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Warfarin found to increase adverse outcomes among patients with IPF
DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.
Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.
“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.
“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”
The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.
In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).
In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).
But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.
They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.
The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.
There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.
Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).
In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).
A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.
The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.
The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.
“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”
Dr. King had no disclosures.
DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.
Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.
“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.
“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”
The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.
In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).
In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).
But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.
They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.
The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.
There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.
Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).
In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).
A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.
The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.
The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.
“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”
Dr. King had no disclosures.
DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.
Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.
“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.
“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”
The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.
In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).
In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).
But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.
They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.
The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.
There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.
Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).
In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).
A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.
The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.
The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.
“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”
Dr. King had no disclosures.
REPORTING FROM ATS 2019
MS patients pay big price for breaks from DMT
SEATTLE – Patients with multiple sclerosis (MS) who stopped taking their disease-modifying therapy (DMT) for more than 60 days had significantly higher rates of relapse, hospitalization, emergency department visits and outpatient visits, a new study finds. Their nonmedication health care costs were higher, too.
“This information will help to inform patients about downstream economic risks of being off therapy. This may also help to inform payers of the importance of making DMTs easily and quickly available to patients with MS to prevent greater costs of health care resource utilization down the road,” study lead author Jacqueline A. Nicholas, MD, MPH, a clinical neuroimmunologist at OhioHealth Multiple Sclerosis Center, said in an interview. She spoke prior to the presentation of the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Dr. Nicholas and her colleagues launched their study to better understand the economic and medical impacts of lapses in oral DMT.
The researchers used a claims database to track 8,779 patients with MS during 2011-2015 who had at least one claim for an oral DMT drug. The subjects were aged 18-63; 15% had a drug lapse of more than 60 days. After propensity matching, the subjects in both groups – 60-day lapse or not – had a mean age of 44 years.
An analysis found that “lapses in oral DMT use led to increased relapses, increased health care utilization, and higher costs incurred by individuals with MS,” Dr. Nicholas said.
Over an 18-month follow-up period, those with drug lapses of more than 60 days had 28% more relapses than did the other subjects (mean 1.2 vs. 0.8; P less than .0001).
Those with lapses greater than 60 days also had 40% more hospitalizations (0.2 vs. 0.1; P = .0003), 25% more emergency department visits (0.6 vs. 0.5; P = .0098), and 22% more outpatient visits (6.2 vs. 4.8; P less than .0001).
Nonmedication costs were 25% higher among patients with a greater than 60-day lapse ($16,012 vs. $12,092; P = .0006).
Moving forward, the researchers wrote, “more research is needed to better understand the reasons for lapses in therapy and the impact of lapse timing and lapse duration on outcomes in patients with MS receiving once- or twice-daily oral [disease-modifying drugs].”
The researchers noted that they don’t have information about the reasons why patients lapsed. They added that the information comes mainly from commercial insurers.
EMD Serono, a division of Merck KGaA, provided funding for the study. Dr. Nicholas disclosed grant support from EMD Serono, and two other study authors are employees of the company. Another two authors worked for a consulting firm that received funding from EMD Serono to conduct the study.
SEATTLE – Patients with multiple sclerosis (MS) who stopped taking their disease-modifying therapy (DMT) for more than 60 days had significantly higher rates of relapse, hospitalization, emergency department visits and outpatient visits, a new study finds. Their nonmedication health care costs were higher, too.
“This information will help to inform patients about downstream economic risks of being off therapy. This may also help to inform payers of the importance of making DMTs easily and quickly available to patients with MS to prevent greater costs of health care resource utilization down the road,” study lead author Jacqueline A. Nicholas, MD, MPH, a clinical neuroimmunologist at OhioHealth Multiple Sclerosis Center, said in an interview. She spoke prior to the presentation of the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Dr. Nicholas and her colleagues launched their study to better understand the economic and medical impacts of lapses in oral DMT.
The researchers used a claims database to track 8,779 patients with MS during 2011-2015 who had at least one claim for an oral DMT drug. The subjects were aged 18-63; 15% had a drug lapse of more than 60 days. After propensity matching, the subjects in both groups – 60-day lapse or not – had a mean age of 44 years.
An analysis found that “lapses in oral DMT use led to increased relapses, increased health care utilization, and higher costs incurred by individuals with MS,” Dr. Nicholas said.
Over an 18-month follow-up period, those with drug lapses of more than 60 days had 28% more relapses than did the other subjects (mean 1.2 vs. 0.8; P less than .0001).
Those with lapses greater than 60 days also had 40% more hospitalizations (0.2 vs. 0.1; P = .0003), 25% more emergency department visits (0.6 vs. 0.5; P = .0098), and 22% more outpatient visits (6.2 vs. 4.8; P less than .0001).
Nonmedication costs were 25% higher among patients with a greater than 60-day lapse ($16,012 vs. $12,092; P = .0006).
Moving forward, the researchers wrote, “more research is needed to better understand the reasons for lapses in therapy and the impact of lapse timing and lapse duration on outcomes in patients with MS receiving once- or twice-daily oral [disease-modifying drugs].”
The researchers noted that they don’t have information about the reasons why patients lapsed. They added that the information comes mainly from commercial insurers.
EMD Serono, a division of Merck KGaA, provided funding for the study. Dr. Nicholas disclosed grant support from EMD Serono, and two other study authors are employees of the company. Another two authors worked for a consulting firm that received funding from EMD Serono to conduct the study.
SEATTLE – Patients with multiple sclerosis (MS) who stopped taking their disease-modifying therapy (DMT) for more than 60 days had significantly higher rates of relapse, hospitalization, emergency department visits and outpatient visits, a new study finds. Their nonmedication health care costs were higher, too.
“This information will help to inform patients about downstream economic risks of being off therapy. This may also help to inform payers of the importance of making DMTs easily and quickly available to patients with MS to prevent greater costs of health care resource utilization down the road,” study lead author Jacqueline A. Nicholas, MD, MPH, a clinical neuroimmunologist at OhioHealth Multiple Sclerosis Center, said in an interview. She spoke prior to the presentation of the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Dr. Nicholas and her colleagues launched their study to better understand the economic and medical impacts of lapses in oral DMT.
The researchers used a claims database to track 8,779 patients with MS during 2011-2015 who had at least one claim for an oral DMT drug. The subjects were aged 18-63; 15% had a drug lapse of more than 60 days. After propensity matching, the subjects in both groups – 60-day lapse or not – had a mean age of 44 years.
An analysis found that “lapses in oral DMT use led to increased relapses, increased health care utilization, and higher costs incurred by individuals with MS,” Dr. Nicholas said.
Over an 18-month follow-up period, those with drug lapses of more than 60 days had 28% more relapses than did the other subjects (mean 1.2 vs. 0.8; P less than .0001).
