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First addiction medicine certification exam slated for fall 2017
The certification exam for the new subspecialty of addiction medicine will be held in fall 2017, the American Board of Preventive Medicine and the Addiction Medicine Foundation announced.
“We recognize the importance of providing certification in addiction medicine for physicians who have expertise and demonstrated knowledge in the prevention and treatment of substance use disorders,” ABPM President Marie Krousel-Wood, MD, said in a statement. “The advances in physician certification and training in addiction medicine set the stage to engage all of medicine as strong partners in addressing this critical public health issue.”
1) Have an appropriate medical degree or its equivalent.
2) Have current certification by at least one American Board of Medical Specialties member board.
3) Complete specified education and training or experience in the subspecialty field through either the Practice Pathway or an Accreditation Council for Graduate Medical Education–accredited fellowship training pathway.
4) Have a current, unrestricted, and valid license to practice medicine.
During the first 5 years the exam is administered, physicians will use the Practice Pathway to meet certification eligibility requirements. The includes a minimum of 1,920 hours engaged in the practice of addiction medicine occurring over at least 24 of the previous 60 months prior to the application, though the 24 months need not be continuous. Credit for completing a non-ACGME–accredited fellowship may be substituted for the time in practice requirements.
Dates and updates to the application process will be posted on ABPM’s website as they become available.
The American Society of Addiction Medicine announced a review course scheduled for July 27-29, 2017, in Dallas, to help prepare physicians for the certification exam.
The certification exam for the new subspecialty of addiction medicine will be held in fall 2017, the American Board of Preventive Medicine and the Addiction Medicine Foundation announced.
“We recognize the importance of providing certification in addiction medicine for physicians who have expertise and demonstrated knowledge in the prevention and treatment of substance use disorders,” ABPM President Marie Krousel-Wood, MD, said in a statement. “The advances in physician certification and training in addiction medicine set the stage to engage all of medicine as strong partners in addressing this critical public health issue.”
1) Have an appropriate medical degree or its equivalent.
2) Have current certification by at least one American Board of Medical Specialties member board.
3) Complete specified education and training or experience in the subspecialty field through either the Practice Pathway or an Accreditation Council for Graduate Medical Education–accredited fellowship training pathway.
4) Have a current, unrestricted, and valid license to practice medicine.
During the first 5 years the exam is administered, physicians will use the Practice Pathway to meet certification eligibility requirements. The includes a minimum of 1,920 hours engaged in the practice of addiction medicine occurring over at least 24 of the previous 60 months prior to the application, though the 24 months need not be continuous. Credit for completing a non-ACGME–accredited fellowship may be substituted for the time in practice requirements.
Dates and updates to the application process will be posted on ABPM’s website as they become available.
The American Society of Addiction Medicine announced a review course scheduled for July 27-29, 2017, in Dallas, to help prepare physicians for the certification exam.
The certification exam for the new subspecialty of addiction medicine will be held in fall 2017, the American Board of Preventive Medicine and the Addiction Medicine Foundation announced.
“We recognize the importance of providing certification in addiction medicine for physicians who have expertise and demonstrated knowledge in the prevention and treatment of substance use disorders,” ABPM President Marie Krousel-Wood, MD, said in a statement. “The advances in physician certification and training in addiction medicine set the stage to engage all of medicine as strong partners in addressing this critical public health issue.”
1) Have an appropriate medical degree or its equivalent.
2) Have current certification by at least one American Board of Medical Specialties member board.
3) Complete specified education and training or experience in the subspecialty field through either the Practice Pathway or an Accreditation Council for Graduate Medical Education–accredited fellowship training pathway.
4) Have a current, unrestricted, and valid license to practice medicine.
During the first 5 years the exam is administered, physicians will use the Practice Pathway to meet certification eligibility requirements. The includes a minimum of 1,920 hours engaged in the practice of addiction medicine occurring over at least 24 of the previous 60 months prior to the application, though the 24 months need not be continuous. Credit for completing a non-ACGME–accredited fellowship may be substituted for the time in practice requirements.
Dates and updates to the application process will be posted on ABPM’s website as they become available.
The American Society of Addiction Medicine announced a review course scheduled for July 27-29, 2017, in Dallas, to help prepare physicians for the certification exam.
Sigma-1 agonist presses forward after positive results in small Alzheimer’s trial
SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.
Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.
The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional endpoints were secondary. It comprised only 32 patients at baseline, 25 of whom completed both the 5-week, randomized, dose-finding, crossover trial and the 52-week, open-label, extension study. There was no placebo comparator. Instead, the study used three different sets of historical control data taken from other Alzheimer’s studies.
Nevertheless, the positive results are enough to propel ANAVEX 2-73 forward. The company will continue to treat and follow the extension study cohort, and plans to launch a placebo-controlled study in 2017, said Dr. Macfarlane, head of clinical governance for The Dementia Centre in Melbourne.
The 5-week, randomized, dose-finding, crossover trial started one group of patients on 30 or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 or 50 mg/day oral ANAVEX 2-73 for 11 days. This was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last 6 months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.
The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
In preclinical testing, ANAVEX 2-73 showed an additional cognitive property, seeming to display a cognition-enhancing effect in both wild-type and AD model mice.
The mean age of the patients in the extension study was 71 years. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable, but Dr. Macfarlane didn’t discuss detailed dosing.
The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.
The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By study’s end, that had decreased to a mean of 1 point. The biggest change was seen in insomnia; all patients who endorsed it at baseline reported it gone by 12 weeks into treatment.
Patients also reported improvements in their ability to work or do other activities, in anxiety, agitation, hypochondriasis, and insight.
The P300 wave amplitude showed a small initial bump from about 6 to 7 microvolts by 4 weeks, and then a dip back down to about 6 microvolts until about week 32. Thereafter it steadily improved, landing at around 8 microvolts by 57 weeks – a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s cohort, which dropped to about 4 microvolts over a 52-week period while patients were taking donepezil.
The study employed a second historical control group in another cognitive assessment using the Computerized Cogstate Alzheimer’s Battery. All subjects in the large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to grow.
At 57 weeks, the mean MMSE score was stable, hovering around the baseline of 20. The ADCS-ADL declined slightly, from a mean of around 70 to around 65.
Finally, the investigators used yet another historical cohort as a comparator in a statistical analysis of projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point bump in score on the MMSE (P less than .016) and a 4-point benefit on the ADCS-ADL (P less than .019).
“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”
Nearly all patients (98%) had some sort of adverse event, but most of them were mild transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out because of adverse events (delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care AD medications.
Dr. Macfarlane has no financial interest in ANAVEX 2-73. He reported consultancies with Eli Lilly, Janssen-Cilag, and Lundbeck.
[email protected]
On Twitter @alz_gal
SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.
Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.
The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional endpoints were secondary. It comprised only 32 patients at baseline, 25 of whom completed both the 5-week, randomized, dose-finding, crossover trial and the 52-week, open-label, extension study. There was no placebo comparator. Instead, the study used three different sets of historical control data taken from other Alzheimer’s studies.
Nevertheless, the positive results are enough to propel ANAVEX 2-73 forward. The company will continue to treat and follow the extension study cohort, and plans to launch a placebo-controlled study in 2017, said Dr. Macfarlane, head of clinical governance for The Dementia Centre in Melbourne.
The 5-week, randomized, dose-finding, crossover trial started one group of patients on 30 or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 or 50 mg/day oral ANAVEX 2-73 for 11 days. This was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last 6 months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.
The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
In preclinical testing, ANAVEX 2-73 showed an additional cognitive property, seeming to display a cognition-enhancing effect in both wild-type and AD model mice.
The mean age of the patients in the extension study was 71 years. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable, but Dr. Macfarlane didn’t discuss detailed dosing.
The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.
The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By study’s end, that had decreased to a mean of 1 point. The biggest change was seen in insomnia; all patients who endorsed it at baseline reported it gone by 12 weeks into treatment.
Patients also reported improvements in their ability to work or do other activities, in anxiety, agitation, hypochondriasis, and insight.
The P300 wave amplitude showed a small initial bump from about 6 to 7 microvolts by 4 weeks, and then a dip back down to about 6 microvolts until about week 32. Thereafter it steadily improved, landing at around 8 microvolts by 57 weeks – a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s cohort, which dropped to about 4 microvolts over a 52-week period while patients were taking donepezil.
The study employed a second historical control group in another cognitive assessment using the Computerized Cogstate Alzheimer’s Battery. All subjects in the large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to grow.
At 57 weeks, the mean MMSE score was stable, hovering around the baseline of 20. The ADCS-ADL declined slightly, from a mean of around 70 to around 65.
Finally, the investigators used yet another historical cohort as a comparator in a statistical analysis of projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point bump in score on the MMSE (P less than .016) and a 4-point benefit on the ADCS-ADL (P less than .019).
“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”
Nearly all patients (98%) had some sort of adverse event, but most of them were mild transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out because of adverse events (delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care AD medications.
Dr. Macfarlane has no financial interest in ANAVEX 2-73. He reported consultancies with Eli Lilly, Janssen-Cilag, and Lundbeck.
[email protected]
On Twitter @alz_gal
SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.
Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.
The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional endpoints were secondary. It comprised only 32 patients at baseline, 25 of whom completed both the 5-week, randomized, dose-finding, crossover trial and the 52-week, open-label, extension study. There was no placebo comparator. Instead, the study used three different sets of historical control data taken from other Alzheimer’s studies.
Nevertheless, the positive results are enough to propel ANAVEX 2-73 forward. The company will continue to treat and follow the extension study cohort, and plans to launch a placebo-controlled study in 2017, said Dr. Macfarlane, head of clinical governance for The Dementia Centre in Melbourne.
The 5-week, randomized, dose-finding, crossover trial started one group of patients on 30 or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 or 50 mg/day oral ANAVEX 2-73 for 11 days. This was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last 6 months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke.
The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
In preclinical testing, ANAVEX 2-73 showed an additional cognitive property, seeming to display a cognition-enhancing effect in both wild-type and AD model mice.
The mean age of the patients in the extension study was 71 years. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable, but Dr. Macfarlane didn’t discuss detailed dosing.
The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale was also employed as a neuropsychiatric symptom measure.
The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By study’s end, that had decreased to a mean of 1 point. The biggest change was seen in insomnia; all patients who endorsed it at baseline reported it gone by 12 weeks into treatment.
Patients also reported improvements in their ability to work or do other activities, in anxiety, agitation, hypochondriasis, and insight.
The P300 wave amplitude showed a small initial bump from about 6 to 7 microvolts by 4 weeks, and then a dip back down to about 6 microvolts until about week 32. Thereafter it steadily improved, landing at around 8 microvolts by 57 weeks – a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s cohort, which dropped to about 4 microvolts over a 52-week period while patients were taking donepezil.
The study employed a second historical control group in another cognitive assessment using the Computerized Cogstate Alzheimer’s Battery. All subjects in the large Australian prospective cohort study, called AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to grow.
