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Erythropoietin Bolus After PCI Fails to Reduce Infarct Size
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
FROM JAMA
Major Finding: Infarct size was no different on cardiac MR between patients who received an IV bolus of epoetin-alfa and those who received a placebo infusion within 4 hours of successful PCI.
Data Source: A multicenter, prospective, randomized phase II clinical trial involving 222 STEMI patients who underwent PCI as a primary or rescue reperfusion strategy.
Disclosures: This study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
Erythropoietin Bolus After PCI Fails to Reduce Infarct Size
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
FROM JAMA
Erythropoietin Bolus After PCI Fails to Reduce Infarct Size
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
The results of this rigorous clinical trial "seem to settle the debate about whether there is a therapeutic role for erythropoietin administration during primary PCI [percutaneous coronary intervention] and is a useful negative finding," said Dr. Deepak L. Bhatt.
Moreover, the safety findings raise concerns about the use of epoetin alfa for any indication – including anemia, for which it is widely prescribed – in patients likely to develop MI.
"The totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals. Until compelling data become available to support routine use of these agents in patients with anemia, it would be prudent to minimize their use, especially for patients at high risk for cardiovascular disease or with an acute ischemic syndrome," Dr. Bhatt said.
When the use of erythropoietin is necessary, "it will be important to educate patients about the potential risks of ischemia so they are aware of the signs and symptoms and know to seek help should an ischemic or thrombotic syndrome develop," he added.
Dr. Bhatt is with the Veterans Administration Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston. He reported ties to AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and the Medicines Company. He has received honoraria from Duke Clinical Research Institute unrelated to the REVEAL study. These remarks were taken from his editorial accompanying Dr. Najjar’s report (JAMA 2011;305:1908-9).
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
An intravenous bolus of epoetin alfa in ST-segment elevation myocardial infarction patients who have successful primary or rescue percutaneous coronary intervention does not reduce infarct size, according to a report in the May 11 issue of JAMA.
To the contrary, the treatment was associated with an increased infarct size in the subgroup of patients older than age 70 years, said Dr. Samer S. Najjar of the MedStar Health Research Institute at Washington Hospital Center and his associates.
In addition, the erythropoietin bolus increased the rate of adverse cardiovascular events, including stent thrombosis. Taken together with the results of previous studies, these findings "indicate that no clinical study to date has shown any beneficial effect of erythropoietin on infarct size measured by cardiac magnetic resonance."
Moreover, "Due to ... safety findings, temporary withholding of erythropoietin in patients who are receiving this medication for labeled indications and who sustain an MI merits further study," they added.
Preclinical and animal studies have demonstrated that beyond its effects on red blood cell production, erythropoietin is cardioprotective during ischemia and reperfusion, significantly reducing infarct size and improving left ventricular (LV) function, presumably through its antiapoptotic and angiogenic properties. Dr. Najjar and his colleagues performed a phase II multicenter clinical trial to assess the safety and efficacy of receiving a single IV bolus of epoetin alfa within 4 hours of successful percutaneous coronary intervention (PCI) in 222 ST-segment elevation myocardial infarction (STEMI) patients.
The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) study subjects were enrolled at 22 U.S. medical centers, stratified according to age and infarct location, and randomly assigned to receive either epoetin alfa or saline placebo infusion in a double-blind fashion. They underwent cardiac magnetic resonance imaging (CMR) to assess infarct size 2-6 days after receiving the infusion, then again after 12 weeks.
The primary efficacy end point – infarct size at the first CMR measurement – was no different between patients who received active medication and those who received placebo, the investigators said (JAMA 2011;305:1863-72).
There also was no difference between the two groups in infarct size at 12 weeks nor in infarct mass at either time point.
In a subgroup analysis, patients aged 70 years and older showed a 41% increase in mean infarct size with active treatment. In older patients who received epoetin alfa, the infarct was approximately 20% of the entire LV mass, compared with only 12% in the placebo group.
The rates of adverse events (55%) and serious adverse events (20%) were significantly higher with epoetin alfa than with placebo (41% and 10%, respectively). The composite outcome of death, MI, stroke, or stent thrombosis occurred in 4% of the group receiving active treatment, compared with 0% in the placebo group.
