Mitchel L. Zoler, PhD

NEW YORK – During the period 1996-2007, hospitalization rates for psychiatric disorders among American children aged 5-13 years rose dramatically, nearly doubling during that period.

Concurrently, psychiatric hospitalizations for U.S. adolescents (aged 14-19 years) also rose substantially, by 42%. During the same period, psychiatric hospitalizations rose modestly (by 8%) for adults aged 20-64 years, whereas psychiatric hospitalizations for Americans aged 65 or older fell dramatically, Joseph C. Blader, Ph.D., said while presenting a poster at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The reasons behind these changes and their implications for the quality of care American psychiatric patients receive remain unclear, said Dr. Blader, a researcher in the division of child and adolescent psychiatry at the State University of New York at Stony Brook. However, the shifts in hospitalization rates – especially the larger such shifts among children and adolescents – raise concerns that demand further analysis, he said.

"It’s not a good thing" that substantially more children and adolescents require hospitalization for psychiatric diagnoses, Dr. Blader said in an interview. The shifts "represent a significant development in mental health treatment in the United States," he said in the poster.

The data Dr. Blader analyzed came from the National Hospital Discharge Survey, and also showed that in 1996-2007, payment for the psychiatric hospitalizations underwent a significant shift away from private insurance coverage and toward an increased share of the hospitalizations paid for by government agencies, most typically Medicaid. Again, the implications of this – and how it might play into the increased hospitalization rates – remain unclear.

According to Dr. Blader, the questions now are, Does the rise in hospitalizations result from "problems in the level of services provided by community care," and has "more cost shifting" of patients into Medicaid from private insurance led to or resulted from the rise in hospitalizations?

"Beneficiaries of publicly funded inpatient care may have become disproportionately vulnerable to psychiatric emergencies," or perhaps the effect "indicates better outpatient care among the privately insured," he said in his poster. "In many states, privately insured patients with extended psychiatric hospitalizations become eligible for Medicaid coverage."

He noted that during the period studied, the psychiatric field has made a diagnostic shift: More children who engage in injurious behavior are being labeled with bipolar disorder. He also speculated that the increasingly complex polypharmacy treatment of psychiatric patients, including children, might be a factor boosting hospitalizations.

"When a child is on many medications and a crisis occurs, the physician may not be sure what to do, which drug to stop," and thus may feel it’s safer to hospitalize and manage the child or adolescent there, Dr. Blader said in an interview.

However, he dismissed the notion that clinical criteria for hospitalization shifted during the period examined. "It’s unlikely that there was a lower threshold for hospitalization" in 2007 compared with 11 years earlier, he said.

The National Hospital Discharge Survey, run by the Centers for Disease Control and Prevention, collected data from 366,000 U.S. hospitalizations in 2007.

Survey data showed that in 1996-2007, the rate of hospitalization for a primary diagnosis of a psychiatric disorder in children aged 5-13 years rose from 15.6 per 10,000 U.S. residents to 28.3. In adolescents aged 14-19 years, the rate rose from 68.4 per 10,000 to 96.9, while in those aged 20-64 years, the rate increased from 92.1 per 10,000 to 99.1. All of the changes were statistically significant. Dr. Blader’s poster did not report rates for patients aged 65 or older, but in his analysis, this number fell "dramatically" from 1996 to 2007, he said.

During the period studied, private insurance coverage of these psychiatric hospitalizations among children fell from 36% of cases to 23%, while government-based sources of payment rose from 63% of cases to 71%. Among adolescents, private payment fell from 52% of cases to 22% while government coverage rose from 44% to 62%. Among adults, private coverage fell from 36% to 23%, while government coverage was flat, at 58% in 1996 and 59% in 2007.

The impact of both increases in hospitalization rates as well as increased population levels also led to substantial boosts in total days hospitalized for primary psychiatric diagnoses among children and adolescents, but not in adults. For children, total hospitalized days soared from 644,461 in 1996 to 1,528,117 in 2007. Among adolescents, total days rose from 1,317,660 in 1996 to 2,115,905 in 2007.

Dr. Blader had no disclosures.

NEW YORK – During the period 1996-2007, hospitalization rates for psychiatric disorders among American children aged 5-13 years rose dramatically, nearly doubling during that period.

Concurrently, psychiatric hospitalizations for U.S. adolescents (aged 14-19 years) also rose substantially, by 42%. During the same period, psychiatric hospitalizations rose modestly (by 8%) for adults aged 20-64 years, whereas psychiatric hospitalizations for Americans aged 65 or older fell dramatically, Joseph C. Blader, Ph.D., said while presenting a poster at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The reasons behind these changes and their implications for the quality of care American psychiatric patients receive remain unclear, said Dr. Blader, a researcher in the division of child and adolescent psychiatry at the State University of New York at Stony Brook. However, the shifts in hospitalization rates – especially the larger such shifts among children and adolescents – raise concerns that demand further analysis, he said.

"It’s not a good thing" that substantially more children and adolescents require hospitalization for psychiatric diagnoses, Dr. Blader said in an interview. The shifts "represent a significant development in mental health treatment in the United States," he said in the poster.

The data Dr. Blader analyzed came from the National Hospital Discharge Survey, and also showed that in 1996-2007, payment for the psychiatric hospitalizations underwent a significant shift away from private insurance coverage and toward an increased share of the hospitalizations paid for by government agencies, most typically Medicaid. Again, the implications of this – and how it might play into the increased hospitalization rates – remain unclear.

According to Dr. Blader, the questions now are, Does the rise in hospitalizations result from "problems in the level of services provided by community care," and has "more cost shifting" of patients into Medicaid from private insurance led to or resulted from the rise in hospitalizations?

"Beneficiaries of publicly funded inpatient care may have become disproportionately vulnerable to psychiatric emergencies," or perhaps the effect "indicates better outpatient care among the privately insured," he said in his poster. "In many states, privately insured patients with extended psychiatric hospitalizations become eligible for Medicaid coverage."

He noted that during the period studied, the psychiatric field has made a diagnostic shift: More children who engage in injurious behavior are being labeled with bipolar disorder. He also speculated that the increasingly complex polypharmacy treatment of psychiatric patients, including children, might be a factor boosting hospitalizations.

"When a child is on many medications and a crisis occurs, the physician may not be sure what to do, which drug to stop," and thus may feel it’s safer to hospitalize and manage the child or adolescent there, Dr. Blader said in an interview.

However, he dismissed the notion that clinical criteria for hospitalization shifted during the period examined. "It’s unlikely that there was a lower threshold for hospitalization" in 2007 compared with 11 years earlier, he said.

The National Hospital Discharge Survey, run by the Centers for Disease Control and Prevention, collected data from 366,000 U.S. hospitalizations in 2007.

Survey data showed that in 1996-2007, the rate of hospitalization for a primary diagnosis of a psychiatric disorder in children aged 5-13 years rose from 15.6 per 10,000 U.S. residents to 28.3. In adolescents aged 14-19 years, the rate rose from 68.4 per 10,000 to 96.9, while in those aged 20-64 years, the rate increased from 92.1 per 10,000 to 99.1. All of the changes were statistically significant. Dr. Blader’s poster did not report rates for patients aged 65 or older, but in his analysis, this number fell "dramatically" from 1996 to 2007, he said.

