROCKET AF, said the differences in TTR were primarily due to geography and culture.

In addition, TTR is not a surrogate for risk and benefit. Rivaroxaban patients had less disabling stroke and a decreased occurrence of hemorrhagic strokes and intracranial and fatal bleeding, he said. "If you go according to what is most valued by those who will be prescribing and those contemplating the treatment, rivaroxaban has a favorable risk-benefit balance," said Dr. Califf, who spoke to the efficacy of rivaroxaban on behalf of Johnson & Johnson at the meeting.

However, Dr. Nissen said, "It would have been more prudent to make sure the course of warfarin met the highest contemporary standards," he said, "and that didn’t happen." Since the TTR "was well below other studies," it introduced a "level of uncertainty as to the efficacy."

The seed of doubt had already been planted by the FDA’s own reviewers. Dr. Martin Rose, from the FDA’s Cardiovascular and Renal Drug Products Division, said that rivaroxaban had not met the standard applied to dabigatran. In ROCKET AF, the drug did not prove a "robust noninferiority."

Most of the FDA advisers, however, were satisfied that rivaroxaban would offer a reasonable alternative to patients who could not tolerate warfarin or dabigatran.

Rivaroxaban is already on the market, having been approved by the FDA in July for the prevention of deep vein thrombosis (DVT) in knee or hip replacement surgery.

The company is looking forward to the second approval. "We are pleased with the committee’s recommendation and look forward to working with the FDA to help make this important therapy available in the U.S.," said Dr. Peter M. DiBattiste, Global Therapeutic Area Head of Cardiovascular and Metabolism at Johnson & Johnson/Bayer in a statement issued after the meeting.