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Effective monitoring of DMTs for multiple sclerosis can be tricky
NEW ORLEANS – Safety and efficacy laboratory monitoring of adherence to disease-modifying therapies for multiple sclerosis remains challenging, results from a small pilot study showed.
In an effort to determine if select patients on specific DMTs are receiving appropriate and adequate monitoring as outlined by each DMT’s internal guidance document, Felecia Hart, PharmD, and her associates retrospectively reviewed existing patients treated for MS at the Rocky Mountain Multiple Sclerosis Center at the University of Colorado, Denver, between June 1, 2013, and June 1, 2016.
“What we wanted to know was, if patients are getting their infusions or lab work done elsewhere, are we properly documenting it and keeping track of it?” Dr. Hart said in an interview at the meeting. “We’re not looking for core outcomes yet.”
Dr. Hart, a clinical pharmacy neurology fellow at the Skaggs School of Pharmacy and Pharmaceutical Sciences on the University of Colorado Anschutz Medical Campus, reported preliminary results from 50 patients treated with natalizumab and 50 treated with fingolimod. Among those treated with natalizumab, 49 had vitamin D measured within 6 months of drug initiation, 49 had a complete blood count measured within 1 year of drug initiation, and 49 had a comprehensive metabolic panel (CMP) measured within 1 year of drug initiation. “Interestingly, the absent CBC and CMP were from different patients,” she said.
Among patients treated with fingolimod, all had CBC/CMP measured within 1 year of drug initiation, 48 had vitamin D measured within 6 months of drug initiation, and 47 had documented macular optical coherence tomography at baseline, but the proportion of patients who had adequate documentation for other recommended assessments declined significantly. For example, only 19 of 50 had a documented repeat echocardiography within 3 months of drug initiation. Also, several baseline measurements required prior to drug initiation were documented poorly or in an untimely manner. Four patients had their HIV-1 and -2 antibody measured after drug initiation, three had hepatitis B virus surface antigen measured after drug initiation, and three had varicella measured after drug initiation.
Even though the MS center has an electronic medical record system, Dr. Hart and her associates found it difficult to obtain and monitor the parameters of interest. “I’ve been working with our EMR for 6 years, so I know how to navigate it well,” she said. “But I found it difficult to do a simple chart review and find what I wanted to. We have a labs tab in our chart, but the difficulty became including patients who were coming from outside of our center. The lab and the order were referenced in a note but there was never any documentation after that. There are too many holes in getting it documented correctly.”
The findings suggest that having a dedicated clinician such as a clinical pharmacist to oversee pharmacovigilance may improve patient outcomes and ensure that safety and efficacy monitoring doesn’t inadvertently get overlooked because of difficulties with adequate documentation. “That would be ideal,” Dr. Hart said.
She reported having no financial disclosures.
NEW ORLEANS – Safety and efficacy laboratory monitoring of adherence to disease-modifying therapies for multiple sclerosis remains challenging, results from a small pilot study showed.
In an effort to determine if select patients on specific DMTs are receiving appropriate and adequate monitoring as outlined by each DMT’s internal guidance document, Felecia Hart, PharmD, and her associates retrospectively reviewed existing patients treated for MS at the Rocky Mountain Multiple Sclerosis Center at the University of Colorado, Denver, between June 1, 2013, and June 1, 2016.
“What we wanted to know was, if patients are getting their infusions or lab work done elsewhere, are we properly documenting it and keeping track of it?” Dr. Hart said in an interview at the meeting. “We’re not looking for core outcomes yet.”
Dr. Hart, a clinical pharmacy neurology fellow at the Skaggs School of Pharmacy and Pharmaceutical Sciences on the University of Colorado Anschutz Medical Campus, reported preliminary results from 50 patients treated with natalizumab and 50 treated with fingolimod. Among those treated with natalizumab, 49 had vitamin D measured within 6 months of drug initiation, 49 had a complete blood count measured within 1 year of drug initiation, and 49 had a comprehensive metabolic panel (CMP) measured within 1 year of drug initiation. “Interestingly, the absent CBC and CMP were from different patients,” she said.
Among patients treated with fingolimod, all had CBC/CMP measured within 1 year of drug initiation, 48 had vitamin D measured within 6 months of drug initiation, and 47 had documented macular optical coherence tomography at baseline, but the proportion of patients who had adequate documentation for other recommended assessments declined significantly. For example, only 19 of 50 had a documented repeat echocardiography within 3 months of drug initiation. Also, several baseline measurements required prior to drug initiation were documented poorly or in an untimely manner. Four patients had their HIV-1 and -2 antibody measured after drug initiation, three had hepatitis B virus surface antigen measured after drug initiation, and three had varicella measured after drug initiation.
Even though the MS center has an electronic medical record system, Dr. Hart and her associates found it difficult to obtain and monitor the parameters of interest. “I’ve been working with our EMR for 6 years, so I know how to navigate it well,” she said. “But I found it difficult to do a simple chart review and find what I wanted to. We have a labs tab in our chart, but the difficulty became including patients who were coming from outside of our center. The lab and the order were referenced in a note but there was never any documentation after that. There are too many holes in getting it documented correctly.”
The findings suggest that having a dedicated clinician such as a clinical pharmacist to oversee pharmacovigilance may improve patient outcomes and ensure that safety and efficacy monitoring doesn’t inadvertently get overlooked because of difficulties with adequate documentation. “That would be ideal,” Dr. Hart said.
She reported having no financial disclosures.
NEW ORLEANS – Safety and efficacy laboratory monitoring of adherence to disease-modifying therapies for multiple sclerosis remains challenging, results from a small pilot study showed.
In an effort to determine if select patients on specific DMTs are receiving appropriate and adequate monitoring as outlined by each DMT’s internal guidance document, Felecia Hart, PharmD, and her associates retrospectively reviewed existing patients treated for MS at the Rocky Mountain Multiple Sclerosis Center at the University of Colorado, Denver, between June 1, 2013, and June 1, 2016.
“What we wanted to know was, if patients are getting their infusions or lab work done elsewhere, are we properly documenting it and keeping track of it?” Dr. Hart said in an interview at the meeting. “We’re not looking for core outcomes yet.”
Dr. Hart, a clinical pharmacy neurology fellow at the Skaggs School of Pharmacy and Pharmaceutical Sciences on the University of Colorado Anschutz Medical Campus, reported preliminary results from 50 patients treated with natalizumab and 50 treated with fingolimod. Among those treated with natalizumab, 49 had vitamin D measured within 6 months of drug initiation, 49 had a complete blood count measured within 1 year of drug initiation, and 49 had a comprehensive metabolic panel (CMP) measured within 1 year of drug initiation. “Interestingly, the absent CBC and CMP were from different patients,” she said.
Among patients treated with fingolimod, all had CBC/CMP measured within 1 year of drug initiation, 48 had vitamin D measured within 6 months of drug initiation, and 47 had documented macular optical coherence tomography at baseline, but the proportion of patients who had adequate documentation for other recommended assessments declined significantly. For example, only 19 of 50 had a documented repeat echocardiography within 3 months of drug initiation. Also, several baseline measurements required prior to drug initiation were documented poorly or in an untimely manner. Four patients had their HIV-1 and -2 antibody measured after drug initiation, three had hepatitis B virus surface antigen measured after drug initiation, and three had varicella measured after drug initiation.
Even though the MS center has an electronic medical record system, Dr. Hart and her associates found it difficult to obtain and monitor the parameters of interest. “I’ve been working with our EMR for 6 years, so I know how to navigate it well,” she said. “But I found it difficult to do a simple chart review and find what I wanted to. We have a labs tab in our chart, but the difficulty became including patients who were coming from outside of our center. The lab and the order were referenced in a note but there was never any documentation after that. There are too many holes in getting it documented correctly.”
The findings suggest that having a dedicated clinician such as a clinical pharmacist to oversee pharmacovigilance may improve patient outcomes and ensure that safety and efficacy monitoring doesn’t inadvertently get overlooked because of difficulties with adequate documentation. “That would be ideal,” Dr. Hart said.
She reported having no financial disclosures.
AT THE CMSC ANNUAL MEETING
Key clinical point:
Major finding: Among patients treated with fingolimod, only 19 of 50 had a documented repeat ECG within 3 months of drug initiation. Also, several baseline measurements required prior to drug initiation were documented poorly or in an untimely manner.
Data source: Preliminary results from a retrospective review of 50 patients treated with natalizumab and 50 treated with fingolimod.
Disclosures: Dr. Hart reported having no financial disclosures.
Lactulose plus albumin is more effective than lactulose alone for treatment of hepatic encephalopathy
Clinical Question: Is the combination of lactulose plus albumin more effective than lactulose alone for treatment of hepatic encephalopathy?
Background: Hepatic encephalopathy is caused by the effect of toxins that build up in the bloodstream when the liver is not able to perform its normal functions. Lactulose is primarily directed at the reduction of blood ammonia levels. Albumin is thought to minimize oxidative injury and improve circulatory dysfunction present in cirrhosis.
Setting: Tertiary care centers in India.
Synopsis: 120 patients with overt hepatic encephalopathy were randomized to treatment with lactulose plus albumin (1.5 gm/kg/day; n = 60), versus lactulose alone (n = 60). Patients with serum creatinine greater than 1.5 mg/dL on admission, active alcohol intake less than 4 weeks prior to presentation, other metabolic encephalopathies, or hepatocellular carcinoma were excluded. Treatment was continued up to a maximum of 10 days until complete resolution of hepatic encephalopathy as assessed independently by two expert hepatologists.
Of patients receiving lactulose plus albumin, 75% had complete reversal of hepatic encephalopathy within 10 days, compared with 53% of patients receiving lactulose alone (P = .03). Patients in lactulose plus albumin group had shorter hospital length-of-stay (6.4 vs. 8.6 days; P = .01). There was lower mortality at 10 days in the lactulose plus albumin group (18.3% vs. 31.6%; P = .04).
Limitations of the study include the noted exclusion factors, including presence of alcohol intake, limitation to a single country (India), and a relatively high mortality rate in both groups.
Bottom Line: Combination of lactulose plus albumin is more effective than lactulose alone at reversing hepatic encephalopathy and is also associated with decreased length-of-stay and mortality.
Reference: Sharma BC, Singh J, Srivastava S, et al. A randomized controlled trial comparing lactulose plus albumin with lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol. Published online Nov 25, 2016. doi: 10.1111/jgh.13666.
Dr. Huang is associate clinical professor in the division of hospital medicine, department of medicine, University of California, San Diego.
Clinical Question: Is the combination of lactulose plus albumin more effective than lactulose alone for treatment of hepatic encephalopathy?