During the period studied, private insurance coverage of these psychiatric hospitalizations among children fell from 36% of cases to 23%, while government-based sources of payment rose from 63% of cases to 71%. Among adolescents, private payment fell from 52% of cases to 22% while government coverage rose from 44% to 62%. Among adults, private coverage fell from 36% to 23%, while government coverage was flat, at 58% in 1996 and 59% in 2007.

The impact of both increases in hospitalization rates as well as increased population levels also led to substantial boosts in total days hospitalized for primary psychiatric diagnoses among children and adolescents, but not in adults. For children, total hospitalized days soared from 644,461 in 1996 to 1,528,117 in 2007. Among adolescents, total days rose from 1,317,660 in 1996 to 2,115,905 in 2007.

Dr. Blader had no disclosures.

NEW YORK – During the period 1996-2007, hospitalization rates for psychiatric disorders among American children aged 5-13 years rose dramatically, nearly doubling during that period.

Concurrently, psychiatric hospitalizations for U.S. adolescents (aged 14-19 years) also rose substantially, by 42%. During the same period, psychiatric hospitalizations rose modestly (by 8%) for adults aged 20-64 years, whereas psychiatric hospitalizations for Americans aged 65 or older fell dramatically, Joseph C. Blader, Ph.D., said while presenting a poster at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The reasons behind these changes and their implications for the quality of care American psychiatric patients receive remain unclear, said Dr. Blader, a researcher in the division of child and adolescent psychiatry at the State University of New York at Stony Brook. However, the shifts in hospitalization rates – especially the larger such shifts among children and adolescents – raise concerns that demand further analysis, he said.

"It’s not a good thing" that substantially more children and adolescents require hospitalization for psychiatric diagnoses, Dr. Blader said in an interview. The shifts "represent a significant development in mental health treatment in the United States," he said in the poster.

The data Dr. Blader analyzed came from the National Hospital Discharge Survey, and also showed that in 1996-2007, payment for the psychiatric hospitalizations underwent a significant shift away from private insurance coverage and toward an increased share of the hospitalizations paid for by government agencies, most typically Medicaid. Again, the implications of this – and how it might play into the increased hospitalization rates – remain unclear.

According to Dr. Blader, the questions now are, Does the rise in hospitalizations result from "problems in the level of services provided by community care," and has "more cost shifting" of patients into Medicaid from private insurance led to or resulted from the rise in hospitalizations?

"Beneficiaries of publicly funded inpatient care may have become disproportionately vulnerable to psychiatric emergencies," or perhaps the effect "indicates better outpatient care among the privately insured," he said in his poster. "In many states, privately insured patients with extended psychiatric hospitalizations become eligible for Medicaid coverage."

He noted that during the period studied, the psychiatric field has made a diagnostic shift: More children who engage in injurious behavior are being labeled with bipolar disorder. He also speculated that the increasingly complex polypharmacy treatment of psychiatric patients, including children, might be a factor boosting hospitalizations.

"When a child is on many medications and a crisis occurs, the physician may not be sure what to do, which drug to stop," and thus may feel it’s safer to hospitalize and manage the child or adolescent there, Dr. Blader said in an interview.

However, he dismissed the notion that clinical criteria for hospitalization shifted during the period examined. "It’s unlikely that there was a lower threshold for hospitalization" in 2007 compared with 11 years earlier, he said.

The National Hospital Discharge Survey, run by the Centers for Disease Control and Prevention, collected data from 366,000 U.S. hospitalizations in 2007.

Survey data showed that in 1996-2007, the rate of hospitalization for a primary diagnosis of a psychiatric disorder in children aged 5-13 years rose from 15.6 per 10,000 U.S. residents to 28.3. In adolescents aged 14-19 years, the rate rose from 68.4 per 10,000 to 96.9, while in those aged 20-64 years, the rate increased from 92.1 per 10,000 to 99.1. All of the changes were statistically significant. Dr. Blader’s poster did not report rates for patients aged 65 or older, but in his analysis, this number fell "dramatically" from 1996 to 2007, he said.

During the period studied, private insurance coverage of these psychiatric hospitalizations among children fell from 36% of cases to 23%, while government-based sources of payment rose from 63% of cases to 71%. Among adolescents, private payment fell from 52% of cases to 22% while government coverage rose from 44% to 62%. Among adults, private coverage fell from 36% to 23%, while government coverage was flat, at 58% in 1996 and 59% in 2007.

The impact of both increases in hospitalization rates as well as increased population levels also led to substantial boosts in total days hospitalized for primary psychiatric diagnoses among children and adolescents, but not in adults. For children, total hospitalized days soared from 644,461 in 1996 to 1,528,117 in 2007. Among adolescents, total days rose from 1,317,660 in 1996 to 2,115,905 in 2007.

Dr. Blader had no disclosures.

CHICAGO – Last fall, physicians at Vanderbilt University Medical Center began routinely testing all patients who were scheduled for coronary catheterization with a broad genotyping screen that – among other things – would identify whether they had a problem activating clopidogrel.

By mid-November, the program had tested about 300 patients, including 10 found to have a poor-metabolizer genotype in the hepatic-enzyme gene CYP2C19 that would likely blunt the efficacy of a conventional clopidogrel dose. Many of the 10 patients received a doubled dose to compensate, whereas others who weren’t aged 75 or older received the pricier, alternative agent prasugrel.

This experience marked the first phase of a new Vanderbilt program that will expand over time to include other patients in line to receive a drug with a pharmacogenetic dimension, Dr. Dan M. Roden said at the annual scientific sessions of the American Heart Association.

The genotyping program will soon expand to include patients who are scheduled for knee- or hip-replacement surgery, anticipating their need to start on warfarin. Genotype data can also help physicians select the best dosage for starting a warfarin regimen, said Dr. Roden, a cardiologist and assistant vice chancellor for personalized medicine at Vanderbilt in Nashville, Tenn.

Subsequent expansion plans are not yet set, but other candidates for genotyping include patients who are either already on or at an increased risk for soon starting tamoxifen, abacavir, azathioprine, 6-mercaptopurine, codeine, or "virtually any antidepressant or most antipsychotics," Dr. Roden said in an interview.

"In the long perspective, every 50-year-old" is a good bet to eventually receive at least one drug for which a dosage adjustment based on genotype is warranted, but – stopping short of such global use right now – the Vanderbilt program will instead gradually phase in new groups of patients to the offer of genotyping.

"Implementation is a huge challenge. In my opinion, this will only work with preemptive implementation. Electronic records are not just repositories of information, but are nimble enough to provide support at the time of a prescription," he said. "The way it ought to work is, a physician prescribes a drug and the electronic system recognizes [that] the drug has a genetic element and goes into the patient’s record and finds the genotype information" to decide whether to flash a screen alert about the patient’s genotype and the implications.

The program, known as PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) launched on Sept. 15. It uses a genotyping panel sold on the U.S. market by Illumina that screens for 184 different genetic polymorphisms in 34 genes that affect the absorption, distribution, metabolism, or excretion of various drugs. Test results get posted into the record within a day of specimen collection.

So far, Vanderbilt itself has completely funded the program, which involved a year of planning and "a huge amount of money," said Dr. Roden, adding that the program is the first of its kind worldwide. PREDICT is expected to improve patient outcomes and its developers hope to eventually convince payers to cover the cost.

Dr. Roden reported that he is or has been a consultant to Merck, Novartis, Sanofi-Aventis, Daiichi Sankyo, and Astellas and has received royalties from Clinical Data Inc.