Taken together with the results of previous studies, these clinical trial findings confirm that "the promising cytoprotective effects of erythropoietin observed in animal models have not been reproduced in clinical studies of acute MI," Dr. Najjar and associates said.
Dr. Najjar’s study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
FROM JAMA
Major Finding: Infarct size was no different on cardiac MR between patients who received an IV bolus of epoetin-alfa and those who received a placebo infusion within 4 hours of successful PCI.
Data Source: A multicenter, prospective, randomized phase II clinical trial involving 222 STEMI patients who underwent PCI as a primary or rescue reperfusion strategy.
Disclosures: This study was sponsored by the National Institute on Aging. Centocor Ortho Biotech provided the study medication and Florida Biologix provided the matching placebo. Dr. Najjar and his associates reported ties to numerous industry sources.
Most With Stable CAD Go Straight to PCI, Skip Optimal Medical Therapy
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
FROM JAMA
Major Finding: Of patients with stable CAD undergoing PCI after COURAGE study results were published, 45% received optimal medical therapy before the procedure.
Data Source: An observational study of 467,211 patients with stable CAD who underwent PCI and were enrolled in the American College of Cardiology’s CathPCI registry.
Disclosures: This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Most With Stable CAD Go Straight to PCI, Skip Optimal Medical Therapy
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
FROM JAMA
Most With Stable CAD Go Straight to PCI, Skip Optimal Medical Therapy
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
Contrary to clinical practice guidelines and simple logic, most patients with stable coronary artery disease are not given optimal medical therapy before undergoing percutaneous coronary intervention, according to results of an observational registry study published in the May 11 issue of JAMA.
Even after "the most definitive randomized trial" comparing the two approaches concluded in March 2007 that PCI is no more effective than optimal medical therapy at preventing MI or death in stable CAD, there was little change in this pattern, said Dr. William B. Borden of the departments of medicine and public health at Weill Cornell Medical College in New York, and his associates.
"Some physicians may believe that stents are better than medical therapy for patients with stable CAD, even in the absence of evidence to support this view," they noted.
Dr. Borden and his colleagues assessed practice patterns regarding the use of optimal medical therapy before and after PCI using data from the national CathPCI Registry. They examined a 19-month interval before publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial results (N. Engl. J. Med. 2007;356:1503-16) and a 24-month period afterward, to determine whether physicians adopted those findings into clinical practice.
The study population comprised 467,211 patients treated at 1,013 U.S. hospitals, which constituted about 28% of the total CathPCI population during the study period. Optimal medical therapy was defined as being prescribed aspirin, a beta-blocker, and a statin before PCI and being prescribed aspirin or thienopyridine, a beta-blocker, a statin, and an ACE inhibitor or angiotensin receptor blocker after PCI, or having specific contraindications to these medications.
Overall, fewer than half of PCI patients – 45% – received optimal medical therapy before undergoing PCI. Current guidelines recommend maximizing medical therapy because that often relieves symptoms, obviating the need for PCI.
The rates of optimal medical therapy increased only slightly after publication of the COURAGE results, from 43% to 45%. This increase "was of little clinical significance," the investigators said (JAMA 2011:305:1882-9).
Clinicians did use PCI as an opportunity to improve patients’ medical regimens throughout the entire study period. The proportion of patients who received optimal medical therapy after PCI was significantly higher, at 65%, than that before the procedure (42%). However, the proportion of patients receiving optimal medical therapy after PCI did not change significantly after publication of the COURAGE results (66%), compared with before (64%), they noted.
"The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather [ought to] be a shared responsibility with the primary physicians caring for the patient," Dr. Borden and his associates said.
"Our findings suggest a promising possibility of developing better care through better collaboration. Although patients with stable CAD who are receiving PCI are often only in the hospital for less than 24 hours, multidisciplinary teams could use this time to optimize a patient’s medical regimen, use the ‘teachable moment’ of an invasive procedure to impart to patients the importance of medication adherence, and engage the patient in a program that supports the transition of care so that important medications are implemented," they said.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
FROM JAMA
Major Finding: Of patients with stable CAD undergoing PCI after COURAGE study results were published, 45% received optimal medical therapy before the procedure.