At 57 weeks, the mean MMSE score was stable, hovering around the baseline of 20. The ADCS-ADL declined slightly, from a mean of around 70 to around 65.
Finally, the investigators used yet another historical cohort as a comparator in a statistical analysis of projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point bump in score on the MMSE (P less than .016) and a 4-point benefit on the ADCS-ADL (P less than .019).
“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”
Nearly all patients (98%) had some sort of adverse event, but most of them were mild transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out because of adverse events (delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care AD medications.
Dr. Macfarlane has no financial interest in ANAVEX 2-73. He reported consultancies with Eli Lilly, Janssen-Cilag, and Lundbeck.
[email protected]
On Twitter @alz_gal
AT CTAD
Key clinical point:
Major finding: At 57 weeks, the mean MMSE score stayed around the baseline of 20. The ADCS-ADL declined slightly, from about 70 to 65.
Data source: A phase IIa study comprising 32 patients, 25 of whom completed 57 weeks of treatment.
Disclosures: Dr. Macfarlane has no financial ties with Anavex Life Sciences, which is developing the drug. He reported consultancies with Eli Lilly, Janssen-Cilag, and Lundbeck.
Two-test sequence identifies sporadic Creutzfeldt-Jakob with 100% sensitivity, specificity
The sequential use of two diagnostic tests – one assessing cerebrospinal fluid and the other assessing nasal swabs – identifies sporadic Creutzfeldt-Jakob disease with virtually 100% sensitivity and specificity, according to a report published online Dec. 12 in JAMA Neurology.
“Patients with sporadic CJD show great variability in clinical signs and pathologic lesions,” which makes distinguishing the disorder from other neurodegenerative abnormalities challenging. Researchers assessed the performance of two diagnostic tests in a case-control study involving 86 patients referred because of clinical suspicion of CJD, 81 control subjects who had other neurologic disorders, and 23 control subjects who had no neurologic disorders. The final diagnoses of the 86 case patients were established either at postmortem examination or when a definite alternative diagnosis was made, said Matilde Bongianni, PhD, of the department of neurosciences, biomedicine, and movement sciences at the University of Verona (Italy) and associates.
The first diagnostic test was a second-generation real-time quaking-induced conversion (RT-QuIC) assay that detects femtograms of an abnormal CJD-specific prion protein in the cerebrospinal fluid (CSF), which has been reported to have a diagnostic sensitivity of 96%. The second diagnostic test applied the RT-QuIC to brushings from the olfactory mucosa using a soft, flocked nasal swab rather than the more invasive and painful cytobrush, which has been reported to have a diagnostic sensitivity of 97%.
By using these two tests sequentially, the investigators were able to identify all cases of CJD and distinguish affected patients from all the control subjects. Alternative diagnoses were immediately pursued in the 17 case patients in whom CJD was ruled out, and 5 of them were successfully treated for other abnormalities, the investigators said (JAMA Neurol. 2016 Dec 12. doi: 10.1001/jamaneurol.2016.4614).
“Our results suggest that the application of RT-QuIC testing will improve the accuracy and speed of sporadic CJD diagnosis compared with internationally recognized antemortem diagnostic criteria,” Dr. Bongianni and associates wrote.
“A positive RT-QuIC finding in the CSF of patients with progressive neurologic signs should be sufficient to establish a diagnosis of probable CJD and would make olfactory mucosa sampling unnecessary. However, when the RT-QuIC CSF finding is negative or lumbar puncture is not feasible, olfactory mucosa sampling would become necessary to confirm prion disease or to divert to alternative diagnoses,” they added.
The study was supported by the Alliance Biosecure Foundation, the University of Verona, and the National Institute of Allergy and Infectious Diseases. The investigators reported having no relevant financial disclosures.
At last we have a truly practical, inexpensive, and accurate procedure for diagnosing sporadic CJD, thanks to the impeccably conducted and convincing work of Dr. Bongianni and associates.
Testing the CSF and then the olfactory mucosa using the RT-QuIC assay should soon become the standard approach for diagnosing CJD, possibly replacing current CSF tests for 14-3-3 and tau proteins. This assay also could be extended to an even larger patient population if it is included in routine laboratory examinations of all patients who have mental/behavioral or cerebellar signs, regardless of their presumed diagnosis.
Because only four of eight mutation-positive symptomatic patients with genetic forms of prion disease tested positive, there may be some future cases of sporadic CJD with false-negative test results or it may be the case that genetic forms have a different timing and spread of misfolded prion protein through the CSF and nasal mucosa.
Paul Brown, MD, is a retired senior investigator at the Laboratory of Central Nervous System Studies at the National Institutes of Health, Bethesda, Md. He reported having no relevant financial disclosures. Dr. Brown made these remarks in an accompanying editorial (JAMA Neurol. 2016 Dec 12. doi: 10.1001/jamaneurol.2016.4877).
At last we have a truly practical, inexpensive, and accurate procedure for diagnosing sporadic CJD, thanks to the impeccably conducted and convincing work of Dr. Bongianni and associates.
Testing the CSF and then the olfactory mucosa using the RT-QuIC assay should soon become the standard approach for diagnosing CJD, possibly replacing current CSF tests for 14-3-3 and tau proteins. This assay also could be extended to an even larger patient population if it is included in routine laboratory examinations of all patients who have mental/behavioral or cerebellar signs, regardless of their presumed diagnosis.
Because only four of eight mutation-positive symptomatic patients with genetic forms of prion disease tested positive, there may be some future cases of sporadic CJD with false-negative test results or it may be the case that genetic forms have a different timing and spread of misfolded prion protein through the CSF and nasal mucosa.
Paul Brown, MD, is a retired senior investigator at the Laboratory of Central Nervous System Studies at the National Institutes of Health, Bethesda, Md. He reported having no relevant financial disclosures. Dr. Brown made these remarks in an accompanying editorial (JAMA Neurol. 2016 Dec 12. doi: 10.1001/jamaneurol.2016.4877).
At last we have a truly practical, inexpensive, and accurate procedure for diagnosing sporadic CJD, thanks to the impeccably conducted and convincing work of Dr. Bongianni and associates.
Testing the CSF and then the olfactory mucosa using the RT-QuIC assay should soon become the standard approach for diagnosing CJD, possibly replacing current CSF tests for 14-3-3 and tau proteins. This assay also could be extended to an even larger patient population if it is included in routine laboratory examinations of all patients who have mental/behavioral or cerebellar signs, regardless of their presumed diagnosis.
Because only four of eight mutation-positive symptomatic patients with genetic forms of prion disease tested positive, there may be some future cases of sporadic CJD with false-negative test results or it may be the case that genetic forms have a different timing and spread of misfolded prion protein through the CSF and nasal mucosa.
Paul Brown, MD, is a retired senior investigator at the Laboratory of Central Nervous System Studies at the National Institutes of Health, Bethesda, Md. He reported having no relevant financial disclosures. Dr. Brown made these remarks in an accompanying editorial (JAMA Neurol. 2016 Dec 12. doi: 10.1001/jamaneurol.2016.4877).
The sequential use of two diagnostic tests – one assessing cerebrospinal fluid and the other assessing nasal swabs – identifies sporadic Creutzfeldt-Jakob disease with virtually 100% sensitivity and specificity, according to a report published online Dec. 12 in JAMA Neurology.
“Patients with sporadic CJD show great variability in clinical signs and pathologic lesions,” which makes distinguishing the disorder from other neurodegenerative abnormalities challenging. Researchers assessed the performance of two diagnostic tests in a case-control study involving 86 patients referred because of clinical suspicion of CJD, 81 control subjects who had other neurologic disorders, and 23 control subjects who had no neurologic disorders. The final diagnoses of the 86 case patients were established either at postmortem examination or when a definite alternative diagnosis was made, said Matilde Bongianni, PhD, of the department of neurosciences, biomedicine, and movement sciences at the University of Verona (Italy) and associates.
The first diagnostic test was a second-generation real-time quaking-induced conversion (RT-QuIC) assay that detects femtograms of an abnormal CJD-specific prion protein in the cerebrospinal fluid (CSF), which has been reported to have a diagnostic sensitivity of 96%. The second diagnostic test applied the RT-QuIC to brushings from the olfactory mucosa using a soft, flocked nasal swab rather than the more invasive and painful cytobrush, which has been reported to have a diagnostic sensitivity of 97%.
By using these two tests sequentially, the investigators were able to identify all cases of CJD and distinguish affected patients from all the control subjects. Alternative diagnoses were immediately pursued in the 17 case patients in whom CJD was ruled out, and 5 of them were successfully treated for other abnormalities, the investigators said (JAMA Neurol. 2016 Dec 12. doi: 10.1001/jamaneurol.2016.4614).
“Our results suggest that the application of RT-QuIC testing will improve the accuracy and speed of sporadic CJD diagnosis compared with internationally recognized antemortem diagnostic criteria,” Dr. Bongianni and associates wrote.
“A positive RT-QuIC finding in the CSF of patients with progressive neurologic signs should be sufficient to establish a diagnosis of probable CJD and would make olfactory mucosa sampling unnecessary. However, when the RT-QuIC CSF finding is negative or lumbar puncture is not feasible, olfactory mucosa sampling would become necessary to confirm prion disease or to divert to alternative diagnoses,” they added.
The study was supported by the Alliance Biosecure Foundation, the University of Verona, and the National Institute of Allergy and Infectious Diseases. The investigators reported having no relevant financial disclosures.
The sequential use of two diagnostic tests – one assessing cerebrospinal fluid and the other assessing nasal swabs – identifies sporadic Creutzfeldt-Jakob disease with virtually 100% sensitivity and specificity, according to a report published online Dec. 12 in JAMA Neurology.
“Patients with sporadic CJD show great variability in clinical signs and pathologic lesions,” which makes distinguishing the disorder from other neurodegenerative abnormalities challenging. Researchers assessed the performance of two diagnostic tests in a case-control study involving 86 patients referred because of clinical suspicion of CJD, 81 control subjects who had other neurologic disorders, and 23 control subjects who had no neurologic disorders. The final diagnoses of the 86 case patients were established either at postmortem examination or when a definite alternative diagnosis was made, said Matilde Bongianni, PhD, of the department of neurosciences, biomedicine, and movement sciences at the University of Verona (Italy) and associates.
The first diagnostic test was a second-generation real-time quaking-induced conversion (RT-QuIC) assay that detects femtograms of an abnormal CJD-specific prion protein in the cerebrospinal fluid (CSF), which has been reported to have a diagnostic sensitivity of 96%. The second diagnostic test applied the RT-QuIC to brushings from the olfactory mucosa using a soft, flocked nasal swab rather than the more invasive and painful cytobrush, which has been reported to have a diagnostic sensitivity of 97%.