CHICAGO – Last fall, physicians at Vanderbilt University Medical Center began routinely testing all patients who were scheduled for coronary catheterization with a broad genotyping screen that – among other things – would identify whether they had a problem activating clopidogrel.

By mid-November, the program had tested about 300 patients, including 10 found to have a poor-metabolizer genotype in the hepatic-enzyme gene CYP2C19 that would likely blunt the efficacy of a conventional clopidogrel dose. Many of the 10 patients received a doubled dose to compensate, whereas others who weren’t aged 75 or older received the pricier, alternative agent prasugrel.

This experience marked the first phase of a new Vanderbilt program that will expand over time to include other patients in line to receive a drug with a pharmacogenetic dimension, Dr. Dan M. Roden said at the annual scientific sessions of the American Heart Association.

The genotyping program will soon expand to include patients who are scheduled for knee- or hip-replacement surgery, anticipating their need to start on warfarin. Genotype data can also help physicians select the best dosage for starting a warfarin regimen, said Dr. Roden, a cardiologist and assistant vice chancellor for personalized medicine at Vanderbilt in Nashville, Tenn.

Subsequent expansion plans are not yet set, but other candidates for genotyping include patients who are either already on or at an increased risk for soon starting tamoxifen, abacavir, azathioprine, 6-mercaptopurine, codeine, or "virtually any antidepressant or most antipsychotics," Dr. Roden said in an interview.

"In the long perspective, every 50-year-old" is a good bet to eventually receive at least one drug for which a dosage adjustment based on genotype is warranted, but – stopping short of such global use right now – the Vanderbilt program will instead gradually phase in new groups of patients to the offer of genotyping.

"Implementation is a huge challenge. In my opinion, this will only work with preemptive implementation. Electronic records are not just repositories of information, but are nimble enough to provide support at the time of a prescription," he said. "The way it ought to work is, a physician prescribes a drug and the electronic system recognizes [that] the drug has a genetic element and goes into the patient’s record and finds the genotype information" to decide whether to flash a screen alert about the patient’s genotype and the implications.

The program, known as PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) launched on Sept. 15. It uses a genotyping panel sold on the U.S. market by Illumina that screens for 184 different genetic polymorphisms in 34 genes that affect the absorption, distribution, metabolism, or excretion of various drugs. Test results get posted into the record within a day of specimen collection.

So far, Vanderbilt itself has completely funded the program, which involved a year of planning and "a huge amount of money," said Dr. Roden, adding that the program is the first of its kind worldwide. PREDICT is expected to improve patient outcomes and its developers hope to eventually convince payers to cover the cost.

Dr. Roden reported that he is or has been a consultant to Merck, Novartis, Sanofi-Aventis, Daiichi Sankyo, and Astellas and has received royalties from Clinical Data Inc.

CHICAGO – Last fall, physicians at Vanderbilt University Medical Center began routinely testing all patients who were scheduled for coronary catheterization with a broad genotyping screen that – among other things – would identify whether they had a problem activating clopidogrel.

By mid-November, the program had tested about 300 patients, including 10 found to have a poor-metabolizer genotype in the hepatic-enzyme gene CYP2C19 that would likely blunt the efficacy of a conventional clopidogrel dose. Many of the 10 patients received a doubled dose to compensate, whereas others who weren’t aged 75 or older received the pricier, alternative agent prasugrel.

This experience marked the first phase of a new Vanderbilt program that will expand over time to include other patients in line to receive a drug with a pharmacogenetic dimension, Dr. Dan M. Roden said at the annual scientific sessions of the American Heart Association.

The genotyping program will soon expand to include patients who are scheduled for knee- or hip-replacement surgery, anticipating their need to start on warfarin. Genotype data can also help physicians select the best dosage for starting a warfarin regimen, said Dr. Roden, a cardiologist and assistant vice chancellor for personalized medicine at Vanderbilt in Nashville, Tenn.

Subsequent expansion plans are not yet set, but other candidates for genotyping include patients who are either already on or at an increased risk for soon starting tamoxifen, abacavir, azathioprine, 6-mercaptopurine, codeine, or "virtually any antidepressant or most antipsychotics," Dr. Roden said in an interview.

"In the long perspective, every 50-year-old" is a good bet to eventually receive at least one drug for which a dosage adjustment based on genotype is warranted, but – stopping short of such global use right now – the Vanderbilt program will instead gradually phase in new groups of patients to the offer of genotyping.

"Implementation is a huge challenge. In my opinion, this will only work with preemptive implementation. Electronic records are not just repositories of information, but are nimble enough to provide support at the time of a prescription," he said. "The way it ought to work is, a physician prescribes a drug and the electronic system recognizes [that] the drug has a genetic element and goes into the patient’s record and finds the genotype information" to decide whether to flash a screen alert about the patient’s genotype and the implications.

The program, known as PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) launched on Sept. 15. It uses a genotyping panel sold on the U.S. market by Illumina that screens for 184 different genetic polymorphisms in 34 genes that affect the absorption, distribution, metabolism, or excretion of various drugs. Test results get posted into the record within a day of specimen collection.

So far, Vanderbilt itself has completely funded the program, which involved a year of planning and "a huge amount of money," said Dr. Roden, adding that the program is the first of its kind worldwide. PREDICT is expected to improve patient outcomes and its developers hope to eventually convince payers to cover the cost.

Dr. Roden reported that he is or has been a consultant to Merck, Novartis, Sanofi-Aventis, Daiichi Sankyo, and Astellas and has received royalties from Clinical Data Inc.

CHICAGO – Last fall, physicians at Vanderbilt University Medical Center began routinely testing all patients who were scheduled for coronary catheterization with a broad genotyping screen that – among other things – would identify whether they had a problem activating clopidogrel.

By mid-November, the program had tested about 300 patients, including 10 found to have a poor-metabolizer genotype in the hepatic-enzyme gene CYP2C19 that would likely blunt the efficacy of a conventional clopidogrel dose. Many of the 10 patients received a doubled dose to compensate, whereas others who weren’t aged 75 or older received the pricier, alternative agent prasugrel.

This experience marked the first phase of a new Vanderbilt program that will expand over time to include other patients in line to receive a drug with a pharmacogenetic dimension, Dr. Dan M. Roden said at the annual scientific sessions of the American Heart Association.

The genotyping program will soon expand to include patients who are scheduled for knee- or hip-replacement surgery, anticipating their need to start on warfarin. Genotype data can also help physicians select the best dosage for starting a warfarin regimen, said Dr. Roden, a cardiologist and assistant vice chancellor for personalized medicine at Vanderbilt in Nashville, Tenn.

Subsequent expansion plans are not yet set, but other candidates for genotyping include patients who are either already on or at an increased risk for soon starting tamoxifen, abacavir, azathioprine, 6-mercaptopurine, codeine, or "virtually any antidepressant or most antipsychotics," Dr. Roden said in an interview.

"In the long perspective, every 50-year-old" is a good bet to eventually receive at least one drug for which a dosage adjustment based on genotype is warranted, but – stopping short of such global use right now – the Vanderbilt program will instead gradually phase in new groups of patients to the offer of genotyping.

"Implementation is a huge challenge. In my opinion, this will only work with preemptive implementation. Electronic records are not just repositories of information, but are nimble enough to provide support at the time of a prescription," he said. "The way it ought to work is, a physician prescribes a drug and the electronic system recognizes [that] the drug has a genetic element and goes into the patient’s record and finds the genotype information" to decide whether to flash a screen alert about the patient’s genotype and the implications.