Data Source: An observational study of 467,211 patients with stable CAD who underwent PCI and were enrolled in the American College of Cardiology’s CathPCI registry.
Disclosures: This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry, with additional support from Weill Cornell Medical College and the Agency for Healthcare Research and Quality. Dr. Borden reported ties to Kowa Company.
"Enormous Complexity" of Cardiovascular Disease Prescriptions Impairs Adherence
Patients with cardiovascular disease face "enormous complexity" in managing their prescriptions, and it directly interferes with their adherence to medication, according to a study published online May 9 in Archives of Internal Medicine.
Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.
Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking long-term cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents "represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States."
Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed.
The researchers also estimated patient adherence by calculating the number of days the medication was available.
The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs.
The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the study findings may not apply to uninsured patients.
During a 3-month "complexity assessment" period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians.
"More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy," Dr. Choudhry and his colleagues wrote (Arch. Intern. Med. 2011;171:814-22).
Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs.
After the data were adjusted to control for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit (that is, had less refill consolidation) were found to be substantially less adherent to their prescribed therapy.
For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit – those who had the least refill consolidation – had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation.
"The magnitude of these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order," the investigators wrote.
"These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications)," Dr. Choudhry and his colleagues said.
This study was limited in that the investigators were unable to determine why patients filled prescriptions on multiple visits or at multiple pharmacies, to account for unmeasured factors such as patients’ health-seeking behavior or organizational skills, or to account for differences in insurance plans that may have affected prescription-related behavior, they added.
In an accompanying editorial, Dr. Amanda H. Salanitro and Dr. Sunil Kripalani said that despite its limitations, this study "provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence." Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates.
To improve adherence, physicians "can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a pharmacy ‘home’ ... might also be helpful for maintaining an accurate medication list and avoiding drug-drug interactions.
"Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing," Dr. Salanitro and Dr. Kripalani, both of Vanderbilt University, Nashville, Tenn., said (Arch. Intern. Med. 2011;171:822-3).
This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures.
Patients with cardiovascular disease face "enormous complexity" in managing their prescriptions, and it directly interferes with their adherence to medication, according to a study published online May 9 in Archives of Internal Medicine.
Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.
Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking long-term cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents "represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States."
Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed.
The researchers also estimated patient adherence by calculating the number of days the medication was available.
The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs.
The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the study findings may not apply to uninsured patients.
During a 3-month "complexity assessment" period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians.
"More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy," Dr. Choudhry and his colleagues wrote (Arch. Intern. Med. 2011;171:814-22).
Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs.
After the data were adjusted to control for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit (that is, had less refill consolidation) were found to be substantially less adherent to their prescribed therapy.
For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit – those who had the least refill consolidation – had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation.
"The magnitude of these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order," the investigators wrote.
"These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications)," Dr. Choudhry and his colleagues said.
This study was limited in that the investigators were unable to determine why patients filled prescriptions on multiple visits or at multiple pharmacies, to account for unmeasured factors such as patients’ health-seeking behavior or organizational skills, or to account for differences in insurance plans that may have affected prescription-related behavior, they added.
In an accompanying editorial, Dr. Amanda H. Salanitro and Dr. Sunil Kripalani said that despite its limitations, this study "provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence." Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates.
To improve adherence, physicians "can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a pharmacy ‘home’ ... might also be helpful for maintaining an accurate medication list and avoiding drug-drug interactions.
"Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing," Dr. Salanitro and Dr. Kripalani, both of Vanderbilt University, Nashville, Tenn., said (Arch. Intern. Med. 2011;171:822-3).
This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures.
Patients with cardiovascular disease face "enormous complexity" in managing their prescriptions, and it directly interferes with their adherence to medication, according to a study published online May 9 in Archives of Internal Medicine.
Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.
Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking long-term cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents "represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States."
Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed.
The researchers also estimated patient adherence by calculating the number of days the medication was available.
The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs.
The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the study findings may not apply to uninsured patients.
During a 3-month "complexity assessment" period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians.