Those with lapses greater than 60 days also had 40% more hospitalizations (0.2 vs. 0.1; P = .0003), 25% more emergency department visits (0.6 vs. 0.5; P = .0098), and 22% more outpatient visits (6.2 vs. 4.8; P less than .0001).
Nonmedication costs were 25% higher among patients with a greater than 60-day lapse ($16,012 vs. $12,092; P = .0006).
Moving forward, the researchers wrote, “more research is needed to better understand the reasons for lapses in therapy and the impact of lapse timing and lapse duration on outcomes in patients with MS receiving once- or twice-daily oral [disease-modifying drugs].”
The researchers noted that they don’t have information about the reasons why patients lapsed. They added that the information comes mainly from commercial insurers.
EMD Serono, a division of Merck KGaA, provided funding for the study. Dr. Nicholas disclosed grant support from EMD Serono, and two other study authors are employees of the company. Another two authors worked for a consulting firm that received funding from EMD Serono to conduct the study.
REPORTING FROM CMSC 2019
Evidence lacking in treatments for pain in MS
SEATTLE – When it comes to pain in patients with multiple sclerosis, two pain specialists offered this advice: Mind the gap. While pain is a major burden in MS, there’s a huge hole in research about the best treatments. That means medical professionals and patients can only rely on a few signposts for navigation.
But the medical literature does offer glimmers of insight into drug treatments, said Brett R. Stacey, MD, and Pamela Stitzlein Davies, MS, ARNP, FAANP, both of the University of Washington, Seattle, in presentations at the annual meeting of the Consortium of Multiple Sclerosis Centers.
An estimated 44%-66% of patients with MS report pain. Their experiences are similar to those of other patients with pain, Dr. Stacey said, although there are some exceptions. Trigeminal neuralgia is not uncommon in patients with MS, and level of pain fluctuates markedly in MS patients.
“There are no [Food and Drug Administration]–approved drugs specifically for painful MS. There are few clinical trials and no first-line evidence about first-choice medicine,” Dr. Stacey said. As a result, he said, all drug options are off-label.
Based on his experience, the best first-line options for pain in MS appear to be the antidepressants duloxetine (Cymbalta), venlafaxine (Effexor), nortriptyline (Pamelor), desipramine (Norpramin), and amitriptyline, as well as the nerve pain drugs pregabalin (Lyrica) and gabapentin.
In regard to antidepressants, “most patients you give these medications to are not going to have a meaningful response. None of them are typically a home run” for pain in MS, Dr. Stacey said.
Duloxetine, he added, is expensive even as a generic, and nausea is possible within the first few days. It’s time to try something else if nausea sticks around for 5 days, he said.
However, there is a special benefit for duloxetine, he said: “For lower back pain, nothing is better. But that doesn’t mean the evidence is fantastic.”
Gabapentin, he said, “is relatively benign in terms of serious adverse effects,” although significant weight gain is possible. “It does not work for pain that doesn’t have a sensitization element. A lot of people throw gabapentin at things for which it will never work.”
Pregabalin, on the other hand, “can be potentially effective when other things like gabapentin and tricyclics have failed,” he said.
Second-line treatments include the lidocaine patch, tramadol, and the capsaicin 8% patch (Qutenza). And third-line treatments include botulinum toxin A and opioids.
Ms. Davies, who focused her presentation on opioids and pain in MS, agreed about the appropriate role of opioids. “They should be considered third-line, fourth-line, fifth-line, further down,” she said. “There’s a limited role for them in pain related to MS,” she said, specifically in regard to neuropathic pain.
There’s very little research into opioids in MS, she added, and their role is limited by side effects and the possibility of overdose.
Another option is low-dose naltrexone (Revia, Vivitrol), a drug used to treat alcohol and drug dependence. “Here in our clinic, patient after patient asks about naltrexone for everything,” Dr. Stacey said.
The treatment requires the use of a compounding pharmacy, he said, and evidence in MS consists of small studies with mixed results.
Dr. Stacey also addressed trigeminal neuralgia, which affects an estimated 5%-10% of patients with MS. For this condition, he said, “everything works less well in MS patients than non-MS patients.” Drug treatments include the seizure/nerve pain medication carbamazepine (Equetro, Carbatrol, Tegretol) and the seizure medication oxcarbazepine (Oxtellar, Trileptal), he said. Surgery is also an option.
SEATTLE – When it comes to pain in patients with multiple sclerosis, two pain specialists offered this advice: Mind the gap. While pain is a major burden in MS, there’s a huge hole in research about the best treatments. That means medical professionals and patients can only rely on a few signposts for navigation.
But the medical literature does offer glimmers of insight into drug treatments, said Brett R. Stacey, MD, and Pamela Stitzlein Davies, MS, ARNP, FAANP, both of the University of Washington, Seattle, in presentations at the annual meeting of the Consortium of Multiple Sclerosis Centers.
An estimated 44%-66% of patients with MS report pain. Their experiences are similar to those of other patients with pain, Dr. Stacey said, although there are some exceptions. Trigeminal neuralgia is not uncommon in patients with MS, and level of pain fluctuates markedly in MS patients.
“There are no [Food and Drug Administration]–approved drugs specifically for painful MS. There are few clinical trials and no first-line evidence about first-choice medicine,” Dr. Stacey said. As a result, he said, all drug options are off-label.
Based on his experience, the best first-line options for pain in MS appear to be the antidepressants duloxetine (Cymbalta), venlafaxine (Effexor), nortriptyline (Pamelor), desipramine (Norpramin), and amitriptyline, as well as the nerve pain drugs pregabalin (Lyrica) and gabapentin.
In regard to antidepressants, “most patients you give these medications to are not going to have a meaningful response. None of them are typically a home run” for pain in MS, Dr. Stacey said.
Duloxetine, he added, is expensive even as a generic, and nausea is possible within the first few days. It’s time to try something else if nausea sticks around for 5 days, he said.
However, there is a special benefit for duloxetine, he said: “For lower back pain, nothing is better. But that doesn’t mean the evidence is fantastic.”
Gabapentin, he said, “is relatively benign in terms of serious adverse effects,” although significant weight gain is possible. “It does not work for pain that doesn’t have a sensitization element. A lot of people throw gabapentin at things for which it will never work.”
Pregabalin, on the other hand, “can be potentially effective when other things like gabapentin and tricyclics have failed,” he said.
Second-line treatments include the lidocaine patch, tramadol, and the capsaicin 8% patch (Qutenza). And third-line treatments include botulinum toxin A and opioids.
Ms. Davies, who focused her presentation on opioids and pain in MS, agreed about the appropriate role of opioids. “They should be considered third-line, fourth-line, fifth-line, further down,” she said. “There’s a limited role for them in pain related to MS,” she said, specifically in regard to neuropathic pain.