The program, known as PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) launched on Sept. 15. It uses a genotyping panel sold on the U.S. market by Illumina that screens for 184 different genetic polymorphisms in 34 genes that affect the absorption, distribution, metabolism, or excretion of various drugs. Test results get posted into the record within a day of specimen collection.

So far, Vanderbilt itself has completely funded the program, which involved a year of planning and "a huge amount of money," said Dr. Roden, adding that the program is the first of its kind worldwide. PREDICT is expected to improve patient outcomes and its developers hope to eventually convince payers to cover the cost.

Dr. Roden reported that he is or has been a consultant to Merck, Novartis, Sanofi-Aventis, Daiichi Sankyo, and Astellas and has received royalties from Clinical Data Inc.

CHICAGO – Last fall, physicians at Vanderbilt University Medical Center began routinely testing all patients who were scheduled for coronary catheterization with a broad genotyping screen that – among other things – would identify whether they had a problem activating clopidogrel.

By mid-November, the program had tested about 300 patients, including 10 found to have a poor-metabolizer genotype in the hepatic-enzyme gene CYP2C19 that would likely blunt the efficacy of a conventional clopidogrel dose. Many of the 10 patients received a doubled dose to compensate, whereas others who weren’t aged 75 or older received the pricier, alternative agent prasugrel.

This experience marked the first phase of a new Vanderbilt program that will expand over time to include other patients in line to receive a drug with a pharmacogenetic dimension, Dr. Dan M. Roden said at the annual scientific sessions of the American Heart Association.

The genotyping program will soon expand to include patients who are scheduled for knee- or hip-replacement surgery, anticipating their need to start on warfarin. Genotype data can also help physicians select the best dosage for starting a warfarin regimen, said Dr. Roden, a cardiologist and assistant vice chancellor for personalized medicine at Vanderbilt in Nashville, Tenn.

Subsequent expansion plans are not yet set, but other candidates for genotyping include patients who are either already on or at an increased risk for soon starting tamoxifen, abacavir, azathioprine, 6-mercaptopurine, codeine, or "virtually any antidepressant or most antipsychotics," Dr. Roden said in an interview.

"In the long perspective, every 50-year-old" is a good bet to eventually receive at least one drug for which a dosage adjustment based on genotype is warranted, but – stopping short of such global use right now – the Vanderbilt program will instead gradually phase in new groups of patients to the offer of genotyping.

"Implementation is a huge challenge. In my opinion, this will only work with preemptive implementation. Electronic records are not just repositories of information, but are nimble enough to provide support at the time of a prescription," he said. "The way it ought to work is, a physician prescribes a drug and the electronic system recognizes [that] the drug has a genetic element and goes into the patient’s record and finds the genotype information" to decide whether to flash a screen alert about the patient’s genotype and the implications.

The program, known as PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) launched on Sept. 15. It uses a genotyping panel sold on the U.S. market by Illumina that screens for 184 different genetic polymorphisms in 34 genes that affect the absorption, distribution, metabolism, or excretion of various drugs. Test results get posted into the record within a day of specimen collection.

So far, Vanderbilt itself has completely funded the program, which involved a year of planning and "a huge amount of money," said Dr. Roden, adding that the program is the first of its kind worldwide. PREDICT is expected to improve patient outcomes and its developers hope to eventually convince payers to cover the cost.

Dr. Roden reported that he is or has been a consultant to Merck, Novartis, Sanofi-Aventis, Daiichi Sankyo, and Astellas and has received royalties from Clinical Data Inc.

CHICAGO – Last fall, physicians at Vanderbilt University Medical Center began routinely testing all patients who were scheduled for coronary catheterization with a broad genotyping screen that – among other things – would identify whether they had a problem activating clopidogrel.

By mid-November, the program had tested about 300 patients, including 10 found to have a poor-metabolizer genotype in the hepatic-enzyme gene CYP2C19 that would likely blunt the efficacy of a conventional clopidogrel dose. Many of the 10 patients received a doubled dose to compensate, whereas others who weren’t aged 75 or older received the pricier, alternative agent prasugrel.

This experience marked the first phase of a new Vanderbilt program that will expand over time to include other patients in line to receive a drug with a pharmacogenetic dimension, Dr. Dan M. Roden said at the annual scientific sessions of the American Heart Association.

The genotyping program will soon expand to include patients who are scheduled for knee- or hip-replacement surgery, anticipating their need to start on warfarin. Genotype data can also help physicians select the best dosage for starting a warfarin regimen, said Dr. Roden, a cardiologist and assistant vice chancellor for personalized medicine at Vanderbilt in Nashville, Tenn.

Subsequent expansion plans are not yet set, but other candidates for genotyping include patients who are either already on or at an increased risk for soon starting tamoxifen, abacavir, azathioprine, 6-mercaptopurine, codeine, or "virtually any antidepressant or most antipsychotics," Dr. Roden said in an interview.

"In the long perspective, every 50-year-old" is a good bet to eventually receive at least one drug for which a dosage adjustment based on genotype is warranted, but – stopping short of such global use right now – the Vanderbilt program will instead gradually phase in new groups of patients to the offer of genotyping.

"Implementation is a huge challenge. In my opinion, this will only work with preemptive implementation. Electronic records are not just repositories of information, but are nimble enough to provide support at the time of a prescription," he said. "The way it ought to work is, a physician prescribes a drug and the electronic system recognizes [that] the drug has a genetic element and goes into the patient’s record and finds the genotype information" to decide whether to flash a screen alert about the patient’s genotype and the implications.

The program, known as PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) launched on Sept. 15. It uses a genotyping panel sold on the U.S. market by Illumina that screens for 184 different genetic polymorphisms in 34 genes that affect the absorption, distribution, metabolism, or excretion of various drugs. Test results get posted into the record within a day of specimen collection.

So far, Vanderbilt itself has completely funded the program, which involved a year of planning and "a huge amount of money," said Dr. Roden, adding that the program is the first of its kind worldwide. PREDICT is expected to improve patient outcomes and its developers hope to eventually convince payers to cover the cost.

Dr. Roden reported that he is or has been a consultant to Merck, Novartis, Sanofi-Aventis, Daiichi Sankyo, and Astellas and has received royalties from Clinical Data Inc.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Rivaroxaban, the first in class, oral factor Xa inhibitor, showed noninferiority to warfarin for preventing stroke and other embolic events in a pivotal trial with more than 14,000 atrial fibrillation patients.

But with the report of these results at the annual scientific sessions of the American Heart Association coming less than 2 weeks after the release of dabigatran, the rival, new anticoagulant that came onto the U.S. market on Nov. 3, the question by many people who heard the results was not just how rivaroxaban compared with warfarin but how to weigh its clinical role versus dabigatran.

Cardiologists had no firm answer, and expect none until rivaroxaban and dabigatran go head to head in a trial. But talk at the meeting about both drugs made it clear that warfarin’s time as the go-to anticoagulant for atrial fibrillation patients had passed. Both of the new drugs eliminate the regular dose monitoring and adjustment required for patients on warfarin.

How rivaroxaban compares with dabigatran "is the inevitable question," said Dr. Kenneth W. Mahaffey, a cardiologist at Duke University in Durham, N.C., who reported the results from 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). He noted the pitfalls in comparing the outcomes of ROCKET AF with results from the pivotal trial for dabigatran, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (N. Engl. J Med.2009;361:1139-51). ROCKET AF enrolled substantially sicker patients, with an average CHADS score of 3.5 compared with an average 2.1 score in RE-LY, and ROCKET AF was run in a double-blind, double-dummy fashion while in RE-LY patients and physicians knew who received dabigatran or warfarin.