By using these two tests sequentially, the investigators were able to identify all cases of CJD and distinguish affected patients from all the control subjects. Alternative diagnoses were immediately pursued in the 17 case patients in whom CJD was ruled out, and 5 of them were successfully treated for other abnormalities, the investigators said (JAMA Neurol. 2016 Dec 12. doi: 10.1001/jamaneurol.2016.4614).
“Our results suggest that the application of RT-QuIC testing will improve the accuracy and speed of sporadic CJD diagnosis compared with internationally recognized antemortem diagnostic criteria,” Dr. Bongianni and associates wrote.
“A positive RT-QuIC finding in the CSF of patients with progressive neurologic signs should be sufficient to establish a diagnosis of probable CJD and would make olfactory mucosa sampling unnecessary. However, when the RT-QuIC CSF finding is negative or lumbar puncture is not feasible, olfactory mucosa sampling would become necessary to confirm prion disease or to divert to alternative diagnoses,” they added.
The study was supported by the Alliance Biosecure Foundation, the University of Verona, and the National Institute of Allergy and Infectious Diseases. The investigators reported having no relevant financial disclosures.
FROM JAMA NEUROLOGY
Key clinical point:
Major finding: By using the RT-QuIC assay first on cerebrospinal fluid samples and then on olfactory mucosal swabbings, all 69 cases of CJD and prion disease were readily distinguished from all 17 cases of other neurologic disorders and from all 104 control subjects.
Data source: A case-control study involving 86 adults with clinical diagnoses of suspected, possible, or probable sporadic CJD; 81 control subjects with other neurologic disorders; and 23 control subjects with no neurologic disorders.
Disclosures: This study was supported by the Alliance Biosecure Foundation, the University of Verona, and the National Institute of Allergy and Infectious Diseases. Dr. Bongianni and her associates reported having no relevant financial disclosures.
Echocardiogram, exercise testing improve PAH prognostic accuracy
Adding echocardiography and cardiopulmonary exercise testing to baseline right heart catheterization improves prognostic accuracy in idiopathic pulmonary arterial hypertension, according to a prospective Italian study of 102 newly diagnosed patients.
A combination of low right ventricular fractional area change (RVFAC) on echocardiography and low oxygen pulse on cardiopulmonary exercise testing (CPET) “identifies patients at a particularly high risk of clinical deterioration.” Both are markers of right ventricular (RV) function, which is a major determinant of outcome in idiopathic pulmonary arterial hypertension [iPAH], said investigators led by Roberto Badagliacca, MD, of the Sapienza University of Rome (Chest. 2016 Aug 20. pii: S0012-3692(16)56052-8. doi: 10.1016/j.chest.2016.07.036).
PAH diagnosis requires right heart catheterization, and findings have long been known to predict PAH outcome. However, catheterization allows only “an indirect description of RV function,” the investigators said. Recent studies have shown that RV echocardiography and CPET improve the accuracy of heart failure prognosis, so the investigators wanted to see if they’d do the same for PAH.
Their results “strongly suggest that noninvasive measurements related to RV function obtained by combining resting echocardiography and CPET are of added value to right heart catheterization in the assessment of severity and prognostication of PAH,” they said.
During a mean follow-up of 528 days, 54 patients (53%) had clinical worsening, defined as a 15% reduction in 6-minute walk distance from baseline plus a worsening of functional class, nonelective PAH hospitalization, or death.
Baseline functional class and cardiac index proved to be independent predictors of clinical worsening. Adding echocardiographic and CPET variables independently improved prognostic power (area under the curve, 0.81 vs. 0.66; P = .005).
Compared with patients with high RVFAC and high oxygen pulse at baseline, patients with low RVFAC and low oxygen pulse had a 99.8 increase in the hazard ratio for clinical worsening, and those with high RVFAC and low oxygen had a 29.4 increase (P = .0001).
Several echocardiographic variables for RV function have previously been reported as independent predictors of PAH outcome. “The new finding here is that RVFAC outperformed other echocardiographic indices of systolic function,” the investigators wrote.
“As for peak oxygen pulse, this variable is thought to assess maximum [stroke volume],” assumed to be determined by RV function; MRI-determined stroke volume has been previously shown to be an important predictor of survival in PAH,” they said.
The mean age in the study was 52 years, mean functional class was 2.7, and mean 6-minute walk distance was 430 m; 62 subjects were women. The most relevant comorbidities were diabetes in 5 patients, hypercholesterolemia in 10, thyroid diseases in 6, and clinical depression in 7. Patients with severe tricuspid regurgitation or exercise-induced opening of the foramen ovale were excluded. However, a reanalysis including patients with exercise-induced right to left shunting showed the same independent predictors of PAH outcome.
After diagnosis, patients were treated with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids.
Dr. Badagliacca reported speaker and adviser fees from United Therapeutics, Dompe, GSK, and Bayer. His colleagues reported no conflicts of interest.
Adding echocardiography and cardiopulmonary exercise testing to baseline right heart catheterization improves prognostic accuracy in idiopathic pulmonary arterial hypertension, according to a prospective Italian study of 102 newly diagnosed patients.
A combination of low right ventricular fractional area change (RVFAC) on echocardiography and low oxygen pulse on cardiopulmonary exercise testing (CPET) “identifies patients at a particularly high risk of clinical deterioration.” Both are markers of right ventricular (RV) function, which is a major determinant of outcome in idiopathic pulmonary arterial hypertension [iPAH], said investigators led by Roberto Badagliacca, MD, of the Sapienza University of Rome (Chest. 2016 Aug 20. pii: S0012-3692(16)56052-8. doi: 10.1016/j.chest.2016.07.036).
PAH diagnosis requires right heart catheterization, and findings have long been known to predict PAH outcome. However, catheterization allows only “an indirect description of RV function,” the investigators said. Recent studies have shown that RV echocardiography and CPET improve the accuracy of heart failure prognosis, so the investigators wanted to see if they’d do the same for PAH.
Their results “strongly suggest that noninvasive measurements related to RV function obtained by combining resting echocardiography and CPET are of added value to right heart catheterization in the assessment of severity and prognostication of PAH,” they said.
During a mean follow-up of 528 days, 54 patients (53%) had clinical worsening, defined as a 15% reduction in 6-minute walk distance from baseline plus a worsening of functional class, nonelective PAH hospitalization, or death.
Baseline functional class and cardiac index proved to be independent predictors of clinical worsening. Adding echocardiographic and CPET variables independently improved prognostic power (area under the curve, 0.81 vs. 0.66; P = .005).
Compared with patients with high RVFAC and high oxygen pulse at baseline, patients with low RVFAC and low oxygen pulse had a 99.8 increase in the hazard ratio for clinical worsening, and those with high RVFAC and low oxygen had a 29.4 increase (P = .0001).
Several echocardiographic variables for RV function have previously been reported as independent predictors of PAH outcome. “The new finding here is that RVFAC outperformed other echocardiographic indices of systolic function,” the investigators wrote.
“As for peak oxygen pulse, this variable is thought to assess maximum [stroke volume],” assumed to be determined by RV function; MRI-determined stroke volume has been previously shown to be an important predictor of survival in PAH,” they said.
The mean age in the study was 52 years, mean functional class was 2.7, and mean 6-minute walk distance was 430 m; 62 subjects were women. The most relevant comorbidities were diabetes in 5 patients, hypercholesterolemia in 10, thyroid diseases in 6, and clinical depression in 7. Patients with severe tricuspid regurgitation or exercise-induced opening of the foramen ovale were excluded. However, a reanalysis including patients with exercise-induced right to left shunting showed the same independent predictors of PAH outcome.
After diagnosis, patients were treated with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids.
Dr. Badagliacca reported speaker and adviser fees from United Therapeutics, Dompe, GSK, and Bayer. His colleagues reported no conflicts of interest.
Adding echocardiography and cardiopulmonary exercise testing to baseline right heart catheterization improves prognostic accuracy in idiopathic pulmonary arterial hypertension, according to a prospective Italian study of 102 newly diagnosed patients.
A combination of low right ventricular fractional area change (RVFAC) on echocardiography and low oxygen pulse on cardiopulmonary exercise testing (CPET) “identifies patients at a particularly high risk of clinical deterioration.” Both are markers of right ventricular (RV) function, which is a major determinant of outcome in idiopathic pulmonary arterial hypertension [iPAH], said investigators led by Roberto Badagliacca, MD, of the Sapienza University of Rome (Chest. 2016 Aug 20. pii: S0012-3692(16)56052-8. doi: 10.1016/j.chest.2016.07.036).
PAH diagnosis requires right heart catheterization, and findings have long been known to predict PAH outcome. However, catheterization allows only “an indirect description of RV function,” the investigators said. Recent studies have shown that RV echocardiography and CPET improve the accuracy of heart failure prognosis, so the investigators wanted to see if they’d do the same for PAH.
Their results “strongly suggest that noninvasive measurements related to RV function obtained by combining resting echocardiography and CPET are of added value to right heart catheterization in the assessment of severity and prognostication of PAH,” they said.
During a mean follow-up of 528 days, 54 patients (53%) had clinical worsening, defined as a 15% reduction in 6-minute walk distance from baseline plus a worsening of functional class, nonelective PAH hospitalization, or death.
Baseline functional class and cardiac index proved to be independent predictors of clinical worsening. Adding echocardiographic and CPET variables independently improved prognostic power (area under the curve, 0.81 vs. 0.66; P = .005).
Compared with patients with high RVFAC and high oxygen pulse at baseline, patients with low RVFAC and low oxygen pulse had a 99.8 increase in the hazard ratio for clinical worsening, and those with high RVFAC and low oxygen had a 29.4 increase (P = .0001).
Several echocardiographic variables for RV function have previously been reported as independent predictors of PAH outcome. “The new finding here is that RVFAC outperformed other echocardiographic indices of systolic function,” the investigators wrote.
“As for peak oxygen pulse, this variable is thought to assess maximum [stroke volume],” assumed to be determined by RV function; MRI-determined stroke volume has been previously shown to be an important predictor of survival in PAH,” they said.
The mean age in the study was 52 years, mean functional class was 2.7, and mean 6-minute walk distance was 430 m; 62 subjects were women. The most relevant comorbidities were diabetes in 5 patients, hypercholesterolemia in 10, thyroid diseases in 6, and clinical depression in 7. Patients with severe tricuspid regurgitation or exercise-induced opening of the foramen ovale were excluded. However, a reanalysis including patients with exercise-induced right to left shunting showed the same independent predictors of PAH outcome.
After diagnosis, patients were treated with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids.
Dr. Badagliacca reported speaker and adviser fees from United Therapeutics, Dompe, GSK, and Bayer. His colleagues reported no conflicts of interest.
FROM CHEST
Key clinical point:
Major finding: Baseline functional class and cardiac index proved to be independent predictors of clinical worsening. Adding echocardiographic and CPET variables independently improved prognostic power (area under the curve, 0.81 vs. 0.66; P = .005).
Data source: A prospective Italian study of 102 newly diagnosed patients.