"More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy," Dr. Choudhry and his colleagues wrote (Arch. Intern. Med. 2011;171:814-22).
Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs.
After the data were adjusted to control for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit (that is, had less refill consolidation) were found to be substantially less adherent to their prescribed therapy.
For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit – those who had the least refill consolidation – had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation.
"The magnitude of these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order," the investigators wrote.
"These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications)," Dr. Choudhry and his colleagues said.
This study was limited in that the investigators were unable to determine why patients filled prescriptions on multiple visits or at multiple pharmacies, to account for unmeasured factors such as patients’ health-seeking behavior or organizational skills, or to account for differences in insurance plans that may have affected prescription-related behavior, they added.
In an accompanying editorial, Dr. Amanda H. Salanitro and Dr. Sunil Kripalani said that despite its limitations, this study "provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence." Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates.
To improve adherence, physicians "can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a pharmacy ‘home’ ... might also be helpful for maintaining an accurate medication list and avoiding drug-drug interactions.
"Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing," Dr. Salanitro and Dr. Kripalani, both of Vanderbilt University, Nashville, Tenn., said (Arch. Intern. Med. 2011;171:822-3).
This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures.
FROM ARCHIVES OF INTERNAL MEDICINE
Major Finding: During a 3-month period, patients with cardiovascular disease filled a mean of 11 prescriptions written by two physicians for medications in six different drug classes at five pharmacy visits. A subgroup of 10% of these patients filled prescriptions written by four physicians for 23 medications in 11 drug classes at two or more pharmacies.
Data Source: A cohort study of prescription practices in a nationally representative sample of 1.8 million statin users and 1.4 million ACEI/ARB users observed for 1 year.
Disclosures: This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark.
"Enormous Complexity" of Cardiovascular Disease Prescriptions Impairs Adherence
Patients with cardiovascular disease face "enormous complexity" in managing their prescriptions, and it directly interferes with their adherence to medication, according to a study published online May 9 in Archives of Internal Medicine.
Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.
Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking long-term cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents "represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States."
Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed.
The researchers also estimated patient adherence by calculating the number of days the medication was available.
The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs.
The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the study findings may not apply to uninsured patients.
During a 3-month "complexity assessment" period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians.
"More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy," Dr. Choudhry and his colleagues wrote (Arch. Intern. Med. 2011;171:814-22).
Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs.
After the data were adjusted to control for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit (that is, had less refill consolidation) were found to be substantially less adherent to their prescribed therapy.
For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit – those who had the least refill consolidation – had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation.
"The magnitude of these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order," the investigators wrote.
"These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications)," Dr. Choudhry and his colleagues said.
This study was limited in that the investigators were unable to determine why patients filled prescriptions on multiple visits or at multiple pharmacies, to account for unmeasured factors such as patients’ health-seeking behavior or organizational skills, or to account for differences in insurance plans that may have affected prescription-related behavior, they added.
In an accompanying editorial, Dr. Amanda H. Salanitro and Dr. Sunil Kripalani said that despite its limitations, this study "provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence." Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates.
To improve adherence, physicians "can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a pharmacy ‘home’ ... might also be helpful for maintaining an accurate medication list and avoiding drug-drug interactions.
"Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing," Dr. Salanitro and Dr. Kripalani, both of Vanderbilt University, Nashville, Tenn., said (Arch. Intern. Med. 2011;171:822-3).
This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures.
Patients with cardiovascular disease face "enormous complexity" in managing their prescriptions, and it directly interferes with their adherence to medication, according to a study published online May 9 in Archives of Internal Medicine.
Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.
Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking long-term cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents "represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States."
Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed.
The researchers also estimated patient adherence by calculating the number of days the medication was available.
The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs.
The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the study findings may not apply to uninsured patients.
During a 3-month "complexity assessment" period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians.
"More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy," Dr. Choudhry and his colleagues wrote (Arch. Intern. Med. 2011;171:814-22).
Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs.
After the data were adjusted to control for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit (that is, had less refill consolidation) were found to be substantially less adherent to their prescribed therapy.
For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit – those who had the least refill consolidation – had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation.