Dr. Mahaffey’s coinvestigator in ROCKET AF, Dr. Robert M. Califf, agreed. The researchers who ran ROCKET AF "have been discussing [the comparison of rivaroxaban and dabigatran] incessantly, but there is no scientifically valid way to compare the two, so we’ll be left with our feelings." Dr. Califf cited his 84-year-old mother, on warfarin and in remission from multiple myeloma, who has been unhappy with her monitoring regimen. "I can assure you that she will go on one of these two new drugs just because of convenience, but she can afford it," said Dr. Califf, professor of cardiology at Duke. "Cost will ultimately have to be a factor that we need to be sensitive about."

Price will likely be a major factor in deciding the role for both alternatives to warfarin, and the cost calculation is not simple. No price yet exists for rivaroxaban, an agent not yet approved for sale in any country. But on Nov. 3, Boehringer-Ingelheim, the company that markets dabigatran (Pradaxa), announced that the direct thrombin inhibitor was available for U.S. sale at a wholesale price of $6.75/day for either two 150-mg pills or two 75-mg pills, the two dosages approved for U.S. use by the Food and Drug Administration. A recent, informal survey of several large, U.S. retail pharmacies found the 150-mg dose often selling for just under $8 per day. That compares with a drug cost for generic warfarin of usually less than $1 a day. But the price of warfarin therapy also includes the substantial cost for laboratory monitoring of patients on warfarin and the cost of the complications patients have when they are either over- or under-anticoagulated with warfarin.

An analysis published online Nov. 1 presented a cost-effectiveness analysis of dabigatran compared with warfarin (Ann. Intern. Med. 2010, Nov. 1 [epub ahead of print 0003-4819-154-1-201101040-00289v2]). According to the analysis, at a daily cost of $8, treatment of patients with atrial fibrillation with dabigatran had an incremental cost-effectiveness ratio of about $12,500 per quality adjusted life year compared with warfarin, said Dr. James V. Freeman, a cardiologist at Stanford (Calif.) University and lead author of the cost-effectiveness analysis. Although this figure is still subject to adjustment based on newly updated clinical-event data in RE-LY, an incremental cost-effectiveness ratio of "roughly $10,000-$20,000 is likely in the ballpark" based on current dabigatran pricing, Dr. Freeman said in an interview.

"This is in a range generally considered very cost effective. By comparison, implantable cardioverter defibrillators have been estimated to have an incremental cost-effectiveness ratio of $34,000-$70,000 per quality adjusted life year, compared with control therapy," he said.

Even if calculations show that dabigatran is cost effective, a monthly prescription could still deliver a patient an unexpectedly high drug bill. "We’ve been very careful, in this early phase, that patients don’t get whacked with a $200 bill they can’t pay," said Dr. Peter R. Kowey, a cardiologist and professor of medicine at Thomas Jefferson University in Philadelphia. "We call each insurance company to make sure the patient will have some kind of compensation. That’s our biggest concern with dabigatran."

In most other respects, dabigatran is a winner so far, Dr. Kowey said. The RE-LY results showed the 150 mg b.i.d. dosage had superior efficacy compared with warfarin, while in ROCKET AF, rivaroxaban proved noninferior but failed to show significant superiority in an intention-to-treat analysis (rivaroxaban showed significant superiority to warfarin in the on-treatment analysis.

"That’s where I get stuck, on the superiority thing," Dr. Kowey said in an interview. "One drug proved itself better than warfarin in a gigantic trial, the other didn’t." Based on what he called the "pristine" RE-LY results, "if you need to pick one of these anticoagulants for your patient it would have to be dabigatran," Dr. Kowey said.

Despite dabigatran’s advantages, he warned physicians against precipitously switching patients who are well controlled on warfarin to dabigatran. "You can’t pull the rug out" from patients. "I hope physicians won’t make that mistake." He noted that some patients maintain a "rock stable" anticoagulated state on warfarin, the drug itself is cheap, and some patients enjoy the social contact they have by regularly returning to their anticoagulation clinic. On the other hand, patients should know that dabigatran is an option, with its superior stroke prevention and reduced cerebral hemorrhage rate compared with warfarin, he said.

Other experts weren’t as sure about dabigatran’s edge over rivaroxaban, citing rivaroxaban’s performance in ROCKET AF in patients with a high comorbidity profile based on their average CHADS score of 3.5. Rivaroxaban’s performance in very sick patients in ROCKET AF was "very impressive," commented Dr. Christine M. Albert, a cardiologist and director of the Center for Arrhythmia Prevention at Brigham and Women’s Hospital in Boston. "We may put a patient on rivaroxaban rather than dabigatran because RE-LY was not done in such a sick population. We’ll probably individualize [use of each drug] based on which patients were studied in each trial," Dr. Albert said in an interview.

Others cited additional considerations needed when prescribing dabigatran, warfarin, and eventually rivaroxaban. "Dabigatran is 80% renally cleared. That will pose problems for some patients, and there is some gastrointestinal bleeding and some dyspepsia with dabigatran," said Dr. Elaine M. Hylek, a cardiologist and warfarin specialist at Boston University. I can’t say that warfarin will disappear. There will be some compelling reasons why warfarin will remain."

A limitation for rivaroxaban is that it is hepatically metabolized, which may pose difficulties or at least require dose adjustment for patients with liver disease who are prescribed rivaroxaban, noted Dr. Gordon F. Tomaselli, professor of medicine and chief of cardiology at Johns Hopkins University in Baltimore.

But availability of dabigatran, and the promise from the ROCKET HF results that rivaroxaban will soon join it on the market, spells the end of warfarin treatment for the vast majority of atrial fibrillation patients, Dr. Tomaselli predicted.

"Over the course of the next year, a lot of my patients will change from warfarin to one of these two [new] drugs," he said in an interview. "What I hear from patients now who are on warfarin is, ‘When can I start with the new drug so that I can stop the rat poison?’"

ROCKET AF was sponsored by Bayer, the company developing rivaroxaban (Xarelto). RE-LY was sponsored by Boehringer-Ingelheim, the company marketing dabigatran (Pradaxa).

Dr. Mahaffey has received consulting fees and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi Aventis. He has also received research grants from Portola, Regado, and The Medicines Company.

Dr. Califf has been a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson–Scios. Dr. Kowey has been a consultant to Astellas, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Blue Ash, Gilead, GlaxoSmithKline, HUYA, Johnson & Johnson, Medtronic, Novartis, Otsuka, Pfizer, Procter & Gamble, Sanofi Aventis, Sequel, Solvay, and St. Jude. He has been a speaker for Sanofi Aventis, he owns stock in Cardionet, and he has received honoraria from GlaxoSmithKline.

Dr. Albert has been a consultant to Novartis, worked on a study sponsored by GlaxoSmithKline, and received research support from St. Jude. Dr. Hylek has served on advisory boards for Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. She had received research grants from Bristol-Myers Squibb and Ortho-McNeil. Dr. Tomaselli had no disclosures.

CHICAGO – Patients with posttraumatic stress disorder had an increased prevalence of coronary artery disease as well as an increased risk of death in a retrospective analysis of more than 30,000 patients.