There’s very little research into opioids in MS, she added, and their role is limited by side effects and the possibility of overdose.
Another option is low-dose naltrexone (Revia, Vivitrol), a drug used to treat alcohol and drug dependence. “Here in our clinic, patient after patient asks about naltrexone for everything,” Dr. Stacey said.
The treatment requires the use of a compounding pharmacy, he said, and evidence in MS consists of small studies with mixed results.
Dr. Stacey also addressed trigeminal neuralgia, which affects an estimated 5%-10% of patients with MS. For this condition, he said, “everything works less well in MS patients than non-MS patients.” Drug treatments include the seizure/nerve pain medication carbamazepine (Equetro, Carbatrol, Tegretol) and the seizure medication oxcarbazepine (Oxtellar, Trileptal), he said. Surgery is also an option.
SEATTLE – When it comes to pain in patients with multiple sclerosis, two pain specialists offered this advice: Mind the gap. While pain is a major burden in MS, there’s a huge hole in research about the best treatments. That means medical professionals and patients can only rely on a few signposts for navigation.
But the medical literature does offer glimmers of insight into drug treatments, said Brett R. Stacey, MD, and Pamela Stitzlein Davies, MS, ARNP, FAANP, both of the University of Washington, Seattle, in presentations at the annual meeting of the Consortium of Multiple Sclerosis Centers.
An estimated 44%-66% of patients with MS report pain. Their experiences are similar to those of other patients with pain, Dr. Stacey said, although there are some exceptions. Trigeminal neuralgia is not uncommon in patients with MS, and level of pain fluctuates markedly in MS patients.
“There are no [Food and Drug Administration]–approved drugs specifically for painful MS. There are few clinical trials and no first-line evidence about first-choice medicine,” Dr. Stacey said. As a result, he said, all drug options are off-label.
Based on his experience, the best first-line options for pain in MS appear to be the antidepressants duloxetine (Cymbalta), venlafaxine (Effexor), nortriptyline (Pamelor), desipramine (Norpramin), and amitriptyline, as well as the nerve pain drugs pregabalin (Lyrica) and gabapentin.
In regard to antidepressants, “most patients you give these medications to are not going to have a meaningful response. None of them are typically a home run” for pain in MS, Dr. Stacey said.
Duloxetine, he added, is expensive even as a generic, and nausea is possible within the first few days. It’s time to try something else if nausea sticks around for 5 days, he said.
However, there is a special benefit for duloxetine, he said: “For lower back pain, nothing is better. But that doesn’t mean the evidence is fantastic.”
Gabapentin, he said, “is relatively benign in terms of serious adverse effects,” although significant weight gain is possible. “It does not work for pain that doesn’t have a sensitization element. A lot of people throw gabapentin at things for which it will never work.”
Pregabalin, on the other hand, “can be potentially effective when other things like gabapentin and tricyclics have failed,” he said.
Second-line treatments include the lidocaine patch, tramadol, and the capsaicin 8% patch (Qutenza). And third-line treatments include botulinum toxin A and opioids.
Ms. Davies, who focused her presentation on opioids and pain in MS, agreed about the appropriate role of opioids. “They should be considered third-line, fourth-line, fifth-line, further down,” she said. “There’s a limited role for them in pain related to MS,” she said, specifically in regard to neuropathic pain.
There’s very little research into opioids in MS, she added, and their role is limited by side effects and the possibility of overdose.
Another option is low-dose naltrexone (Revia, Vivitrol), a drug used to treat alcohol and drug dependence. “Here in our clinic, patient after patient asks about naltrexone for everything,” Dr. Stacey said.
The treatment requires the use of a compounding pharmacy, he said, and evidence in MS consists of small studies with mixed results.
Dr. Stacey also addressed trigeminal neuralgia, which affects an estimated 5%-10% of patients with MS. For this condition, he said, “everything works less well in MS patients than non-MS patients.” Drug treatments include the seizure/nerve pain medication carbamazepine (Equetro, Carbatrol, Tegretol) and the seizure medication oxcarbazepine (Oxtellar, Trileptal), he said. Surgery is also an option.
EXPERT ANALYSIS FROM CMSC 2019
Which interventions can treat cognitive fatigue?
SEATTLE – Cognitive fatigue in patients with neurologic disease is a common problem with few objectively studied treatments, according to a systematic review presented at the annual meeting of the Consortium of Multiple Sclerosis Centers., the review authors said.
One other objective trial found that Fampridine-SR (Ampyra) did not reduce cognitive fatigue in patients with multiple sclerosis (MS).
The researchers screened for studies across various neurologic conditions, and found that both trials were in patients with MS, “suggesting that more emphasis is given to this issue in this population,” said review author Alyssa Lindsay-Brown, a researcher at Ottawa Hospital Research Institute, and her collaborators. “This review highlighted the paucity of interventions designed to target objectively measured cognitive fatigability and demonstrates the need for further research in this area.”
Investigators have examined self-reported fatigue in patients with neurologic disease, but objective cognitive fatigability, the inability to maintain optimal task performance during a sustained cognitive task, is not well understood, and the best approach to treating cognitive fatigue is unclear, said Ms. Lindsay-Brown and colleagues. To determine how researchers objectively measure cognitive fatigability and summarize currently available treatments, they conducted a systematic literature review.
The researchers registered the review protocol with the PROSPERO international prospective register of systematic reviews and searched databases for studies that objectively measured cognitive fatigability in patients with neurologic disorders aged 18-65 years. They searched for randomized controlled trials, case-control studies, and case reports and case series published in English between 1980 and February 2019.
The authors reviewed the studies using a modified Cochrane Data Extraction Template and assessed their quality and risk of bias. They decided in advance to group studies according to whether they evaluated pharmacologic, procedural, or behavioral interventions.
The search initially yielded 431 records, and the authors assessed 28 full-text articles for possible inclusion. They ultimately included 2 studies in their qualitative synthesis.
A 2017 pharmacologic study by Morrow et al. sought to determine whether Fampridine-SR objectively improves cognitive fatigability in 60 patients with MS (Mult Scler Relat Disord. 2017 Jan;11:4-9.). This study compared the number of responses from the last third to the first third on the Paced Auditory Serial Addition Test (PASAT). Patients performed better with placebo than with Fampridine-SR.
A 2018 procedural study by Fiene at al. assessed tDCS over the prefrontal cortex in 15 patients with MS (J Neurol. 2018 Mar;265[3]:607-17.). The investigators objectively measured P300 event-related potential and reaction times on an alertness test. Compared with sham, anodal tDCS increased P300 amplitude and reduced fatigue-related decrements in reaction time.
