FDA makes dabigatran contraindicated for mechanical valves

The FDA has declared the anticoagulant dabigatran contraindicated for patients with a mechanical heart valve, following anecdotal reports of blood clots forming on mechanical prosthetic valves and the abrupt stoppage of a phase II trial that had been testing dabigatran in this patient population.

"The U.S. Food and Drug Administration is informing health care professionals and the public that the blood thinner Pradaxa [dabigatran etexilate mesylate] should not be used to prevent stroke or blood clots in patients with mechanical heart valves," the agency said in a Drug Safety Communication.

"Health care professionals should promptly transition any patient with a mechanical heart valve who is taking Pradaxa to another medication," the agency added.

The statement also noted that the European-based, randomized phase II study to evaluate the safety and pharmacokinetics of oral dabigatran versus warfarin in patients after heart valve replacement (RE-ALIGN) (Am. Heart J. 2012;163:931-7) had been halted earlier in December by Boehringer Ingelheim, the company that markets Pradaxa, because the dabigatran-treated patients had shown an excess of strokes, myocardial infarctions, and blood clots that formed on the valves. Patients on dabigatran also had more episodes of bleeding after valve surgery than did patients on warfarin.

Although Boehringer Ingelheim and the researchers who ran the RE-ALIGN trial have not yet released the details of exactly what happened in the study, a report appeared in October from a group of cardiac surgeons at the Ottawa (Ont.) Heart Institute on their experience with two patients with mechanical heart valves who developed a thrombus on their valves and significant symptoms within 2 or 3 months of being switched from warfarin to dabigatran by their primary care physicians (J. Am. Coll. Cardiol. 2012;60:1710-1). These switches, which occurred even though dabigatran treatment in patients with mechanical prosthetic valves is an off-label use, probably represent the tip of the iceberg, said Dr. Munir Boodhwani, a cardiac surgeon at the Heart Institute and lead author of the two case reports.

"I suspect [this off-label use] is more common than we know. We see the problems, but we don’t know the denominator," he said in an interview. "In Ottawa, we routinely evaluate heart valve recipients every 6-12 months, and we have seen a few patients who had been switched from warfarin to dabigatran or another new oral anticoagulant. It has not been just one or two isolated cases. When we see these patients, we switch them back, and we send a message to their physician who made the switch that maybe this was not a good idea."

One of the cases he and his associates reported was a 51-year-old woman with a mechanical aortic valve who had been on warfarin for 8 years without complications and then was switched to 150 mg dabigatran twice daily by her general practitioner. Within 2 months, she developed crackles and a systolic murmur, and an echocardiogram revealed severe prosthetic aortic valve stenosis and a probable mass on the prosthesis. She arrived at the Heart Institute in cardiogenic shock and had cardiac arrest in the operating room. Surgery revealed an extensive thrombus on the valve, which was replaced. After surgery she had a complete recovery.

The second reported case was a 59-year-old woman with a mechanical mitral valve who had been on warfarin treatment without complications for about 4 years before being switched by her family physicians to 150 mg dabigatran twice daily. She developed progressive dyspnea, and an echocardiogram revealed a large thrombus on the valve. She underwent valve replacement and had an uneventful recovery.

Although phase III trial results showed dabigatran safe and effective for preventing blood clots and strokes in patients with nonvalvular atrial fibrillation, "atrial fibrillation is very different in a patient with a mechanical heart valve," Dr. Boodhwani said. "You cannot translate efficacy for one population to another. For atrial fibrillation, dosages of 110 mg b.i.d. and 150 mg b.i.d were effective [in the RE-LY trial; N. Engl. J. Med. 2009;361:1139-51], but in RE-ALIGN, dabigatran seems to have not been effective even at a dosage of 300 mg b.i.d. I think that Boehringer Ingelheim and the other companies that make the new anticoagulants need to go back to the drawing board and do more preclinical studies to determine what is a safe and effective dosage for anticoagulating patients with mechanical heart valves. It will likely need a higher dose, and then the question will be, What is the bleeding risk?"