"We have proof for the first time based on coronary artery calcium that coronary artery disease is related to PTSD [posttraumatic stress disorder]," Dr. Ramin Ebrahimi said at the annual scientific sessions of the American Heart Association. "There is a significant association between the presence of PTSD, coronary atherosclerosis, and mortality independent of conventional risk factors."

"PTSD can be viewed, in a preliminary way, as a risk factor. While the findings have not been validated in a prospective, longitudinal study, this was a very large study with 286,000 people including more than 30,000 with PTSD," said Dr. Ebrahimi, codirector of the coronary catheterization laboratory at the VA Greater Los Angeles Healthcare System. "An early, integrative psychological and medical evaluation may be indicated to identify PTSD patients and improve quality of life and clinical outcomes." Studies have not yet examined the role that treatment of PTSD can play in mitigating the severity of coronary atherosclerosis and reducing mortality, Dr. Ebrahimi added.

Although proving a link between PTSD and coronary disease requires more evidence, an immediate message from the results so far is that physicians, especially primary care physicians, should be more aware of the high prevalence of PTSD. "It’s very prevalent, perhaps as high as 10% of the general population," Dr. Ebrahimi said in an interview. In addition, diagnosing PTSD identifies a patient who warrants a more careful assessment for coronary disease, he added.

"Dr. Ebrahimi’s report represents one of the largest studies to date to document a significant relationship between PTSD and mortality," with an effect size roughly comparable to prior reports, commented Donald Edmondson, Ph.D., a psychologist in the Center for Behavioral Cardiovascular Health at Columbia University in New York. "In the context of the full body of research on this topic, the findings are quite convincing," he said in an interview.

While the VA study looked exclusively at military veterans, the findings are likely generalizable to people with PTSD who did not serve in the military, Dr. Ebrahimi said.

PTSD occurs in many contexts. For example, about 15% of patients who have an acute coronary syndrome event develop PTSD, noted Dr. Edmondson.

According to both Dr. Ebrahimi and Dr. Edmondson, the link between PTSD, coronary artery disease, and mortality may involve autonomic arousal, endothelial dysfunction, and inflammation. "We are still in the beginning stages of mapping the complex, systemic cardiovascular effects of PTSD, but we will probably find that all of the effects we see indicate a single, underlying pathology attributable to the psychological and physiological state of PTSD," Dr. Edmondson said. But he added that he’d like to see additional, confirmatory evidence of a PTSD and coronary disease link before suggesting a more aggressive coronary work-up in PTSD patients.

Dr. Ebrahimi and his associates reviewed electronic medical records for 286,194 veterans of the U.S. military cared for in the Southern California district of the VA system. Their average age was 63, and 85% were men. This group included 30,460 (11%) diagnosed with PTSD. Patients received a PTSD diagnosis if they had positive results on two diagnostic tools, the PTSD Checklist-Military, and the Clinician Administered PTSD Scale.

During an average follow-up of 116 months, mortality occurred in 17% of those with PTSD and in 10% of those without PTSD, a statistically significant difference. In an analysis that adjusted for baseline differences, veterans with PTSD had a 2.4-fold increased risk of dying, compared with those without PTSD.

The VA staff ran coronary calcium scoring on 637 of the veterans, and found calcium in 76% of the PTSD patients and in 59% of veterans without PTSD, a statistically significant difference. The calcium score averaged 448 in those with PTSD and 332 in those without the disorder, also a statistically significant difference.

The researchers performed several other analyses of mortality rates during follow-up to assess the interaction of mortality risk and PTSD across the spectrum of coronary disease. For example, among the veterans who underwent coronary calcium scoring, those with a score of zero and PTSD had no significantly increased mortality during follow-up, compared with those without PTSD. However, among those with a calcium score of 1-100, PTSD increased mortality by a statistically significant 23%. Among those with a score of 101-400, PTSD boosted mortality by a significant 51%, and among those with a calcium score of more than 400, PTSD raised mortality by a significant 81%, compared with veterans without PTSD. All these relative risks were adjusted for baseline differences in age, gender, diabetes, hypertension, hypercholesterolemia, family history of coronary disease, and smoking history.

In a separate talk at the meeting, Dr. Edmondson presented data that also implicated PTSD in exacerbating coronary artery disease. He and his associates studied 261 patients hospitalized for acute coronary syndrome. One month following their event, 39 (15%) of the patients scored high on a screen for intrusions symptoms, one of the three symptom clusters that define PTSD. During an average follow-up of 42 months, the patients with a high number of intrusions had a statistically significant, threefold higher rate of either a repeat acute coronary syndrome event or death that was independent of other prognostic factors.

Dr. Ebrahimi and Dr. Edmondson said they had no disclosures.

CHICAGO – Patients with posttraumatic stress disorder had an increased prevalence of coronary artery disease as well as an increased risk of death in a retrospective analysis of more than 30,000 patients.

"We have proof for the first time based on coronary artery calcium that coronary artery disease is related to PTSD [posttraumatic stress disorder]," Dr. Ramin Ebrahimi said at the annual scientific sessions of the American Heart Association. "There is a significant association between the presence of PTSD, coronary atherosclerosis, and mortality independent of conventional risk factors."

"PTSD can be viewed, in a preliminary way, as a risk factor. While the findings have not been validated in a prospective, longitudinal study, this was a very large study with 286,000 people including more than 30,000 with PTSD," said Dr. Ebrahimi, codirector of the coronary catheterization laboratory at the VA Greater Los Angeles Healthcare System. "An early, integrative psychological and medical evaluation may be indicated to identify PTSD patients and improve quality of life and clinical outcomes." Studies have not yet examined the role that treatment of PTSD can play in mitigating the severity of coronary atherosclerosis and reducing mortality, Dr. Ebrahimi added.

Although proving a link between PTSD and coronary disease requires more evidence, an immediate message from the results so far is that physicians, especially primary care physicians, should be more aware of the high prevalence of PTSD. "It’s very prevalent, perhaps as high as 10% of the general population," Dr. Ebrahimi said in an interview. In addition, diagnosing PTSD identifies a patient who warrants a more careful assessment for coronary disease, he added.

"Dr. Ebrahimi’s report represents one of the largest studies to date to document a significant relationship between PTSD and mortality," with an effect size roughly comparable to prior reports, commented Donald Edmondson, Ph.D., a psychologist in the Center for Behavioral Cardiovascular Health at Columbia University in New York. "In the context of the full body of research on this topic, the findings are quite convincing," he said in an interview.

While the VA study looked exclusively at military veterans, the findings are likely generalizable to people with PTSD who did not serve in the military, Dr. Ebrahimi said.

PTSD occurs in many contexts. For example, about 15% of patients who have an acute coronary syndrome event develop PTSD, noted Dr. Edmondson.

According to both Dr. Ebrahimi and Dr. Edmondson, the link between PTSD, coronary artery disease, and mortality may involve autonomic arousal, endothelial dysfunction, and inflammation. "We are still in the beginning stages of mapping the complex, systemic cardiovascular effects of PTSD, but we will probably find that all of the effects we see indicate a single, underlying pathology attributable to the psychological and physiological state of PTSD," Dr. Edmondson said. But he added that he’d like to see additional, confirmatory evidence of a PTSD and coronary disease link before suggesting a more aggressive coronary work-up in PTSD patients.

Dr. Ebrahimi and his associates reviewed electronic medical records for 286,194 veterans of the U.S. military cared for in the Southern California district of the VA system. Their average age was 63, and 85% were men. This group included 30,460 (11%) diagnosed with PTSD. Patients received a PTSD diagnosis if they had positive results on two diagnostic tools, the PTSD Checklist-Military, and the Clinician Administered PTSD Scale.