Disclosures: The lead investigator reported speaker and adviser fees from United Therapeutics, Dompe, GSK, and Bayer.
TAVR concerns hinder use in younger, lower-risk patients
NEW ORLEANS – Despite increasing use of transcatheter aortic valve replacement for patients with severe aortic stenosis at intermediate risk for surgery, the procedure is meeting selected resistance because of ongoing concerns about the procedure’s limitations.
As more data emerge from randomized trials and registries, cardiologists and cardiothoracic surgeons see the choice between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) for patients at intermediate surgical risk as something to individualize based on factors that include age, the type of TAVR access possible (transfemoral or an alternative route), and of course, patient preference. An added variable is the constant stream of new data that keeps TAVR in flux, with improved and smaller valves and delivery systems coming onto the market that eclipse the experience and lessons learned from older TAVR systems.
In intermediate-risk patients, usually defined as those with a Society of Thoracic Surgeons (STS) mortality risk score of 4%-8%, “I think you can go either way,” said Frank W. Sellke, MD, at the American Heart Association scientific sessions.
“If a patient is 90 years old and can’t expect to live more than a couple of years, you use TAVR; but if the patient is 55 years old and can expect to live 30 years, I would recommend SAVR,” said Dr. Sellke, professor and chief of cardiothoracic surgery at Brown University in Providence, R.I.
He rattled off four things about TAVR that keep it from being for everyone: periprocedural vascular complications, higher rates of paravalvular leak than with surgery, leaflet thrombosis (a phenomenon with unclear clinical consequences), and undocumented long-term durability.
Dr. Sellke made these comments while discussing the report at the meeting on registry data collected from nearly 6,000 intermediate-risk patients who underwent TAVR or SAVR in Germany during January 2011 through December 2013 and assembled in the German Aortic Valve Registry. During that 3-year period, German TAVR patients could receive either the SAPIEN XT valve or the CoreValve, two TAVR systems that now have been superseded in both Europe and the United States by next-generation systems, SAPIEN 3 and Evolut R.
Limitations of a transthoracic approach
Another factor limiting TAVR is the endovascular approach. The best TAVR results by far have come from using a transfemoral approach for endovascular valve placement, but experts estimate that today at least 10% of patients considered for TAVR have a vascular anatomy that makes the transfemoral TAVR impossible. In the past, when such patients underwent TAVR, it was via either a transapical or transaortic approach (collectively called transthoracic), although additional endovascular entry sites are now being tested.
The limitations of transthoracic TAVR were underscored by results from a prespecified quality-of-life analysis done as part of the PARTNER 2 trial that compared the SAPIEN XT system with SAVR in intermediate-risk patients (N Engl J Med. 2016 April 27;374[17]:1609-20).
In contrast, the patients in the study who had their TAVR done by a transthoracic route had a statistically nonsignificant incremental gain in their KCCQ score, compared with randomized SAVR patients, after 1 month, and their incremental rise in KCCQ score was not clinically meaningful.
The investigators measured KCCQ scores at both 1 and 2 years after treatment, and they were similar regardless of whether patients had undergone TAVR or SAVR in both the transfemoral and transthoracic subgroups. All the quality-of-life benefit from TAVR compared with SAVR occurred only during the first month (and possibly for a few additional months beyond that) and only in TAVR patients treated by the transfemoral route. Dr. Cohen stressed that the SAVR patients in both the transfemoral and transthoracic subgroups had very similar outcomes, showing that patient differences could not explain why the transfemoral patients received a much greater incremental benefit, compared with the SAVR patients, at 1 month than did the transthoracic patients.
“A transthoracic TAVR approach may not be preferable to SAVR, at least in the short to intermediate term,” said Dr. Cohen. “There is no benefit from TAVR, compared with SAVR, if you can’t do it transfemorally, although emerging evidence has suggested that other nontransfemoral approaches that stay out of the chest may provide benefit similar to transfemoral TAVR. The message is, stay out of the chest,” he concluded.
Concerns about durability
The durability of TAVR valves is another concern that has recently been influencing patients as they decide between TAVR and SAVR, said Dr. Smith. “A lot of patients don’t want TAVR because of their concerns about its durability.” These patients usually cite evidence reported in May 2016 at the annual congress of the European Association of Percutaneous Cardiovascular Interventions in Paris by Danny Dvir, MD, on longer-term follow-up of 378 patients who underwent TAVR at either of two pioneering centers. A retrospective review suggested a valve degeneration rate of about 50% after 8 years, Dr. Dvir reported.
This report “has gotten a lot of penetration over the Internet, and a lot of patients don’t like the uncertainty” about TAVR durability that this report produced. “A lot of the time now, patients come in with a fixed idea of whether they want TAVR or SAVR,” Dr. Smith said.
Dr. Smith essentially agreed with Dr. Sellke on the current role for TAVR relative to SAVR in lower-risk patients.
“If the patient is clearly intermediate risk, with an STS mortality risk of more than 6% and is at least 80 years old, then they’ll have TAVR 99% of the time. But if it’s a 75 year old with an STS score of 3.2% and otherwise healthy, the best choice is not as clear.”
Another cardiothoracic surgeon with lots of TAVR experience, Michael J. Reardon, MD, has much more enthusiasm for TAVR. “In my practice, I use TAVR exclusively in patients at least 80 years old. I don‘t care how healthy they look,” said Dr. Reardon, professor of cardiovascular surgery at Houston Methodist. He acknowledged that broader use of TAVR for intermediate-risk patients is getting push back from other cardiothoracic surgeons.
Dr. Sellke is one such surgeon, and he called uncertain TAVR valve durability the deciding factor. “We need longer-term data on [TAVR] valve longevity before we routinely put them into intermediate- or low-risk patients,” he said during a panel discussion at the meeting.
Dr. Reardon highlighted that newer TAVR systems have been reducing problems such as paravalvular leaks and the need for pacemakers following placement of self-expanding TAVR valves. Despite these technical improvements, the final frontier for TAVR for lower-risk patients is valve durability, Dr. Reardon said in an interview.
“I’m convinced the durability is there, and that any 80-year-old patient who is anatomically suited for transfemoral TAVR should get it no matter now healthy they look. If their likely survival is 15 years or less, then they are reasonable candidates for TAVR.”
Dr. Sellke had no relevant disclosures. PARTNER 2 was funded by Edwards, the company that markets Sapient TAVR systems. Dr. Cohen had no relevant disclosures. Dr. Smith has been an investigator in the PARTNER studies. Dr. Reardon has been a consultant to Medtronic, the company that markets the CoreValve and Evolut R TAVR systems.
[email protected]
On Twitter @mitchelzoler
NEW ORLEANS – Despite increasing use of transcatheter aortic valve replacement for patients with severe aortic stenosis at intermediate risk for surgery, the procedure is meeting selected resistance because of ongoing concerns about the procedure’s limitations.
As more data emerge from randomized trials and registries, cardiologists and cardiothoracic surgeons see the choice between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) for patients at intermediate surgical risk as something to individualize based on factors that include age, the type of TAVR access possible (transfemoral or an alternative route), and of course, patient preference. An added variable is the constant stream of new data that keeps TAVR in flux, with improved and smaller valves and delivery systems coming onto the market that eclipse the experience and lessons learned from older TAVR systems.
In intermediate-risk patients, usually defined as those with a Society of Thoracic Surgeons (STS) mortality risk score of 4%-8%, “I think you can go either way,” said Frank W. Sellke, MD, at the American Heart Association scientific sessions.
“If a patient is 90 years old and can’t expect to live more than a couple of years, you use TAVR; but if the patient is 55 years old and can expect to live 30 years, I would recommend SAVR,” said Dr. Sellke, professor and chief of cardiothoracic surgery at Brown University in Providence, R.I.
He rattled off four things about TAVR that keep it from being for everyone: periprocedural vascular complications, higher rates of paravalvular leak than with surgery, leaflet thrombosis (a phenomenon with unclear clinical consequences), and undocumented long-term durability.
Dr. Sellke made these comments while discussing the report at the meeting on registry data collected from nearly 6,000 intermediate-risk patients who underwent TAVR or SAVR in Germany during January 2011 through December 2013 and assembled in the German Aortic Valve Registry. During that 3-year period, German TAVR patients could receive either the SAPIEN XT valve or the CoreValve, two TAVR systems that now have been superseded in both Europe and the United States by next-generation systems, SAPIEN 3 and Evolut R.
Limitations of a transthoracic approach
Another factor limiting TAVR is the endovascular approach. The best TAVR results by far have come from using a transfemoral approach for endovascular valve placement, but experts estimate that today at least 10% of patients considered for TAVR have a vascular anatomy that makes the transfemoral TAVR impossible. In the past, when such patients underwent TAVR, it was via either a transapical or transaortic approach (collectively called transthoracic), although additional endovascular entry sites are now being tested.
The limitations of transthoracic TAVR were underscored by results from a prespecified quality-of-life analysis done as part of the PARTNER 2 trial that compared the SAPIEN XT system with SAVR in intermediate-risk patients (N Engl J Med. 2016 April 27;374[17]:1609-20).
In contrast, the patients in the study who had their TAVR done by a transthoracic route had a statistically nonsignificant incremental gain in their KCCQ score, compared with randomized SAVR patients, after 1 month, and their incremental rise in KCCQ score was not clinically meaningful.
The investigators measured KCCQ scores at both 1 and 2 years after treatment, and they were similar regardless of whether patients had undergone TAVR or SAVR in both the transfemoral and transthoracic subgroups. All the quality-of-life benefit from TAVR compared with SAVR occurred only during the first month (and possibly for a few additional months beyond that) and only in TAVR patients treated by the transfemoral route. Dr. Cohen stressed that the SAVR patients in both the transfemoral and transthoracic subgroups had very similar outcomes, showing that patient differences could not explain why the transfemoral patients received a much greater incremental benefit, compared with the SAVR patients, at 1 month than did the transthoracic patients.
“A transthoracic TAVR approach may not be preferable to SAVR, at least in the short to intermediate term,” said Dr. Cohen. “There is no benefit from TAVR, compared with SAVR, if you can’t do it transfemorally, although emerging evidence has suggested that other nontransfemoral approaches that stay out of the chest may provide benefit similar to transfemoral TAVR. The message is, stay out of the chest,” he concluded.
Concerns about durability
The durability of TAVR valves is another concern that has recently been influencing patients as they decide between TAVR and SAVR, said Dr. Smith. “A lot of patients don’t want TAVR because of their concerns about its durability.” These patients usually cite evidence reported in May 2016 at the annual congress of the European Association of Percutaneous Cardiovascular Interventions in Paris by Danny Dvir, MD, on longer-term follow-up of 378 patients who underwent TAVR at either of two pioneering centers. A retrospective review suggested a valve degeneration rate of about 50% after 8 years, Dr. Dvir reported.