"The magnitude of these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order," the investigators wrote.
"These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications)," Dr. Choudhry and his colleagues said.
This study was limited in that the investigators were unable to determine why patients filled prescriptions on multiple visits or at multiple pharmacies, to account for unmeasured factors such as patients’ health-seeking behavior or organizational skills, or to account for differences in insurance plans that may have affected prescription-related behavior, they added.
In an accompanying editorial, Dr. Amanda H. Salanitro and Dr. Sunil Kripalani said that despite its limitations, this study "provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence." Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates.
To improve adherence, physicians "can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a pharmacy ‘home’ ... might also be helpful for maintaining an accurate medication list and avoiding drug-drug interactions.
"Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing," Dr. Salanitro and Dr. Kripalani, both of Vanderbilt University, Nashville, Tenn., said (Arch. Intern. Med. 2011;171:822-3).
This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures.
Patients with cardiovascular disease face "enormous complexity" in managing their prescriptions, and it directly interferes with their adherence to medication, according to a study published online May 9 in Archives of Internal Medicine.
Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.
Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking long-term cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents "represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States."
Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed.
The researchers also estimated patient adherence by calculating the number of days the medication was available.
The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs.
The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the study findings may not apply to uninsured patients.
During a 3-month "complexity assessment" period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians.
"More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy," Dr. Choudhry and his colleagues wrote (Arch. Intern. Med. 2011;171:814-22).
Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs.
After the data were adjusted to control for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit (that is, had less refill consolidation) were found to be substantially less adherent to their prescribed therapy.
For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit – those who had the least refill consolidation – had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation.
"The magnitude of these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order," the investigators wrote.
"These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications)," Dr. Choudhry and his colleagues said.
This study was limited in that the investigators were unable to determine why patients filled prescriptions on multiple visits or at multiple pharmacies, to account for unmeasured factors such as patients’ health-seeking behavior or organizational skills, or to account for differences in insurance plans that may have affected prescription-related behavior, they added.
In an accompanying editorial, Dr. Amanda H. Salanitro and Dr. Sunil Kripalani said that despite its limitations, this study "provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence." Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates.
To improve adherence, physicians "can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a pharmacy ‘home’ ... might also be helpful for maintaining an accurate medication list and avoiding drug-drug interactions.
"Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing," Dr. Salanitro and Dr. Kripalani, both of Vanderbilt University, Nashville, Tenn., said (Arch. Intern. Med. 2011;171:822-3).
This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures.
FROM ARCHIVES OF INTERNAL MEDICINE
Major Finding: During a 3-month period, patients with cardiovascular disease filled a mean of 11 prescriptions written by two physicians for medications in six different drug classes at five pharmacy visits. A subgroup of 10% of these patients filled prescriptions written by four physicians for 23 medications in 11 drug classes at two or more pharmacies.
Data Source: A cohort study of prescription practices in a nationally representative sample of 1.8 million statin users and 1.4 million ACEI/ARB users observed for 1 year.
Disclosures: This study was supported by CVS Caremark, with additional support from the National Heart, Lung, and Blood Institute. Two of the coauthors are employees of CVS Caremark.
RA Patients Taking Rituximab Are at Risk for PML
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.
"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.
"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.
This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.
"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.
"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.
This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.
"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.
"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.
This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
FROM ARCHIVES OF NEUROLOGY
Major Finding: Patients given rituximab for refractory RA are at "modest" risk of developing progressive multifocal leukoencephalopathy, with an estimated incidence of 1 case of PML per 25,000 drug exposures.
Data Source: Case studies of five RA patients who developed PML after receiving rituximab.
Disclosures: This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
RA Patients Taking Rituximab Are at Risk for PML
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.
"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.
"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.
This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.
"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.
"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.
This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.
"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.
"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.
This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
FROM ARCHIVES OF NEUROLOGY
Major Finding: Patients given rituximab for refractory RA are at "modest" risk of developing progressive multifocal leukoencephalopathy, with an estimated incidence of 1 case of PML per 25,000 drug exposures.
Data Source: Case studies of five RA patients who developed PML after receiving rituximab.
Disclosures: This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.