The safety and efficacy results from nonvalvular atrial fibrillation patients in RE-LY are impossible to extrapolate to patients with mechanical valves, agreed Dr. Michael D. Ezekowitz, who was a coprincipal investigator for RE-LY but had no involvement in RE-ALIGN.

"It may be that a direct thrombin inhibitor [such as dabigatran] is not the drug of choice for preventing clots from forming on the surface of valves," Dr. Ezekowtiz said in an interview. "We have nearly 50 years of experience using warfarin for patients with mechanical heart valves, and that is clearly the drug of choice. This [RE-ALIGN] was probably a high-risk trial" in terms of trying to show that a new drug was at least as safe and effective as warfarin for heart valve patients.

Dr. Ezekowitz stressed that he has not been privy to any details of the RE-ALIGN results, but he suggested that it is hard to imagine that higher dabigatran dosages than the 300 mg b.i.d tested in RE-ALIGN could be used safely. "I was principal investigator for a phase II dabigatran study in atrial fibrillation, the PETRO [Prevention of Embolic and Thrombotic Events in Patients With Persistent AF] study (Am. J. Cardiol. 2007;100:1419-26). We tested up to 300 mg b.i.d., and in older atrial fibrillation patients this caused an excess of gastrointestinal bleeds and we decided to abandon that dosage in further testing. From a purely practical standpoint, I doubt whether a dabigatran dosage of more than 150 mg b.i.d would be tolerable," said Dr. Ezekowitz, professor of medicine at Jefferson Medical College in Philadelphia and director of atrial fibrillation research and education at the Cardiovascular Research Foundation in New York.

Some community physicians seem to have been mistakenly lured into prescribing dabigatran or other new anticoagulants to mechanical heart valve patients, perhaps because these physicians equated the newer drugs with better performance, Dr. Boodhwani said. But extrapolating the atrial fibrillation experience to heart-valve patients is premature, he warned.

"There is the potential for patients to die on these drugs. The off-label use can potentially be quite dangerous."

The FDA’s action and termination of the RE-ALIGN trial should send physicians a strong warning, he said. "This doesn’t close the door to future use of these drugs for mechanical valve patients, but physicians and industry need to be more cautious. The problems with warfarin need solutions, but only in a step-by-step way."

Dr. Boodhwani said he had no relevant financial disclosures. Dr. Ezekowitz said he has been a consultant to, has received honoraria as a lecturer on behalf of, and has received research funding from Boehringer Ingelheim, as well as from other drug companies that market antithrombotic drugs.

[email protected]

On Twitter @mitchelzoler

The FDA has declared the anticoagulant dabigatran contraindicated for patients with a mechanical heart valve, following anecdotal reports of blood clots forming on mechanical prosthetic valves and the abrupt stoppage of a phase II trial that had been testing dabigatran in this patient population.

"The U.S. Food and Drug Administration is informing health care professionals and the public that the blood thinner Pradaxa [dabigatran etexilate mesylate] should not be used to prevent stroke or blood clots in patients with mechanical heart valves," the agency said in a Drug Safety Communication.

"Health care professionals should promptly transition any patient with a mechanical heart valve who is taking Pradaxa to another medication," the agency added.

The statement also noted that the European-based, randomized phase II study to evaluate the safety and pharmacokinetics of oral dabigatran versus warfarin in patients after heart valve replacement (RE-ALIGN) (Am. Heart J. 2012;163:931-7) had been halted earlier in December by Boehringer Ingelheim, the company that markets Pradaxa, because the dabigatran-treated patients had shown an excess of strokes, myocardial infarctions, and blood clots that formed on the valves. Patients on dabigatran also had more episodes of bleeding after valve surgery than did patients on warfarin.