During an average follow-up of 116 months, mortality occurred in 17% of those with PTSD and in 10% of those without PTSD, a statistically significant difference. In an analysis that adjusted for baseline differences, veterans with PTSD had a 2.4-fold increased risk of dying, compared with those without PTSD.

The VA staff ran coronary calcium scoring on 637 of the veterans, and found calcium in 76% of the PTSD patients and in 59% of veterans without PTSD, a statistically significant difference. The calcium score averaged 448 in those with PTSD and 332 in those without the disorder, also a statistically significant difference.

The researchers performed several other analyses of mortality rates during follow-up to assess the interaction of mortality risk and PTSD across the spectrum of coronary disease. For example, among the veterans who underwent coronary calcium scoring, those with a score of zero and PTSD had no significantly increased mortality during follow-up, compared with those without PTSD. However, among those with a calcium score of 1-100, PTSD increased mortality by a statistically significant 23%. Among those with a score of 101-400, PTSD boosted mortality by a significant 51%, and among those with a calcium score of more than 400, PTSD raised mortality by a significant 81%, compared with veterans without PTSD. All these relative risks were adjusted for baseline differences in age, gender, diabetes, hypertension, hypercholesterolemia, family history of coronary disease, and smoking history.

In a separate talk at the meeting, Dr. Edmondson presented data that also implicated PTSD in exacerbating coronary artery disease. He and his associates studied 261 patients hospitalized for acute coronary syndrome. One month following their event, 39 (15%) of the patients scored high on a screen for intrusions symptoms, one of the three symptom clusters that define PTSD. During an average follow-up of 42 months, the patients with a high number of intrusions had a statistically significant, threefold higher rate of either a repeat acute coronary syndrome event or death that was independent of other prognostic factors.

Dr. Ebrahimi and Dr. Edmondson said they had no disclosures.

CHICAGO – Patients with posttraumatic stress disorder had an increased prevalence of coronary artery disease as well as an increased risk of death in a retrospective analysis of more than 30,000 patients.

"We have proof for the first time based on coronary artery calcium that coronary artery disease is related to PTSD [posttraumatic stress disorder]," Dr. Ramin Ebrahimi said at the annual scientific sessions of the American Heart Association. "There is a significant association between the presence of PTSD, coronary atherosclerosis, and mortality independent of conventional risk factors."

"PTSD can be viewed, in a preliminary way, as a risk factor. While the findings have not been validated in a prospective, longitudinal study, this was a very large study with 286,000 people including more than 30,000 with PTSD," said Dr. Ebrahimi, codirector of the coronary catheterization laboratory at the VA Greater Los Angeles Healthcare System. "An early, integrative psychological and medical evaluation may be indicated to identify PTSD patients and improve quality of life and clinical outcomes." Studies have not yet examined the role that treatment of PTSD can play in mitigating the severity of coronary atherosclerosis and reducing mortality, Dr. Ebrahimi added.

Although proving a link between PTSD and coronary disease requires more evidence, an immediate message from the results so far is that physicians, especially primary care physicians, should be more aware of the high prevalence of PTSD. "It’s very prevalent, perhaps as high as 10% of the general population," Dr. Ebrahimi said in an interview. In addition, diagnosing PTSD identifies a patient who warrants a more careful assessment for coronary disease, he added.

"Dr. Ebrahimi’s report represents one of the largest studies to date to document a significant relationship between PTSD and mortality," with an effect size roughly comparable to prior reports, commented Donald Edmondson, Ph.D., a psychologist in the Center for Behavioral Cardiovascular Health at Columbia University in New York. "In the context of the full body of research on this topic, the findings are quite convincing," he said in an interview.

While the VA study looked exclusively at military veterans, the findings are likely generalizable to people with PTSD who did not serve in the military, Dr. Ebrahimi said.

PTSD occurs in many contexts. For example, about 15% of patients who have an acute coronary syndrome event develop PTSD, noted Dr. Edmondson.

According to both Dr. Ebrahimi and Dr. Edmondson, the link between PTSD, coronary artery disease, and mortality may involve autonomic arousal, endothelial dysfunction, and inflammation. "We are still in the beginning stages of mapping the complex, systemic cardiovascular effects of PTSD, but we will probably find that all of the effects we see indicate a single, underlying pathology attributable to the psychological and physiological state of PTSD," Dr. Edmondson said. But he added that he’d like to see additional, confirmatory evidence of a PTSD and coronary disease link before suggesting a more aggressive coronary work-up in PTSD patients.

Dr. Ebrahimi and his associates reviewed electronic medical records for 286,194 veterans of the U.S. military cared for in the Southern California district of the VA system. Their average age was 63, and 85% were men. This group included 30,460 (11%) diagnosed with PTSD. Patients received a PTSD diagnosis if they had positive results on two diagnostic tools, the PTSD Checklist-Military, and the Clinician Administered PTSD Scale.

During an average follow-up of 116 months, mortality occurred in 17% of those with PTSD and in 10% of those without PTSD, a statistically significant difference. In an analysis that adjusted for baseline differences, veterans with PTSD had a 2.4-fold increased risk of dying, compared with those without PTSD.

The VA staff ran coronary calcium scoring on 637 of the veterans, and found calcium in 76% of the PTSD patients and in 59% of veterans without PTSD, a statistically significant difference. The calcium score averaged 448 in those with PTSD and 332 in those without the disorder, also a statistically significant difference.

The researchers performed several other analyses of mortality rates during follow-up to assess the interaction of mortality risk and PTSD across the spectrum of coronary disease. For example, among the veterans who underwent coronary calcium scoring, those with a score of zero and PTSD had no significantly increased mortality during follow-up, compared with those without PTSD. However, among those with a calcium score of 1-100, PTSD increased mortality by a statistically significant 23%. Among those with a score of 101-400, PTSD boosted mortality by a significant 51%, and among those with a calcium score of more than 400, PTSD raised mortality by a significant 81%, compared with veterans without PTSD. All these relative risks were adjusted for baseline differences in age, gender, diabetes, hypertension, hypercholesterolemia, family history of coronary disease, and smoking history.

In a separate talk at the meeting, Dr. Edmondson presented data that also implicated PTSD in exacerbating coronary artery disease. He and his associates studied 261 patients hospitalized for acute coronary syndrome. One month following their event, 39 (15%) of the patients scored high on a screen for intrusions symptoms, one of the three symptom clusters that define PTSD. During an average follow-up of 42 months, the patients with a high number of intrusions had a statistically significant, threefold higher rate of either a repeat acute coronary syndrome event or death that was independent of other prognostic factors.

Dr. Ebrahimi and Dr. Edmondson said they had no disclosures.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – A third-generation, investigational left ventricular assist device performed at least as well as current devices on the market, and also showed signs of important benefits like reduced infections and bleeding during 6 months of follow-up as a bridge to heart transplant in 140 patients in a pivotal, multicenter study.

Based on results from the ADVANCE (Evaluation of the HeartWare Ventricular Assist System for the Treatment of Advanced Heart Failure) study, HeartWare – the company developing the new device – said that it would seek marketing approval from the Food and Drug Administration for the HeartWare ventricular assist device (VAD) as a bridge to transplant before the year’s end. A small, continuous-flow pump, the HeartWare VAD is implanted in the pericardium with no need for a pocket. Experts who heard the new data cautioned that although the results so far look fine, the long-term durability and performance of the new VAD need assessment compared with the current standard, the HeartMate II.