This report “has gotten a lot of penetration over the Internet, and a lot of patients don’t like the uncertainty” about TAVR durability that this report produced. “A lot of the time now, patients come in with a fixed idea of whether they want TAVR or SAVR,” Dr. Smith said.
Dr. Smith essentially agreed with Dr. Sellke on the current role for TAVR relative to SAVR in lower-risk patients.
“If the patient is clearly intermediate risk, with an STS mortality risk of more than 6% and is at least 80 years old, then they’ll have TAVR 99% of the time. But if it’s a 75 year old with an STS score of 3.2% and otherwise healthy, the best choice is not as clear.”
Another cardiothoracic surgeon with lots of TAVR experience, Michael J. Reardon, MD, has much more enthusiasm for TAVR. “In my practice, I use TAVR exclusively in patients at least 80 years old. I don‘t care how healthy they look,” said Dr. Reardon, professor of cardiovascular surgery at Houston Methodist. He acknowledged that broader use of TAVR for intermediate-risk patients is getting push back from other cardiothoracic surgeons.
Dr. Sellke is one such surgeon, and he called uncertain TAVR valve durability the deciding factor. “We need longer-term data on [TAVR] valve longevity before we routinely put them into intermediate- or low-risk patients,” he said during a panel discussion at the meeting.
Dr. Reardon highlighted that newer TAVR systems have been reducing problems such as paravalvular leaks and the need for pacemakers following placement of self-expanding TAVR valves. Despite these technical improvements, the final frontier for TAVR for lower-risk patients is valve durability, Dr. Reardon said in an interview.
“I’m convinced the durability is there, and that any 80-year-old patient who is anatomically suited for transfemoral TAVR should get it no matter now healthy they look. If their likely survival is 15 years or less, then they are reasonable candidates for TAVR.”
Dr. Sellke had no relevant disclosures. PARTNER 2 was funded by Edwards, the company that markets Sapient TAVR systems. Dr. Cohen had no relevant disclosures. Dr. Smith has been an investigator in the PARTNER studies. Dr. Reardon has been a consultant to Medtronic, the company that markets the CoreValve and Evolut R TAVR systems.
[email protected]
On Twitter @mitchelzoler
NEW ORLEANS – Despite increasing use of transcatheter aortic valve replacement for patients with severe aortic stenosis at intermediate risk for surgery, the procedure is meeting selected resistance because of ongoing concerns about the procedure’s limitations.
As more data emerge from randomized trials and registries, cardiologists and cardiothoracic surgeons see the choice between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) for patients at intermediate surgical risk as something to individualize based on factors that include age, the type of TAVR access possible (transfemoral or an alternative route), and of course, patient preference. An added variable is the constant stream of new data that keeps TAVR in flux, with improved and smaller valves and delivery systems coming onto the market that eclipse the experience and lessons learned from older TAVR systems.
In intermediate-risk patients, usually defined as those with a Society of Thoracic Surgeons (STS) mortality risk score of 4%-8%, “I think you can go either way,” said Frank W. Sellke, MD, at the American Heart Association scientific sessions.
“If a patient is 90 years old and can’t expect to live more than a couple of years, you use TAVR; but if the patient is 55 years old and can expect to live 30 years, I would recommend SAVR,” said Dr. Sellke, professor and chief of cardiothoracic surgery at Brown University in Providence, R.I.
He rattled off four things about TAVR that keep it from being for everyone: periprocedural vascular complications, higher rates of paravalvular leak than with surgery, leaflet thrombosis (a phenomenon with unclear clinical consequences), and undocumented long-term durability.
Dr. Sellke made these comments while discussing the report at the meeting on registry data collected from nearly 6,000 intermediate-risk patients who underwent TAVR or SAVR in Germany during January 2011 through December 2013 and assembled in the German Aortic Valve Registry. During that 3-year period, German TAVR patients could receive either the SAPIEN XT valve or the CoreValve, two TAVR systems that now have been superseded in both Europe and the United States by next-generation systems, SAPIEN 3 and Evolut R.
Limitations of a transthoracic approach
Another factor limiting TAVR is the endovascular approach. The best TAVR results by far have come from using a transfemoral approach for endovascular valve placement, but experts estimate that today at least 10% of patients considered for TAVR have a vascular anatomy that makes the transfemoral TAVR impossible. In the past, when such patients underwent TAVR, it was via either a transapical or transaortic approach (collectively called transthoracic), although additional endovascular entry sites are now being tested.
The limitations of transthoracic TAVR were underscored by results from a prespecified quality-of-life analysis done as part of the PARTNER 2 trial that compared the SAPIEN XT system with SAVR in intermediate-risk patients (N Engl J Med. 2016 April 27;374[17]:1609-20).
In contrast, the patients in the study who had their TAVR done by a transthoracic route had a statistically nonsignificant incremental gain in their KCCQ score, compared with randomized SAVR patients, after 1 month, and their incremental rise in KCCQ score was not clinically meaningful.
The investigators measured KCCQ scores at both 1 and 2 years after treatment, and they were similar regardless of whether patients had undergone TAVR or SAVR in both the transfemoral and transthoracic subgroups. All the quality-of-life benefit from TAVR compared with SAVR occurred only during the first month (and possibly for a few additional months beyond that) and only in TAVR patients treated by the transfemoral route. Dr. Cohen stressed that the SAVR patients in both the transfemoral and transthoracic subgroups had very similar outcomes, showing that patient differences could not explain why the transfemoral patients received a much greater incremental benefit, compared with the SAVR patients, at 1 month than did the transthoracic patients.
“A transthoracic TAVR approach may not be preferable to SAVR, at least in the short to intermediate term,” said Dr. Cohen. “There is no benefit from TAVR, compared with SAVR, if you can’t do it transfemorally, although emerging evidence has suggested that other nontransfemoral approaches that stay out of the chest may provide benefit similar to transfemoral TAVR. The message is, stay out of the chest,” he concluded.
Concerns about durability
The durability of TAVR valves is another concern that has recently been influencing patients as they decide between TAVR and SAVR, said Dr. Smith. “A lot of patients don’t want TAVR because of their concerns about its durability.” These patients usually cite evidence reported in May 2016 at the annual congress of the European Association of Percutaneous Cardiovascular Interventions in Paris by Danny Dvir, MD, on longer-term follow-up of 378 patients who underwent TAVR at either of two pioneering centers. A retrospective review suggested a valve degeneration rate of about 50% after 8 years, Dr. Dvir reported.
This report “has gotten a lot of penetration over the Internet, and a lot of patients don’t like the uncertainty” about TAVR durability that this report produced. “A lot of the time now, patients come in with a fixed idea of whether they want TAVR or SAVR,” Dr. Smith said.
Dr. Smith essentially agreed with Dr. Sellke on the current role for TAVR relative to SAVR in lower-risk patients.
“If the patient is clearly intermediate risk, with an STS mortality risk of more than 6% and is at least 80 years old, then they’ll have TAVR 99% of the time. But if it’s a 75 year old with an STS score of 3.2% and otherwise healthy, the best choice is not as clear.”
Another cardiothoracic surgeon with lots of TAVR experience, Michael J. Reardon, MD, has much more enthusiasm for TAVR. “In my practice, I use TAVR exclusively in patients at least 80 years old. I don‘t care how healthy they look,” said Dr. Reardon, professor of cardiovascular surgery at Houston Methodist. He acknowledged that broader use of TAVR for intermediate-risk patients is getting push back from other cardiothoracic surgeons.
Dr. Sellke is one such surgeon, and he called uncertain TAVR valve durability the deciding factor. “We need longer-term data on [TAVR] valve longevity before we routinely put them into intermediate- or low-risk patients,” he said during a panel discussion at the meeting.
Dr. Reardon highlighted that newer TAVR systems have been reducing problems such as paravalvular leaks and the need for pacemakers following placement of self-expanding TAVR valves. Despite these technical improvements, the final frontier for TAVR for lower-risk patients is valve durability, Dr. Reardon said in an interview.
“I’m convinced the durability is there, and that any 80-year-old patient who is anatomically suited for transfemoral TAVR should get it no matter now healthy they look. If their likely survival is 15 years or less, then they are reasonable candidates for TAVR.”
Dr. Sellke had no relevant disclosures. PARTNER 2 was funded by Edwards, the company that markets Sapient TAVR systems. Dr. Cohen had no relevant disclosures. Dr. Smith has been an investigator in the PARTNER studies. Dr. Reardon has been a consultant to Medtronic, the company that markets the CoreValve and Evolut R TAVR systems.
[email protected]
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM THE AHA SCIENTIFIC SESSIONS
Mass spectrometry of gastric aspirates can predict RDS in premature infants
A mass spectrometry test was able to rapidly measure lung maturity in premature infants at risk for respiratory distress syndrome (RDS), according to Henrik Verder, MD, of Holbaek (Denmark) University Hospital, and his associates.
Samples of gastric aspirates were taken from 136 infants with gestation periods of 24-31 weeks, and analyzed with mass spectrometry. Of this group, 61 developed RDS, and 7 died before the end of the study period. With a lecithin/sphingomyelin (L/S) cut-off ratio of 2.2, sensitivity of the mass spectrometry test was 92%, specificity was 73%, positive predictive value was 74%, and negative predictive was value of 92%. Sensitivity was high for all gestational age groups, the investigators noted.
Oropharyngeal secretions were sampled from an additional group of 59 infants and analyzed using spectrometry, with an L/S cut-off value of 3.7; however sensitivity and specificity were lower than for gastric aspirates.
“This test could help identify which infants will benefit from very early surfactant treatment, with the potential to significantly improve clinical outcomes resulting in less severe RDS, less need of mechanical ventilation and oxygen and less severe bronchopulmonary dysplasia,” the investigators concluded.
Find the study in Acta Paediatrica (2016. doi: 10.1111/apa.13683)
A mass spectrometry test was able to rapidly measure lung maturity in premature infants at risk for respiratory distress syndrome (RDS), according to Henrik Verder, MD, of Holbaek (Denmark) University Hospital, and his associates.
Samples of gastric aspirates were taken from 136 infants with gestation periods of 24-31 weeks, and analyzed with mass spectrometry. Of this group, 61 developed RDS, and 7 died before the end of the study period. With a lecithin/sphingomyelin (L/S) cut-off ratio of 2.2, sensitivity of the mass spectrometry test was 92%, specificity was 73%, positive predictive value was 74%, and negative predictive was value of 92%. Sensitivity was high for all gestational age groups, the investigators noted.
Oropharyngeal secretions were sampled from an additional group of 59 infants and analyzed using spectrometry, with an L/S cut-off value of 3.7; however sensitivity and specificity were lower than for gastric aspirates.
“This test could help identify which infants will benefit from very early surfactant treatment, with the potential to significantly improve clinical outcomes resulting in less severe RDS, less need of mechanical ventilation and oxygen and less severe bronchopulmonary dysplasia,” the investigators concluded.
Find the study in Acta Paediatrica (2016. doi: 10.1111/apa.13683)
A mass spectrometry test was able to rapidly measure lung maturity in premature infants at risk for respiratory distress syndrome (RDS), according to Henrik Verder, MD, of Holbaek (Denmark) University Hospital, and his associates.
Samples of gastric aspirates were taken from 136 infants with gestation periods of 24-31 weeks, and analyzed with mass spectrometry. Of this group, 61 developed RDS, and 7 died before the end of the study period. With a lecithin/sphingomyelin (L/S) cut-off ratio of 2.2, sensitivity of the mass spectrometry test was 92%, specificity was 73%, positive predictive value was 74%, and negative predictive was value of 92%. Sensitivity was high for all gestational age groups, the investigators noted.
Oropharyngeal secretions were sampled from an additional group of 59 infants and analyzed using spectrometry, with an L/S cut-off value of 3.7; however sensitivity and specificity were lower than for gastric aspirates.
“This test could help identify which infants will benefit from very early surfactant treatment, with the potential to significantly improve clinical outcomes resulting in less severe RDS, less need of mechanical ventilation and oxygen and less severe bronchopulmonary dysplasia,” the investigators concluded.
Find the study in Acta Paediatrica (2016. doi: 10.1111/apa.13683)
Senate sends 21st Century Cures bill to president
With little debate and less dissent, the Senate passed the 21st Century Cures bill and sent it to President Obama for his promised signature.
The legislation passed the House by an overwhelming 392-26 vote on Nov. 30. Key provisions of the bill (H.R. 34) include:
• Food and Drug Administration reforms, including expedited review for certain medical devices, streamlined review for drug/device combinations, and increased patient involvement in the drug approval process, with $500 million to implement the reforms.
• $4.8 billion over 10 years for key biomedical research efforts including the BRAIN Initiative, the Cancer Moonshot, and the Precision Medicine Initiative.
• $1 billion in grants to states over a 2-year period to help supplement opioid abuse prevention and treatment activities.
• Provisions to improve the interoperability of EHRs.
• Provisions to improve treatment of serious mental illness.
“This bipartisan legislation – which [Senate] Majority Leader Mitch McConnell [R-Ky.] has called ‘the most important legislation Congress will pass this year’ – will help us take advantage of the breathtaking advances in biomedical research and bring those innovations to doctors’ offices and patients’ medicine cabinets around the county,” Sen. Lamar Alexander (R-Tenn.), chair of the Senate Health, Education, Labor, and Pensions Committee, said in a statement.
“The most important prescription drug-related crisis facing our country right now is the skyrocketing price of prescription drugs. This bill does not even deal with that issue,” Sen. Sanders said on the Senate floor. “How can we talk about a bill dealing with the pharmaceutical industry without addressing the elephant in the room, which is the fact that we pay the highest prices in the world for medicine?”
In his weekly address on Dec. 3, President Obama promised to “sign [the bill] as soon as it reaches my desk.”
Gregory Twachtman contributed to this report.
[email protected]
On Twitter @denisefulton
With little debate and less dissent, the Senate passed the 21st Century Cures bill and sent it to President Obama for his promised signature.
The legislation passed the House by an overwhelming 392-26 vote on Nov. 30. Key provisions of the bill (H.R. 34) include:
• Food and Drug Administration reforms, including expedited review for certain medical devices, streamlined review for drug/device combinations, and increased patient involvement in the drug approval process, with $500 million to implement the reforms.
• $4.8 billion over 10 years for key biomedical research efforts including the BRAIN Initiative, the Cancer Moonshot, and the Precision Medicine Initiative.
• $1 billion in grants to states over a 2-year period to help supplement opioid abuse prevention and treatment activities.
• Provisions to improve the interoperability of EHRs.
• Provisions to improve treatment of serious mental illness.
“This bipartisan legislation – which [Senate] Majority Leader Mitch McConnell [R-Ky.] has called ‘the most important legislation Congress will pass this year’ – will help us take advantage of the breathtaking advances in biomedical research and bring those innovations to doctors’ offices and patients’ medicine cabinets around the county,” Sen. Lamar Alexander (R-Tenn.), chair of the Senate Health, Education, Labor, and Pensions Committee, said in a statement.
“The most important prescription drug-related crisis facing our country right now is the skyrocketing price of prescription drugs. This bill does not even deal with that issue,” Sen. Sanders said on the Senate floor. “How can we talk about a bill dealing with the pharmaceutical industry without addressing the elephant in the room, which is the fact that we pay the highest prices in the world for medicine?”
In his weekly address on Dec. 3, President Obama promised to “sign [the bill] as soon as it reaches my desk.”
Gregory Twachtman contributed to this report.
[email protected]
On Twitter @denisefulton
With little debate and less dissent, the Senate passed the 21st Century Cures bill and sent it to President Obama for his promised signature.
The legislation passed the House by an overwhelming 392-26 vote on Nov. 30. Key provisions of the bill (H.R. 34) include:
• Food and Drug Administration reforms, including expedited review for certain medical devices, streamlined review for drug/device combinations, and increased patient involvement in the drug approval process, with $500 million to implement the reforms.
• $4.8 billion over 10 years for key biomedical research efforts including the BRAIN Initiative, the Cancer Moonshot, and the Precision Medicine Initiative.
• $1 billion in grants to states over a 2-year period to help supplement opioid abuse prevention and treatment activities.
• Provisions to improve the interoperability of EHRs.
• Provisions to improve treatment of serious mental illness.
“This bipartisan legislation – which [Senate] Majority Leader Mitch McConnell [R-Ky.] has called ‘the most important legislation Congress will pass this year’ – will help us take advantage of the breathtaking advances in biomedical research and bring those innovations to doctors’ offices and patients’ medicine cabinets around the county,” Sen. Lamar Alexander (R-Tenn.), chair of the Senate Health, Education, Labor, and Pensions Committee, said in a statement.
“The most important prescription drug-related crisis facing our country right now is the skyrocketing price of prescription drugs. This bill does not even deal with that issue,” Sen. Sanders said on the Senate floor. “How can we talk about a bill dealing with the pharmaceutical industry without addressing the elephant in the room, which is the fact that we pay the highest prices in the world for medicine?”
In his weekly address on Dec. 3, President Obama promised to “sign [the bill] as soon as it reaches my desk.”
Gregory Twachtman contributed to this report.
[email protected]
On Twitter @denisefulton
Stem cell therapy for STEMI falls short at 2 years
NEW ORLEANS – Longer follow-up has not altered initial negative findings of the randomized phase II TIME trial, which tested the efficacy of early intracoronary stem cell therapy, given on day 3 or 7 after an ST-segment acute MI (STEMI). However, loss of the sickest patients from follow-up may have influenced the findings.
“When TIME (Transplantation in Myocardial Infarction Evaluation) was developed several years ago, the optimal timing for cell delivery following myocardial infarction was not known and had not been directly tested in a prospective clinical trial,” explained lead investigator Jay H. Traverse, MD, director of research at the Minneapolis Heart Institute Foundation and a senior consulting cardiologist at the Abbott Northwestern Hospital, Minneapolis.
With the new, additional follow-up out to 2 years in 85 patients, both groups saw further gains in LV ejection fraction and further reductions in LV infarct size, as well as stable LV end-diastolic volume index, but still with no significant differences between them.
Of note, however, 10 of the patients lost to follow-up were lost because they received implantable cardioverter defibrillators (ICDs) and, given technologic limitations at the time, could no longer undergo cardiac MRI, Dr. Traverse noted. “These 10 patients are important as we look at the long-term follow-up of TIME because these patients were more likely to have the most severe LV dysfunction and most remodeled left ventricles. This [subset] represents a limitation to long-term follow-up studies in this population.”
Challenges to research
Two challenging issues seen in many trials of cell therapy for cardiovascular disease are their underpowered nature and the changing natural history of the disease, according to session comoderator Timothy D. Henry, MD, head of cardiology at Cedars-Sinai in Los Angeles.
“One of the things with the TIME trial that’s striking, really, is that even though these are high-risk patients, there was almost no mortality in 2 years,” he commented. “Second of all... there were no differences in ejection fraction, but that’s because you are missing 30% of people. And your missing 30% of people are the sick people, so of course if you are just going to follow normal people for 2 years, you’re going to have normal results.”
“What you are seeing is a little bit illusory because all the sick patients got ICDs and we could no longer image them at that time,” Dr. Traverse agreed. “That will be less of an issue in some of our future trials that we have started now, like CONCERT and SENECA, where we are now able to do MRI analysis of people with devices. So that will certainly help.”
Nonetheless, all trials in similar patient populations are plagued by substantial rates of dropout over time and faced with improving outcomes generally, because of better medical therapy, he acknowledged. “You can see as far as the natural history, even taking into account the ICD changes that would have lowered volumes, people are pretty stable on medical therapy. Their ejection fractions and volumes out to 2 years were really quite stable. We have certainly impacted that.”
That issue raises the question of whether investigators should be using other endpoints going forward, according to session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute in Houston.
“One of the things I’ve seen over and over in this field is constantly evolving questions about which endpoints we should follow and what constitutes positive effects,” she commented. “So given the natural history, what are the endpoints we should be using?”
“Patients don’t care what their ejection fraction is per se. But they want to know if they have to get an ICD or if they will be hospitalized for heart failure, and their family is affected if they die,” Dr. Traverse replied. “We definitely need these hard endpoints. The problem is that you need so many patients with these hard endpoints that [the trials] are just financially not very doable. So that’s a big issue.”
Trial details
Patients enrolled in TIME had a first anterior STEMI, underwent reperfusion by angioplasty and stenting, and had LV dysfunction with an ejection fraction of 45% or lower. They all received either autologous bone marrow mononuclear cells or placebo on day 3 or day 7 after their MI by intracoronary infusion.
Of the initial 120 randomized patients, 10 patients were lost to follow-up because of receipt of an ICD, 3 had died (1 each from cardiovascular causes, pancreatitis, and hemorrhagic stroke), 7 were lost to follow-up for other reasons, and 15 had acquired other contraindications to MRI, according to Dr. Traverse.
At 2 years, the remaining patients in both the cell therapy and placebo groups had roughly 5% absolute increases in LV ejection fraction from baseline and roughly 45% reductions in infarct size from baseline, with no significant differences between groups.
When all patients were combined, about half were determined to have had microvascular obstruction at baseline. This finding was an adverse prognostic factor, associated with poorer recovery of LV function over time, greater adverse LV remodeling, and a higher likelihood of receiving an ICD, Dr. Traverse reported.
He has received a research grant from the National Heart, Lung, and Blood Institute, which sponsored the TIME trial.
NEW ORLEANS – Longer follow-up has not altered initial negative findings of the randomized phase II TIME trial, which tested the efficacy of early intracoronary stem cell therapy, given on day 3 or 7 after an ST-segment acute MI (STEMI). However, loss of the sickest patients from follow-up may have influenced the findings.