The search did not identify any behavioral interventions for objective cognitive fatigability. “Given the known benefit of behavioral interventions at improving subjectively measured fatigue, future research should investigate whether these effects are transferable to objectively measured cognitive fatigability,” the review authors concluded. “If behavioral interventions demonstrate promise, then future studies should evaluate these against the beneficial, but preliminary, outcomes from tDCS.”
The authors had no disclosures.
SOURCE: Lindsay-Brown A et al. CMSC 2019, Abstract NNN10.
SEATTLE – Cognitive fatigue in patients with neurologic disease is a common problem with few objectively studied treatments, according to a systematic review presented at the annual meeting of the Consortium of Multiple Sclerosis Centers., the review authors said.
One other objective trial found that Fampridine-SR (Ampyra) did not reduce cognitive fatigue in patients with multiple sclerosis (MS).
The researchers screened for studies across various neurologic conditions, and found that both trials were in patients with MS, “suggesting that more emphasis is given to this issue in this population,” said review author Alyssa Lindsay-Brown, a researcher at Ottawa Hospital Research Institute, and her collaborators. “This review highlighted the paucity of interventions designed to target objectively measured cognitive fatigability and demonstrates the need for further research in this area.”
Investigators have examined self-reported fatigue in patients with neurologic disease, but objective cognitive fatigability, the inability to maintain optimal task performance during a sustained cognitive task, is not well understood, and the best approach to treating cognitive fatigue is unclear, said Ms. Lindsay-Brown and colleagues. To determine how researchers objectively measure cognitive fatigability and summarize currently available treatments, they conducted a systematic literature review.
The researchers registered the review protocol with the PROSPERO international prospective register of systematic reviews and searched databases for studies that objectively measured cognitive fatigability in patients with neurologic disorders aged 18-65 years. They searched for randomized controlled trials, case-control studies, and case reports and case series published in English between 1980 and February 2019.
The authors reviewed the studies using a modified Cochrane Data Extraction Template and assessed their quality and risk of bias. They decided in advance to group studies according to whether they evaluated pharmacologic, procedural, or behavioral interventions.
The search initially yielded 431 records, and the authors assessed 28 full-text articles for possible inclusion. They ultimately included 2 studies in their qualitative synthesis.
A 2017 pharmacologic study by Morrow et al. sought to determine whether Fampridine-SR objectively improves cognitive fatigability in 60 patients with MS (Mult Scler Relat Disord. 2017 Jan;11:4-9.). This study compared the number of responses from the last third to the first third on the Paced Auditory Serial Addition Test (PASAT). Patients performed better with placebo than with Fampridine-SR.
A 2018 procedural study by Fiene at al. assessed tDCS over the prefrontal cortex in 15 patients with MS (J Neurol. 2018 Mar;265[3]:607-17.). The investigators objectively measured P300 event-related potential and reaction times on an alertness test. Compared with sham, anodal tDCS increased P300 amplitude and reduced fatigue-related decrements in reaction time.
The search did not identify any behavioral interventions for objective cognitive fatigability. “Given the known benefit of behavioral interventions at improving subjectively measured fatigue, future research should investigate whether these effects are transferable to objectively measured cognitive fatigability,” the review authors concluded. “If behavioral interventions demonstrate promise, then future studies should evaluate these against the beneficial, but preliminary, outcomes from tDCS.”
The authors had no disclosures.
SOURCE: Lindsay-Brown A et al. CMSC 2019, Abstract NNN10.
SEATTLE – Cognitive fatigue in patients with neurologic disease is a common problem with few objectively studied treatments, according to a systematic review presented at the annual meeting of the Consortium of Multiple Sclerosis Centers., the review authors said.
One other objective trial found that Fampridine-SR (Ampyra) did not reduce cognitive fatigue in patients with multiple sclerosis (MS).
The researchers screened for studies across various neurologic conditions, and found that both trials were in patients with MS, “suggesting that more emphasis is given to this issue in this population,” said review author Alyssa Lindsay-Brown, a researcher at Ottawa Hospital Research Institute, and her collaborators. “This review highlighted the paucity of interventions designed to target objectively measured cognitive fatigability and demonstrates the need for further research in this area.”
Investigators have examined self-reported fatigue in patients with neurologic disease, but objective cognitive fatigability, the inability to maintain optimal task performance during a sustained cognitive task, is not well understood, and the best approach to treating cognitive fatigue is unclear, said Ms. Lindsay-Brown and colleagues. To determine how researchers objectively measure cognitive fatigability and summarize currently available treatments, they conducted a systematic literature review.
The researchers registered the review protocol with the PROSPERO international prospective register of systematic reviews and searched databases for studies that objectively measured cognitive fatigability in patients with neurologic disorders aged 18-65 years. They searched for randomized controlled trials, case-control studies, and case reports and case series published in English between 1980 and February 2019.
The authors reviewed the studies using a modified Cochrane Data Extraction Template and assessed their quality and risk of bias. They decided in advance to group studies according to whether they evaluated pharmacologic, procedural, or behavioral interventions.
The search initially yielded 431 records, and the authors assessed 28 full-text articles for possible inclusion. They ultimately included 2 studies in their qualitative synthesis.
A 2017 pharmacologic study by Morrow et al. sought to determine whether Fampridine-SR objectively improves cognitive fatigability in 60 patients with MS (Mult Scler Relat Disord. 2017 Jan;11:4-9.). This study compared the number of responses from the last third to the first third on the Paced Auditory Serial Addition Test (PASAT). Patients performed better with placebo than with Fampridine-SR.
A 2018 procedural study by Fiene at al. assessed tDCS over the prefrontal cortex in 15 patients with MS (J Neurol. 2018 Mar;265[3]:607-17.). The investigators objectively measured P300 event-related potential and reaction times on an alertness test. Compared with sham, anodal tDCS increased P300 amplitude and reduced fatigue-related decrements in reaction time.
The search did not identify any behavioral interventions for objective cognitive fatigability. “Given the known benefit of behavioral interventions at improving subjectively measured fatigue, future research should investigate whether these effects are transferable to objectively measured cognitive fatigability,” the review authors concluded. “If behavioral interventions demonstrate promise, then future studies should evaluate these against the beneficial, but preliminary, outcomes from tDCS.”
The authors had no disclosures.
SOURCE: Lindsay-Brown A et al. CMSC 2019, Abstract NNN10.
REPORTING FROM CMSC 2019
Testifying about the standard of care outside of your specialty
I have no idea what the standard of care in cardiology is. Or nephrology, endocrinology, or pulmonary medicine.
Nor do I think anyone in those fields tries to keep up to date on the latest in epilepsy, migraines, or Parkinson’s disease. They have their fields, I have mine. That’s the whole point of being a specialist: Medicine is too vast a subject for one person to know everything about it. Even my own field is further divided into subspecialties like vascular disease, neuromuscular disorders, and dementia, so I imagine other fields are, too.
