FDA News

FDA panel does not recommend approval of vernakalant for AF

C. Michael Gibson
C. Michael Gibson

Citing safety concerns, the Cardiovascular and Renal Drug Advisory Committee of the FDA voted 2-11 against approval of vernakalant for the rapid conversion of recent-onset atrial fibrillation.

The committee expressed concerns about adverse events associated with vernakalant hydrochloride solution (Brinavess, Correvio International Sàrl), including hypotension, bradycardia, ventricular arrhythmias and, in the most extreme cases, death. Committee members also cited difficulties in predicting which patients might experience adverse events.

The company sought approval for vernakalant for rapid conversion of recent-onset AF to sinus rhythm in patients with AF duration no longer than 7 days among those who did not have surgery and AF duration no longer than 3 days among those who had cardiac surgery.

“I’m looking for what’s the advantage, and I’m not seeing it,” C. Michael Gibson, MD, MS, professor of medicine at Harvard Medical School and president of the combined non-profit Baim and PERFUSE Research Institutes, a member of the committee, said after the vote. “It’s convenience, but … I’m not sure it’s necessarily an advantage to the health status of an individual patient. We take risk, but here the risk was unpredictable. When you have an unpredictable risk, I think it really makes it much more concerning as a health care provider.”

Paul M. Ridker

Although the majority of the committee voted against approval, panelist Paul M. Ridker, MD, MPH, FACC, FAHA, Eugene Braunwald Professor of Medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, said how the idea of pharmacologic cardioversion should not be thrown out completely.

He said, “I don’t want this vote to imply that we should shut down pharmacologic cardioversion in general as an approach, nor that this drug as an approach should necessarily be abandoned. I probably would encourage the FDA to consider lifting the clinical hold and allowing the sponsor to figure out some study designs that would answer some of these critical questions so that we could come back here with more data on the benefit-to-risk ratio, because I suspect there are patients that this is a good idea for. I just haven’t been convinced who they are.”

Julia B. Lewis, MD, chairperson of the Cardiovascular and Renal Drugs Advisory Committee of the FDA, said there may be some hesitation with lifting the clinical hold on vernakalant.

“I actually am concerned about lifting the clinical hold only because I think that the animal data support what was seen in albeit a [low] number of humans, and I think it would be challenging to ask a patient to volunteer,” she said.

Despite the hesitation felt among most committee members, John H. Alexander, MD, MHSc, professor of medicine in the division of cardiology at Duke University School of Medicine, said that findings from the postmarket SPECTRUM study conducted after the FDA requested more data in 2008 were helpful. The SPECTRUM study found that vernakalant was effective for rapid conversion of recent-onset AF, which was accompanied by lower rates of AF-related symptoms. Sinus rhythm was maintained in most patients in study out to 7 days.

He said, “I was more reassured by the SPECTRUM data, and I think there is a low-risk population where the convenience factor of this drug that would provide an important option for providers and patients outweighs the relatively low risk of serious complications. Patient selection is key, and I think more work needs to be done on identifying the patient population that has a favorable risk-benefit profile. I think there’s a pretty clear really low-risk population, I think there’s a pretty clear really high-risk population and I think there’s this huge gray zone, which is a big problem.”

In a presentation on behalf of the sponsor, A. John Camm, MD, FRCP, professor of clinical cardiology at St. Georges University of London, said the drug is approved in 41 other countries, including Canada, for the proposed indication and it has a Class IA indication for AF termination in the European AF guidelines.

Discussion questions

In addition to the vote, three discussion questions were addressed during the meeting. The first was whether the safety profile of vernakalant was adequately characterized. Although some committee members felt reassured by the additional data from the SPECTRUM study, concerns remained about very-low risk patients, as they may be difficult to identify due to lack of universal health care records or the lack of evaluations, particularly in younger patients. Underrepresentation of patients from the United States in the SPECTRUM study was a concern, some committee members stated.

Another question focused on the efficacy and safety profiles of alternative approaches such as ibutilide (Corvert, Pfizer) and electrical cardioversion for patients with AF. The committee was mixed regarding electrical cardioversion and ibutilide; some members said they are effective, while others said how they may not be as safe as originally believed.

The last question addressed potential restrictions on patients or on the conditions of use if vernakalant were approved. The committee voiced interest in exploring the mechanism of action of vernakalant either by comparison within a trial or by echocardiography. There was an agreement regarding restrictions in its use focused on cardiologists, electrophysiologists and doctors who are Risk Evaluation and Mitigation Strategy certified in an attempt to take into consideration the multidisciplinary team that would care for the patient.

New, rehashed information

This meeting revisited some of what was discussed in another Cardiovascular and Renal Drugs Advisory Committee meeting in 2007 but with additional information requested by the FDA in 2008 in a complete response letter.

Peter R. Kowey
Peter R. Kowey

“Safety is the principle that guides the selection and use of every single antiarrhythmic drug in clinical practice,” Cardiology Today Arrhythmia Disorders Section Editor Peter R. Kowey, MD, the William Wikoff Smith Chair in Cardiovascular Research at the Lankenau Institute for Medical Research, chairman emeritus of cardiology at Main Line Health and professor of medicine and clinical pharmacology at Jefferson Medical College, said during the presentation. “Vernakalant will absolutely be no different.”

Several representatives and medical professionals on behalf of Correvio International Sàrl presented information on the unmet need of an additional pharmacological treatment for patients with recent-onset AF.

“Although pharmacologic conversion is recommended in appropriate patients with recent-onset AF, it is simply not used in the United States,” Kowey said during the presentation. “This is unfortunate since pharmacologic conversion has several potential benefits for a subset of patients with recent-onset AF.”

Peter K.S. Siegl, PhD, a nonclinical pharmacologist for Correvio International Sàrl, mentioned the importance of patient selection despite the potential risks. “For all drugs with mechanism-based negative inotropic effects, there’s a risk for decreased cardiac output and hypotension in patients with significant uncompensated left ventricular dysfunction; therefore, appropriate patient selection and monitoring are important to mitigate the risks associated with these drugs.”

The company discussed a pre-infusion checklist to assist in patient selection, in which one of any of the following conditions would prevent health care providers from administering vernakalant:

  • systolic BP less than 100 mm Hg or receipt of fluid resuscitation or inotropes to maintain a BP greater than 100 mm Hg;
  • severe HF;
  • clinically significant aortic stenosis;
  • severe bradycardia, sinus node dysfunction or second- and third-degree heart block without a pacemaker;
  • prolonged QT interval at baseline;
  • ACS in the last 30 days; and
  • receipt of an IV rhythm control antiarrhythmic drug within 4 hours of and in the first 4 hours following the administration of vernakalant.

FDA staff members expressed concern about the checklist in their presentations.

“We have concerns about the adequacy of this tool for identifying patients who might experience serious cardiovascular adverse events after the vernakalant infusion,” Preston Dunnmon, MD, medical officer of the division of cardiovascular and renal products of the FDA’s Center for Drug Evaluation and Research, said during the agency’s presentation. “We find these items problematic in that patients who did not demonstrate low baseline blood pressures, severe bradycardia, QRS or QT prolongations, heart failure [or] valvular heart disease went on to experience these events in the controlled clinical trials, in SPECTRUM and in the postmarket setting. We had seen reports of these events in all these places.”

The agency did not find substantial downsides regarding the use of ibutilide and electrical cardioversion in patients with AF.

“Literature research did not identify any instances of ibutilide-related death during index hospital stay among patients who otherwise could have been enrolled in ACT V,” an early trial of vernakalant, Daniel Woronow, MD, FACC, medical officer of the division of pharmacovigilance I of the FDA, said during the presentation. “Electrical cardioversion is generally successful in rapidly converting atrial fibrillation to sinus rhythm. Electrical cardioversion literature did not identify any … deaths causally related to electrical cardioversion despite most of these studies including patients with more severe baseline comorbidities than in ACT V. Electrical cardioversion related serious adverse events that are non-transient and not self-limited occur uncommonly or rarely despite most of these electrical cardioversion studies including patients with more severe baseline comorbidities than in the ACT V study.” – by Darlene Dobkowski

Disclosures: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures. Dunnmon, Lewis and Woronow are employees of the FDA. Camm and Kowey report they are paid consultants for Correvio International Sàrl. Siegl is an employee of Correvio International Sàrl.

C. Michael Gibson
C. Michael Gibson

Citing safety concerns, the Cardiovascular and Renal Drug Advisory Committee of the FDA voted 2-11 against approval of vernakalant for the rapid conversion of recent-onset atrial fibrillation.

The committee expressed concerns about adverse events associated with vernakalant hydrochloride solution (Brinavess, Correvio International Sàrl), including hypotension, bradycardia, ventricular arrhythmias and, in the most extreme cases, death. Committee members also cited difficulties in predicting which patients might experience adverse events.

The company sought approval for vernakalant for rapid conversion of recent-onset AF to sinus rhythm in patients with AF duration no longer than 7 days among those who did not have surgery and AF duration no longer than 3 days among those who had cardiac surgery.

“I’m looking for what’s the advantage, and I’m not seeing it,” C. Michael Gibson, MD, MS, professor of medicine at Harvard Medical School and president of the combined non-profit Baim and PERFUSE Research Institutes, a member of the committee, said after the vote. “It’s convenience, but … I’m not sure it’s necessarily an advantage to the health status of an individual patient. We take risk, but here the risk was unpredictable. When you have an unpredictable risk, I think it really makes it much more concerning as a health care provider.”

Paul M. Ridker

Although the majority of the committee voted against approval, panelist Paul M. Ridker, MD, MPH, FACC, FAHA, Eugene Braunwald Professor of Medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, said how the idea of pharmacologic cardioversion should not be thrown out completely.

He said, “I don’t want this vote to imply that we should shut down pharmacologic cardioversion in general as an approach, nor that this drug as an approach should necessarily be abandoned. I probably would encourage the FDA to consider lifting the clinical hold and allowing the sponsor to figure out some study designs that would answer some of these critical questions so that we could come back here with more data on the benefit-to-risk ratio, because I suspect there are patients that this is a good idea for. I just haven’t been convinced who they are.”

Julia B. Lewis, MD, chairperson of the Cardiovascular and Renal Drugs Advisory Committee of the FDA, said there may be some hesitation with lifting the clinical hold on vernakalant.

“I actually am concerned about lifting the clinical hold only because I think that the animal data support what was seen in albeit a [low] number of humans, and I think it would be challenging to ask a patient to volunteer,” she said.

Despite the hesitation felt among most committee members, John H. Alexander, MD, MHSc, professor of medicine in the division of cardiology at Duke University School of Medicine, said that findings from the postmarket SPECTRUM study conducted after the FDA requested more data in 2008 were helpful. The SPECTRUM study found that vernakalant was effective for rapid conversion of recent-onset AF, which was accompanied by lower rates of AF-related symptoms. Sinus rhythm was maintained in most patients in study out to 7 days.

He said, “I was more reassured by the SPECTRUM data, and I think there is a low-risk population where the convenience factor of this drug that would provide an important option for providers and patients outweighs the relatively low risk of serious complications. Patient selection is key, and I think more work needs to be done on identifying the patient population that has a favorable risk-benefit profile. I think there’s a pretty clear really low-risk population, I think there’s a pretty clear really high-risk population and I think there’s this huge gray zone, which is a big problem.”

In a presentation on behalf of the sponsor, A. John Camm, MD, FRCP, professor of clinical cardiology at St. Georges University of London, said the drug is approved in 41 other countries, including Canada, for the proposed indication and it has a Class IA indication for AF termination in the European AF guidelines.

Discussion questions

In addition to the vote, three discussion questions were addressed during the meeting. The first was whether the safety profile of vernakalant was adequately characterized. Although some committee members felt reassured by the additional data from the SPECTRUM study, concerns remained about very-low risk patients, as they may be difficult to identify due to lack of universal health care records or the lack of evaluations, particularly in younger patients. Underrepresentation of patients from the United States in the SPECTRUM study was a concern, some committee members stated.

Another question focused on the efficacy and safety profiles of alternative approaches such as ibutilide (Corvert, Pfizer) and electrical cardioversion for patients with AF. The committee was mixed regarding electrical cardioversion and ibutilide; some members said they are effective, while others said how they may not be as safe as originally believed.

The last question addressed potential restrictions on patients or on the conditions of use if vernakalant were approved. The committee voiced interest in exploring the mechanism of action of vernakalant either by comparison within a trial or by echocardiography. There was an agreement regarding restrictions in its use focused on cardiologists, electrophysiologists and doctors who are Risk Evaluation and Mitigation Strategy certified in an attempt to take into consideration the multidisciplinary team that would care for the patient.

New, rehashed information

This meeting revisited some of what was discussed in another Cardiovascular and Renal Drugs Advisory Committee meeting in 2007 but with additional information requested by the FDA in 2008 in a complete response letter.

Peter R. Kowey
Peter R. Kowey

“Safety is the principle that guides the selection and use of every single antiarrhythmic drug in clinical practice,” Cardiology Today Arrhythmia Disorders Section Editor Peter R. Kowey, MD, the William Wikoff Smith Chair in Cardiovascular Research at the Lankenau Institute for Medical Research, chairman emeritus of cardiology at Main Line Health and professor of medicine and clinical pharmacology at Jefferson Medical College, said during the presentation. “Vernakalant will absolutely be no different.”

Several representatives and medical professionals on behalf of Correvio International Sàrl presented information on the unmet need of an additional pharmacological treatment for patients with recent-onset AF.

“Although pharmacologic conversion is recommended in appropriate patients with recent-onset AF, it is simply not used in the United States,” Kowey said during the presentation. “This is unfortunate since pharmacologic conversion has several potential benefits for a subset of patients with recent-onset AF.”

Peter K.S. Siegl, PhD, a nonclinical pharmacologist for Correvio International Sàrl, mentioned the importance of patient selection despite the potential risks. “For all drugs with mechanism-based negative inotropic effects, there’s a risk for decreased cardiac output and hypotension in patients with significant uncompensated left ventricular dysfunction; therefore, appropriate patient selection and monitoring are important to mitigate the risks associated with these drugs.”

The company discussed a pre-infusion checklist to assist in patient selection, in which one of any of the following conditions would prevent health care providers from administering vernakalant:

  • systolic BP less than 100 mm Hg or receipt of fluid resuscitation or inotropes to maintain a BP greater than 100 mm Hg;
  • severe HF;
  • clinically significant aortic stenosis;
  • severe bradycardia, sinus node dysfunction or second- and third-degree heart block without a pacemaker;
  • prolonged QT interval at baseline;
  • ACS in the last 30 days; and
  • receipt of an IV rhythm control antiarrhythmic drug within 4 hours of and in the first 4 hours following the administration of vernakalant.

FDA staff members expressed concern about the checklist in their presentations.

“We have concerns about the adequacy of this tool for identifying patients who might experience serious cardiovascular adverse events after the vernakalant infusion,” Preston Dunnmon, MD, medical officer of the division of cardiovascular and renal products of the FDA’s Center for Drug Evaluation and Research, said during the agency’s presentation. “We find these items problematic in that patients who did not demonstrate low baseline blood pressures, severe bradycardia, QRS or QT prolongations, heart failure [or] valvular heart disease went on to experience these events in the controlled clinical trials, in SPECTRUM and in the postmarket setting. We had seen reports of these events in all these places.”

The agency did not find substantial downsides regarding the use of ibutilide and electrical cardioversion in patients with AF.

“Literature research did not identify any instances of ibutilide-related death during index hospital stay among patients who otherwise could have been enrolled in ACT V,” an early trial of vernakalant, Daniel Woronow, MD, FACC, medical officer of the division of pharmacovigilance I of the FDA, said during the presentation. “Electrical cardioversion is generally successful in rapidly converting atrial fibrillation to sinus rhythm. Electrical cardioversion literature did not identify any … deaths causally related to electrical cardioversion despite most of these studies including patients with more severe baseline comorbidities than in ACT V. Electrical cardioversion related serious adverse events that are non-transient and not self-limited occur uncommonly or rarely despite most of these electrical cardioversion studies including patients with more severe baseline comorbidities than in the ACT V study.” – by Darlene Dobkowski

Disclosures: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures. Dunnmon, Lewis and Woronow are employees of the FDA. Camm and Kowey report they are paid consultants for Correvio International Sàrl. Siegl is an employee of Correvio International Sàrl.