Background: Hepatic encephalopathy is caused by the effect of toxins that build up in the bloodstream when the liver is not able to perform its normal functions. Lactulose is primarily directed at the reduction of blood ammonia levels. Albumin is thought to minimize oxidative injury and improve circulatory dysfunction present in cirrhosis.
Setting: Tertiary care centers in India.
Synopsis: 120 patients with overt hepatic encephalopathy were randomized to treatment with lactulose plus albumin (1.5 gm/kg/day; n = 60), versus lactulose alone (n = 60). Patients with serum creatinine greater than 1.5 mg/dL on admission, active alcohol intake less than 4 weeks prior to presentation, other metabolic encephalopathies, or hepatocellular carcinoma were excluded. Treatment was continued up to a maximum of 10 days until complete resolution of hepatic encephalopathy as assessed independently by two expert hepatologists.
Of patients receiving lactulose plus albumin, 75% had complete reversal of hepatic encephalopathy within 10 days, compared with 53% of patients receiving lactulose alone (P = .03). Patients in lactulose plus albumin group had shorter hospital length-of-stay (6.4 vs. 8.6 days; P = .01). There was lower mortality at 10 days in the lactulose plus albumin group (18.3% vs. 31.6%; P = .04).
Limitations of the study include the noted exclusion factors, including presence of alcohol intake, limitation to a single country (India), and a relatively high mortality rate in both groups.
Bottom Line: Combination of lactulose plus albumin is more effective than lactulose alone at reversing hepatic encephalopathy and is also associated with decreased length-of-stay and mortality.
Reference: Sharma BC, Singh J, Srivastava S, et al. A randomized controlled trial comparing lactulose plus albumin with lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol. Published online Nov 25, 2016. doi: 10.1111/jgh.13666.
Dr. Huang is associate clinical professor in the division of hospital medicine, department of medicine, University of California, San Diego.
Clinical Question: Is the combination of lactulose plus albumin more effective than lactulose alone for treatment of hepatic encephalopathy?
Background: Hepatic encephalopathy is caused by the effect of toxins that build up in the bloodstream when the liver is not able to perform its normal functions. Lactulose is primarily directed at the reduction of blood ammonia levels. Albumin is thought to minimize oxidative injury and improve circulatory dysfunction present in cirrhosis.
Setting: Tertiary care centers in India.
Synopsis: 120 patients with overt hepatic encephalopathy were randomized to treatment with lactulose plus albumin (1.5 gm/kg/day; n = 60), versus lactulose alone (n = 60). Patients with serum creatinine greater than 1.5 mg/dL on admission, active alcohol intake less than 4 weeks prior to presentation, other metabolic encephalopathies, or hepatocellular carcinoma were excluded. Treatment was continued up to a maximum of 10 days until complete resolution of hepatic encephalopathy as assessed independently by two expert hepatologists.
Of patients receiving lactulose plus albumin, 75% had complete reversal of hepatic encephalopathy within 10 days, compared with 53% of patients receiving lactulose alone (P = .03). Patients in lactulose plus albumin group had shorter hospital length-of-stay (6.4 vs. 8.6 days; P = .01). There was lower mortality at 10 days in the lactulose plus albumin group (18.3% vs. 31.6%; P = .04).
Limitations of the study include the noted exclusion factors, including presence of alcohol intake, limitation to a single country (India), and a relatively high mortality rate in both groups.
Bottom Line: Combination of lactulose plus albumin is more effective than lactulose alone at reversing hepatic encephalopathy and is also associated with decreased length-of-stay and mortality.
Reference: Sharma BC, Singh J, Srivastava S, et al. A randomized controlled trial comparing lactulose plus albumin with lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol. Published online Nov 25, 2016. doi: 10.1111/jgh.13666.
Dr. Huang is associate clinical professor in the division of hospital medicine, department of medicine, University of California, San Diego.
VIDEO: Hyperinflammatory ARDS responds to simvastatin
WASHINGTON – Acute respiratory distress syndrome (ARDS) appears to exist in at least two major forms, and one of these, the hyperinflammatory form, seemed responsive to simvastatin in a post-hoc analysis of trial data.
The other version of ARDs is a hypoinflammatory form, which occurred in 70% of ARDS patients in most of the analyses that have been done.
Researchers classified the 540 ARDS patients enrolled in a 2014 study of simvastatin as either hyperinflammatory or hypoinflammatory. Separating out the hyperinflammatory patients created a subclass that responded to simvastatin, with a 13% absolute reduction in mortality during follow-up, compared with no response among patients in the hypoinflammatory group, Carolyn S. Calfee, MD, said at an international conference of the American Thoracic Society.
“Hyperinflammatory patients treated with simvastatin may have improved outcomes, compared with hypoinflammatory* patients treated with placebo,” said Dr. Calfee, a pulmonologist at the University of California, San Francisco.
The finding raises the possibility that simvastatin, as well as other statins, may be an effective treatment for selected patients with ARDS, but proving this requires new prospective, randomized trials in hyperinflammatory patients, Dr. Calfee said in a video interview.
Currently, the tests Dr. Calfee uses to distinguish hyperinflammatory and hypoinflammatory ARDS patients take about 6-8 hours to complete. A “point of care test to stratify patients in real time,” is needed to further study the various forms of ARDs, Dr. Calfee noted. A critical next step would be the development of a “practical, rapid, bedside assay” to ease identification of hyperinflammatory ARDS patients. “The work we’ve done prior seems to indicate that we are going to definitely need to measure biomarkers in order to identity these subgroups,” she noted.
Hypoinflammatory patients also merit study, she added. Although hyperinflammatory patients have significant worse mortality rates, the hypoinflammatory subclass includes about 70% of ARDS patients, “so we need to better understand how to potentially treat this group.”
Dr. Calfee and her associates first reported finding the two ARDS subclasses, what they also call subphenotypes or endotypes, in two separate cohorts of ARDS patients in a 2014 report (Lancet Resp Med. 2014 Aug;2[8]:611-20). Then, they confirmed the finding in a third ARDS cohort in a 2017 report (Amer J Resp Crit Care Med. 2017 Feb 1;195[3]:331-8). These reports have documented other characteristics of the hyperinflammatory ARDS subclass: hypotension, metabolic acidosis, more frequent treatment with vasopressors, and a higher prevalence of sepsis and shock. Concurrent with the 2017 report, an editorial hailed the finding as “the dawn of personalized medicine for ARDS” (Amer J resp Crit Care Med. 2017 Feb 1;195[3]: 280-1).
To build on this, Dr. Calfee and her associates applied their method for identifying ARDS subclasses to a different cohort of 540 patients enrolled in the The HARP (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction)–2 study, a multicenter UK and Irish study designed to test the efficacy of daily simvastatin treatment in a heterogeneous group of ARDS patients. A 2014 report of the study’s primary results showed no significant effect from simvastatin for increasing the number of ventilator-free days nor did the drug improve any other measured efficacy endpoints (New Engl J Med. 2014 Oct 30;371[18]:1695-703).
Applying a statistical analysis called “latent class analysis,” which is designed to recognize subclass groupings that might not be readily apparent, Dr. Calfee and her team first confirmed that, in this fourth cohort, the ARDS patients again split into a hyperinflammatory subclass, in this case including 188 (35%) of the cohort, and a hypoinflammatory subclass with 352 (65%) patients. The next step was to see what impact simvastatin treatment had in each of the two patient subclasses. They focused the analysis on a secondary outcome in HARP-2, 28-day survival.
They found that simvastatin produced no significant difference in 28-day survival, compared with placebo among the hypoinflammatory patients, but, in the hyperinflammatory subclass, 28-day survival was 68% for patients on simvastatin and 55% for those on placebo, a statistically significant difference, Dr. Calfee reported (Am J Resp Crit Care Med. 2017;195:A6749).
“I’m excited that we are seeing, for the first time, a different response to pharmacotherapy” after dividing ARDS patients into these two subclasses, she said. But, the work remains in an early stage, she cautioned. “We need to test treatments [like statins] prospectively.” The new finding for simvastatin “is not the same as showing benefit in a prospective, randomized trial.”
In the meantime, Dr. Calfee plans to apply the same analytic approach to data collected in another failed statin trial in ARDS patients, the SAILS trial. That study failed to show benefit from rosuvastatin treatment in an unselected population of patients with sepsis-associated ARDS (New Engl J Med. 2014 June 5;370[23]:2191-200).
Dr. Calfee is a consultant to Bayer, Boehringer Ingelheim, and GlaxoSmithKline. She received research funding from GlaxoSmithKline.
[email protected]
On Twitter @mitchelzoler
*An earlier version of this article misquoted Dr. Calfee.
WASHINGTON – Acute respiratory distress syndrome (ARDS) appears to exist in at least two major forms, and one of these, the hyperinflammatory form, seemed responsive to simvastatin in a post-hoc analysis of trial data.
The other version of ARDs is a hypoinflammatory form, which occurred in 70% of ARDS patients in most of the analyses that have been done.
Researchers classified the 540 ARDS patients enrolled in a 2014 study of simvastatin as either hyperinflammatory or hypoinflammatory. Separating out the hyperinflammatory patients created a subclass that responded to simvastatin, with a 13% absolute reduction in mortality during follow-up, compared with no response among patients in the hypoinflammatory group, Carolyn S. Calfee, MD, said at an international conference of the American Thoracic Society.
“Hyperinflammatory patients treated with simvastatin may have improved outcomes, compared with hypoinflammatory* patients treated with placebo,” said Dr. Calfee, a pulmonologist at the University of California, San Francisco.
The finding raises the possibility that simvastatin, as well as other statins, may be an effective treatment for selected patients with ARDS, but proving this requires new prospective, randomized trials in hyperinflammatory patients, Dr. Calfee said in a video interview.
Currently, the tests Dr. Calfee uses to distinguish hyperinflammatory and hypoinflammatory ARDS patients take about 6-8 hours to complete. A “point of care test to stratify patients in real time,” is needed to further study the various forms of ARDs, Dr. Calfee noted. A critical next step would be the development of a “practical, rapid, bedside assay” to ease identification of hyperinflammatory ARDS patients. “The work we’ve done prior seems to indicate that we are going to definitely need to measure biomarkers in order to identity these subgroups,” she noted.
Hypoinflammatory patients also merit study, she added. Although hyperinflammatory patients have significant worse mortality rates, the hypoinflammatory subclass includes about 70% of ARDS patients, “so we need to better understand how to potentially treat this group.”