Yet, there are still states where a physician of a different specialty can testify as to the standard of care in others for malpractice cases.
Think about that. An orthopedist testifying as to the competence of an ob.gyn. An adult neurologist claiming to be up to date on pediatric allergies. A family practice doctor stating what a neurosurgeon should be doing. All in a court of law, the most dreaded scenario for most of us.
Fortunately, there are several states that require an expert witness to be an actively-practicing, board-certified, specialist in the same field as the person they’re testifying against.
However, . While a good defense attorney can hopefully pick this apart, the average jury is not composed of people with medical training. To many lay people, “a doctor is a doctor,” and it’s very hard to emphasize the degree of specialty differences to them.
This difference is one (but certainly not the only) factor that drives the different malpractice costs between states. You’d think requiring own-field standard of care would be one of the least contentious malpractice reforms to make, but these days people fight tooth and nail about everything. The result of these battles is that states with the lowest malpractice rates tend to attract more physicians, and states with the highest can have trouble finding qualified people. In the long run, that only hurts those who need medical care.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I have no idea what the standard of care in cardiology is. Or nephrology, endocrinology, or pulmonary medicine.
Nor do I think anyone in those fields tries to keep up to date on the latest in epilepsy, migraines, or Parkinson’s disease. They have their fields, I have mine. That’s the whole point of being a specialist: Medicine is too vast a subject for one person to know everything about it. Even my own field is further divided into subspecialties like vascular disease, neuromuscular disorders, and dementia, so I imagine other fields are, too.
Yet, there are still states where a physician of a different specialty can testify as to the standard of care in others for malpractice cases.
Think about that. An orthopedist testifying as to the competence of an ob.gyn. An adult neurologist claiming to be up to date on pediatric allergies. A family practice doctor stating what a neurosurgeon should be doing. All in a court of law, the most dreaded scenario for most of us.
Fortunately, there are several states that require an expert witness to be an actively-practicing, board-certified, specialist in the same field as the person they’re testifying against.
However, . While a good defense attorney can hopefully pick this apart, the average jury is not composed of people with medical training. To many lay people, “a doctor is a doctor,” and it’s very hard to emphasize the degree of specialty differences to them.
This difference is one (but certainly not the only) factor that drives the different malpractice costs between states. You’d think requiring own-field standard of care would be one of the least contentious malpractice reforms to make, but these days people fight tooth and nail about everything. The result of these battles is that states with the lowest malpractice rates tend to attract more physicians, and states with the highest can have trouble finding qualified people. In the long run, that only hurts those who need medical care.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I have no idea what the standard of care in cardiology is. Or nephrology, endocrinology, or pulmonary medicine.
Nor do I think anyone in those fields tries to keep up to date on the latest in epilepsy, migraines, or Parkinson’s disease. They have their fields, I have mine. That’s the whole point of being a specialist: Medicine is too vast a subject for one person to know everything about it. Even my own field is further divided into subspecialties like vascular disease, neuromuscular disorders, and dementia, so I imagine other fields are, too.
Yet, there are still states where a physician of a different specialty can testify as to the standard of care in others for malpractice cases.
Think about that. An orthopedist testifying as to the competence of an ob.gyn. An adult neurologist claiming to be up to date on pediatric allergies. A family practice doctor stating what a neurosurgeon should be doing. All in a court of law, the most dreaded scenario for most of us.
Fortunately, there are several states that require an expert witness to be an actively-practicing, board-certified, specialist in the same field as the person they’re testifying against.
However, . While a good defense attorney can hopefully pick this apart, the average jury is not composed of people with medical training. To many lay people, “a doctor is a doctor,” and it’s very hard to emphasize the degree of specialty differences to them.
This difference is one (but certainly not the only) factor that drives the different malpractice costs between states. You’d think requiring own-field standard of care would be one of the least contentious malpractice reforms to make, but these days people fight tooth and nail about everything. The result of these battles is that states with the lowest malpractice rates tend to attract more physicians, and states with the highest can have trouble finding qualified people. In the long run, that only hurts those who need medical care.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Measles cases now at highest level since 1992
With 971 cases of measles reported after just 5 months of 2019, the United States has hit another dubious milestone by surpassing the 963 cases reported in the preelimination year of 1994, according to the Centers for Disease Control and Prevention.
That leaves 1992, when there were 2,237 cases reported, as the next big obstacle on measles’ current path of distinction, the CDC data show. Only 312 cases were reported in 1993.
“Outbreaks in New York City and Rockland County, New York have continued for nearly 8 months. That loss would be a huge blow for the nation and erase the hard work done by all levels of public health,” the CDC said May 30.
The CDC defines measles elimination as “the absence of continuous disease transmission for 12 months or more in a specific geographic area” and notes that “measles is no longer endemic [constantly present] in the United States.”
“Measles is preventable and the way to end this outbreak is to ensure that all children and adults who can get vaccinated, do get vaccinated. Again, I want to reassure parents that vaccines are safe, they do not cause autism. The greater danger is the disease that vaccination prevents,” CDC director Robert Redfield, MD, said in a statement.
With 971 cases of measles reported after just 5 months of 2019, the United States has hit another dubious milestone by surpassing the 963 cases reported in the preelimination year of 1994, according to the Centers for Disease Control and Prevention.
That leaves 1992, when there were 2,237 cases reported, as the next big obstacle on measles’ current path of distinction, the CDC data show. Only 312 cases were reported in 1993.
“Outbreaks in New York City and Rockland County, New York have continued for nearly 8 months. That loss would be a huge blow for the nation and erase the hard work done by all levels of public health,” the CDC said May 30.
The CDC defines measles elimination as “the absence of continuous disease transmission for 12 months or more in a specific geographic area” and notes that “measles is no longer endemic [constantly present] in the United States.”
“Measles is preventable and the way to end this outbreak is to ensure that all children and adults who can get vaccinated, do get vaccinated. Again, I want to reassure parents that vaccines are safe, they do not cause autism. The greater danger is the disease that vaccination prevents,” CDC director Robert Redfield, MD, said in a statement.
With 971 cases of measles reported after just 5 months of 2019, the United States has hit another dubious milestone by surpassing the 963 cases reported in the preelimination year of 1994, according to the Centers for Disease Control and Prevention.
That leaves 1992, when there were 2,237 cases reported, as the next big obstacle on measles’ current path of distinction, the CDC data show. Only 312 cases were reported in 1993.
“Outbreaks in New York City and Rockland County, New York have continued for nearly 8 months. That loss would be a huge blow for the nation and erase the hard work done by all levels of public health,” the CDC said May 30.
The CDC defines measles elimination as “the absence of continuous disease transmission for 12 months or more in a specific geographic area” and notes that “measles is no longer endemic [constantly present] in the United States.”