“When TIME (Transplantation in Myocardial Infarction Evaluation) was developed several years ago, the optimal timing for cell delivery following myocardial infarction was not known and had not been directly tested in a prospective clinical trial,” explained lead investigator Jay H. Traverse, MD, director of research at the Minneapolis Heart Institute Foundation and a senior consulting cardiologist at the Abbott Northwestern Hospital, Minneapolis.
With the new, additional follow-up out to 2 years in 85 patients, both groups saw further gains in LV ejection fraction and further reductions in LV infarct size, as well as stable LV end-diastolic volume index, but still with no significant differences between them.
Of note, however, 10 of the patients lost to follow-up were lost because they received implantable cardioverter defibrillators (ICDs) and, given technologic limitations at the time, could no longer undergo cardiac MRI, Dr. Traverse noted. “These 10 patients are important as we look at the long-term follow-up of TIME because these patients were more likely to have the most severe LV dysfunction and most remodeled left ventricles. This [subset] represents a limitation to long-term follow-up studies in this population.”
Challenges to research
Two challenging issues seen in many trials of cell therapy for cardiovascular disease are their underpowered nature and the changing natural history of the disease, according to session comoderator Timothy D. Henry, MD, head of cardiology at Cedars-Sinai in Los Angeles.
“One of the things with the TIME trial that’s striking, really, is that even though these are high-risk patients, there was almost no mortality in 2 years,” he commented. “Second of all... there were no differences in ejection fraction, but that’s because you are missing 30% of people. And your missing 30% of people are the sick people, so of course if you are just going to follow normal people for 2 years, you’re going to have normal results.”
“What you are seeing is a little bit illusory because all the sick patients got ICDs and we could no longer image them at that time,” Dr. Traverse agreed. “That will be less of an issue in some of our future trials that we have started now, like CONCERT and SENECA, where we are now able to do MRI analysis of people with devices. So that will certainly help.”
Nonetheless, all trials in similar patient populations are plagued by substantial rates of dropout over time and faced with improving outcomes generally, because of better medical therapy, he acknowledged. “You can see as far as the natural history, even taking into account the ICD changes that would have lowered volumes, people are pretty stable on medical therapy. Their ejection fractions and volumes out to 2 years were really quite stable. We have certainly impacted that.”
That issue raises the question of whether investigators should be using other endpoints going forward, according to session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute in Houston.
“One of the things I’ve seen over and over in this field is constantly evolving questions about which endpoints we should follow and what constitutes positive effects,” she commented. “So given the natural history, what are the endpoints we should be using?”
“Patients don’t care what their ejection fraction is per se. But they want to know if they have to get an ICD or if they will be hospitalized for heart failure, and their family is affected if they die,” Dr. Traverse replied. “We definitely need these hard endpoints. The problem is that you need so many patients with these hard endpoints that [the trials] are just financially not very doable. So that’s a big issue.”
Trial details
Patients enrolled in TIME had a first anterior STEMI, underwent reperfusion by angioplasty and stenting, and had LV dysfunction with an ejection fraction of 45% or lower. They all received either autologous bone marrow mononuclear cells or placebo on day 3 or day 7 after their MI by intracoronary infusion.
Of the initial 120 randomized patients, 10 patients were lost to follow-up because of receipt of an ICD, 3 had died (1 each from cardiovascular causes, pancreatitis, and hemorrhagic stroke), 7 were lost to follow-up for other reasons, and 15 had acquired other contraindications to MRI, according to Dr. Traverse.
At 2 years, the remaining patients in both the cell therapy and placebo groups had roughly 5% absolute increases in LV ejection fraction from baseline and roughly 45% reductions in infarct size from baseline, with no significant differences between groups.
When all patients were combined, about half were determined to have had microvascular obstruction at baseline. This finding was an adverse prognostic factor, associated with poorer recovery of LV function over time, greater adverse LV remodeling, and a higher likelihood of receiving an ICD, Dr. Traverse reported.
He has received a research grant from the National Heart, Lung, and Blood Institute, which sponsored the TIME trial.
NEW ORLEANS – Longer follow-up has not altered initial negative findings of the randomized phase II TIME trial, which tested the efficacy of early intracoronary stem cell therapy, given on day 3 or 7 after an ST-segment acute MI (STEMI). However, loss of the sickest patients from follow-up may have influenced the findings.
“When TIME (Transplantation in Myocardial Infarction Evaluation) was developed several years ago, the optimal timing for cell delivery following myocardial infarction was not known and had not been directly tested in a prospective clinical trial,” explained lead investigator Jay H. Traverse, MD, director of research at the Minneapolis Heart Institute Foundation and a senior consulting cardiologist at the Abbott Northwestern Hospital, Minneapolis.
With the new, additional follow-up out to 2 years in 85 patients, both groups saw further gains in LV ejection fraction and further reductions in LV infarct size, as well as stable LV end-diastolic volume index, but still with no significant differences between them.
Of note, however, 10 of the patients lost to follow-up were lost because they received implantable cardioverter defibrillators (ICDs) and, given technologic limitations at the time, could no longer undergo cardiac MRI, Dr. Traverse noted. “These 10 patients are important as we look at the long-term follow-up of TIME because these patients were more likely to have the most severe LV dysfunction and most remodeled left ventricles. This [subset] represents a limitation to long-term follow-up studies in this population.”
Challenges to research
Two challenging issues seen in many trials of cell therapy for cardiovascular disease are their underpowered nature and the changing natural history of the disease, according to session comoderator Timothy D. Henry, MD, head of cardiology at Cedars-Sinai in Los Angeles.
“One of the things with the TIME trial that’s striking, really, is that even though these are high-risk patients, there was almost no mortality in 2 years,” he commented. “Second of all... there were no differences in ejection fraction, but that’s because you are missing 30% of people. And your missing 30% of people are the sick people, so of course if you are just going to follow normal people for 2 years, you’re going to have normal results.”
“What you are seeing is a little bit illusory because all the sick patients got ICDs and we could no longer image them at that time,” Dr. Traverse agreed. “That will be less of an issue in some of our future trials that we have started now, like CONCERT and SENECA, where we are now able to do MRI analysis of people with devices. So that will certainly help.”
Nonetheless, all trials in similar patient populations are plagued by substantial rates of dropout over time and faced with improving outcomes generally, because of better medical therapy, he acknowledged. “You can see as far as the natural history, even taking into account the ICD changes that would have lowered volumes, people are pretty stable on medical therapy. Their ejection fractions and volumes out to 2 years were really quite stable. We have certainly impacted that.”
That issue raises the question of whether investigators should be using other endpoints going forward, according to session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute in Houston.
“One of the things I’ve seen over and over in this field is constantly evolving questions about which endpoints we should follow and what constitutes positive effects,” she commented. “So given the natural history, what are the endpoints we should be using?”
“Patients don’t care what their ejection fraction is per se. But they want to know if they have to get an ICD or if they will be hospitalized for heart failure, and their family is affected if they die,” Dr. Traverse replied. “We definitely need these hard endpoints. The problem is that you need so many patients with these hard endpoints that [the trials] are just financially not very doable. So that’s a big issue.”
Trial details
Patients enrolled in TIME had a first anterior STEMI, underwent reperfusion by angioplasty and stenting, and had LV dysfunction with an ejection fraction of 45% or lower. They all received either autologous bone marrow mononuclear cells or placebo on day 3 or day 7 after their MI by intracoronary infusion.
Of the initial 120 randomized patients, 10 patients were lost to follow-up because of receipt of an ICD, 3 had died (1 each from cardiovascular causes, pancreatitis, and hemorrhagic stroke), 7 were lost to follow-up for other reasons, and 15 had acquired other contraindications to MRI, according to Dr. Traverse.
At 2 years, the remaining patients in both the cell therapy and placebo groups had roughly 5% absolute increases in LV ejection fraction from baseline and roughly 45% reductions in infarct size from baseline, with no significant differences between groups.
When all patients were combined, about half were determined to have had microvascular obstruction at baseline. This finding was an adverse prognostic factor, associated with poorer recovery of LV function over time, greater adverse LV remodeling, and a higher likelihood of receiving an ICD, Dr. Traverse reported.
He has received a research grant from the National Heart, Lung, and Blood Institute, which sponsored the TIME trial.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: At 2 years, differences in LV ejection fraction, infarct size, and end-diastolic volume index between the cell therapy and placebo groups remained nonsignificant.
Data source: TIME, a randomized, phase II trial of intracoronary delivery of autologous bone marrow mononuclear cells in 120 patients with ST-segment acute MI and LV dysfunction.
Disclosures: Dr. Traverse has received a research grant from the National Heart, Lung, and Blood Institute.
Lupus patients may be shortchanged on lipid management
WASHINGTON – Many patients with systemic lupus erythematosus may not be getting lipid testing or statin prescriptions despite having risk factors and even frank cardiovascular conditions, according to a large Medicaid database study presented at the annual meeting of the American College of Rheumatology.
The study found that systemic lupus erythematosus (SLE) patients were half as likely to get a lipid screening and 77% less likely to get a statin prescription, compared with patients with diabetes, a group that has a similarly elevated baseline CV disease risk.
This is concerning because it has been shown in several studies that SLE patients have higher rates of CV events than do age- and sex-matched patients with diabetes, and hyperlipidemia has been associated with CV disease in SLE patients. However, no studies have directly demonstrated reduced CV disease risk with statin use in SLE patients, unlike the general population and in those with diabetes, and so no clear guidelines exist, said lead study author Sarah Chen, MD, a rheumatology fellow at Brigham and Women’s Hospital, Boston.
Analyses of 1 year of billing records for each patient showed that SLE patients visited their doctor significantly more often than did the diabetes patients during their index year (mean of 4.7 vs. 3.2 visits). They were more likely to have a renal manifestation of their disease (13% vs. 4%). Although hypertension was similar among lupus and diabetes patients (35% vs. 40%), lupus patients were less likely to have hyperlipidemia (11% vs. 24%) but more likely to have concurrent cardiovascular disease, defined as angina, heart attack, atherosclerosis, percutaneous coronary intervention, coronary artery bypass grafting, stroke, or peripheral artery disease (13% vs. 10%).
Overall, 27% of lupus patients and 42% of diabetes patients had at least one lipid screen during their study year. This proportion stayed steady among diabetes patients as they aged, but rose significantly among lupus patients from 23% in the youngest group of 18-39 years to 32% of the oldest group of 50-65 years.
“This suggests that diabetes patients are getting consistent cardiovascular assessment as they age, while lupus patients are not,” Dr. Chen said at the meeting.
Statin prescriptions were also significantly less common among lupus patients overall (12% vs. 33%). The proportion of lupus patients who got at least one statin prescription increased with age, from 7% in the youngest group to 21% in the oldest group. But it increased more among diabetes patients, from 23% among the youngest to 42% among the oldest, Dr. Chen noted.