Dr. Calfee and her associates first reported finding the two ARDS subclasses, what they also call subphenotypes or endotypes, in two separate cohorts of ARDS patients in a 2014 report (Lancet Resp Med. 2014 Aug;2[8]:611-20). Then, they confirmed the finding in a third ARDS cohort in a 2017 report (Amer J Resp Crit Care Med. 2017 Feb 1;195[3]:331-8). These reports have documented other characteristics of the hyperinflammatory ARDS subclass: hypotension, metabolic acidosis, more frequent treatment with vasopressors, and a higher prevalence of sepsis and shock. Concurrent with the 2017 report, an editorial hailed the finding as “the dawn of personalized medicine for ARDS” (Amer J resp Crit Care Med. 2017 Feb 1;195[3]: 280-1).
To build on this, Dr. Calfee and her associates applied their method for identifying ARDS subclasses to a different cohort of 540 patients enrolled in the The HARP (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction)–2 study, a multicenter UK and Irish study designed to test the efficacy of daily simvastatin treatment in a heterogeneous group of ARDS patients. A 2014 report of the study’s primary results showed no significant effect from simvastatin for increasing the number of ventilator-free days nor did the drug improve any other measured efficacy endpoints (New Engl J Med. 2014 Oct 30;371[18]:1695-703).
Applying a statistical analysis called “latent class analysis,” which is designed to recognize subclass groupings that might not be readily apparent, Dr. Calfee and her team first confirmed that, in this fourth cohort, the ARDS patients again split into a hyperinflammatory subclass, in this case including 188 (35%) of the cohort, and a hypoinflammatory subclass with 352 (65%) patients. The next step was to see what impact simvastatin treatment had in each of the two patient subclasses. They focused the analysis on a secondary outcome in HARP-2, 28-day survival.
They found that simvastatin produced no significant difference in 28-day survival, compared with placebo among the hypoinflammatory patients, but, in the hyperinflammatory subclass, 28-day survival was 68% for patients on simvastatin and 55% for those on placebo, a statistically significant difference, Dr. Calfee reported (Am J Resp Crit Care Med. 2017;195:A6749).
“I’m excited that we are seeing, for the first time, a different response to pharmacotherapy” after dividing ARDS patients into these two subclasses, she said. But, the work remains in an early stage, she cautioned. “We need to test treatments [like statins] prospectively.” The new finding for simvastatin “is not the same as showing benefit in a prospective, randomized trial.”
In the meantime, Dr. Calfee plans to apply the same analytic approach to data collected in another failed statin trial in ARDS patients, the SAILS trial. That study failed to show benefit from rosuvastatin treatment in an unselected population of patients with sepsis-associated ARDS (New Engl J Med. 2014 June 5;370[23]:2191-200).
Dr. Calfee is a consultant to Bayer, Boehringer Ingelheim, and GlaxoSmithKline. She received research funding from GlaxoSmithKline.
[email protected]
On Twitter @mitchelzoler
*An earlier version of this article misquoted Dr. Calfee.
WASHINGTON – Acute respiratory distress syndrome (ARDS) appears to exist in at least two major forms, and one of these, the hyperinflammatory form, seemed responsive to simvastatin in a post-hoc analysis of trial data.
The other version of ARDs is a hypoinflammatory form, which occurred in 70% of ARDS patients in most of the analyses that have been done.
Researchers classified the 540 ARDS patients enrolled in a 2014 study of simvastatin as either hyperinflammatory or hypoinflammatory. Separating out the hyperinflammatory patients created a subclass that responded to simvastatin, with a 13% absolute reduction in mortality during follow-up, compared with no response among patients in the hypoinflammatory group, Carolyn S. Calfee, MD, said at an international conference of the American Thoracic Society.
“Hyperinflammatory patients treated with simvastatin may have improved outcomes, compared with hypoinflammatory* patients treated with placebo,” said Dr. Calfee, a pulmonologist at the University of California, San Francisco.
The finding raises the possibility that simvastatin, as well as other statins, may be an effective treatment for selected patients with ARDS, but proving this requires new prospective, randomized trials in hyperinflammatory patients, Dr. Calfee said in a video interview.
Currently, the tests Dr. Calfee uses to distinguish hyperinflammatory and hypoinflammatory ARDS patients take about 6-8 hours to complete. A “point of care test to stratify patients in real time,” is needed to further study the various forms of ARDs, Dr. Calfee noted. A critical next step would be the development of a “practical, rapid, bedside assay” to ease identification of hyperinflammatory ARDS patients. “The work we’ve done prior seems to indicate that we are going to definitely need to measure biomarkers in order to identity these subgroups,” she noted.
Hypoinflammatory patients also merit study, she added. Although hyperinflammatory patients have significant worse mortality rates, the hypoinflammatory subclass includes about 70% of ARDS patients, “so we need to better understand how to potentially treat this group.”
Dr. Calfee and her associates first reported finding the two ARDS subclasses, what they also call subphenotypes or endotypes, in two separate cohorts of ARDS patients in a 2014 report (Lancet Resp Med. 2014 Aug;2[8]:611-20). Then, they confirmed the finding in a third ARDS cohort in a 2017 report (Amer J Resp Crit Care Med. 2017 Feb 1;195[3]:331-8). These reports have documented other characteristics of the hyperinflammatory ARDS subclass: hypotension, metabolic acidosis, more frequent treatment with vasopressors, and a higher prevalence of sepsis and shock. Concurrent with the 2017 report, an editorial hailed the finding as “the dawn of personalized medicine for ARDS” (Amer J resp Crit Care Med. 2017 Feb 1;195[3]: 280-1).
To build on this, Dr. Calfee and her associates applied their method for identifying ARDS subclasses to a different cohort of 540 patients enrolled in the The HARP (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction)–2 study, a multicenter UK and Irish study designed to test the efficacy of daily simvastatin treatment in a heterogeneous group of ARDS patients. A 2014 report of the study’s primary results showed no significant effect from simvastatin for increasing the number of ventilator-free days nor did the drug improve any other measured efficacy endpoints (New Engl J Med. 2014 Oct 30;371[18]:1695-703).
Applying a statistical analysis called “latent class analysis,” which is designed to recognize subclass groupings that might not be readily apparent, Dr. Calfee and her team first confirmed that, in this fourth cohort, the ARDS patients again split into a hyperinflammatory subclass, in this case including 188 (35%) of the cohort, and a hypoinflammatory subclass with 352 (65%) patients. The next step was to see what impact simvastatin treatment had in each of the two patient subclasses. They focused the analysis on a secondary outcome in HARP-2, 28-day survival.
They found that simvastatin produced no significant difference in 28-day survival, compared with placebo among the hypoinflammatory patients, but, in the hyperinflammatory subclass, 28-day survival was 68% for patients on simvastatin and 55% for those on placebo, a statistically significant difference, Dr. Calfee reported (Am J Resp Crit Care Med. 2017;195:A6749).
“I’m excited that we are seeing, for the first time, a different response to pharmacotherapy” after dividing ARDS patients into these two subclasses, she said. But, the work remains in an early stage, she cautioned. “We need to test treatments [like statins] prospectively.” The new finding for simvastatin “is not the same as showing benefit in a prospective, randomized trial.”
In the meantime, Dr. Calfee plans to apply the same analytic approach to data collected in another failed statin trial in ARDS patients, the SAILS trial. That study failed to show benefit from rosuvastatin treatment in an unselected population of patients with sepsis-associated ARDS (New Engl J Med. 2014 June 5;370[23]:2191-200).
Dr. Calfee is a consultant to Bayer, Boehringer Ingelheim, and GlaxoSmithKline. She received research funding from GlaxoSmithKline.
[email protected]
On Twitter @mitchelzoler
*An earlier version of this article misquoted Dr. Calfee.
AT ATS 2017
Key clinical point:
Major finding: Among hyperinflammatory ARDS patients, 28-day survival was 68% with simvastatin and 55% with placebo, a statistically significant difference.
Data source: A post-hoc analysis of a multicenter randomized trial of 540 patients.
Disclosures: Dr. Calfee is a consultant to Bayer, Boehringer Ingelheim, and GlaxoSmithKline. She received research funding from GlaxoSmithKline.
Coexisting Autoimmune Disorders May Influence Clinical Outcomes in MS
NEW ORLEANS—Patients with multiple sclerosis (MS) had increased rates of in-hospital mortality and discharge to nursing facilities, compared with patients with MS plus a coexisting autoimmune disorder, according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. 
“The findings in this study suggest that a coexisting autoimmune disorder may in fact lessen the severity of the immune dysregulation of MS, which leads to improved health outcomes,” said Malik M. Adil, MD, a neurology resident at the Ochsner Clinic Foundation in New Orleans, and colleagues.
Studies have suggested an association between MS and autoimmune disorders, but research concerning clinical outcomes is limited. To determine whether coexisting autoimmune disorders affect outcomes in patients with MS, Dr. Adil and colleagues analyzed Nationwide Inpatient Survey data files from 2006 to 2010. The researchers classified patients with MS into two groups: an MS group (without coexisting autoimmune disorders) and an MS Plus group (with coexisting autoimmune disorders).
The investigators then compared the rate of clinical outcomes (ie, in-hospital mortality, discharge to home, discharge to nursing facilities, length of stay, and total charges) between the MS and MS Plus groups. Dr. Adil and colleagues used multivariate analysis to adjust for potential confounders when assessing in-hospital outcomes.
Of 115,120 patients with MS, 18,796 were in the MS Plus group. The adjusted odds of in-hospital mortality and of discharge to nursing facilities were significantly higher in the MS group, compared with the MS Plus group (odds ratios, 4.67 and 1.16, respectively). Length of stay and mean hospital charges were significantly higher in the MS Plus group, compared with the MS group.
A possible explanation for the findings is that coexisting autoimmune diseases involve different effector T cells that may regulate the effect of other effector T cells, said the authors. “Other possible explanations of better outcome in the MS Plus group might be the use of chronic immune suppressive agents in addition to MS immunotherapy, and multidisciplinary management,” they added.
NEW ORLEANS—Patients with multiple sclerosis (MS) had increased rates of in-hospital mortality and discharge to nursing facilities, compared with patients with MS plus a coexisting autoimmune disorder, according to research presented at the 31st Annual Meeting of the Consortium of MS Centers.
“The findings in this study suggest that a coexisting autoimmune disorder may in fact lessen the severity of the immune dysregulation of MS, which leads to improved health outcomes,” said Malik M. Adil, MD, a neurology resident at the Ochsner Clinic Foundation in New Orleans, and colleagues.
Studies have suggested an association between MS and autoimmune disorders, but research concerning clinical outcomes is limited. To determine whether coexisting autoimmune disorders affect outcomes in patients with MS, Dr. Adil and colleagues analyzed Nationwide Inpatient Survey data files from 2006 to 2010. The researchers classified patients with MS into two groups: an MS group (without coexisting autoimmune disorders) and an MS Plus group (with coexisting autoimmune disorders).
The investigators then compared the rate of clinical outcomes (ie, in-hospital mortality, discharge to home, discharge to nursing facilities, length of stay, and total charges) between the MS and MS Plus groups. Dr. Adil and colleagues used multivariate analysis to adjust for potential confounders when assessing in-hospital outcomes.
Of 115,120 patients with MS, 18,796 were in the MS Plus group. The adjusted odds of in-hospital mortality and of discharge to nursing facilities were significantly higher in the MS group, compared with the MS Plus group (odds ratios, 4.67 and 1.16, respectively). Length of stay and mean hospital charges were significantly higher in the MS Plus group, compared with the MS group.
A possible explanation for the findings is that coexisting autoimmune diseases involve different effector T cells that may regulate the effect of other effector T cells, said the authors. “Other possible explanations of better outcome in the MS Plus group might be the use of chronic immune suppressive agents in addition to MS immunotherapy, and multidisciplinary management,” they added.
NEW ORLEANS—Patients with multiple sclerosis (MS) had increased rates of in-hospital mortality and discharge to nursing facilities, compared with patients with MS plus a coexisting autoimmune disorder, according to research presented at the 31st Annual Meeting of the Consortium of MS Centers.
“The findings in this study suggest that a coexisting autoimmune disorder may in fact lessen the severity of the immune dysregulation of MS, which leads to improved health outcomes,” said Malik M. Adil, MD, a neurology resident at the Ochsner Clinic Foundation in New Orleans, and colleagues.
Studies have suggested an association between MS and autoimmune disorders, but research concerning clinical outcomes is limited. To determine whether coexisting autoimmune disorders affect outcomes in patients with MS, Dr. Adil and colleagues analyzed Nationwide Inpatient Survey data files from 2006 to 2010. The researchers classified patients with MS into two groups: an MS group (without coexisting autoimmune disorders) and an MS Plus group (with coexisting autoimmune disorders).
The investigators then compared the rate of clinical outcomes (ie, in-hospital mortality, discharge to home, discharge to nursing facilities, length of stay, and total charges) between the MS and MS Plus groups. Dr. Adil and colleagues used multivariate analysis to adjust for potential confounders when assessing in-hospital outcomes.
Of 115,120 patients with MS, 18,796 were in the MS Plus group. The adjusted odds of in-hospital mortality and of discharge to nursing facilities were significantly higher in the MS group, compared with the MS Plus group (odds ratios, 4.67 and 1.16, respectively). Length of stay and mean hospital charges were significantly higher in the MS Plus group, compared with the MS group.
A possible explanation for the findings is that coexisting autoimmune diseases involve different effector T cells that may regulate the effect of other effector T cells, said the authors. “Other possible explanations of better outcome in the MS Plus group might be the use of chronic immune suppressive agents in addition to MS immunotherapy, and multidisciplinary management,” they added.
Caffeine therapy of VLBW neonates reduces later motor impairment
SAN FRANCISCO – The 11-year follow-up results of the Caffeine for Apnea of Prematurity randomized, placebo-controlled trial has established the benefits of methylated xanthine therapy in the form of caffeine for very-low-birth-weight (VLBW) neonates in lessening the risk of motor impairment.
“The latest findings bolster the value of caffeine therapy to address apnea of prematurity in VLBW neonates. The CAP trial has provided compelling evidence for the use of caffeine even before this latest finding of improved motor function at age 11 years,” said presenter and the CAP trial’s principal investigator Barbara Schmidt, MD, of McMaster University, Hamilton, Ont.
At least 5 of every 1,000 live-born babies are very premature with a VLBW. Up of 40% die or survive with lasting disabilities. One cause of mortality or disability is apnea. Apnea can be lessened by treatment with methylxanthines such as caffeine, she noted. However, at the time the CAP trial began, it was unclear whether the therapy posed a danger by worsening the damage caused by lack of oxygen.
“Very few studies have followed more recent cohorts of very preterm infants to middle school age. Therefore, it was difficult to anticipate actual rates of functional impairment, and the possible effect of caffeine on those rates,” said Dr. Schmidt.
As reported about a decade ago, the CAP trial involving VLBW infants randomized to caffeine therapy or placebo established the short-term safety and effectiveness of the therapy in terms of reducing cerebral palsy and cognitive delay (N Engl J Med. 2007;357:1893-902).
Follow-ups at 18 months and 5 years revealed the benefits of caffeine therapy in reducing the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability. The present follow-up data assessed academic performance, motor function, and behavior in 1,202 children with a median age of 11 years. Of these, 602 had received caffeine therapy and 600 had been randomized to the placebo group. Data at age 11 years was available for 457 and 463 of the children randomized to caffeine therapy or placebo, respectively.
The primary outcome was functional impairment, which was indicated by at least one of poor academic performance (with at least one standard score more than two standard deviations below the mean on the Wide Range Achievement Test, 4th edition), motor impairment (percentile rank of 5 or less on the Movement Assessment Battery for Children, Second Edition), and behavior problems (Total Problem T score more than two standard deviations above the mean on the Child Behavior Checklist).
Functional impairment was evident in 145 the 457 (32%) children who had received caffeine therapy and 174 of the 463 (38%) who had not. The rates of 32% and 38% were statistically similar (P = .07). In the individual functional outcomes, the caffeine and placebo groups also were similar in terms of poor academic performance (14% vs. 13%; P = .58) and behavior (11% vs. 8%, respectively; P = .22).
However, caffeine therapy was associated with a reduced risk of motor impairment at age 11 years, compared with those in the placebo group (20% vs. 28%, respectively; odds ratio [OR], 0.66; 95% confidence interval [CI], 0.48-0.90; P = .009). The number of children needed to treat to lessen motor impairment in one child was 13 (95% CI, 8-42).
“Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments at age 11 years. However, caffeine therapy reduced the risk of motor impairment 11 years later,” said Dr. Schmidt. Whether caffeine therapy using higher doses or longer treatment duration is equally risk free is uncertain and further studies, which are not planned, would be needed, she said.
These 11-year follow-up findings of the CAP trial were published online in JAMA Pediatrics (2017, Apr 24. doi: 10.1001/jamapediatrics.2017.0238).
The sponsor of study was McMaster University. The study was funded by the Canadian Institutes of Health Research and the National Health and Medical Research Council of Australia. Dr. Schmidt had no relevant financial disclosures to report.
SAN FRANCISCO – The 11-year follow-up results of the Caffeine for Apnea of Prematurity randomized, placebo-controlled trial has established the benefits of methylated xanthine therapy in the form of caffeine for very-low-birth-weight (VLBW) neonates in lessening the risk of motor impairment.
“The latest findings bolster the value of caffeine therapy to address apnea of prematurity in VLBW neonates. The CAP trial has provided compelling evidence for the use of caffeine even before this latest finding of improved motor function at age 11 years,” said presenter and the CAP trial’s principal investigator Barbara Schmidt, MD, of McMaster University, Hamilton, Ont.
At least 5 of every 1,000 live-born babies are very premature with a VLBW. Up of 40% die or survive with lasting disabilities. One cause of mortality or disability is apnea. Apnea can be lessened by treatment with methylxanthines such as caffeine, she noted. However, at the time the CAP trial began, it was unclear whether the therapy posed a danger by worsening the damage caused by lack of oxygen.
“Very few studies have followed more recent cohorts of very preterm infants to middle school age. Therefore, it was difficult to anticipate actual rates of functional impairment, and the possible effect of caffeine on those rates,” said Dr. Schmidt.
As reported about a decade ago, the CAP trial involving VLBW infants randomized to caffeine therapy or placebo established the short-term safety and effectiveness of the therapy in terms of reducing cerebral palsy and cognitive delay (N Engl J Med. 2007;357:1893-902).
Follow-ups at 18 months and 5 years revealed the benefits of caffeine therapy in reducing the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability. The present follow-up data assessed academic performance, motor function, and behavior in 1,202 children with a median age of 11 years. Of these, 602 had received caffeine therapy and 600 had been randomized to the placebo group. Data at age 11 years was available for 457 and 463 of the children randomized to caffeine therapy or placebo, respectively.
The primary outcome was functional impairment, which was indicated by at least one of poor academic performance (with at least one standard score more than two standard deviations below the mean on the Wide Range Achievement Test, 4th edition), motor impairment (percentile rank of 5 or less on the Movement Assessment Battery for Children, Second Edition), and behavior problems (Total Problem T score more than two standard deviations above the mean on the Child Behavior Checklist).
Functional impairment was evident in 145 the 457 (32%) children who had received caffeine therapy and 174 of the 463 (38%) who had not. The rates of 32% and 38% were statistically similar (P = .07). In the individual functional outcomes, the caffeine and placebo groups also were similar in terms of poor academic performance (14% vs. 13%; P = .58) and behavior (11% vs. 8%, respectively; P = .22).
However, caffeine therapy was associated with a reduced risk of motor impairment at age 11 years, compared with those in the placebo group (20% vs. 28%, respectively; odds ratio [OR], 0.66; 95% confidence interval [CI], 0.48-0.90; P = .009). The number of children needed to treat to lessen motor impairment in one child was 13 (95% CI, 8-42).
“Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments at age 11 years. However, caffeine therapy reduced the risk of motor impairment 11 years later,” said Dr. Schmidt. Whether caffeine therapy using higher doses or longer treatment duration is equally risk free is uncertain and further studies, which are not planned, would be needed, she said.
These 11-year follow-up findings of the CAP trial were published online in JAMA Pediatrics (2017, Apr 24. doi: 10.1001/jamapediatrics.2017.0238).
The sponsor of study was McMaster University. The study was funded by the Canadian Institutes of Health Research and the National Health and Medical Research Council of Australia. Dr. Schmidt had no relevant financial disclosures to report.
SAN FRANCISCO – The 11-year follow-up results of the Caffeine for Apnea of Prematurity randomized, placebo-controlled trial has established the benefits of methylated xanthine therapy in the form of caffeine for very-low-birth-weight (VLBW) neonates in lessening the risk of motor impairment.
“The latest findings bolster the value of caffeine therapy to address apnea of prematurity in VLBW neonates. The CAP trial has provided compelling evidence for the use of caffeine even before this latest finding of improved motor function at age 11 years,” said presenter and the CAP trial’s principal investigator Barbara Schmidt, MD, of McMaster University, Hamilton, Ont.
At least 5 of every 1,000 live-born babies are very premature with a VLBW. Up of 40% die or survive with lasting disabilities. One cause of mortality or disability is apnea. Apnea can be lessened by treatment with methylxanthines such as caffeine, she noted. However, at the time the CAP trial began, it was unclear whether the therapy posed a danger by worsening the damage caused by lack of oxygen.
“Very few studies have followed more recent cohorts of very preterm infants to middle school age. Therefore, it was difficult to anticipate actual rates of functional impairment, and the possible effect of caffeine on those rates,” said Dr. Schmidt.
As reported about a decade ago, the CAP trial involving VLBW infants randomized to caffeine therapy or placebo established the short-term safety and effectiveness of the therapy in terms of reducing cerebral palsy and cognitive delay (N Engl J Med. 2007;357:1893-902).
Follow-ups at 18 months and 5 years revealed the benefits of caffeine therapy in reducing the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability. The present follow-up data assessed academic performance, motor function, and behavior in 1,202 children with a median age of 11 years. Of these, 602 had received caffeine therapy and 600 had been randomized to the placebo group. Data at age 11 years was available for 457 and 463 of the children randomized to caffeine therapy or placebo, respectively.
The primary outcome was functional impairment, which was indicated by at least one of poor academic performance (with at least one standard score more than two standard deviations below the mean on the Wide Range Achievement Test, 4th edition), motor impairment (percentile rank of 5 or less on the Movement Assessment Battery for Children, Second Edition), and behavior problems (Total Problem T score more than two standard deviations above the mean on the Child Behavior Checklist).
Functional impairment was evident in 145 the 457 (32%) children who had received caffeine therapy and 174 of the 463 (38%) who had not. The rates of 32% and 38% were statistically similar (P = .07). In the individual functional outcomes, the caffeine and placebo groups also were similar in terms of poor academic performance (14% vs. 13%; P = .58) and behavior (11% vs. 8%, respectively; P = .22).
However, caffeine therapy was associated with a reduced risk of motor impairment at age 11 years, compared with those in the placebo group (20% vs. 28%, respectively; odds ratio [OR], 0.66; 95% confidence interval [CI], 0.48-0.90; P = .009). The number of children needed to treat to lessen motor impairment in one child was 13 (95% CI, 8-42).
“Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments at age 11 years. However, caffeine therapy reduced the risk of motor impairment 11 years later,” said Dr. Schmidt. Whether caffeine therapy using higher doses or longer treatment duration is equally risk free is uncertain and further studies, which are not planned, would be needed, she said.
These 11-year follow-up findings of the CAP trial were published online in JAMA Pediatrics (2017, Apr 24. doi: 10.1001/jamapediatrics.2017.0238).
The sponsor of study was McMaster University. The study was funded by the Canadian Institutes of Health Research and the National Health and Medical Research Council of Australia. Dr. Schmidt had no relevant financial disclosures to report.
AT PAS 17
Key clinical point:
Major finding: At the 11-year follow-up, motor impairment was identified in 20% of those who received caffeine therapy versus 28% of those in the placebo group (P = .009).
Data source: Multicenter, randomized, placebo-controlled trial (NCT00182312).
Disclosures: The sponsor of study was McMaster University. The study was funded by the Canadian Institutes of Health Research and the National Health and Medical Research Council of Australia. Dr. Schmidt had no relevant financial disclosures to report.
FDA approves Rebinyn for hemophilia B treatment
The Food and Drug Administration has approved Rebinyn (nonacog beta pegol, N9-GP) for the treatment of hemophilia B, according to a statement from Novo Nordisk.
Caused by deficient blood clotting factor IX activity, hemophilia B affects about 5,000 people in the United States. The disease is chronic and inherited and causes prolonged and spontaneous bleeding, particularly into muscles, joints, or internal organs. Rebinyn is intended to control and treat bleeding episodes, as well as provide perioperative management of bleeding.
Find the full statement about Rebinyn’s approval on the Novo Nordisk website.
The Food and Drug Administration has approved Rebinyn (nonacog beta pegol, N9-GP) for the treatment of hemophilia B, according to a statement from Novo Nordisk.
Caused by deficient blood clotting factor IX activity, hemophilia B affects about 5,000 people in the United States. The disease is chronic and inherited and causes prolonged and spontaneous bleeding, particularly into muscles, joints, or internal organs. Rebinyn is intended to control and treat bleeding episodes, as well as provide perioperative management of bleeding.
Find the full statement about Rebinyn’s approval on the Novo Nordisk website.
The Food and Drug Administration has approved Rebinyn (nonacog beta pegol, N9-GP) for the treatment of hemophilia B, according to a statement from Novo Nordisk.
Caused by deficient blood clotting factor IX activity, hemophilia B affects about 5,000 people in the United States. The disease is chronic and inherited and causes prolonged and spontaneous bleeding, particularly into muscles, joints, or internal organs. Rebinyn is intended to control and treat bleeding episodes, as well as provide perioperative management of bleeding.
Find the full statement about Rebinyn’s approval on the Novo Nordisk website.
Adenomyosis increasingly is a concern
“WHY ARE THERE DELAYS IN THE DIAGNOSIS OF ENDOMETRIOSIS?”
ROBERT L. BARBIERI, MD (EDITORIAL; MARCH 2017)
Adenomyosis increasingly is a concern
Dr. Barbieri’s article on delay in diagnosis of endometriosis is timely and important. I agree that family history is very important, but often the mother had a hysterectomy at a relatively young age for heavy bleeding that was blamed on fibroids.
Adenomyosis seems to be increasing in prevalence and may be suggested by cystic changes in the endometrium on 3D ultrasonography. The patient often reports dark brown spotting before or after periods. The second day of the period is very heavy, and cramping may precede the period. Sometimes you can note punctate lesions on the cervix that cause a very friable cervix that is likely to bleed after the patient has coitus or a Pap smear. Adenomyosis may cause much of the troublesome bleeding seen after medroxyprogesterone acetate injection, insertion of a levonorgestrel-containing intrauterine device, etonogestrel implant placement, and even birth control pills, and it is often dismissed as dysfunctional uterine bleeding. The dark brown blood may represent blood exiting the crypts of the endometrium.
It is concerning that patients who are treated aggressively for adenomyosis in order to get pregnant seem to be at increased risk for retained placenta and decreased uterine tone in the third stage of labor. Certainly this makes intuitive sense if one surmises that the endometrium is abnormally deep into the myometrium, allowing for microscopic placental invasion and myometrial dysfunction.
Most troubling is the warning from the public health community regarding endocrine disruptors. Could BPA (bisphenol A) be contaminating our plastic water bottles and be causing an epidemic of younger-onset adenomyosis? It is certainly something worth studying.
John Lewis, MD
Waterbury, Connecticut
Endometriosis patients receive delayed diagnosis, ineffective treatments
Several points came to mind reading Dr. Barbieri’s article. First, with the surge in deep infiltrating endometriosis as reported in the literature, one has to ask about treating mild disease with hormones initially. Disease can and does progress with hormonal suppression, I assume because endometriosis makes its own estrogen. Yet when the surge is noticed, the recommendation, at least in Europe, is that we should look at pollution.
Second, I have to wonder why it is not reported that older women have endometriosis. I manage a 20,000-member education board for endometriosis patients and many of those seeking help are older and often already castrated. When I can find them access to advanced surgical skill, they are found to have active endometriosis.
The patients seeking more information (gaining 300 a week) have failed all that gynecology has to offer except expert surgical excision of their disease. In my view, gynecology in general has failed this patient population. I have worked with endometriosis patients for 32 years, and 75% of them have been dismissed as neurotic, with average time to diagnosis 9 years after symptoms appear.
It seems that the symptom profile found in endometriosis patients is not well known, and once the disease is diagnosed, the treatment options are ineffective.
Nancy Petersen, RN
Portland, Oregon
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
“WHY ARE THERE DELAYS IN THE DIAGNOSIS OF ENDOMETRIOSIS?”
ROBERT L. BARBIERI, MD (EDITORIAL; MARCH 2017)
Adenomyosis increasingly is a concern
Dr. Barbieri’s article on delay in diagnosis of endometriosis is timely and important. I agree that family history is very important, but often the mother had a hysterectomy at a relatively young age for heavy bleeding that was blamed on fibroids.
Adenomyosis seems to be increasing in prevalence and may be suggested by cystic changes in the endometrium on 3D ultrasonography. The patient often reports dark brown spotting before or after periods. The second day of the period is very heavy, and cramping may precede the period. Sometimes you can note punctate lesions on the cervix that cause a very friable cervix that is likely to bleed after the patient has coitus or a Pap smear. Adenomyosis may cause much of the troublesome bleeding seen after medroxyprogesterone acetate injection, insertion of a levonorgestrel-containing intrauterine device, etonogestrel implant placement, and even birth control pills, and it is often dismissed as dysfunctional uterine bleeding. The dark brown blood may represent blood exiting the crypts of the endometrium.
It is concerning that patients who are treated aggressively for adenomyosis in order to get pregnant seem to be at increased risk for retained placenta and decreased uterine tone in the third stage of labor. Certainly this makes intuitive sense if one surmises that the endometrium is abnormally deep into the myometrium, allowing for microscopic placental invasion and myometrial dysfunction.
Most troubling is the warning from the public health community regarding endocrine disruptors. Could BPA (bisphenol A) be contaminating our plastic water bottles and be causing an epidemic of younger-onset adenomyosis? It is certainly something worth studying.
John Lewis, MD
Waterbury, Connecticut
Endometriosis patients receive delayed diagnosis, ineffective treatments
Several points came to mind reading Dr. Barbieri’s article. First, with the surge in deep infiltrating endometriosis as reported in the literature, one has to ask about treating mild disease with hormones initially. Disease can and does progress with hormonal suppression, I assume because endometriosis makes its own estrogen. Yet when the surge is noticed, the recommendation, at least in Europe, is that we should look at pollution.
Second, I have to wonder why it is not reported that older women have endometriosis. I manage a 20,000-member education board for endometriosis patients and many of those seeking help are older and often already castrated. When I can find them access to advanced surgical skill, they are found to have active endometriosis.
The patients seeking more information (gaining 300 a week) have failed all that gynecology has to offer except expert surgical excision of their disease. In my view, gynecology in general has failed this patient population. I have worked with endometriosis patients for 32 years, and 75% of them have been dismissed as neurotic, with average time to diagnosis 9 years after symptoms appear.
It seems that the symptom profile found in endometriosis patients is not well known, and once the disease is diagnosed, the treatment options are ineffective.
Nancy Petersen, RN
Portland, Oregon
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
“WHY ARE THERE DELAYS IN THE DIAGNOSIS OF ENDOMETRIOSIS?”
ROBERT L. BARBIERI, MD (EDITORIAL; MARCH 2017)
Adenomyosis increasingly is a concern
Dr. Barbieri’s article on delay in diagnosis of endometriosis is timely and important. I agree that family history is very important, but often the mother had a hysterectomy at a relatively young age for heavy bleeding that was blamed on fibroids.
Adenomyosis seems to be increasing in prevalence and may be suggested by cystic changes in the endometrium on 3D ultrasonography. The patient often reports dark brown spotting before or after periods. The second day of the period is very heavy, and cramping may precede the period. Sometimes you can note punctate lesions on the cervix that cause a very friable cervix that is likely to bleed after the patient has coitus or a Pap smear. Adenomyosis may cause much of the troublesome bleeding seen after medroxyprogesterone acetate injection, insertion of a levonorgestrel-containing intrauterine device, etonogestrel implant placement, and even birth control pills, and it is often dismissed as dysfunctional uterine bleeding. The dark brown blood may represent blood exiting the crypts of the endometrium.
It is concerning that patients who are treated aggressively for adenomyosis in order to get pregnant seem to be at increased risk for retained placenta and decreased uterine tone in the third stage of labor. Certainly this makes intuitive sense if one surmises that the endometrium is abnormally deep into the myometrium, allowing for microscopic placental invasion and myometrial dysfunction.
Most troubling is the warning from the public health community regarding endocrine disruptors. Could BPA (bisphenol A) be contaminating our plastic water bottles and be causing an epidemic of younger-onset adenomyosis? It is certainly something worth studying.
John Lewis, MD
Waterbury, Connecticut
Endometriosis patients receive delayed diagnosis, ineffective treatments
Several points came to mind reading Dr. Barbieri’s article. First, with the surge in deep infiltrating endometriosis as reported in the literature, one has to ask about treating mild disease with hormones initially. Disease can and does progress with hormonal suppression, I assume because endometriosis makes its own estrogen. Yet when the surge is noticed, the recommendation, at least in Europe, is that we should look at pollution.
Second, I have to wonder why it is not reported that older women have endometriosis. I manage a 20,000-member education board for endometriosis patients and many of those seeking help are older and often already castrated. When I can find them access to advanced surgical skill, they are found to have active endometriosis.
The patients seeking more information (gaining 300 a week) have failed all that gynecology has to offer except expert surgical excision of their disease. In my view, gynecology in general has failed this patient population. I have worked with endometriosis patients for 32 years, and 75% of them have been dismissed as neurotic, with average time to diagnosis 9 years after symptoms appear.
It seems that the symptom profile found in endometriosis patients is not well known, and once the disease is diagnosed, the treatment options are ineffective.
Nancy Petersen, RN
Portland, Oregon
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Drainage, irrigation, and fibrinolytic therapy held safe, effective for PHVD
SAN FRANCISCO – The 10-year follow-up of neonates treated for posthemorrhagic ventricular dilatation (PHVD) has demonstrated the long-term success of drainage, irrigation, and fibrinolytic therapy (DRIFT), with a cognitive advantage in the now school-age children evident, compared with those neonates who had not received the therapy.
“Children in the DRIFT group had a 23-point cognitive quotient advantage and were nine times more likely to be alive without severe cognitive disability at 10 years,” presenter and DRIFT investigator Karen Luyt, MBChB, PhD, of the University of Bristol and St. Michael’s Hospital, Bristol, England, said at the Pediatric Academic Societies meeting.
PHVD carries a high risk of disabilities in cognition and movement. DRIFT was developed as a way to wash out the ventricles in the brain to clear the effects of bleeding, with the goal of reducing neurodevelopmental disability. In the technique, catheters are inserted into the affected ventricles and are used to deliver an anti-clotting agent (alteplase) and to drain the bloody fluid. The catheters remain in place for a time as a conduit for artificial cerebrospinal fluid (CSF) containing antibiotics.
In the DRIFT trial, 77 preterm infants were randomized to DRIFT (n = 39) or the standard treatment of siphoning off cerebrospinal fluid to restrict brain expansion (n = 38). At 2 years, the DRIFT group displayed fewer cases of severe disability and cognitive disability, and death (Pediatrics. 2010 Apr;125[4]:e852-8).
Dr. Luyt summarized the final 10-year data from 52 school-age children (28 treated using DRIFT and 24 treated in the standard manner). The primary outcomes in the school-age children were cognitive quotient (CQ) and survival without severe cognitive disability. Secondary outcomes included visual function, sensory and motor disabilities, and emotional or behavior problems.
The age at the time of treatment randomization was 19 days in the DRIFT group and 19 days in the standard group. The DRIFT group was composed of more males (79% vs. 63%) and newborns with lower birth weight (336 vs. 535 grams). The gestational age and the prevalence of grade 4 intraventricular hemorrhage were similar between the groups.
DRIFT increased cognitive ability at 10 years (P = .096). Adjustment for gender, birth weight, and grade of intraventricular hemorrhage strengthened this association, with the DRIFT group having an average advantage in CQ score of 23.5 points (P = .009), which translated to a 2.5-year advantage in cognitive ability. When the data was further adjusted by ruling out the three children (two in the DRIFT group and one in the standard treatment group) who died between the 2- and 10-year follow-ups, the CQ score advantage remained (20 points; P = .029).
The other primary outcome of survival without severe cognitive disability also favored DRIFT, with an unadjusted odds ratio (OR) of 3.3 (95% confidence interval [CI] 1.1-10.4 (P = .037) and adjusted (as above) OR of 8.9 (95% CI, 1.9-42.3; P = .006). Fewer children in the DRIFT group were attending schools with an expertise in special needs (OR, 0.27; 95% CI, 0.07-1.05; P = .059). No differences between the groups were evident for the secondary outcomes.
The number needed to treat to prevent death or severe cognitive disability was four.
Dr. Luyt’s recommendation that DRIFT become the standard of care for neonatal intraventricular hemorrhage comes with the caveat of increased secondary bleeding, which caused the trial to be halted after a planned external safety monitoring review. Children who already had been treated were followed up, with no further recruitment. In her response to a question from the audience regarding her endorsement of DRIFT despite the trial’s halt, Dr. Luyt pointed to the comparable safety profiles of the two groups, the superior outcomes in the DRIFT group, and the knowledge that modifications made to the technique in the intervening years have reduced the possibility of secondary bleeds.
The sponsor of study was Dr. Birgit Whitman of the University of Bristol. The study was funded by the National Institute of Health’s Health Technology Assessment Programme. Dr. Luyt disclosed the off-label use of alteplase.
SAN FRANCISCO – The 10-year follow-up of neonates treated for posthemorrhagic ventricular dilatation (PHVD) has demonstrated the long-term success of drainage, irrigation, and fibrinolytic therapy (DRIFT), with a cognitive advantage in the now school-age children evident, compared with those neonates who had not received the therapy.
“Children in the DRIFT group had a 23-point cognitive quotient advantage and were nine times more likely to be alive without severe cognitive disability at 10 years,” presenter and DRIFT investigator Karen Luyt, MBChB, PhD, of the University of Bristol and St. Michael’s Hospital, Bristol, England, said at the Pediatric Academic Societies meeting.
PHVD carries a high risk of disabilities in cognition and movement. DRIFT was developed as a way to wash out the ventricles in the brain to clear the effects of bleeding, with the goal of reducing neurodevelopmental disability. In the technique, catheters are inserted into the affected ventricles and are used to deliver an anti-clotting agent (alteplase) and to drain the bloody fluid. The catheters remain in place for a time as a conduit for artificial cerebrospinal fluid (CSF) containing antibiotics.
In the DRIFT trial, 77 preterm infants were randomized to DRIFT (n = 39) or the standard treatment of siphoning off cerebrospinal fluid to restrict brain expansion (n = 38). At 2 years, the DRIFT group displayed fewer cases of severe disability and cognitive disability, and death (Pediatrics. 2010 Apr;125[4]:e852-8).
Dr. Luyt summarized the final 10-year data from 52 school-age children (28 treated using DRIFT and 24 treated in the standard manner). The primary outcomes in the school-age children were cognitive quotient (CQ) and survival without severe cognitive disability. Secondary outcomes included visual function, sensory and motor disabilities, and emotional or behavior problems.
The age at the time of treatment randomization was 19 days in the DRIFT group and 19 days in the standard group. The DRIFT group was composed of more males (79% vs. 63%) and newborns with lower birth weight (336 vs. 535 grams). The gestational age and the prevalence of grade 4 intraventricular hemorrhage were similar between the groups.
DRIFT increased cognitive ability at 10 years (P = .096). Adjustment for gender, birth weight, and grade of intraventricular hemorrhage strengthened this association, with the DRIFT group having an average advantage in CQ score of 23.5 points (P = .009), which translated to a 2.5-year advantage in cognitive ability. When the data was further adjusted by ruling out the three children (two in the DRIFT group and one in the standard treatment group) who died between the 2- and 10-year follow-ups, the CQ score advantage remained (20 points; P = .029).
The other primary outcome of survival without severe cognitive disability also favored DRIFT, with an unadjusted odds ratio (OR) of 3.3 (95% confidence interval [CI] 1.1-10.4 (P = .037) and adjusted (as above) OR of 8.9 (95% CI, 1.9-42.3; P = .006). Fewer children in the DRIFT group were attending schools with an expertise in special needs (OR, 0.27; 95% CI, 0.07-1.05; P = .059). No differences between the groups were evident for the secondary outcomes.
The number needed to treat to prevent death or severe cognitive disability was four.
Dr. Luyt’s recommendation that DRIFT become the standard of care for neonatal intraventricular hemorrhage comes with the caveat of increased secondary bleeding, which caused the trial to be halted after a planned external safety monitoring review. Children who already had been treated were followed up, with no further recruitment. In her response to a question from the audience regarding her endorsement of DRIFT despite the trial’s halt, Dr. Luyt pointed to the comparable safety profiles of the two groups, the superior outcomes in the DRIFT group, and the knowledge that modifications made to the technique in the intervening years have reduced the possibility of secondary bleeds.
The sponsor of study was Dr. Birgit Whitman of the University of Bristol. The study was funded by the National Institute of Health’s Health Technology Assessment Programme. Dr. Luyt disclosed the off-label use of alteplase.
SAN FRANCISCO – The 10-year follow-up of neonates treated for posthemorrhagic ventricular dilatation (PHVD) has demonstrated the long-term success of drainage, irrigation, and fibrinolytic therapy (DRIFT), with a cognitive advantage in the now school-age children evident, compared with those neonates who had not received the therapy.
“Children in the DRIFT group had a 23-point cognitive quotient advantage and were nine times more likely to be alive without severe cognitive disability at 10 years,” presenter and DRIFT investigator Karen Luyt, MBChB, PhD, of the University of Bristol and St. Michael’s Hospital, Bristol, England, said at the Pediatric Academic Societies meeting.
PHVD carries a high risk of disabilities in cognition and movement. DRIFT was developed as a way to wash out the ventricles in the brain to clear the effects of bleeding, with the goal of reducing neurodevelopmental disability. In the technique, catheters are inserted into the affected ventricles and are used to deliver an anti-clotting agent (alteplase) and to drain the bloody fluid. The catheters remain in place for a time as a conduit for artificial cerebrospinal fluid (CSF) containing antibiotics.
In the DRIFT trial, 77 preterm infants were randomized to DRIFT (n = 39) or the standard treatment of siphoning off cerebrospinal fluid to restrict brain expansion (n = 38). At 2 years, the DRIFT group displayed fewer cases of severe disability and cognitive disability, and death (Pediatrics. 2010 Apr;125[4]:e852-8).
Dr. Luyt summarized the final 10-year data from 52 school-age children (28 treated using DRIFT and 24 treated in the standard manner). The primary outcomes in the school-age children were cognitive quotient (CQ) and survival without severe cognitive disability. Secondary outcomes included visual function, sensory and motor disabilities, and emotional or behavior problems.
The age at the time of treatment randomization was 19 days in the DRIFT group and 19 days in the standard group. The DRIFT group was composed of more males (79% vs. 63%) and newborns with lower birth weight (336 vs. 535 grams). The gestational age and the prevalence of grade 4 intraventricular hemorrhage were similar between the groups.
DRIFT increased cognitive ability at 10 years (P = .096). Adjustment for gender, birth weight, and grade of intraventricular hemorrhage strengthened this association, with the DRIFT group having an average advantage in CQ score of 23.5 points (P = .009), which translated to a 2.5-year advantage in cognitive ability. When the data was further adjusted by ruling out the three children (two in the DRIFT group and one in the standard treatment group) who died between the 2- and 10-year follow-ups, the CQ score advantage remained (20 points; P = .029).
The other primary outcome of survival without severe cognitive disability also favored DRIFT, with an unadjusted odds ratio (OR) of 3.3 (95% confidence interval [CI] 1.1-10.4 (P = .037) and adjusted (as above) OR of 8.9 (95% CI, 1.9-42.3; P = .006). Fewer children in the DRIFT group were attending schools with an expertise in special needs (OR, 0.27; 95% CI, 0.07-1.05; P = .059). No differences between the groups were evident for the secondary outcomes.
The number needed to treat to prevent death or severe cognitive disability was four.
Dr. Luyt’s recommendation that DRIFT become the standard of care for neonatal intraventricular hemorrhage comes with the caveat of increased secondary bleeding, which caused the trial to be halted after a planned external safety monitoring review. Children who already had been treated were followed up, with no further recruitment. In her response to a question from the audience regarding her endorsement of DRIFT despite the trial’s halt, Dr. Luyt pointed to the comparable safety profiles of the two groups, the superior outcomes in the DRIFT group, and the knowledge that modifications made to the technique in the intervening years have reduced the possibility of secondary bleeds.
The sponsor of study was Dr. Birgit Whitman of the University of Bristol. The study was funded by the National Institute of Health’s Health Technology Assessment Programme. Dr. Luyt disclosed the off-label use of alteplase.
AT PAS 17
Key clinical point: The 10-year follow-up data from the Drainage, Irrigation, and Fibrinolytic Therapy (DRIFT) study has confirmed the long-term safety and effectiveness of the intervention in treatment of preterm intraventricular hemorrhage.
Major finding: The DRIFT group had an average advantage in cognitive quotient score of 23.5 points (P = .009), translating to a 2.5 year advantage in cognitive ability.
Data source: Randomized controlled trial of 52 10-year-old children from the DRIFT study.
Disclosures: The sponsor of study was Dr. Birgit Whitman of the University of Bristol. The study was funded by the National Institute of Health’s Health Technology Assessment Programme. Dr. Luyt disclosed the off-label use of alteplase.
A Pathway to Full Practice Authority for Physician Assistants in the VA
On December 13, 2016, the VA announced a change in its medical regulations to permit full practice authority for all VA advanced practice registered nurses (APRNs) when they are acting within the scope of their VA employment.This amendment removed the stipulation requiring physician supervision or collaboration for APRNs. Many states across the U.S. have similar statutes for APRNs.
Not surprisingly, the regulatorychange was met with resistance fromof the physician establishment. “TheAmerican Medical Association (AMA) is disappointed by the Department of Veterans Affairs’ unprecedented proposal to allow advanced practice nurses within the VA to practice independently of a physician’s clinical oversight, regardless of individual state law,” Stephen R. Permut, MD, JD, AMA immediate past-chair wrote in a statement.
The American Academy of Physician Assistants (AAPA) then announced that it was “actively working with senior officials at the VA to institute a similar rule for PAs (physician assistants).” The well-intentioned AAPA statement seems misguided. It implies that PAs should be granted full practice authority because APRNs were granted the authority.
No matter the rational for granting APRNs full practice authority, the VA should not pursue similar regulations for PAs only because APRNs were granted the privilege. If the VA should institute a new amendment granting full practice authority to PAs, this action should be done independent of actions taken by any other nonphysician profession. Full practice authority for PAs should be based on training, clinical experience, and competency. Rather than adjusting the previously established threshold to obtain full practice authority to meet current PA standards, PAs should pursue further training and certification to earn this privilege. Physician assistant didactic and clinical training is based on the same model as training for medical doctors.
Physician assistant programs generally have 1 year of didactic training and 1 year of clinical training before trainees are eligible to take the Physician Assistant National Certifying Exam. Many schools, such as my alma mater, George Washington University School of Medicine, have PA students in the same lecture hall training side by side with medical students.
Medical doctor training generally includes 2 years of didactic training, 2 years of clinical training in medical school, and 3 years of clinical training in residency (for internal medicine) before trainees are eligible to take the American Board of Internal Medicine (ABIM) exam. The didactic training in PA programs mirrors that of medical doctor programs. The real difference in education and preparation is the duration of clinical training; 1 year of clinical training for PAs vs 5 years of clinical training for MDs.
Therefore, my suggestion would be that leaders within the PA profession should work with the ABIM to create a pathway in which PAs who work in the VA could take the ABIM exam after 4 years of clinical experience. If a PA employed by the VA passes the ABIM exam, they would be granted full practice authority within their scope of practice at the VA. This requirement would validate that these PAs warrant this privilege and subsequently satisfy physician concerns by showing that they have passed the same exam required of physicians. Moreover, this additional level of preparation and testing would increase the competency of PAs and the quality of care they provide to the veterans they serve.
On December 13, 2016, the VA announced a change in its medical regulations to permit full practice authority for all VA advanced practice registered nurses (APRNs) when they are acting within the scope of their VA employment.This amendment removed the stipulation requiring physician supervision or collaboration for APRNs. Many states across the U.S. have similar statutes for APRNs.
Not surprisingly, the regulatorychange was met with resistance fromof the physician establishment. “TheAmerican Medical Association (AMA) is disappointed by the Department of Veterans Affairs’ unprecedented proposal to allow advanced practice nurses within the VA to practice independently of a physician’s clinical oversight, regardless of individual state law,” Stephen R. Permut, MD, JD, AMA immediate past-chair wrote in a statement.
The American Academy of Physician Assistants (AAPA) then announced that it was “actively working with senior officials at the VA to institute a similar rule for PAs (physician assistants).” The well-intentioned AAPA statement seems misguided. It implies that PAs should be granted full practice authority because APRNs were granted the authority.
No matter the rational for granting APRNs full practice authority, the VA should not pursue similar regulations for PAs only because APRNs were granted the privilege. If the VA should institute a new amendment granting full practice authority to PAs, this action should be done independent of actions taken by any other nonphysician profession. Full practice authority for PAs should be based on training, clinical experience, and competency. Rather than adjusting the previously established threshold to obtain full practice authority to meet current PA standards, PAs should pursue further training and certification to earn this privilege. Physician assistant didactic and clinical training is based on the same model as training for medical doctors.
Physician assistant programs generally have 1 year of didactic training and 1 year of clinical training before trainees are eligible to take the Physician Assistant National Certifying Exam. Many schools, such as my alma mater, George Washington University School of Medicine, have PA students in the same lecture hall training side by side with medical students.
Medical doctor training generally includes 2 years of didactic training, 2 years of clinical training in medical school, and 3 years of clinical training in residency (for internal medicine) before trainees are eligible to take the American Board of Internal Medicine (ABIM) exam. The didactic training in PA programs mirrors that of medical doctor programs. The real difference in education and preparation is the duration of clinical training; 1 year of clinical training for PAs vs 5 years of clinical training for MDs.
Therefore, my suggestion would be that leaders within the PA profession should work with the ABIM to create a pathway in which PAs who work in the VA could take the ABIM exam after 4 years of clinical experience. If a PA employed by the VA passes the ABIM exam, they would be granted full practice authority within their scope of practice at the VA. This requirement would validate that these PAs warrant this privilege and subsequently satisfy physician concerns by showing that they have passed the same exam required of physicians. Moreover, this additional level of preparation and testing would increase the competency of PAs and the quality of care they provide to the veterans they serve.
On December 13, 2016, the VA announced a change in its medical regulations to permit full practice authority for all VA advanced practice registered nurses (APRNs) when they are acting within the scope of their VA employment.This amendment removed the stipulation requiring physician supervision or collaboration for APRNs. Many states across the U.S. have similar statutes for APRNs.
Not surprisingly, the regulatorychange was met with resistance fromof the physician establishment. “TheAmerican Medical Association (AMA) is disappointed by the Department of Veterans Affairs’ unprecedented proposal to allow advanced practice nurses within the VA to practice independently of a physician’s clinical oversight, regardless of individual state law,” Stephen R. Permut, MD, JD, AMA immediate past-chair wrote in a statement.
The American Academy of Physician Assistants (AAPA) then announced that it was “actively working with senior officials at the VA to institute a similar rule for PAs (physician assistants).” The well-intentioned AAPA statement seems misguided. It implies that PAs should be granted full practice authority because APRNs were granted the authority.
No matter the rational for granting APRNs full practice authority, the VA should not pursue similar regulations for PAs only because APRNs were granted the privilege. If the VA should institute a new amendment granting full practice authority to PAs, this action should be done independent of actions taken by any other nonphysician profession. Full practice authority for PAs should be based on training, clinical experience, and competency. Rather than adjusting the previously established threshold to obtain full practice authority to meet current PA standards, PAs should pursue further training and certification to earn this privilege. Physician assistant didactic and clinical training is based on the same model as training for medical doctors.
Physician assistant programs generally have 1 year of didactic training and 1 year of clinical training before trainees are eligible to take the Physician Assistant National Certifying Exam. Many schools, such as my alma mater, George Washington University School of Medicine, have PA students in the same lecture hall training side by side with medical students.
Medical doctor training generally includes 2 years of didactic training, 2 years of clinical training in medical school, and 3 years of clinical training in residency (for internal medicine) before trainees are eligible to take the American Board of Internal Medicine (ABIM) exam. The didactic training in PA programs mirrors that of medical doctor programs. The real difference in education and preparation is the duration of clinical training; 1 year of clinical training for PAs vs 5 years of clinical training for MDs.
Therefore, my suggestion would be that leaders within the PA profession should work with the ABIM to create a pathway in which PAs who work in the VA could take the ABIM exam after 4 years of clinical experience. If a PA employed by the VA passes the ABIM exam, they would be granted full practice authority within their scope of practice at the VA. This requirement would validate that these PAs warrant this privilege and subsequently satisfy physician concerns by showing that they have passed the same exam required of physicians. Moreover, this additional level of preparation and testing would increase the competency of PAs and the quality of care they provide to the veterans they serve.
Phase II Data Show Safety and Efficacy of Ozanimod for Relapsing MS
NEW ORLEANS—Ozanimod demonstrated durable efficacy with a favorable safety profile in patients continuing ozanimod for 120 weeks or switching from placebo to ozanimod for 96 weeks, according to results of a phase II study presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers. “These data support the ongoing RADIANCE and SUNBEAM phase III studies,” said Brett E. Skolnick, PhD, on behalf of his study collaborators. Dr. Skolnick is an employee of Receptos, a wholly owned subsidiary of Celgene, in San Diego. 
Ozanimod, an oral, once-daily immunomodulator selectively targeting sphingosine 1-phosphate (S1P) receptor-1 and -5 , is in development for relapsing multiple sclerosis (MS). “The increased receptor selectivity of ozanimod and additional pharmaceutical properties may result in a more favorable safety profile versus other nonselective and selective S1P receptor modulators,” said Dr. Skolnick.
In the completed RADIANCE Part A phase II trial, patients with relapsing MS were randomized (1:1:1) to once-daily ozanimod 0.5 mg or 1.0 mg or to placebo for 24 weeks. At week 24, patients could enter a 96-week, blinded extension phase. Patients randomized to ozanimod continued their assigned dose; 85 patients received 0.5 mg, and 81 patients received 1.0 mg. Patients administered placebo were re-randomized (1:1) to ozanimod 0.5 mg (n = 41) or 1.0 mg (n = 42). Ozanimod was dose-escalated over seven days to attenuate first-dose effects.
A total of 89% of patients taking the 0.5 mg dose and 90% of patients taking the 1.0 mg dose completed the extension study. At week 120, 89% to 91% of patients were free of gadolinium-enhancing lesions. Unadjusted annualized relapse rates were 0.31 in the 0.5 mg group and 0.18 in the 1.0 mg group. One or more treatment-emergent adverse events were seen in 79% of patients taking the 0.5 mg dose and in 76% of those taking the 1.0 mg dose. The most common adverse events were increased alanine aminotransferases, nasopharyngitis, and upper respiratory tract infection. Serious treatment-emergent adverse events were seen in 12 patients in the 0.5 mg group and in nine patients in the 1.0 mg group. Mild blunting of the normal diurnal heart rate was observed. The largest mean decrease in heart rate relative to pre-dose was 3.5 bpm at hour 6 on day 1, with no associated symptoms. No type II or 2:1 atrioventricular block was reported.
At week 120, alanine aminotransferase (ALT) levels were three or more times upper limit of normal in 6% of the 0.5 mg group and in 7% of the 1.0 mg group. In the 0.5 mg group, 2% of patients discontinued ozanimod due to increased liver transaminases. Less than 1% of patients in the 1.0 mg group discontinued ozanimod for the same reason. Between baseline and week 120, three patients in the 1.0 mg group had absolute lymphocyte counts below 200 cells/μL; none was associated with severe or serious infection. There were no notable cases of pulmonary adverse events and no cases of macular edema, malignancy-related adverse events, or serious opportunistic infections.
This study was supported by Celgene.
Suggested Reading
Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.
NEW ORLEANS—Ozanimod demonstrated durable efficacy with a favorable safety profile in patients continuing ozanimod for 120 weeks or switching from placebo to ozanimod for 96 weeks, according to results of a phase II study presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers. “These data support the ongoing RADIANCE and SUNBEAM phase III studies,” said Brett E. Skolnick, PhD, on behalf of his study collaborators. Dr. Skolnick is an employee of Receptos, a wholly owned subsidiary of Celgene, in San Diego.
Ozanimod, an oral, once-daily immunomodulator selectively targeting sphingosine 1-phosphate (S1P) receptor-1 and -5 , is in development for relapsing multiple sclerosis (MS). “The increased receptor selectivity of ozanimod and additional pharmaceutical properties may result in a more favorable safety profile versus other nonselective and selective S1P receptor modulators,” said Dr. Skolnick.
In the completed RADIANCE Part A phase II trial, patients with relapsing MS were randomized (1:1:1) to once-daily ozanimod 0.5 mg or 1.0 mg or to placebo for 24 weeks. At week 24, patients could enter a 96-week, blinded extension phase. Patients randomized to ozanimod continued their assigned dose; 85 patients received 0.5 mg, and 81 patients received 1.0 mg. Patients administered placebo were re-randomized (1:1) to ozanimod 0.5 mg (n = 41) or 1.0 mg (n = 42). Ozanimod was dose-escalated over seven days to attenuate first-dose effects.
A total of 89% of patients taking the 0.5 mg dose and 90% of patients taking the 1.0 mg dose completed the extension study. At week 120, 89% to 91% of patients were free of gadolinium-enhancing lesions. Unadjusted annualized relapse rates were 0.31 in the 0.5 mg group and 0.18 in the 1.0 mg group. One or more treatment-emergent adverse events were seen in 79% of patients taking the 0.5 mg dose and in 76% of those taking the 1.0 mg dose. The most common adverse events were increased alanine aminotransferases, nasopharyngitis, and upper respiratory tract infection. Serious treatment-emergent adverse events were seen in 12 patients in the 0.5 mg group and in nine patients in the 1.0 mg group. Mild blunting of the normal diurnal heart rate was observed. The largest mean decrease in heart rate relative to pre-dose was 3.5 bpm at hour 6 on day 1, with no associated symptoms. No type II or 2:1 atrioventricular block was reported.
At week 120, alanine aminotransferase (ALT) levels were three or more times upper limit of normal in 6% of the 0.5 mg group and in 7% of the 1.0 mg group. In the 0.5 mg group, 2% of patients discontinued ozanimod due to increased liver transaminases. Less than 1% of patients in the 1.0 mg group discontinued ozanimod for the same reason. Between baseline and week 120, three patients in the 1.0 mg group had absolute lymphocyte counts below 200 cells/μL; none was associated with severe or serious infection. There were no notable cases of pulmonary adverse events and no cases of macular edema, malignancy-related adverse events, or serious opportunistic infections.
This study was supported by Celgene.
Suggested Reading
Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.
NEW ORLEANS—Ozanimod demonstrated durable efficacy with a favorable safety profile in patients continuing ozanimod for 120 weeks or switching from placebo to ozanimod for 96 weeks, according to results of a phase II study presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers. “These data support the ongoing RADIANCE and SUNBEAM phase III studies,” said Brett E. Skolnick, PhD, on behalf of his study collaborators. Dr. Skolnick is an employee of Receptos, a wholly owned subsidiary of Celgene, in San Diego.
Ozanimod, an oral, once-daily immunomodulator selectively targeting sphingosine 1-phosphate (S1P) receptor-1 and -5 , is in development for relapsing multiple sclerosis (MS). “The increased receptor selectivity of ozanimod and additional pharmaceutical properties may result in a more favorable safety profile versus other nonselective and selective S1P receptor modulators,” said Dr. Skolnick.
In the completed RADIANCE Part A phase II trial, patients with relapsing MS were randomized (1:1:1) to once-daily ozanimod 0.5 mg or 1.0 mg or to placebo for 24 weeks. At week 24, patients could enter a 96-week, blinded extension phase. Patients randomized to ozanimod continued their assigned dose; 85 patients received 0.5 mg, and 81 patients received 1.0 mg. Patients administered placebo were re-randomized (1:1) to ozanimod 0.5 mg (n = 41) or 1.0 mg (n = 42). Ozanimod was dose-escalated over seven days to attenuate first-dose effects.
A total of 89% of patients taking the 0.5 mg dose and 90% of patients taking the 1.0 mg dose completed the extension study. At week 120, 89% to 91% of patients were free of gadolinium-enhancing lesions. Unadjusted annualized relapse rates were 0.31 in the 0.5 mg group and 0.18 in the 1.0 mg group. One or more treatment-emergent adverse events were seen in 79% of patients taking the 0.5 mg dose and in 76% of those taking the 1.0 mg dose. The most common adverse events were increased alanine aminotransferases, nasopharyngitis, and upper respiratory tract infection. Serious treatment-emergent adverse events were seen in 12 patients in the 0.5 mg group and in nine patients in the 1.0 mg group. Mild blunting of the normal diurnal heart rate was observed. The largest mean decrease in heart rate relative to pre-dose was 3.5 bpm at hour 6 on day 1, with no associated symptoms. No type II or 2:1 atrioventricular block was reported.
At week 120, alanine aminotransferase (ALT) levels were three or more times upper limit of normal in 6% of the 0.5 mg group and in 7% of the 1.0 mg group. In the 0.5 mg group, 2% of patients discontinued ozanimod due to increased liver transaminases. Less than 1% of patients in the 1.0 mg group discontinued ozanimod for the same reason. Between baseline and week 120, three patients in the 1.0 mg group had absolute lymphocyte counts below 200 cells/μL; none was associated with severe or serious infection. There were no notable cases of pulmonary adverse events and no cases of macular edema, malignancy-related adverse events, or serious opportunistic infections.
This study was supported by Celgene.
Suggested Reading
Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.