“Measles is preventable and the way to end this outbreak is to ensure that all children and adults who can get vaccinated, do get vaccinated. Again, I want to reassure parents that vaccines are safe, they do not cause autism. The greater danger is the disease that vaccination prevents,” CDC director Robert Redfield, MD, said in a statement.
Artificial intelligence advances optical biopsy
SAN DIEGO – Artificial intelligence is improving the accuracy of optical biopsies, a development that may ultimately avoid the need for tissue biopsies of many low-risk colonic polyps, Michael Byrne, MD, said at the annual Digestive Disease Week.
Dr. Byrne, chief executive officer of Satisfai Health, founder of ai4gi, and gastroenterologist at Vancouver General Hospital; Nicolas Guizard, medical imaging researcher at Imagia; and their colleagues at ai4gi developed a “full clinical workflow” for detecting colonic polyps and performing optical biopsies of the polyps.”
Using narrow band imaging (NBI) enhanced with artificial intelligence, the system was used to review 21,804 colonoscopy frames and it achieved a “near-perfect” diagnostic accuracy of 99.9%. In an assessment of colonoscopy videos that included 125 polyps, the system had 95.9% sensitivity, with a specificity of 91.6% and a negative predictive value of 93.6%, Dr. Byrne said.
The speed of the system’s decision-making is rapid, with a typical reaction time of 360 milliseconds. The system was able to make diagnostic inferences at a rate of 26 milliseconds per frame.
With exposure to more learning experiences, the artificial intelligence system improved and committed to a prediction for 97.6% of the polyps it visualized. Dr. Byrne said this result represented a 12.8% improvement from previously published data on the model’s performance.
Dr. Byrne and his colleagues found the system had a tracking accuracy of 92.8%, meaning that this percentage of polyps was both correctly detected and assigned to a unique identifier for follow-up of the site of each excised polyp over time. The interface worked even when multiple polyps were seen on the same screen.
In a video interview, Dr. Byrne discussed the implications for gastroenterology and plans for a clinical trial for rigorous testing of the model.
ai4gi is developing the AI colonoscopy technology. Dr. Byrne is founder of the ai4gi joint venture, which holds a technology codevelopment agreement with Olympus US.
SAN DIEGO – Artificial intelligence is improving the accuracy of optical biopsies, a development that may ultimately avoid the need for tissue biopsies of many low-risk colonic polyps, Michael Byrne, MD, said at the annual Digestive Disease Week.
Dr. Byrne, chief executive officer of Satisfai Health, founder of ai4gi, and gastroenterologist at Vancouver General Hospital; Nicolas Guizard, medical imaging researcher at Imagia; and their colleagues at ai4gi developed a “full clinical workflow” for detecting colonic polyps and performing optical biopsies of the polyps.”
Using narrow band imaging (NBI) enhanced with artificial intelligence, the system was used to review 21,804 colonoscopy frames and it achieved a “near-perfect” diagnostic accuracy of 99.9%. In an assessment of colonoscopy videos that included 125 polyps, the system had 95.9% sensitivity, with a specificity of 91.6% and a negative predictive value of 93.6%, Dr. Byrne said.
The speed of the system’s decision-making is rapid, with a typical reaction time of 360 milliseconds. The system was able to make diagnostic inferences at a rate of 26 milliseconds per frame.
With exposure to more learning experiences, the artificial intelligence system improved and committed to a prediction for 97.6% of the polyps it visualized. Dr. Byrne said this result represented a 12.8% improvement from previously published data on the model’s performance.
Dr. Byrne and his colleagues found the system had a tracking accuracy of 92.8%, meaning that this percentage of polyps was both correctly detected and assigned to a unique identifier for follow-up of the site of each excised polyp over time. The interface worked even when multiple polyps were seen on the same screen.
In a video interview, Dr. Byrne discussed the implications for gastroenterology and plans for a clinical trial for rigorous testing of the model.
ai4gi is developing the AI colonoscopy technology. Dr. Byrne is founder of the ai4gi joint venture, which holds a technology codevelopment agreement with Olympus US.
SAN DIEGO – Artificial intelligence is improving the accuracy of optical biopsies, a development that may ultimately avoid the need for tissue biopsies of many low-risk colonic polyps, Michael Byrne, MD, said at the annual Digestive Disease Week.
Dr. Byrne, chief executive officer of Satisfai Health, founder of ai4gi, and gastroenterologist at Vancouver General Hospital; Nicolas Guizard, medical imaging researcher at Imagia; and their colleagues at ai4gi developed a “full clinical workflow” for detecting colonic polyps and performing optical biopsies of the polyps.”
Using narrow band imaging (NBI) enhanced with artificial intelligence, the system was used to review 21,804 colonoscopy frames and it achieved a “near-perfect” diagnostic accuracy of 99.9%. In an assessment of colonoscopy videos that included 125 polyps, the system had 95.9% sensitivity, with a specificity of 91.6% and a negative predictive value of 93.6%, Dr. Byrne said.
The speed of the system’s decision-making is rapid, with a typical reaction time of 360 milliseconds. The system was able to make diagnostic inferences at a rate of 26 milliseconds per frame.
With exposure to more learning experiences, the artificial intelligence system improved and committed to a prediction for 97.6% of the polyps it visualized. Dr. Byrne said this result represented a 12.8% improvement from previously published data on the model’s performance.
Dr. Byrne and his colleagues found the system had a tracking accuracy of 92.8%, meaning that this percentage of polyps was both correctly detected and assigned to a unique identifier for follow-up of the site of each excised polyp over time. The interface worked even when multiple polyps were seen on the same screen.
In a video interview, Dr. Byrne discussed the implications for gastroenterology and plans for a clinical trial for rigorous testing of the model.
ai4gi is developing the AI colonoscopy technology. Dr. Byrne is founder of the ai4gi joint venture, which holds a technology codevelopment agreement with Olympus US.
REPORTING FROM DDW 2019
Psoriasis Journal Scan: May 2019
The Broad-Spectrum Impact of Hidradenitis Suppurativa on Quality of Life: A Comparison with Psoriasis.
Sampogna F, Fania L, Mazzanti C, et al. Dermatology. 2019 May 23:1-7.
The aim of this study was to evaluate in detail the QoL impact of HS comparing it with other skin conditions, and in particular with psoriasis. HS had the worst QoL among several skin conditions. Compared to psoriasis the mean symptom score was 69.4 versus 53.7, and the mean psychosocial score was 56.1 versus 32.7. Overall, the scores of patients with HS were higher than those of psoriasis patients on 16 of the 17 items of the Skindex-17.
Suicidality and risk of suicidality in psoriasis: A critical appraisal of two systematic reviews and meta-analyses.