She conducted a multivariate analysis that controlled for age, gender, race, ethnicity, region of residence, socioeconomic status, Charlson Comorbidity Index, and the presence of cardiovascular disease. This determined that lupus patients were 54% less likely to have lipid testing and 77% less likely to get a statin.
A subanalysis found some significant predictors of SLE patients’ receipt of lipid screening. Increasing age increased the odds of screening by 2% per year. Lipid screening was 6% more likely for each additional medication they took. Lupus patients with nephritis were 36% more likely to have a screening than were those without nephritis. Those with existing cardiovascular disease were 11% more likely to have a test than were those without it, although this odds ratio (OR) had a nonsignificant 95% confidence interval of 1.00-1.24.
Hispanic and Asian patients were significantly more likely to receive lipid testing than were whites.
A second subanalysis found significant predictors of lupus patients receiving a statin prescription among lupus patients. With every passing year, the chance of getting a statin increased by 5%; it also increased by 7% for every medication that a patient was taking. Being a male increased the likelihood of receiving a statin prescription by 23%. Lupus nephritis more than doubled the odds of getting a statin (OR, 2.34), and the presence of cardiovascular disease was a similarly strong predictor (OR, 1.95). Hispanics and Asians were more likely to get the medication than were whites.
One significant limitation of the study is a lack of results on lipid testing, particularly in light of the potential effect the results might have had on decisions to prescribe statins.
Dr. Chen had no financial disclosures. The study was supported by a grant from the National Institutes of Health.
[email protected]
On Twitter @alz_gal
WASHINGTON – Many patients with systemic lupus erythematosus may not be getting lipid testing or statin prescriptions despite having risk factors and even frank cardiovascular conditions, according to a large Medicaid database study presented at the annual meeting of the American College of Rheumatology.
The study found that systemic lupus erythematosus (SLE) patients were half as likely to get a lipid screening and 77% less likely to get a statin prescription, compared with patients with diabetes, a group that has a similarly elevated baseline CV disease risk.
This is concerning because it has been shown in several studies that SLE patients have higher rates of CV events than do age- and sex-matched patients with diabetes, and hyperlipidemia has been associated with CV disease in SLE patients. However, no studies have directly demonstrated reduced CV disease risk with statin use in SLE patients, unlike the general population and in those with diabetes, and so no clear guidelines exist, said lead study author Sarah Chen, MD, a rheumatology fellow at Brigham and Women’s Hospital, Boston.
Analyses of 1 year of billing records for each patient showed that SLE patients visited their doctor significantly more often than did the diabetes patients during their index year (mean of 4.7 vs. 3.2 visits). They were more likely to have a renal manifestation of their disease (13% vs. 4%). Although hypertension was similar among lupus and diabetes patients (35% vs. 40%), lupus patients were less likely to have hyperlipidemia (11% vs. 24%) but more likely to have concurrent cardiovascular disease, defined as angina, heart attack, atherosclerosis, percutaneous coronary intervention, coronary artery bypass grafting, stroke, or peripheral artery disease (13% vs. 10%).
Overall, 27% of lupus patients and 42% of diabetes patients had at least one lipid screen during their study year. This proportion stayed steady among diabetes patients as they aged, but rose significantly among lupus patients from 23% in the youngest group of 18-39 years to 32% of the oldest group of 50-65 years.
“This suggests that diabetes patients are getting consistent cardiovascular assessment as they age, while lupus patients are not,” Dr. Chen said at the meeting.
Statin prescriptions were also significantly less common among lupus patients overall (12% vs. 33%). The proportion of lupus patients who got at least one statin prescription increased with age, from 7% in the youngest group to 21% in the oldest group. But it increased more among diabetes patients, from 23% among the youngest to 42% among the oldest, Dr. Chen noted.
She conducted a multivariate analysis that controlled for age, gender, race, ethnicity, region of residence, socioeconomic status, Charlson Comorbidity Index, and the presence of cardiovascular disease. This determined that lupus patients were 54% less likely to have lipid testing and 77% less likely to get a statin.
A subanalysis found some significant predictors of SLE patients’ receipt of lipid screening. Increasing age increased the odds of screening by 2% per year. Lipid screening was 6% more likely for each additional medication they took. Lupus patients with nephritis were 36% more likely to have a screening than were those without nephritis. Those with existing cardiovascular disease were 11% more likely to have a test than were those without it, although this odds ratio (OR) had a nonsignificant 95% confidence interval of 1.00-1.24.
Hispanic and Asian patients were significantly more likely to receive lipid testing than were whites.
A second subanalysis found significant predictors of lupus patients receiving a statin prescription among lupus patients. With every passing year, the chance of getting a statin increased by 5%; it also increased by 7% for every medication that a patient was taking. Being a male increased the likelihood of receiving a statin prescription by 23%. Lupus nephritis more than doubled the odds of getting a statin (OR, 2.34), and the presence of cardiovascular disease was a similarly strong predictor (OR, 1.95). Hispanics and Asians were more likely to get the medication than were whites.
One significant limitation of the study is a lack of results on lipid testing, particularly in light of the potential effect the results might have had on decisions to prescribe statins.
Dr. Chen had no financial disclosures. The study was supported by a grant from the National Institutes of Health.
[email protected]
On Twitter @alz_gal
WASHINGTON – Many patients with systemic lupus erythematosus may not be getting lipid testing or statin prescriptions despite having risk factors and even frank cardiovascular conditions, according to a large Medicaid database study presented at the annual meeting of the American College of Rheumatology.
The study found that systemic lupus erythematosus (SLE) patients were half as likely to get a lipid screening and 77% less likely to get a statin prescription, compared with patients with diabetes, a group that has a similarly elevated baseline CV disease risk.
This is concerning because it has been shown in several studies that SLE patients have higher rates of CV events than do age- and sex-matched patients with diabetes, and hyperlipidemia has been associated with CV disease in SLE patients. However, no studies have directly demonstrated reduced CV disease risk with statin use in SLE patients, unlike the general population and in those with diabetes, and so no clear guidelines exist, said lead study author Sarah Chen, MD, a rheumatology fellow at Brigham and Women’s Hospital, Boston.
Analyses of 1 year of billing records for each patient showed that SLE patients visited their doctor significantly more often than did the diabetes patients during their index year (mean of 4.7 vs. 3.2 visits). They were more likely to have a renal manifestation of their disease (13% vs. 4%). Although hypertension was similar among lupus and diabetes patients (35% vs. 40%), lupus patients were less likely to have hyperlipidemia (11% vs. 24%) but more likely to have concurrent cardiovascular disease, defined as angina, heart attack, atherosclerosis, percutaneous coronary intervention, coronary artery bypass grafting, stroke, or peripheral artery disease (13% vs. 10%).
Overall, 27% of lupus patients and 42% of diabetes patients had at least one lipid screen during their study year. This proportion stayed steady among diabetes patients as they aged, but rose significantly among lupus patients from 23% in the youngest group of 18-39 years to 32% of the oldest group of 50-65 years.
“This suggests that diabetes patients are getting consistent cardiovascular assessment as they age, while lupus patients are not,” Dr. Chen said at the meeting.
Statin prescriptions were also significantly less common among lupus patients overall (12% vs. 33%). The proportion of lupus patients who got at least one statin prescription increased with age, from 7% in the youngest group to 21% in the oldest group. But it increased more among diabetes patients, from 23% among the youngest to 42% among the oldest, Dr. Chen noted.
She conducted a multivariate analysis that controlled for age, gender, race, ethnicity, region of residence, socioeconomic status, Charlson Comorbidity Index, and the presence of cardiovascular disease. This determined that lupus patients were 54% less likely to have lipid testing and 77% less likely to get a statin.
A subanalysis found some significant predictors of SLE patients’ receipt of lipid screening. Increasing age increased the odds of screening by 2% per year. Lipid screening was 6% more likely for each additional medication they took. Lupus patients with nephritis were 36% more likely to have a screening than were those without nephritis. Those with existing cardiovascular disease were 11% more likely to have a test than were those without it, although this odds ratio (OR) had a nonsignificant 95% confidence interval of 1.00-1.24.
Hispanic and Asian patients were significantly more likely to receive lipid testing than were whites.
A second subanalysis found significant predictors of lupus patients receiving a statin prescription among lupus patients. With every passing year, the chance of getting a statin increased by 5%; it also increased by 7% for every medication that a patient was taking. Being a male increased the likelihood of receiving a statin prescription by 23%. Lupus nephritis more than doubled the odds of getting a statin (OR, 2.34), and the presence of cardiovascular disease was a similarly strong predictor (OR, 1.95). Hispanics and Asians were more likely to get the medication than were whites.
One significant limitation of the study is a lack of results on lipid testing, particularly in light of the potential effect the results might have had on decisions to prescribe statins.
Dr. Chen had no financial disclosures. The study was supported by a grant from the National Institutes of Health.
[email protected]
On Twitter @alz_gal
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: Lupus patients were 54% less likely to have lipid level testing and 77% less likely to have a statin prescribed than were diabetes patients.
Data source: A Medicaid database review comprising nearly 20,000 lupus patients and 40,000 diabetes patients during 2007-2010.
Disclosures: Dr. Chen had no financial disclosures. The study was supported by a grant from the National Institutes of Health.
Tocilizumab raises cholesterol, but not cardiovascular events
WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.
Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.
“This has been a lingering question,” he said. “These data are very reassuring. Practitioners can feel comfortable that they’re not inducing harm with this drug in patients with high cardiovascular risk. Now when we’re evaluating RA patients for the best drug, we can make a choice based on other parameters ... how the patient wants to take the drug, for example, or other safety indicators. This study takes away one element of uncertainty.”
Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.
The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.
They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.
The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.
By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.
In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.
The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.
Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.
“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”
Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.
[email protected]
On Twitter @alz_gal
WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.
Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.
“This has been a lingering question,” he said. “These data are very reassuring. Practitioners can feel comfortable that they’re not inducing harm with this drug in patients with high cardiovascular risk. Now when we’re evaluating RA patients for the best drug, we can make a choice based on other parameters ... how the patient wants to take the drug, for example, or other safety indicators. This study takes away one element of uncertainty.”
Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.
The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.
They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.
The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.
By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.
In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.
The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.
Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.
“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”
Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.
[email protected]
On Twitter @alz_gal
WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.
Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.
“This has been a lingering question,” he said. “These data are very reassuring. Practitioners can feel comfortable that they’re not inducing harm with this drug in patients with high cardiovascular risk. Now when we’re evaluating RA patients for the best drug, we can make a choice based on other parameters ... how the patient wants to take the drug, for example, or other safety indicators. This study takes away one element of uncertainty.”
Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.
The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.
They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.
The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.
By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.
In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.
The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.
Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.
“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”
Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.
[email protected]
On Twitter @alz_gal
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: LDL-cholesterol levels rose by almost 12% in the tocilizumab group, but there was no corresponding increase in cardiovascular events.
Data source: ENTRACTE, which randomized 3,080 patients with RA to either tocilizumab or etanercept.
Disclosures: Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.