Although Boehringer Ingelheim and the researchers who ran the RE-ALIGN trial have not yet released the details of exactly what happened in the study, a report appeared in October from a group of cardiac surgeons at the Ottawa (Ont.) Heart Institute on their experience with two patients with mechanical heart valves who developed a thrombus on their valves and significant symptoms within 2 or 3 months of being switched from warfarin to dabigatran by their primary care physicians (J. Am. Coll. Cardiol. 2012;60:1710-1). These switches, which occurred even though dabigatran treatment in patients with mechanical prosthetic valves is an off-label use, probably represent the tip of the iceberg, said Dr. Munir Boodhwani, a cardiac surgeon at the Heart Institute and lead author of the two case reports.

"I suspect [this off-label use] is more common than we know. We see the problems, but we don’t know the denominator," he said in an interview. "In Ottawa, we routinely evaluate heart valve recipients every 6-12 months, and we have seen a few patients who had been switched from warfarin to dabigatran or another new oral anticoagulant. It has not been just one or two isolated cases. When we see these patients, we switch them back, and we send a message to their physician who made the switch that maybe this was not a good idea."

One of the cases he and his associates reported was a 51-year-old woman with a mechanical aortic valve who had been on warfarin for 8 years without complications and then was switched to 150 mg dabigatran twice daily by her general practitioner. Within 2 months, she developed crackles and a systolic murmur, and an echocardiogram revealed severe prosthetic aortic valve stenosis and a probable mass on the prosthesis. She arrived at the Heart Institute in cardiogenic shock and had cardiac arrest in the operating room. Surgery revealed an extensive thrombus on the valve, which was replaced. After surgery she had a complete recovery.

The second reported case was a 59-year-old woman with a mechanical mitral valve who had been on warfarin treatment without complications for about 4 years before being switched by her family physicians to 150 mg dabigatran twice daily. She developed progressive dyspnea, and an echocardiogram revealed a large thrombus on the valve. She underwent valve replacement and had an uneventful recovery.

Although phase III trial results showed dabigatran safe and effective for preventing blood clots and strokes in patients with nonvalvular atrial fibrillation, "atrial fibrillation is very different in a patient with a mechanical heart valve," Dr. Boodhwani said. "You cannot translate efficacy for one population to another. For atrial fibrillation, dosages of 110 mg b.i.d. and 150 mg b.i.d were effective [in the RE-LY trial; N. Engl. J. Med. 2009;361:1139-51], but in RE-ALIGN, dabigatran seems to have not been effective even at a dosage of 300 mg b.i.d. I think that Boehringer Ingelheim and the other companies that make the new anticoagulants need to go back to the drawing board and do more preclinical studies to determine what is a safe and effective dosage for anticoagulating patients with mechanical heart valves. It will likely need a higher dose, and then the question will be, What is the bleeding risk?"

The safety and efficacy results from nonvalvular atrial fibrillation patients in RE-LY are impossible to extrapolate to patients with mechanical valves, agreed Dr. Michael D. Ezekowitz, who was a coprincipal investigator for RE-LY but had no involvement in RE-ALIGN.

"It may be that a direct thrombin inhibitor [such as dabigatran] is not the drug of choice for preventing clots from forming on the surface of valves," Dr. Ezekowtiz said in an interview. "We have nearly 50 years of experience using warfarin for patients with mechanical heart valves, and that is clearly the drug of choice. This [RE-ALIGN] was probably a high-risk trial" in terms of trying to show that a new drug was at least as safe and effective as warfarin for heart valve patients.

Dr. Ezekowitz stressed that he has not been privy to any details of the RE-ALIGN results, but he suggested that it is hard to imagine that higher dabigatran dosages than the 300 mg b.i.d tested in RE-ALIGN could be used safely. "I was principal investigator for a phase II dabigatran study in atrial fibrillation, the PETRO [Prevention of Embolic and Thrombotic Events in Patients With Persistent AF] study (Am. J. Cardiol. 2007;100:1419-26). We tested up to 300 mg b.i.d., and in older atrial fibrillation patients this caused an excess of gastrointestinal bleeds and we decided to abandon that dosage in further testing. From a purely practical standpoint, I doubt whether a dabigatran dosage of more than 150 mg b.i.d would be tolerable," said Dr. Ezekowitz, professor of medicine at Jefferson Medical College in Philadelphia and director of atrial fibrillation research and education at the Cardiovascular Research Foundation in New York.

Some community physicians seem to have been mistakenly lured into prescribing dabigatran or other new anticoagulants to mechanical heart valve patients, perhaps because these physicians equated the newer drugs with better performance, Dr. Boodhwani said. But extrapolating the atrial fibrillation experience to heart-valve patients is premature, he warned.

"There is the potential for patients to die on these drugs. The off-label use can potentially be quite dangerous."

The FDA’s action and termination of the RE-ALIGN trial should send physicians a strong warning, he said. "This doesn’t close the door to future use of these drugs for mechanical valve patients, but physicians and industry need to be more cautious. The problems with warfarin need solutions, but only in a step-by-step way."

Dr. Boodhwani said he had no relevant financial disclosures. Dr. Ezekowitz said he has been a consultant to, has received honoraria as a lecturer on behalf of, and has received research funding from Boehringer Ingelheim, as well as from other drug companies that market antithrombotic drugs.

[email protected]

On Twitter @mitchelzoler

The FDA has declared the anticoagulant dabigatran contraindicated for patients with a mechanical heart valve, following anecdotal reports of blood clots forming on mechanical prosthetic valves and the abrupt stoppage of a phase II trial that had been testing dabigatran in this patient population.

"The U.S. Food and Drug Administration is informing health care professionals and the public that the blood thinner Pradaxa [dabigatran etexilate mesylate] should not be used to prevent stroke or blood clots in patients with mechanical heart valves," the agency said in a Drug Safety Communication.

"Health care professionals should promptly transition any patient with a mechanical heart valve who is taking Pradaxa to another medication," the agency added.

The statement also noted that the European-based, randomized phase II study to evaluate the safety and pharmacokinetics of oral dabigatran versus warfarin in patients after heart valve replacement (RE-ALIGN) (Am. Heart J. 2012;163:931-7) had been halted earlier in December by Boehringer Ingelheim, the company that markets Pradaxa, because the dabigatran-treated patients had shown an excess of strokes, myocardial infarctions, and blood clots that formed on the valves. Patients on dabigatran also had more episodes of bleeding after valve surgery than did patients on warfarin.

Although Boehringer Ingelheim and the researchers who ran the RE-ALIGN trial have not yet released the details of exactly what happened in the study, a report appeared in October from a group of cardiac surgeons at the Ottawa (Ont.) Heart Institute on their experience with two patients with mechanical heart valves who developed a thrombus on their valves and significant symptoms within 2 or 3 months of being switched from warfarin to dabigatran by their primary care physicians (J. Am. Coll. Cardiol. 2012;60:1710-1). These switches, which occurred even though dabigatran treatment in patients with mechanical prosthetic valves is an off-label use, probably represent the tip of the iceberg, said Dr. Munir Boodhwani, a cardiac surgeon at the Heart Institute and lead author of the two case reports.

"I suspect [this off-label use] is more common than we know. We see the problems, but we don’t know the denominator," he said in an interview. "In Ottawa, we routinely evaluate heart valve recipients every 6-12 months, and we have seen a few patients who had been switched from warfarin to dabigatran or another new oral anticoagulant. It has not been just one or two isolated cases. When we see these patients, we switch them back, and we send a message to their physician who made the switch that maybe this was not a good idea."

One of the cases he and his associates reported was a 51-year-old woman with a mechanical aortic valve who had been on warfarin for 8 years without complications and then was switched to 150 mg dabigatran twice daily by her general practitioner. Within 2 months, she developed crackles and a systolic murmur, and an echocardiogram revealed severe prosthetic aortic valve stenosis and a probable mass on the prosthesis. She arrived at the Heart Institute in cardiogenic shock and had cardiac arrest in the operating room. Surgery revealed an extensive thrombus on the valve, which was replaced. After surgery she had a complete recovery.

The second reported case was a 59-year-old woman with a mechanical mitral valve who had been on warfarin treatment without complications for about 4 years before being switched by her family physicians to 150 mg dabigatran twice daily. She developed progressive dyspnea, and an echocardiogram revealed a large thrombus on the valve. She underwent valve replacement and had an uneventful recovery.

Although phase III trial results showed dabigatran safe and effective for preventing blood clots and strokes in patients with nonvalvular atrial fibrillation, "atrial fibrillation is very different in a patient with a mechanical heart valve," Dr. Boodhwani said. "You cannot translate efficacy for one population to another. For atrial fibrillation, dosages of 110 mg b.i.d. and 150 mg b.i.d were effective [in the RE-LY trial; N. Engl. J. Med. 2009;361:1139-51], but in RE-ALIGN, dabigatran seems to have not been effective even at a dosage of 300 mg b.i.d. I think that Boehringer Ingelheim and the other companies that make the new anticoagulants need to go back to the drawing board and do more preclinical studies to determine what is a safe and effective dosage for anticoagulating patients with mechanical heart valves. It will likely need a higher dose, and then the question will be, What is the bleeding risk?"

The safety and efficacy results from nonvalvular atrial fibrillation patients in RE-LY are impossible to extrapolate to patients with mechanical valves, agreed Dr. Michael D. Ezekowitz, who was a coprincipal investigator for RE-LY but had no involvement in RE-ALIGN.

"It may be that a direct thrombin inhibitor [such as dabigatran] is not the drug of choice for preventing clots from forming on the surface of valves," Dr. Ezekowtiz said in an interview. "We have nearly 50 years of experience using warfarin for patients with mechanical heart valves, and that is clearly the drug of choice. This [RE-ALIGN] was probably a high-risk trial" in terms of trying to show that a new drug was at least as safe and effective as warfarin for heart valve patients.

Dr. Ezekowitz stressed that he has not been privy to any details of the RE-ALIGN results, but he suggested that it is hard to imagine that higher dabigatran dosages than the 300 mg b.i.d tested in RE-ALIGN could be used safely. "I was principal investigator for a phase II dabigatran study in atrial fibrillation, the PETRO [Prevention of Embolic and Thrombotic Events in Patients With Persistent AF] study (Am. J. Cardiol. 2007;100:1419-26). We tested up to 300 mg b.i.d., and in older atrial fibrillation patients this caused an excess of gastrointestinal bleeds and we decided to abandon that dosage in further testing. From a purely practical standpoint, I doubt whether a dabigatran dosage of more than 150 mg b.i.d would be tolerable," said Dr. Ezekowitz, professor of medicine at Jefferson Medical College in Philadelphia and director of atrial fibrillation research and education at the Cardiovascular Research Foundation in New York.

Some community physicians seem to have been mistakenly lured into prescribing dabigatran or other new anticoagulants to mechanical heart valve patients, perhaps because these physicians equated the newer drugs with better performance, Dr. Boodhwani said. But extrapolating the atrial fibrillation experience to heart-valve patients is premature, he warned.

"There is the potential for patients to die on these drugs. The off-label use can potentially be quite dangerous."

The FDA’s action and termination of the RE-ALIGN trial should send physicians a strong warning, he said. "This doesn’t close the door to future use of these drugs for mechanical valve patients, but physicians and industry need to be more cautious. The problems with warfarin need solutions, but only in a step-by-step way."

Dr. Boodhwani said he had no relevant financial disclosures. Dr. Ezekowitz said he has been a consultant to, has received honoraria as a lecturer on behalf of, and has received research funding from Boehringer Ingelheim, as well as from other drug companies that market antithrombotic drugs.

[email protected]

On Twitter @mitchelzoler