Matterne U, Baumeister SE, Apfelbacher C. Br J Dermatol. 2019 May 10.
Chi et al. and Singh et al each conducted a systematic review and meta-analysis of observational studies examining the relationship between suicidality and psoriasis. Singh et al. concluded that patients with psoriasis have a significantly higher risk of suicidal ideation, suicide attempts, and completed suicides, while Chi et al concluded that the available limited, very low-quality evidence does not support the notion of an association between psoriasis on the one hand, and suicide, suicidal ideation and attempts on the other.
Psoriasis and Inflammatory Bowel Disease.
Cottone M, Sapienza C, Macaluso FS, Cannizzaro M. Dig Dis. 2019 May 10:1-7.
Inflammatory bowel disease (IBD) and psoriasis (PS) are associated conditions. The reason for this association lies in the sharing of predisposition genes and common immunological mechanisms. This review will focus on the interplay between IBD and PS, with details on prevalence and phenotype of PS in IBD, genetics, pathogenetic pathways, and therapy.
Psoriasis in HIV infection: an update.
Alpalhão M, Borges-Costa J, Filipe P. Int J STD AIDS. 2019 May;30(6):596-604.
A review of the available literature to highlight the updated evidence on psoriasis in HIV-infected individuals, particularly in regards to its epidemiology, proposed pathophysiology, clinical presentation, currently available therapeutic options, and future perspectives.
All-cause and cause-specific mortality in psoriasis: A systematic review and meta-analysis.
Dhana A, Yen H, Yen H, Cho E. J Am Acad Dermatol. 2019 May;80(5):1332-1343.
A systematic review and meta-analysis of mortality risk in psoriasis that included studies reporting all-cause or cause-specific mortality risk estimates in psoriasis patients compared with general population or subjects free of psoriasis. The pooled RRs for cardiovascular mortality were 1.15 (95% CI 1.09-1.21) in psoriasis, 1.05 (95% CI 0.92-1.20) in mild psoriasis, and 1.38 (95% CI 1.09-1.74) in severe psoriasis. For noncardiovascular causes, mortality risk from liver disease, kidney disease, and infection was significantly increased in psoriasis, regardless of disease severity.
The Broad-Spectrum Impact of Hidradenitis Suppurativa on Quality of Life: A Comparison with Psoriasis.
Sampogna F, Fania L, Mazzanti C, et al. Dermatology. 2019 May 23:1-7.
The aim of this study was to evaluate in detail the QoL impact of HS comparing it with other skin conditions, and in particular with psoriasis. HS had the worst QoL among several skin conditions. Compared to psoriasis the mean symptom score was 69.4 versus 53.7, and the mean psychosocial score was 56.1 versus 32.7. Overall, the scores of patients with HS were higher than those of psoriasis patients on 16 of the 17 items of the Skindex-17.
Suicidality and risk of suicidality in psoriasis: A critical appraisal of two systematic reviews and meta-analyses.
Matterne U, Baumeister SE, Apfelbacher C. Br J Dermatol. 2019 May 10.
Chi et al. and Singh et al each conducted a systematic review and meta-analysis of observational studies examining the relationship between suicidality and psoriasis. Singh et al. concluded that patients with psoriasis have a significantly higher risk of suicidal ideation, suicide attempts, and completed suicides, while Chi et al concluded that the available limited, very low-quality evidence does not support the notion of an association between psoriasis on the one hand, and suicide, suicidal ideation and attempts on the other.
Psoriasis and Inflammatory Bowel Disease.
Cottone M, Sapienza C, Macaluso FS, Cannizzaro M. Dig Dis. 2019 May 10:1-7.
Inflammatory bowel disease (IBD) and psoriasis (PS) are associated conditions. The reason for this association lies in the sharing of predisposition genes and common immunological mechanisms. This review will focus on the interplay between IBD and PS, with details on prevalence and phenotype of PS in IBD, genetics, pathogenetic pathways, and therapy.
Psoriasis in HIV infection: an update.
Alpalhão M, Borges-Costa J, Filipe P. Int J STD AIDS. 2019 May;30(6):596-604.
A review of the available literature to highlight the updated evidence on psoriasis in HIV-infected individuals, particularly in regards to its epidemiology, proposed pathophysiology, clinical presentation, currently available therapeutic options, and future perspectives.
All-cause and cause-specific mortality in psoriasis: A systematic review and meta-analysis.
Dhana A, Yen H, Yen H, Cho E. J Am Acad Dermatol. 2019 May;80(5):1332-1343.
A systematic review and meta-analysis of mortality risk in psoriasis that included studies reporting all-cause or cause-specific mortality risk estimates in psoriasis patients compared with general population or subjects free of psoriasis. The pooled RRs for cardiovascular mortality were 1.15 (95% CI 1.09-1.21) in psoriasis, 1.05 (95% CI 0.92-1.20) in mild psoriasis, and 1.38 (95% CI 1.09-1.74) in severe psoriasis. For noncardiovascular causes, mortality risk from liver disease, kidney disease, and infection was significantly increased in psoriasis, regardless of disease severity.
The Broad-Spectrum Impact of Hidradenitis Suppurativa on Quality of Life: A Comparison with Psoriasis.
Sampogna F, Fania L, Mazzanti C, et al. Dermatology. 2019 May 23:1-7.
The aim of this study was to evaluate in detail the QoL impact of HS comparing it with other skin conditions, and in particular with psoriasis. HS had the worst QoL among several skin conditions. Compared to psoriasis the mean symptom score was 69.4 versus 53.7, and the mean psychosocial score was 56.1 versus 32.7. Overall, the scores of patients with HS were higher than those of psoriasis patients on 16 of the 17 items of the Skindex-17.
Suicidality and risk of suicidality in psoriasis: A critical appraisal of two systematic reviews and meta-analyses.
Matterne U, Baumeister SE, Apfelbacher C. Br J Dermatol. 2019 May 10.
Chi et al. and Singh et al each conducted a systematic review and meta-analysis of observational studies examining the relationship between suicidality and psoriasis. Singh et al. concluded that patients with psoriasis have a significantly higher risk of suicidal ideation, suicide attempts, and completed suicides, while Chi et al concluded that the available limited, very low-quality evidence does not support the notion of an association between psoriasis on the one hand, and suicide, suicidal ideation and attempts on the other.
Psoriasis and Inflammatory Bowel Disease.
Cottone M, Sapienza C, Macaluso FS, Cannizzaro M. Dig Dis. 2019 May 10:1-7.
Inflammatory bowel disease (IBD) and psoriasis (PS) are associated conditions. The reason for this association lies in the sharing of predisposition genes and common immunological mechanisms. This review will focus on the interplay between IBD and PS, with details on prevalence and phenotype of PS in IBD, genetics, pathogenetic pathways, and therapy.