"Implantation of the HeartWare VAD pump in the pericardial space was associated with a very high probability of success at 180 days," said Dr. Keith D. Aaronson at the annual scientific sessions of the American Heart Association. The 92% of patients who received the HeartWare VAD and were either alive with their device or had received a heart transplant during the 180 days after device placement was "the highest rate ever reported in any left VAD [LVAD] study," said Dr. Aaronson, medical director of the heart failure program at the University of Michigan in Ann Arbor.

"The survival and the success of the HeartWare VAD are excellent outcomes," Dr. Aaronson said. The question of which VAD works better – the HeartWare model or the HeartMate II – "comes down to the adverse event profile for the two devices. The only way to know for sure [which device is better] is to compare them head to head." A trial now underway compares the two VADs as destination therapy for patients who are unable to get a heart transplant, he noted.

"The HeartMate II has been a good workhorse. People know how to use it and are comfortable with it. When the HeartWare device comes out, people will want to use it, and surgeons seem to like the idea of implanting the device directly in the heart. But [questions like] which is the best kind of VAD, where do you put it, and what’s the best way to anticoagulate patients [are] not clear. The HeartMate VAD advances one piece of the puzzle, but the upcoming trials that will compare the VADs head to head will give us a lot more answers," commented Dr. Mariell L. Jessup, professor of medicine and medical director of the heart and vascular center at the University of Pennsylvania in Philadelphia.

"This is the first successful completion of a bridge-to-transplant trial with a control" group of patients, noted Dr. Lynne Warner Stevenson, professor of medicine and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital in Boston. "We all know that the bridge results are not the same as the destination results."

The HeartWare VAD arm of the study ran at 30 U.S. sites during August 2008–February 2010. The researchers screened 157 patients to find 140 who met the enrollment criteria, including having New York Heart Association class IV heart failure and being listed for a heart transplant. Surgeons ultimately placed the HeartWare VAD in 137 patients. The control arm included 499 U.S. patients who received a commercially available LVAD during the same period and were registered in the INTERMACS (Interagency Registry for Mechanical Assisted Circulatory Support) system. By the first half of 2009, 94% of these INTERMACS control patients received a HeartMate II as their LVAD, and throughout the 18 months of the study Dr. Aaronson estimated that all but 3%-4% of the control patients received a HeartMate II. The average age of the VAD recipients was 53 years, and about a quarter were women.

After 180 days, 63% of the HeartWare VAD recipients remained alive with their device in place, and 29% had received a heart transplant, 4% had their device switched for another VAD, and 4% had died. The overall 92% success rate in this group was comparable with a 90% overall success rate among the control patients in the INTERMACS registry. The similar rates in the two arms met the prespecified criteria for noninferiority of the new device. But the HeartWare VAD did not show statistically significant superiority to the control devices, either in an unadjusted analysis or after adjustment in a propensity analysis, Dr. Aaronson said.

Mortality during the first 30 days following device placement ran 1.4% in the HeartWare group and 3.4% in the control patients. The 1.4% perioperative rate in the HeartWare recipients was "remarkable," Dr. Aaronson said, and was "comparable to the rate in patients electively receiving an aortic valve replacement."

The HeartWare recipients also showed statistically significant and clinically meaningful improvements in their quality of life. Their average scores on the Kansas City Cardiomyopathy Questionnaire for clinical summary and overall summary rose from a level consistent with severe heart failure at baseline to a level indicating mild heart failure 3 months after device placement. Their average EuroQol 5D self-rating showed an increase after 3 months that was comparable with "what is usually reported for heart transplant recipients," Dr. Aaronson said.

As Dr. Aaronson noted, much attention focused on adverse events. His analysis compared the rates seen in the 140 HeartWare VAD recipients vs. 281 patients who received the HeartMate II VAD in a multicenter study done during 2005-2008 that led to HeartMate II’s approval (J. Am. Coll. Cardiol. 2009;54:312-21). In the HeartWare series, bleeding at gastrointestinal sites occurred at a rate of 25% per patient-year, and bleeds requiring surgery occurred in 27% per patient-year. In the HeartMate II series, bleeds needing surgery occurred in 45% per patient-year, with no report on gastrointestinal bleeds. The 25% per patient-year gastrointestinal-bleeding rate in the HeartWare patients was "relatively low, about one-third the rate that’s been reported" by individual centers for patients who received the HeartMate II, he said.

"We need to know if there is a meaningful difference in the gastrointestinal bleeding, a key issue for all the nonpulsatile VADs," Dr. Jessup said.

Infection rates with the HeartWare VAD (39% per patient-year) also ran "substantially lower" than the 85% rate reported from the HeartMate II multicenter series. Ventricular arrhythmias also showed a substantial reduction with the HeartWare VAD (13% per patient-year vs. 40% per patient-year in the HeartMate II series).

Ischemic stroke rates with the HeartWare VAD ran 11% per patient-year, similar to the 9% rate seen in the multicenter HeartMate II series. Hemorrhagic stroke occurred at the same rate (5% per patient-year) with both devices. Half of the 10 ischemic strokes in the HeartWare VAD recipients occurred during the first 48 hours following device placement. "We believe they were surgically related; there is a clear learning curve" for placing the HeartWare VAD, Dr. Aaronson said. In addition, he noted that 8 of the 10 patients who had ischemic strokes later recovered to "moderate disability."

Another "key issue" that experience with the HeartWare VAD has so far not addressed is aortic valve insufficiency, Dr. Jessup said. "No one talks about it in these short-term trials, but you really see aortic insufficiency in destination-treatment trials. The longer you see patients [with LVADs], the more you see them developing hypertension and aortic insufficiency. Will there be a difference in the VADs for aortic insufficiency?"

The study was sponsored by HeartWare, the device developer. Dr. Aaronson said that he has received research support from HeartWare, Thoratec, and Terumo. Dr. Jessup is a consultant to Medtronic and a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Stevenson has been a consultant to Medtronic.

CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.

In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.

“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”

Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.

Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.

Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.

The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.

In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.

According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.

Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.

“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”

The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. “When this drug is taken long-term, what will it mean for a patient’s safety,” Dr. Gurbel queried.

Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi-Aventis were all employees of the company that markets clopidogrel (Plavix).

Dr. Gurbel has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi-Aventis, and Schering Plough.

CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.

In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.

“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”

Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.

Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.

Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.

The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.

In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.

According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.

Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.

“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”

The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. “When this drug is taken long-term, what will it mean for a patient’s safety,” Dr. Gurbel queried.

Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi-Aventis were all employees of the company that markets clopidogrel (Plavix).

Dr. Gurbel has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi-Aventis, and Schering Plough.

CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.

In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.

“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”

Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.

Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.

Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.

The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.

In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.

According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.

Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.

“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”

The findings from this new study bring to light another issue, safety. Methyl chloride is a mutagen, possible carcinogen, and liver toxin. “When this drug is taken long-term, what will it mean for a patient’s safety,” Dr. Gurbel queried.

Dr. Thethi and his associates at Loyola said they had no disclosures. Their collaborators from Sanofi-Aventis were all employees of the company that markets clopidogrel (Plavix).

Dr. Gurbel has been a consultant to, and received honoraria and research grants from AstraZeneca, Bayer, Daiichi Sankyo, Lilly, Portola, Pozen, Sanofi-Aventis, and Schering Plough.