Psoriasis in HIV infection: an update.
Alpalhão M, Borges-Costa J, Filipe P. Int J STD AIDS. 2019 May;30(6):596-604.
A review of the available literature to highlight the updated evidence on psoriasis in HIV-infected individuals, particularly in regards to its epidemiology, proposed pathophysiology, clinical presentation, currently available therapeutic options, and future perspectives.
All-cause and cause-specific mortality in psoriasis: A systematic review and meta-analysis.
Dhana A, Yen H, Yen H, Cho E. J Am Acad Dermatol. 2019 May;80(5):1332-1343.
A systematic review and meta-analysis of mortality risk in psoriasis that included studies reporting all-cause or cause-specific mortality risk estimates in psoriasis patients compared with general population or subjects free of psoriasis. The pooled RRs for cardiovascular mortality were 1.15 (95% CI 1.09-1.21) in psoriasis, 1.05 (95% CI 0.92-1.20) in mild psoriasis, and 1.38 (95% CI 1.09-1.74) in severe psoriasis. For noncardiovascular causes, mortality risk from liver disease, kidney disease, and infection was significantly increased in psoriasis, regardless of disease severity.
Studies cast doubt on FDA’s accelerated cancer drug pathway
In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.
Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.
The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.
Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.
Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)
The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).
The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.
While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”
In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.
Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.
For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.
Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.
In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.
Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.
For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.
The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.
That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.
“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.
Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.
“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.
Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.
“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”
The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.
SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.
In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.
Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.
The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.
Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.
Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)
The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).
The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.
While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”
In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.
Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.
For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.
Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.
In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.
Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.
For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.
The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.
That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.
“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.
Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.
“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.
Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.
“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”
The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.
SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.
In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.
Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.
The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.
Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.
Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)
The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).
The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.
While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”
In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.
Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.
For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.
Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.
In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.
Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.
For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.
The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.
That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.
“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.
Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.
“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.
Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.
“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”
The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.
SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.
FROM JAMA INTERNAL MEDICINE
Tofacitinib upped herpes zoster risk in ulcerative colitis
Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.
Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).
With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.
Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.
Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.
Worsening ulcerative colitis was the most common serious adverse event for patients who received both induction and maintenance therapy. For patients on maintenance therapy, only herpes zoster infection had a higher incidence than placebo, which reached statistical significance at the 10-mg dose. These safety findings resemble those in rheumatoid arthritis trials of tofacitinib, and apart from herpes zoster, they also resemble safety data for vedolizumab (an integrin receptor antagonist), and anti-tumor necrosis factor agents in ulcerative colitis, the researchers wrote.
There were four deaths during the entire tofacitinib ulcerative colitis program, for an incidence rate of 0.2 per 100 person-years of exposure. All occurred in patients receiving 10 mg twice daily. Causes of death were dissecting aortic aneurysm, hepatic angiosarcoma, acute myeloid leukemia, and pulmonary embolism in a patient with cholangiocarcinoma that had metastasized to the peritoneum. Recently, concerns about pulmonary embolism have led the European Medicines Agency (EMA) to recommend against the use of 10-mg twice daily tofacitinib dose in patients at increased risk for pulmonary embolism.
“Compared with prior experience with tofacitinib in rheumatoid arthritis, no new or unexpected safety signals were identified,” the researchers concluded. “These
Pfizer makes tofacitinib, funded the individual trials, and paid for medical writing. Dr. Sandborn disclosed grants, personal fees, and nonfinancial support from Pfizer and many other pharmaceutical companies.
SOURCE: Sandborn WJ et al. Clin Gastroenterol Hepatol. 2018 Nov 23. doi: 10.1016/j.cgh.2018.11.035.
Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.
Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).
With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.
Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.
Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.
Worsening ulcerative colitis was the most common serious adverse event for patients who received both induction and maintenance therapy. For patients on maintenance therapy, only herpes zoster infection had a higher incidence than placebo, which reached statistical significance at the 10-mg dose. These safety findings resemble those in rheumatoid arthritis trials of tofacitinib, and apart from herpes zoster, they also resemble safety data for vedolizumab (an integrin receptor antagonist), and anti-tumor necrosis factor agents in ulcerative colitis, the researchers wrote.
There were four deaths during the entire tofacitinib ulcerative colitis program, for an incidence rate of 0.2 per 100 person-years of exposure. All occurred in patients receiving 10 mg twice daily. Causes of death were dissecting aortic aneurysm, hepatic angiosarcoma, acute myeloid leukemia, and pulmonary embolism in a patient with cholangiocarcinoma that had metastasized to the peritoneum. Recently, concerns about pulmonary embolism have led the European Medicines Agency (EMA) to recommend against the use of 10-mg twice daily tofacitinib dose in patients at increased risk for pulmonary embolism.
“Compared with prior experience with tofacitinib in rheumatoid arthritis, no new or unexpected safety signals were identified,” the researchers concluded. “These
Pfizer makes tofacitinib, funded the individual trials, and paid for medical writing. Dr. Sandborn disclosed grants, personal fees, and nonfinancial support from Pfizer and many other pharmaceutical companies.
SOURCE: Sandborn WJ et al. Clin Gastroenterol Hepatol. 2018 Nov 23. doi: 10.1016/j.cgh.2018.11.035.
Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.
Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).
With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.
Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.
Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.
Worsening ulcerative colitis was the most common serious adverse event for patients who received both induction and maintenance therapy. For patients on maintenance therapy, only herpes zoster infection had a higher incidence than placebo, which reached statistical significance at the 10-mg dose. These safety findings resemble those in rheumatoid arthritis trials of tofacitinib, and apart from herpes zoster, they also resemble safety data for vedolizumab (an integrin receptor antagonist), and anti-tumor necrosis factor agents in ulcerative colitis, the researchers wrote.
There were four deaths during the entire tofacitinib ulcerative colitis program, for an incidence rate of 0.2 per 100 person-years of exposure. All occurred in patients receiving 10 mg twice daily. Causes of death were dissecting aortic aneurysm, hepatic angiosarcoma, acute myeloid leukemia, and pulmonary embolism in a patient with cholangiocarcinoma that had metastasized to the peritoneum. Recently, concerns about pulmonary embolism have led the European Medicines Agency (EMA) to recommend against the use of 10-mg twice daily tofacitinib dose in patients at increased risk for pulmonary embolism.
“Compared with prior experience with tofacitinib in rheumatoid arthritis, no new or unexpected safety signals were identified,” the researchers concluded. “These
Pfizer makes tofacitinib, funded the individual trials, and paid for medical writing. Dr. Sandborn disclosed grants, personal fees, and nonfinancial support from Pfizer and many other pharmaceutical companies.
SOURCE: Sandborn WJ et al. Clin Gastroenterol Hepatol. 2018 Nov 23. doi: 10.1016/j.cgh.2018.11.035.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY