Clinical Neurology News

NEW ORLEANS – For patients with Dravet syndrome, a 44% or greater reduction in seizure frequency can be considered a clinically meaningful response, according to a study described at the annual meeting of the American Epilepsy Society. A reduction in seizure frequency of between 60% and 68% is associated with Clinical Global Impression of Improvement (CGI-I) ratings of “very much improved,” as assessed by caregivers and investigators.

“Further analyses from other phase III studies in Dravet syndrome and other patient populations should be performed to confirm these findings and explore other potential factors that contribute to caregiver and investigator CGI-I ratings, such as nonseizure outcomes and tolerability,” said Arnold Gammaitoni, PharmD, vice president of medical and scientific affairs at Zogenix in San Diego, and his colleagues.

A 50% reduction in seizure frequency is conventionally considered to be the cutoff for a clinically meaningful change. To develop an evidence-based definition of clinically meaningful seizure reduction, Dr. Gammaitoni and colleagues examined data from a phase III, randomized, double-blind, placebo-controlled trial of fenfluramine HCl oral solution for the adjunctive treatment of seizures associated with Dravet syndrome. The investigators took an anchor-based approach and examined the percentage change in seizure frequency, along with caregiver and investigator CGI-I ratings.

A total of 119 patients with Dravet syndrome were enrolled and randomized in equal groups to placebo, 0.2 mg/kg per day of fenfluramine HCl, or 0.8 mg/kg per day of fenfluramine HCl. After a 2-week titration period, patients entered a 12-week maintenance period. Patients in the 0.8-mg/kg per day group had a 63.9% greater reduction in seizure frequency than controls did.

After the 14-week titration and maintenance period, caregivers and investigators rated the change in participants’ clinical status from baseline, using the CGI-I scale, on which responses range from 1 (very much improved) to 7 (very much worse). The investigators considered patients with CGI-I scores of 1 or 2 (much improved) to have achieved a clinically meaningful response. A score of 3 (minimally improved) was not considered meaningful. The researchers pooled the results of the three treatment groups for this analysis. They estimated the clinically meaningful percentage change in seizure frequency using receiver operating characteristic analysis of binary CGI-I score, compared with percentage change in seizure frequency, and defined it as the cut-point for which specificity and sensitivity were equal or most similar.

Caregivers and investigators provided CGI-I assessments for 112 patients and 114 patients, respectively. The receiver operating characteristic analysis identified a 44% reduction in seizure frequency as a clinically meaningful cutoff point for caregiver and investigator assessments. Using this threshold, 75%, 46%, and 12.5% of patients in the 0.8-mg/kg per day, 0.2-mg/kg per day, and placebo groups, respectively, achieved a clinically meaningful reduction from baseline in seizure frequency in the phase III study.

“The use of external anchors is one method to define a clinically meaningful change in seizure frequency,” said Dr. Gammaitoni. “Having a defined minimum clinically important difference like this allows clinicians to assess impacts of treatments on an individual patient basis.... This is a chance for others to do similar types of analyses to confirm the findings that we have had in this first study with bigger data sets, in terms of using external anchors and data to define what a clinically meaningful change is.”

Zogenix, which is developing the fenfluramine formulation examined in this study, provided funding for this research.
 

egreb@mdedge.com

SOURCE: Nabbout R et al. AES 2018, Abstract 3.202.

NEW ORLEANS – For patients with Dravet syndrome, a 44% or greater reduction in seizure frequency can be considered a clinically meaningful response, according to a study described at the annual meeting of the American Epilepsy Society. A reduction in seizure frequency of between 60% and 68% is associated with Clinical Global Impression of Improvement (CGI-I) ratings of “very much improved,” as assessed by caregivers and investigators.

“Further analyses from other phase III studies in Dravet syndrome and other patient populations should be performed to confirm these findings and explore other potential factors that contribute to caregiver and investigator CGI-I ratings, such as nonseizure outcomes and tolerability,” said Arnold Gammaitoni, PharmD, vice president of medical and scientific affairs at Zogenix in San Diego, and his colleagues.

A 50% reduction in seizure frequency is conventionally considered to be the cutoff for a clinically meaningful change. To develop an evidence-based definition of clinically meaningful seizure reduction, Dr. Gammaitoni and colleagues examined data from a phase III, randomized, double-blind, placebo-controlled trial of fenfluramine HCl oral solution for the adjunctive treatment of seizures associated with Dravet syndrome. The investigators took an anchor-based approach and examined the percentage change in seizure frequency, along with caregiver and investigator CGI-I ratings.

A total of 119 patients with Dravet syndrome were enrolled and randomized in equal groups to placebo, 0.2 mg/kg per day of fenfluramine HCl, or 0.8 mg/kg per day of fenfluramine HCl. After a 2-week titration period, patients entered a 12-week maintenance period. Patients in the 0.8-mg/kg per day group had a 63.9% greater reduction in seizure frequency than controls did.

After the 14-week titration and maintenance period, caregivers and investigators rated the change in participants’ clinical status from baseline, using the CGI-I scale, on which responses range from 1 (very much improved) to 7 (very much worse). The investigators considered patients with CGI-I scores of 1 or 2 (much improved) to have achieved a clinically meaningful response. A score of 3 (minimally improved) was not considered meaningful. The researchers pooled the results of the three treatment groups for this analysis. They estimated the clinically meaningful percentage change in seizure frequency using receiver operating characteristic analysis of binary CGI-I score, compared with percentage change in seizure frequency, and defined it as the cut-point for which specificity and sensitivity were equal or most similar.

Caregivers and investigators provided CGI-I assessments for 112 patients and 114 patients, respectively. The receiver operating characteristic analysis identified a 44% reduction in seizure frequency as a clinically meaningful cutoff point for caregiver and investigator assessments. Using this threshold, 75%, 46%, and 12.5% of patients in the 0.8-mg/kg per day, 0.2-mg/kg per day, and placebo groups, respectively, achieved a clinically meaningful reduction from baseline in seizure frequency in the phase III study.

“The use of external anchors is one method to define a clinically meaningful change in seizure frequency,” said Dr. Gammaitoni. “Having a defined minimum clinically important difference like this allows clinicians to assess impacts of treatments on an individual patient basis.... This is a chance for others to do similar types of analyses to confirm the findings that we have had in this first study with bigger data sets, in terms of using external anchors and data to define what a clinically meaningful change is.”

Zogenix, which is developing the fenfluramine formulation examined in this study, provided funding for this research.
 

egreb@mdedge.com

SOURCE: Nabbout R et al. AES 2018, Abstract 3.202.

NEW ORLEANS – For patients with Dravet syndrome, a 44% or greater reduction in seizure frequency can be considered a clinically meaningful response, according to a study described at the annual meeting of the American Epilepsy Society. A reduction in seizure frequency of between 60% and 68% is associated with Clinical Global Impression of Improvement (CGI-I) ratings of “very much improved,” as assessed by caregivers and investigators.

“Further analyses from other phase III studies in Dravet syndrome and other patient populations should be performed to confirm these findings and explore other potential factors that contribute to caregiver and investigator CGI-I ratings, such as nonseizure outcomes and tolerability,” said Arnold Gammaitoni, PharmD, vice president of medical and scientific affairs at Zogenix in San Diego, and his colleagues.

A 50% reduction in seizure frequency is conventionally considered to be the cutoff for a clinically meaningful change. To develop an evidence-based definition of clinically meaningful seizure reduction, Dr. Gammaitoni and colleagues examined data from a phase III, randomized, double-blind, placebo-controlled trial of fenfluramine HCl oral solution for the adjunctive treatment of seizures associated with Dravet syndrome. The investigators took an anchor-based approach and examined the percentage change in seizure frequency, along with caregiver and investigator CGI-I ratings.

A total of 119 patients with Dravet syndrome were enrolled and randomized in equal groups to placebo, 0.2 mg/kg per day of fenfluramine HCl, or 0.8 mg/kg per day of fenfluramine HCl. After a 2-week titration period, patients entered a 12-week maintenance period. Patients in the 0.8-mg/kg per day group had a 63.9% greater reduction in seizure frequency than controls did.

After the 14-week titration and maintenance period, caregivers and investigators rated the change in participants’ clinical status from baseline, using the CGI-I scale, on which responses range from 1 (very much improved) to 7 (very much worse). The investigators considered patients with CGI-I scores of 1 or 2 (much improved) to have achieved a clinically meaningful response. A score of 3 (minimally improved) was not considered meaningful. The researchers pooled the results of the three treatment groups for this analysis. They estimated the clinically meaningful percentage change in seizure frequency using receiver operating characteristic analysis of binary CGI-I score, compared with percentage change in seizure frequency, and defined it as the cut-point for which specificity and sensitivity were equal or most similar.

Caregivers and investigators provided CGI-I assessments for 112 patients and 114 patients, respectively. The receiver operating characteristic analysis identified a 44% reduction in seizure frequency as a clinically meaningful cutoff point for caregiver and investigator assessments. Using this threshold, 75%, 46%, and 12.5% of patients in the 0.8-mg/kg per day, 0.2-mg/kg per day, and placebo groups, respectively, achieved a clinically meaningful reduction from baseline in seizure frequency in the phase III study.

“The use of external anchors is one method to define a clinically meaningful change in seizure frequency,” said Dr. Gammaitoni. “Having a defined minimum clinically important difference like this allows clinicians to assess impacts of treatments on an individual patient basis.... This is a chance for others to do similar types of analyses to confirm the findings that we have had in this first study with bigger data sets, in terms of using external anchors and data to define what a clinically meaningful change is.”

Zogenix, which is developing the fenfluramine formulation examined in this study, provided funding for this research.
 

egreb@mdedge.com

SOURCE: Nabbout R et al. AES 2018, Abstract 3.202.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Individuals who have both an elevated lipoprotein levels and a family history of coronary heart disease are at a considerably higher long-term risk for ASCVD. Also today, a device malfunction muddles results for insulin inhaler for Alzheimer’s, it’s time for universal hepatitis C virus screening in the ED, and there is a date for the 2019 Sickle Cell Disease guidelines.

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Individuals who have both an elevated lipoprotein levels and a family history of coronary heart disease are at a considerably higher long-term risk for ASCVD. Also today, a device malfunction muddles results for insulin inhaler for Alzheimer’s, it’s time for universal hepatitis C virus screening in the ED, and there is a date for the 2019 Sickle Cell Disease guidelines.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Individuals who have both an elevated lipoprotein levels and a family history of coronary heart disease are at a considerably higher long-term risk for ASCVD. Also today, a device malfunction muddles results for insulin inhaler for Alzheimer’s, it’s time for universal hepatitis C virus screening in the ED, and there is a date for the 2019 Sickle Cell Disease guidelines.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

CHICAGO – Stroke patients in low to middle income care settings may frequently fail to get timely evidence-based treatments when they’re admitted to the hospital and even when they’re discharged, but a large South American study found that an “all-or-none” approach to a multistep quality-improvement program led to a significant increase in therapy adherence and smoking cessation. The results were reported at the American Heart Association scientific sessions.

“A multifaceted quality-improvement intervention did not result in a significant increase in the composite adherence score for evidence-based therapies in patients with acute ischemic stroke [AIS] or transient ischemic attack [TIA],” said M. Julia Machline-Carrion, MD, PhD, principal investigator of the BRIDGE-Stroke study and a cardiologist at the Hospital for Heart in São Paulo. “However, when using a more conservative ‘all-or-none’ approach of complete adherence, the intervention resulted in improved adherence to evidence-based therapies.”

The quality-improvement program also resulted in a significant increase in the use of thrombolysis and uptake in smoking cessation education by study participants, Dr. Machline-Carrion added.

The study randomized 1,624 patients with AIS or TIA to the multifaceted quality-improvement intervention or routine practice. The intervention consisted of a patient identification system (wristband and printed reminders), a therapeutic plan road map and checklist, case management, educational materials, interactive workshops, and periodic audit and feedback reports to each participating cluster. Colored wristbands were to help promptly identify AIS or TIA patients in the emergency department and other departments they may have been sent to later on, such as the ICU, to avoid delays in initiating recommended therapies.

On average, the composite adherence score was 85.3% for those in the intervention group vs. 77.8% for controls, Dr. Machline-Carrion said. The composite adherence score consisted of 10 quality measures, ranging from early antithrombotics and prophylaxis for deep vein thrombosis to anticoagulation for atrial fibrillation or flutter, and smoking cessation education. “There was no statistically significant difference in the composite adherence score between the intervention group and the usual-care group,” she said.

However, when the researchers applied the all-or-none model – that is, complete adherence to all 10 in-hospital quality measures – the results were strikingly different, Dr. Machline-Carrion said. “Patients in the intervention group were more likely to receive all eligible therapies,” she said: 49.2% vs. 25.3%.

“Despite the established efficacy of several interventions for the management of patients with acute ischemic stroke and transient ischemic attack, the uptake of evidence-based measures remains suboptimal, especially in low- and middle-income countries,” Dr. Machline-Carrion said.

The BRIDGE-Stroke study involved 36 hospitals in Brazil, Argentina, and Peru with full emergency department coverage, central nervous system imaging, and access to recombinant tissue plasminogen activator therapies.

Dr. Machline-Carrion disclosed financial relationships with Amgen and Boehringer Ingelheim. The Brazil Ministry of Health was the lead sponsor of the study.

SOURCE: Machline-Carrion MJ et al. AHA scientific sessions, Abstract 19361.

CHICAGO – Stroke patients in low to middle income care settings may frequently fail to get timely evidence-based treatments when they’re admitted to the hospital and even when they’re discharged, but a large South American study found that an “all-or-none” approach to a multistep quality-improvement program led to a significant increase in therapy adherence and smoking cessation. The results were reported at the American Heart Association scientific sessions.

“A multifaceted quality-improvement intervention did not result in a significant increase in the composite adherence score for evidence-based therapies in patients with acute ischemic stroke [AIS] or transient ischemic attack [TIA],” said M. Julia Machline-Carrion, MD, PhD, principal investigator of the BRIDGE-Stroke study and a cardiologist at the Hospital for Heart in São Paulo. “However, when using a more conservative ‘all-or-none’ approach of complete adherence, the intervention resulted in improved adherence to evidence-based therapies.”

The quality-improvement program also resulted in a significant increase in the use of thrombolysis and uptake in smoking cessation education by study participants, Dr. Machline-Carrion added.

The study randomized 1,624 patients with AIS or TIA to the multifaceted quality-improvement intervention or routine practice. The intervention consisted of a patient identification system (wristband and printed reminders), a therapeutic plan road map and checklist, case management, educational materials, interactive workshops, and periodic audit and feedback reports to each participating cluster. Colored wristbands were to help promptly identify AIS or TIA patients in the emergency department and other departments they may have been sent to later on, such as the ICU, to avoid delays in initiating recommended therapies.

On average, the composite adherence score was 85.3% for those in the intervention group vs. 77.8% for controls, Dr. Machline-Carrion said. The composite adherence score consisted of 10 quality measures, ranging from early antithrombotics and prophylaxis for deep vein thrombosis to anticoagulation for atrial fibrillation or flutter, and smoking cessation education. “There was no statistically significant difference in the composite adherence score between the intervention group and the usual-care group,” she said.

However, when the researchers applied the all-or-none model – that is, complete adherence to all 10 in-hospital quality measures – the results were strikingly different, Dr. Machline-Carrion said. “Patients in the intervention group were more likely to receive all eligible therapies,” she said: 49.2% vs. 25.3%.

“Despite the established efficacy of several interventions for the management of patients with acute ischemic stroke and transient ischemic attack, the uptake of evidence-based measures remains suboptimal, especially in low- and middle-income countries,” Dr. Machline-Carrion said.

The BRIDGE-Stroke study involved 36 hospitals in Brazil, Argentina, and Peru with full emergency department coverage, central nervous system imaging, and access to recombinant tissue plasminogen activator therapies.

Dr. Machline-Carrion disclosed financial relationships with Amgen and Boehringer Ingelheim. The Brazil Ministry of Health was the lead sponsor of the study.

SOURCE: Machline-Carrion MJ et al. AHA scientific sessions, Abstract 19361.

CHICAGO – Stroke patients in low to middle income care settings may frequently fail to get timely evidence-based treatments when they’re admitted to the hospital and even when they’re discharged, but a large South American study found that an “all-or-none” approach to a multistep quality-improvement program led to a significant increase in therapy adherence and smoking cessation. The results were reported at the American Heart Association scientific sessions.

“A multifaceted quality-improvement intervention did not result in a significant increase in the composite adherence score for evidence-based therapies in patients with acute ischemic stroke [AIS] or transient ischemic attack [TIA],” said M. Julia Machline-Carrion, MD, PhD, principal investigator of the BRIDGE-Stroke study and a cardiologist at the Hospital for Heart in São Paulo. “However, when using a more conservative ‘all-or-none’ approach of complete adherence, the intervention resulted in improved adherence to evidence-based therapies.”

The quality-improvement program also resulted in a significant increase in the use of thrombolysis and uptake in smoking cessation education by study participants, Dr. Machline-Carrion added.

The study randomized 1,624 patients with AIS or TIA to the multifaceted quality-improvement intervention or routine practice. The intervention consisted of a patient identification system (wristband and printed reminders), a therapeutic plan road map and checklist, case management, educational materials, interactive workshops, and periodic audit and feedback reports to each participating cluster. Colored wristbands were to help promptly identify AIS or TIA patients in the emergency department and other departments they may have been sent to later on, such as the ICU, to avoid delays in initiating recommended therapies.

On average, the composite adherence score was 85.3% for those in the intervention group vs. 77.8% for controls, Dr. Machline-Carrion said. The composite adherence score consisted of 10 quality measures, ranging from early antithrombotics and prophylaxis for deep vein thrombosis to anticoagulation for atrial fibrillation or flutter, and smoking cessation education. “There was no statistically significant difference in the composite adherence score between the intervention group and the usual-care group,” she said.

However, when the researchers applied the all-or-none model – that is, complete adherence to all 10 in-hospital quality measures – the results were strikingly different, Dr. Machline-Carrion said. “Patients in the intervention group were more likely to receive all eligible therapies,” she said: 49.2% vs. 25.3%.

“Despite the established efficacy of several interventions for the management of patients with acute ischemic stroke and transient ischemic attack, the uptake of evidence-based measures remains suboptimal, especially in low- and middle-income countries,” Dr. Machline-Carrion said.

The BRIDGE-Stroke study involved 36 hospitals in Brazil, Argentina, and Peru with full emergency department coverage, central nervous system imaging, and access to recombinant tissue plasminogen activator therapies.

Dr. Machline-Carrion disclosed financial relationships with Amgen and Boehringer Ingelheim. The Brazil Ministry of Health was the lead sponsor of the study.

SOURCE: Machline-Carrion MJ et al. AHA scientific sessions, Abstract 19361.

It’s happened. A patient is suing you. Now what? Legal experts warn that a doctor’s first steps after a lawsuit can dramatically impact the outcome of the case – for better or worse.

Below, medical malpractice defense attorneys share the most important do’s and don’ts for physicians after they receive a lawsuit notice. Spoiler: Whatever you do, don’t ignore the summons.

• Do contact your insurer and/or risk manager. Once you receive notice of a lawsuit, the first step is calling your medical malpractice insurer and/or risk manager, said Steven Fitzer, a medical liability defense attorney based in Tacoma, Wash. The insurer and risk manager will take the matter from there and advise your next moves. Resist the urge to disregard the notice and hope that the challenge goes away when the patient is no longer angry, he said. Failing to notify the insurer in a timely manner could be a policy violation and affect current or future coverage.

• Don’t contact the plaintiff/patient or patient’s family. Instinctively, many physicians feel compelled to call the patient and attempt to settle the conflict verbally, particularly if they have had a longstanding relationship, Mr. Fitzer said in an interview. Don’t do it.

“In 42 years, I’ve never come across a physician who successfully talked somebody out of a lawsuit, once it was started,” he said. “It’s a pipe dream.”

Keep in mind that conversations with patients after a lawsuit filing can be used against doctors in court and certain words can easily be misconstrued as admissions of guilt.

• Do secure all medical records pertaining to the case. Obtain and print copies of all information relevant to the patient’s suit, such as history, billing records, letters, and medical chart. Store the data in a secure location in preparation for transferring to the insurer and/or attorney, said Michael Moroney, a medical liability defense attorney based in Teaneck, N.J.

• Don’t access or change the record. It may seem tempting to review the plaintiff’s medical record and fix any errors found. However, accessing the patient’s electronic data can appear as an attempt to manipulate or delete relevant data, said Joshua R. Cohen, a medical liability defense attorney based in New York.

“Avoid accessing [the] EMR or PAC system [and] leaving a digital fingerprint,” he said in an interview. “For example, if a radiologist is sued for an alleged failure to diagnose breast cancer, they should not open that study on their computer as an audit trail will show that. Worse is when they start making measurements after the lawsuit which are now discoverable as part of the lawsuit.”

Leave the record alone and let the attorneys handle the data from here on out, he advised.

• Do discuss the patient case openly with your attorney and risk manager. Honesty about all aspects of a medical case from the start sets the right tone for a positive relationship between doctor and attorney, experts say. Help your attorney understand the medicine so that they can speak intelligently about the details to the court and any retained experts, Mr. Fitzer recommended. If disagreements continually arise among physicians and attorneys, and the match fails, consider speaking to the insurer about a change in attorneys.

• Don’t discuss the case. As Mr. Fitzer puts it, “loose lips sink ships.” Physicians lose confidentiality protections when they talk about lawsuit details with third parties, and those conversations could come back to haunt them. This includes colleagues and staff members in the patient’s care loop, said Catherine Flynn, a medical liability defense attorney based in Teaneck, N.J. The third parties could later be questioned by the plaintiff’s attorney about the case, which could harm your defense.

"It’s like that kid game of telephone where you may something to the nurses and then a year later, they’re deposed, and their recollection is very different,” Ms. Flynn said in an interview. “It turns into something that you did not say.”

Your spouse is the exception. Most states protect conversations among spouses and bar husbands and wives from having to testify against their spouse.

• Do alert staff to the lawsuit and track any document requests. Following a lawsuit notice, inform staff that a claim has been filed by a patient – without going into detail. Be alert to document requests by nonpatients and make sure your attorney is aware of such requests. For example, some plaintiffs hire a private investigator to contact the medical practice and attempt to obtain records, Mr. Moroney said. In other cases, the plaintiff’s attorney or their paralegal tries to get copies of the medical chart or billing records.

• Don’t release any patient data to third parties. Ensure that staff members do not provide any patient information to the plaintiff’s attorney or other third parties, Mr. Moroney said. All relevant records should go through your attorney. No questions about the patient or the circumstances of the complaint should be divulged by the doctor or staff members to any third party, he said.

• Do seek emotional support from family and friends. Facing a lawsuit can be draining, both physically and mentally. Make time for self-care and lean on loved ones when needed, Mr. Fitzer said. Sharing your feelings – without going into detail about the case – can help relieve stress and reduce the emotional strain of being sued.

• Don’t isolate yourself. “This can be an isolating experience,” Mr. Fitzer said. “You need support. You need reinforcements. Take care of yourself and your family – they are your biggest source of support.”

It’s happened. A patient is suing you. Now what? Legal experts warn that a doctor’s first steps after a lawsuit can dramatically impact the outcome of the case – for better or worse.

Below, medical malpractice defense attorneys share the most important do’s and don’ts for physicians after they receive a lawsuit notice. Spoiler: Whatever you do, don’t ignore the summons.

• Do contact your insurer and/or risk manager. Once you receive notice of a lawsuit, the first step is calling your medical malpractice insurer and/or risk manager, said Steven Fitzer, a medical liability defense attorney based in Tacoma, Wash. The insurer and risk manager will take the matter from there and advise your next moves. Resist the urge to disregard the notice and hope that the challenge goes away when the patient is no longer angry, he said. Failing to notify the insurer in a timely manner could be a policy violation and affect current or future coverage.

• Don’t contact the plaintiff/patient or patient’s family. Instinctively, many physicians feel compelled to call the patient and attempt to settle the conflict verbally, particularly if they have had a longstanding relationship, Mr. Fitzer said in an interview. Don’t do it.

“In 42 years, I’ve never come across a physician who successfully talked somebody out of a lawsuit, once it was started,” he said. “It’s a pipe dream.”

Keep in mind that conversations with patients after a lawsuit filing can be used against doctors in court and certain words can easily be misconstrued as admissions of guilt.

• Do secure all medical records pertaining to the case. Obtain and print copies of all information relevant to the patient’s suit, such as history, billing records, letters, and medical chart. Store the data in a secure location in preparation for transferring to the insurer and/or attorney, said Michael Moroney, a medical liability defense attorney based in Teaneck, N.J.

• Don’t access or change the record. It may seem tempting to review the plaintiff’s medical record and fix any errors found. However, accessing the patient’s electronic data can appear as an attempt to manipulate or delete relevant data, said Joshua R. Cohen, a medical liability defense attorney based in New York.

“Avoid accessing [the] EMR or PAC system [and] leaving a digital fingerprint,” he said in an interview. “For example, if a radiologist is sued for an alleged failure to diagnose breast cancer, they should not open that study on their computer as an audit trail will show that. Worse is when they start making measurements after the lawsuit which are now discoverable as part of the lawsuit.”

Leave the record alone and let the attorneys handle the data from here on out, he advised.

• Do discuss the patient case openly with your attorney and risk manager. Honesty about all aspects of a medical case from the start sets the right tone for a positive relationship between doctor and attorney, experts say. Help your attorney understand the medicine so that they can speak intelligently about the details to the court and any retained experts, Mr. Fitzer recommended. If disagreements continually arise among physicians and attorneys, and the match fails, consider speaking to the insurer about a change in attorneys.

• Don’t discuss the case. As Mr. Fitzer puts it, “loose lips sink ships.” Physicians lose confidentiality protections when they talk about lawsuit details with third parties, and those conversations could come back to haunt them. This includes colleagues and staff members in the patient’s care loop, said Catherine Flynn, a medical liability defense attorney based in Teaneck, N.J. The third parties could later be questioned by the plaintiff’s attorney about the case, which could harm your defense.

"It’s like that kid game of telephone where you may something to the nurses and then a year later, they’re deposed, and their recollection is very different,” Ms. Flynn said in an interview. “It turns into something that you did not say.”

Your spouse is the exception. Most states protect conversations among spouses and bar husbands and wives from having to testify against their spouse.

• Do alert staff to the lawsuit and track any document requests. Following a lawsuit notice, inform staff that a claim has been filed by a patient – without going into detail. Be alert to document requests by nonpatients and make sure your attorney is aware of such requests. For example, some plaintiffs hire a private investigator to contact the medical practice and attempt to obtain records, Mr. Moroney said. In other cases, the plaintiff’s attorney or their paralegal tries to get copies of the medical chart or billing records.

• Don’t release any patient data to third parties. Ensure that staff members do not provide any patient information to the plaintiff’s attorney or other third parties, Mr. Moroney said. All relevant records should go through your attorney. No questions about the patient or the circumstances of the complaint should be divulged by the doctor or staff members to any third party, he said.

• Do seek emotional support from family and friends. Facing a lawsuit can be draining, both physically and mentally. Make time for self-care and lean on loved ones when needed, Mr. Fitzer said. Sharing your feelings – without going into detail about the case – can help relieve stress and reduce the emotional strain of being sued.

• Don’t isolate yourself. “This can be an isolating experience,” Mr. Fitzer said. “You need support. You need reinforcements. Take care of yourself and your family – they are your biggest source of support.”

It’s happened. A patient is suing you. Now what? Legal experts warn that a doctor’s first steps after a lawsuit can dramatically impact the outcome of the case – for better or worse.

Below, medical malpractice defense attorneys share the most important do’s and don’ts for physicians after they receive a lawsuit notice. Spoiler: Whatever you do, don’t ignore the summons.

• Do contact your insurer and/or risk manager. Once you receive notice of a lawsuit, the first step is calling your medical malpractice insurer and/or risk manager, said Steven Fitzer, a medical liability defense attorney based in Tacoma, Wash. The insurer and risk manager will take the matter from there and advise your next moves. Resist the urge to disregard the notice and hope that the challenge goes away when the patient is no longer angry, he said. Failing to notify the insurer in a timely manner could be a policy violation and affect current or future coverage.

• Don’t contact the plaintiff/patient or patient’s family. Instinctively, many physicians feel compelled to call the patient and attempt to settle the conflict verbally, particularly if they have had a longstanding relationship, Mr. Fitzer said in an interview. Don’t do it.

“In 42 years, I’ve never come across a physician who successfully talked somebody out of a lawsuit, once it was started,” he said. “It’s a pipe dream.”

Keep in mind that conversations with patients after a lawsuit filing can be used against doctors in court and certain words can easily be misconstrued as admissions of guilt.

• Do secure all medical records pertaining to the case. Obtain and print copies of all information relevant to the patient’s suit, such as history, billing records, letters, and medical chart. Store the data in a secure location in preparation for transferring to the insurer and/or attorney, said Michael Moroney, a medical liability defense attorney based in Teaneck, N.J.

• Don’t access or change the record. It may seem tempting to review the plaintiff’s medical record and fix any errors found. However, accessing the patient’s electronic data can appear as an attempt to manipulate or delete relevant data, said Joshua R. Cohen, a medical liability defense attorney based in New York.

“Avoid accessing [the] EMR or PAC system [and] leaving a digital fingerprint,” he said in an interview. “For example, if a radiologist is sued for an alleged failure to diagnose breast cancer, they should not open that study on their computer as an audit trail will show that. Worse is when they start making measurements after the lawsuit which are now discoverable as part of the lawsuit.”

Leave the record alone and let the attorneys handle the data from here on out, he advised.

• Do discuss the patient case openly with your attorney and risk manager. Honesty about all aspects of a medical case from the start sets the right tone for a positive relationship between doctor and attorney, experts say. Help your attorney understand the medicine so that they can speak intelligently about the details to the court and any retained experts, Mr. Fitzer recommended. If disagreements continually arise among physicians and attorneys, and the match fails, consider speaking to the insurer about a change in attorneys.

• Don’t discuss the case. As Mr. Fitzer puts it, “loose lips sink ships.” Physicians lose confidentiality protections when they talk about lawsuit details with third parties, and those conversations could come back to haunt them. This includes colleagues and staff members in the patient’s care loop, said Catherine Flynn, a medical liability defense attorney based in Teaneck, N.J. The third parties could later be questioned by the plaintiff’s attorney about the case, which could harm your defense.

"It’s like that kid game of telephone where you may something to the nurses and then a year later, they’re deposed, and their recollection is very different,” Ms. Flynn said in an interview. “It turns into something that you did not say.”

Your spouse is the exception. Most states protect conversations among spouses and bar husbands and wives from having to testify against their spouse.

• Do alert staff to the lawsuit and track any document requests. Following a lawsuit notice, inform staff that a claim has been filed by a patient – without going into detail. Be alert to document requests by nonpatients and make sure your attorney is aware of such requests. For example, some plaintiffs hire a private investigator to contact the medical practice and attempt to obtain records, Mr. Moroney said. In other cases, the plaintiff’s attorney or their paralegal tries to get copies of the medical chart or billing records.

• Don’t release any patient data to third parties. Ensure that staff members do not provide any patient information to the plaintiff’s attorney or other third parties, Mr. Moroney said. All relevant records should go through your attorney. No questions about the patient or the circumstances of the complaint should be divulged by the doctor or staff members to any third party, he said.

• Do seek emotional support from family and friends. Facing a lawsuit can be draining, both physically and mentally. Make time for self-care and lean on loved ones when needed, Mr. Fitzer said. Sharing your feelings – without going into detail about the case – can help relieve stress and reduce the emotional strain of being sued.

• Don’t isolate yourself. “This can be an isolating experience,” Mr. Fitzer said. “You need support. You need reinforcements. Take care of yourself and your family – they are your biggest source of support.”

A new federal proposal aims to move you away from the keyboard and back face-to-face with your patients.

The draft strategy from the Office of the National Coordinator for Health IT has three aims: to reduce the time and effort to record information in EHRs; to reduce the time and effort required to meet regulatory requirements; and to improve the functionality and ease of use of EHRs.

“This draft strategy includes recommendations that will allow physicians and other clinicians to provide effective care to their patients with a renewed sense of satisfaction for them and their patients,” Andrew Gettinger, MD, chief clinical officer at ONC, and Kate Goodrich, MD, chief medical officer at the Centers for Medicare & Medicaid Services, wrote in a recent blog post. “We are taking one more step toward improving the interoperability and usability of health information by establishing a goal, strategy, and recommendations to reduce regulatory and administrative burdens relating to the use of EHRs.”

To ease documentation burdens, the proposal seeks to “mitigate the EHR-related burden associated with a variety of administrative processes,” the draft strategy notes. “We are considering how reforming certain administrative requirements or optimizing out-of-date requirements for health IT–enabled health care provider work flows can reduce the burden of clinical documentation.”

Specifically, ONC proposes to reduce the overall regulatory burden, leverage data present in the electronic record to reduce the redocumentation, waive certain documentation requirements for participants in advanced alternative payment models (APMs), and promote standardized documentation for ordering and prior authorization.

To improve health IT usability, the draft strategy aims to “address how improvements in the design and use of health IT systems” can reduce burden and calls on clinicians, software developers, and other vendors to collaborate.

To do so, ONC recommends better alignment between EHR design and clinical work flow and making improvements to clinical decision support, as well as improving the presentation of clinical data within EHRs and clinical documentation functionality.

ONC also recommends standardizing basic clinical operations across all EHRs, designing EHR interfaces that are standard to health care delivery, and better integration of the EHR with the exam room.

The draft strategy also includes recommendations to help doctors better understand the financial requirements for successful implementation and optimize the log-in procedures to help reduce burden.

thinkstockphotos.com

EHR reporting strategies “are designed to address many of the programmatic, technical, and operational challenges raised by stakeholders to reduce EHR-related burden associated with program reporting.”

ONC wants to simplify scoring for the “promoting interoperability” performance category in the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program and improving other measures of health IT usage; applying additional data standards to make data access, extraction, and integration across multiple systems easier and less costly; and exploring alternate, less burdensome approaches to electronic quality measurement through pilot programs and reporting program incentives.

Finally, public health reporting strategies “look at a set of topics linked to federal, state, local, territorial, and tribal government policies and public health programs, with a specific focus on EPCS [electronic prescribing for controlled substances] and PDMPs [prescription drug monitoring programs]. Where EHR-related burden remains a key barrier to progress in these areas, there are several recommendations for how stakeholders can advance these burden reduction goals related to public health.”

In this area, ONC is recommending increasing adoption of e-prescribing of controlled substances with access to medication history to better inform prescribing of controlled substances, harmonizing reporting requirements across federally funded programs to streamline reporting requirements, and providing better guidance about HIPPA and federal confidentially requirements governing substance abuse disorder to better facilitate the electronic exchange of health information for patient care.

Comments on the report may be submitted electronically through Jan. 28, 2019.

gtwachtman@mdedge.com

A new federal proposal aims to move you away from the keyboard and back face-to-face with your patients.

The draft strategy from the Office of the National Coordinator for Health IT has three aims: to reduce the time and effort to record information in EHRs; to reduce the time and effort required to meet regulatory requirements; and to improve the functionality and ease of use of EHRs.

“This draft strategy includes recommendations that will allow physicians and other clinicians to provide effective care to their patients with a renewed sense of satisfaction for them and their patients,” Andrew Gettinger, MD, chief clinical officer at ONC, and Kate Goodrich, MD, chief medical officer at the Centers for Medicare & Medicaid Services, wrote in a recent blog post. “We are taking one more step toward improving the interoperability and usability of health information by establishing a goal, strategy, and recommendations to reduce regulatory and administrative burdens relating to the use of EHRs.”

To ease documentation burdens, the proposal seeks to “mitigate the EHR-related burden associated with a variety of administrative processes,” the draft strategy notes. “We are considering how reforming certain administrative requirements or optimizing out-of-date requirements for health IT–enabled health care provider work flows can reduce the burden of clinical documentation.”

Specifically, ONC proposes to reduce the overall regulatory burden, leverage data present in the electronic record to reduce the redocumentation, waive certain documentation requirements for participants in advanced alternative payment models (APMs), and promote standardized documentation for ordering and prior authorization.

To improve health IT usability, the draft strategy aims to “address how improvements in the design and use of health IT systems” can reduce burden and calls on clinicians, software developers, and other vendors to collaborate.

To do so, ONC recommends better alignment between EHR design and clinical work flow and making improvements to clinical decision support, as well as improving the presentation of clinical data within EHRs and clinical documentation functionality.

ONC also recommends standardizing basic clinical operations across all EHRs, designing EHR interfaces that are standard to health care delivery, and better integration of the EHR with the exam room.

The draft strategy also includes recommendations to help doctors better understand the financial requirements for successful implementation and optimize the log-in procedures to help reduce burden.

thinkstockphotos.com

EHR reporting strategies “are designed to address many of the programmatic, technical, and operational challenges raised by stakeholders to reduce EHR-related burden associated with program reporting.”

ONC wants to simplify scoring for the “promoting interoperability” performance category in the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program and improving other measures of health IT usage; applying additional data standards to make data access, extraction, and integration across multiple systems easier and less costly; and exploring alternate, less burdensome approaches to electronic quality measurement through pilot programs and reporting program incentives.

Finally, public health reporting strategies “look at a set of topics linked to federal, state, local, territorial, and tribal government policies and public health programs, with a specific focus on EPCS [electronic prescribing for controlled substances] and PDMPs [prescription drug monitoring programs]. Where EHR-related burden remains a key barrier to progress in these areas, there are several recommendations for how stakeholders can advance these burden reduction goals related to public health.”

In this area, ONC is recommending increasing adoption of e-prescribing of controlled substances with access to medication history to better inform prescribing of controlled substances, harmonizing reporting requirements across federally funded programs to streamline reporting requirements, and providing better guidance about HIPPA and federal confidentially requirements governing substance abuse disorder to better facilitate the electronic exchange of health information for patient care.

Comments on the report may be submitted electronically through Jan. 28, 2019.

gtwachtman@mdedge.com

A new federal proposal aims to move you away from the keyboard and back face-to-face with your patients.

The draft strategy from the Office of the National Coordinator for Health IT has three aims: to reduce the time and effort to record information in EHRs; to reduce the time and effort required to meet regulatory requirements; and to improve the functionality and ease of use of EHRs.

“This draft strategy includes recommendations that will allow physicians and other clinicians to provide effective care to their patients with a renewed sense of satisfaction for them and their patients,” Andrew Gettinger, MD, chief clinical officer at ONC, and Kate Goodrich, MD, chief medical officer at the Centers for Medicare & Medicaid Services, wrote in a recent blog post. “We are taking one more step toward improving the interoperability and usability of health information by establishing a goal, strategy, and recommendations to reduce regulatory and administrative burdens relating to the use of EHRs.”

To ease documentation burdens, the proposal seeks to “mitigate the EHR-related burden associated with a variety of administrative processes,” the draft strategy notes. “We are considering how reforming certain administrative requirements or optimizing out-of-date requirements for health IT–enabled health care provider work flows can reduce the burden of clinical documentation.”

Specifically, ONC proposes to reduce the overall regulatory burden, leverage data present in the electronic record to reduce the redocumentation, waive certain documentation requirements for participants in advanced alternative payment models (APMs), and promote standardized documentation for ordering and prior authorization.

To improve health IT usability, the draft strategy aims to “address how improvements in the design and use of health IT systems” can reduce burden and calls on clinicians, software developers, and other vendors to collaborate.

To do so, ONC recommends better alignment between EHR design and clinical work flow and making improvements to clinical decision support, as well as improving the presentation of clinical data within EHRs and clinical documentation functionality.

ONC also recommends standardizing basic clinical operations across all EHRs, designing EHR interfaces that are standard to health care delivery, and better integration of the EHR with the exam room.

The draft strategy also includes recommendations to help doctors better understand the financial requirements for successful implementation and optimize the log-in procedures to help reduce burden.

thinkstockphotos.com

EHR reporting strategies “are designed to address many of the programmatic, technical, and operational challenges raised by stakeholders to reduce EHR-related burden associated with program reporting.”

ONC wants to simplify scoring for the “promoting interoperability” performance category in the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program and improving other measures of health IT usage; applying additional data standards to make data access, extraction, and integration across multiple systems easier and less costly; and exploring alternate, less burdensome approaches to electronic quality measurement through pilot programs and reporting program incentives.

Finally, public health reporting strategies “look at a set of topics linked to federal, state, local, territorial, and tribal government policies and public health programs, with a specific focus on EPCS [electronic prescribing for controlled substances] and PDMPs [prescription drug monitoring programs]. Where EHR-related burden remains a key barrier to progress in these areas, there are several recommendations for how stakeholders can advance these burden reduction goals related to public health.”

In this area, ONC is recommending increasing adoption of e-prescribing of controlled substances with access to medication history to better inform prescribing of controlled substances, harmonizing reporting requirements across federally funded programs to streamline reporting requirements, and providing better guidance about HIPPA and federal confidentially requirements governing substance abuse disorder to better facilitate the electronic exchange of health information for patient care.

Comments on the report may be submitted electronically through Jan. 28, 2019.

gtwachtman@mdedge.com

I’m getting old and starting to fall apart. Recently, I suffered a lumbar radiculopathy when I injured myself sneezing. (No, really, I did.)

lolostock/Thinkstock

So, as time went by and I didn’t get better, I began looking stuff up. When patients come to me for this, I go through the standard conservative regimen of NSAIDs, physical therapy, steroid tapers ... the standard stuff.

But, when I began looking these things up, I was surprised to find out how much of what we do (at least for lumbar radiculopathy) is taken on faith.

I went through UpToDate, the modern Bible of medicine.

NSAIDs and acetaminophen, to my surprise, have only marginal proof of efficacy for acute lumbosacral radiculopathy pain. Several pooled analyses showed a nonsignificant trend to support their use, and the quality of the data was considered to be low.

Likewise, physical therapy also had “no convincing evidence that such treatments are effective for this indication.” Admittedly, some of the data may be affected by the difficulty in doing sham therapy as part of a placebo controlled-trial.

An oral steroid taper? Again, similar, equivocal data. Marginal improvement in functional capabilities, no improvement in pain, and no improvement in the rate of surgery at 1 year out.

But these are the things that I, and likely most family doctors, physiatrists, and other neurologists recommend on a daily basis. And, in all likelihood, will continue to do so.

Why?

Overall, they are benign when used correctly and in the right patients. That isn’t to say everyone should get them. All drugs have issues, and patients have to be carefully matched to specific treatments.

But, in the grand scheme of “do no harm,” physical therapy, NSAIDs, acetaminophen, or a few days of steroids are reasonably harmless. There certainly are some patients who will benefit, and none of these approaches have clearly been shown to be dangerous.

There’s also patient expectations. They didn’t come to us, or shell out a copay, to be told that “nothing helps, give it time.” We’re the doctors, and they want us to DO SOMETHING. So even if these treatments may be placebos, they still help if for no other reason than (as Voltaire said) to amuse the patient while nature cures the disease.

And getting them better is, after all, a big part of our job.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m getting old and starting to fall apart. Recently, I suffered a lumbar radiculopathy when I injured myself sneezing. (No, really, I did.)

lolostock/Thinkstock

So, as time went by and I didn’t get better, I began looking stuff up. When patients come to me for this, I go through the standard conservative regimen of NSAIDs, physical therapy, steroid tapers ... the standard stuff.

But, when I began looking these things up, I was surprised to find out how much of what we do (at least for lumbar radiculopathy) is taken on faith.

I went through UpToDate, the modern Bible of medicine.

NSAIDs and acetaminophen, to my surprise, have only marginal proof of efficacy for acute lumbosacral radiculopathy pain. Several pooled analyses showed a nonsignificant trend to support their use, and the quality of the data was considered to be low.

Likewise, physical therapy also had “no convincing evidence that such treatments are effective for this indication.” Admittedly, some of the data may be affected by the difficulty in doing sham therapy as part of a placebo controlled-trial.

An oral steroid taper? Again, similar, equivocal data. Marginal improvement in functional capabilities, no improvement in pain, and no improvement in the rate of surgery at 1 year out.

But these are the things that I, and likely most family doctors, physiatrists, and other neurologists recommend on a daily basis. And, in all likelihood, will continue to do so.

Why?

Overall, they are benign when used correctly and in the right patients. That isn’t to say everyone should get them. All drugs have issues, and patients have to be carefully matched to specific treatments.

But, in the grand scheme of “do no harm,” physical therapy, NSAIDs, acetaminophen, or a few days of steroids are reasonably harmless. There certainly are some patients who will benefit, and none of these approaches have clearly been shown to be dangerous.

There’s also patient expectations. They didn’t come to us, or shell out a copay, to be told that “nothing helps, give it time.” We’re the doctors, and they want us to DO SOMETHING. So even if these treatments may be placebos, they still help if for no other reason than (as Voltaire said) to amuse the patient while nature cures the disease.

And getting them better is, after all, a big part of our job.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m getting old and starting to fall apart. Recently, I suffered a lumbar radiculopathy when I injured myself sneezing. (No, really, I did.)

lolostock/Thinkstock

So, as time went by and I didn’t get better, I began looking stuff up. When patients come to me for this, I go through the standard conservative regimen of NSAIDs, physical therapy, steroid tapers ... the standard stuff.

But, when I began looking these things up, I was surprised to find out how much of what we do (at least for lumbar radiculopathy) is taken on faith.

I went through UpToDate, the modern Bible of medicine.

NSAIDs and acetaminophen, to my surprise, have only marginal proof of efficacy for acute lumbosacral radiculopathy pain. Several pooled analyses showed a nonsignificant trend to support their use, and the quality of the data was considered to be low.

Likewise, physical therapy also had “no convincing evidence that such treatments are effective for this indication.” Admittedly, some of the data may be affected by the difficulty in doing sham therapy as part of a placebo controlled-trial.

An oral steroid taper? Again, similar, equivocal data. Marginal improvement in functional capabilities, no improvement in pain, and no improvement in the rate of surgery at 1 year out.

But these are the things that I, and likely most family doctors, physiatrists, and other neurologists recommend on a daily basis. And, in all likelihood, will continue to do so.

Why?

Overall, they are benign when used correctly and in the right patients. That isn’t to say everyone should get them. All drugs have issues, and patients have to be carefully matched to specific treatments.

But, in the grand scheme of “do no harm,” physical therapy, NSAIDs, acetaminophen, or a few days of steroids are reasonably harmless. There certainly are some patients who will benefit, and none of these approaches have clearly been shown to be dangerous.

There’s also patient expectations. They didn’t come to us, or shell out a copay, to be told that “nothing helps, give it time.” We’re the doctors, and they want us to DO SOMETHING. So even if these treatments may be placebos, they still help if for no other reason than (as Voltaire said) to amuse the patient while nature cures the disease.

And getting them better is, after all, a big part of our job.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A crimson November San Diego sunset over the Pacific Ocean. Seeing your parents dance on their 50th wedding anniversary. A stein of cold Oktoberfest beer. Your car, freshly detailed. Your name written in black ink on a Starbucks Pumpkin Latte. A nicely everted surgical wound.

The smile on your daughter’s face when descending the stairs after a huge trick-or-treat score. A perfectly arranged Mayo stand, oh, exactly as you like it. An empty EMR in basket. A flap close on the nose that closes just so.

A Red Sox World series win (again). Lollipop lamb chops sizzling on the grill on a chilly Saturday tailgating morning. The answer to 14 down that leads to all the other answers you’ve desperately been trying to solve. The “ting” sound that Mimosa glasses make toasting Sunday brunch with friends. The next episode of Black Mirror launching automatically. A brilliant orange maple tree against a brilliant blue sky. The fissures on the crust of a still-warm loaf of Italian bread.

An elderly woman, her husband, daughter, and son-in-law who waited weeks and traveled miles to see you because they know you care. And they insist on seeing only you. A man who comes to see you without his wife this time just because he wanted to tell you in person how much they appreciated your care for her in the end. Opening your mailbox to see the September issue of Vogue, waiting for you to tear off the plastic. An as-yet-untouched Sunday New York Times. The sound of wood popping in the fireplace. The string of melted marshmallow down your son’s arm still attached to a s’more at the other end. 7-7-7 on your dollar slot at the casino. Eight-year-old girls at the center of the field celebrating a Sunday morning soccer victory. Departures showing your flight, gate 8, on time.

The smell of incense. The smell of lightly roasting garlic and olive oil. The smell of your wife’s perfume. The smell of wet leaves. The smell of your favorite scented candle. The smell of burning firewood on an early-morning walk in the Rockies. Snow falling. Snow crunching under your feet. Snow melting.

Remembering the uproarious laughter after your belly flop into the pool back in July. Steph Curry shooting a 3 in slow motion. Snoopy floating over 5th Avenue on Thanksgiving morning. The sound of wrapping paper being stuffed into garbage bags when the opening is done. A prior auth letter of approval. The feeling when you turn that first page of a brand-new Stephen King book. The feel of the grip on your fairway wood. Seeing your favorite movie pop up on Amazon Prime. The head massage your stylist gives you when washing your hair. The near pain of a really good massage.

The warmth of a child on your lap. The bark your dog gives when he sees you for the first time today as if it has been a million years. The crack of your favorite beer can opening. The ding when your microwave popcorn is ready. That warm feeling when you realize that, no, you don’t need any filter for that picture, it is ready to post exactly the way it is. The smile on your medical assistant’s face when you hand her a gratitude card. The ping that an email makes when you’re dying to hear back. The pride you feel when you execute a downward-facing dog and the instructor tells everyone to do it just like you. The smell of balsam fir. A podcast episode so good, you sit in your driveway to finish listening. A patient with a delightful British accent. The feel of pasta dough in your hands after adding just the right amount of flour and water so it’s now ready to go. Watching the Red Sox win the World Series (Wait, did I say that already?). The sound of your laptop keyboard clicking away while you write this piece. The feeling that 2019 is going to be your best year ever.



So what are the beautiful things in your life? Sit down right now and list a few (or a lot) of them. I promise it will be a more beautiful place where you are when you’re done.
 

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

A crimson November San Diego sunset over the Pacific Ocean. Seeing your parents dance on their 50th wedding anniversary. A stein of cold Oktoberfest beer. Your car, freshly detailed. Your name written in black ink on a Starbucks Pumpkin Latte. A nicely everted surgical wound.

The smile on your daughter’s face when descending the stairs after a huge trick-or-treat score. A perfectly arranged Mayo stand, oh, exactly as you like it. An empty EMR in basket. A flap close on the nose that closes just so.

A Red Sox World series win (again). Lollipop lamb chops sizzling on the grill on a chilly Saturday tailgating morning. The answer to 14 down that leads to all the other answers you’ve desperately been trying to solve. The “ting” sound that Mimosa glasses make toasting Sunday brunch with friends. The next episode of Black Mirror launching automatically. A brilliant orange maple tree against a brilliant blue sky. The fissures on the crust of a still-warm loaf of Italian bread.

An elderly woman, her husband, daughter, and son-in-law who waited weeks and traveled miles to see you because they know you care. And they insist on seeing only you. A man who comes to see you without his wife this time just because he wanted to tell you in person how much they appreciated your care for her in the end. Opening your mailbox to see the September issue of Vogue, waiting for you to tear off the plastic. An as-yet-untouched Sunday New York Times. The sound of wood popping in the fireplace. The string of melted marshmallow down your son’s arm still attached to a s’more at the other end. 7-7-7 on your dollar slot at the casino. Eight-year-old girls at the center of the field celebrating a Sunday morning soccer victory. Departures showing your flight, gate 8, on time.

The smell of incense. The smell of lightly roasting garlic and olive oil. The smell of your wife’s perfume. The smell of wet leaves. The smell of your favorite scented candle. The smell of burning firewood on an early-morning walk in the Rockies. Snow falling. Snow crunching under your feet. Snow melting.

Remembering the uproarious laughter after your belly flop into the pool back in July. Steph Curry shooting a 3 in slow motion. Snoopy floating over 5th Avenue on Thanksgiving morning. The sound of wrapping paper being stuffed into garbage bags when the opening is done. A prior auth letter of approval. The feeling when you turn that first page of a brand-new Stephen King book. The feel of the grip on your fairway wood. Seeing your favorite movie pop up on Amazon Prime. The head massage your stylist gives you when washing your hair. The near pain of a really good massage.

The warmth of a child on your lap. The bark your dog gives when he sees you for the first time today as if it has been a million years. The crack of your favorite beer can opening. The ding when your microwave popcorn is ready. That warm feeling when you realize that, no, you don’t need any filter for that picture, it is ready to post exactly the way it is. The smile on your medical assistant’s face when you hand her a gratitude card. The ping that an email makes when you’re dying to hear back. The pride you feel when you execute a downward-facing dog and the instructor tells everyone to do it just like you. The smell of balsam fir. A podcast episode so good, you sit in your driveway to finish listening. A patient with a delightful British accent. The feel of pasta dough in your hands after adding just the right amount of flour and water so it’s now ready to go. Watching the Red Sox win the World Series (Wait, did I say that already?). The sound of your laptop keyboard clicking away while you write this piece. The feeling that 2019 is going to be your best year ever.



So what are the beautiful things in your life? Sit down right now and list a few (or a lot) of them. I promise it will be a more beautiful place where you are when you’re done.
 

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

A crimson November San Diego sunset over the Pacific Ocean. Seeing your parents dance on their 50th wedding anniversary. A stein of cold Oktoberfest beer. Your car, freshly detailed. Your name written in black ink on a Starbucks Pumpkin Latte. A nicely everted surgical wound.

The smile on your daughter’s face when descending the stairs after a huge trick-or-treat score. A perfectly arranged Mayo stand, oh, exactly as you like it. An empty EMR in basket. A flap close on the nose that closes just so.

A Red Sox World series win (again). Lollipop lamb chops sizzling on the grill on a chilly Saturday tailgating morning. The answer to 14 down that leads to all the other answers you’ve desperately been trying to solve. The “ting” sound that Mimosa glasses make toasting Sunday brunch with friends. The next episode of Black Mirror launching automatically. A brilliant orange maple tree against a brilliant blue sky. The fissures on the crust of a still-warm loaf of Italian bread.

An elderly woman, her husband, daughter, and son-in-law who waited weeks and traveled miles to see you because they know you care. And they insist on seeing only you. A man who comes to see you without his wife this time just because he wanted to tell you in person how much they appreciated your care for her in the end. Opening your mailbox to see the September issue of Vogue, waiting for you to tear off the plastic. An as-yet-untouched Sunday New York Times. The sound of wood popping in the fireplace. The string of melted marshmallow down your son’s arm still attached to a s’more at the other end. 7-7-7 on your dollar slot at the casino. Eight-year-old girls at the center of the field celebrating a Sunday morning soccer victory. Departures showing your flight, gate 8, on time.

The smell of incense. The smell of lightly roasting garlic and olive oil. The smell of your wife’s perfume. The smell of wet leaves. The smell of your favorite scented candle. The smell of burning firewood on an early-morning walk in the Rockies. Snow falling. Snow crunching under your feet. Snow melting.

Remembering the uproarious laughter after your belly flop into the pool back in July. Steph Curry shooting a 3 in slow motion. Snoopy floating over 5th Avenue on Thanksgiving morning. The sound of wrapping paper being stuffed into garbage bags when the opening is done. A prior auth letter of approval. The feeling when you turn that first page of a brand-new Stephen King book. The feel of the grip on your fairway wood. Seeing your favorite movie pop up on Amazon Prime. The head massage your stylist gives you when washing your hair. The near pain of a really good massage.

The warmth of a child on your lap. The bark your dog gives when he sees you for the first time today as if it has been a million years. The crack of your favorite beer can opening. The ding when your microwave popcorn is ready. That warm feeling when you realize that, no, you don’t need any filter for that picture, it is ready to post exactly the way it is. The smile on your medical assistant’s face when you hand her a gratitude card. The ping that an email makes when you’re dying to hear back. The pride you feel when you execute a downward-facing dog and the instructor tells everyone to do it just like you. The smell of balsam fir. A podcast episode so good, you sit in your driveway to finish listening. A patient with a delightful British accent. The feel of pasta dough in your hands after adding just the right amount of flour and water so it’s now ready to go. Watching the Red Sox win the World Series (Wait, did I say that already?). The sound of your laptop keyboard clicking away while you write this piece. The feeling that 2019 is going to be your best year ever.



So what are the beautiful things in your life? Sit down right now and list a few (or a lot) of them. I promise it will be a more beautiful place where you are when you’re done.
 

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

One in four patients with type 1 or 2 diabetes reported underusing insulin due to cost. Also today, methotrexate fails to cut cardiovascular events, a single-item scale is effective for assessing sleep quality, and deaths from opioid overdose for inpatients with sickle cell disease do not match those of general inpatients.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

One in four patients with type 1 or 2 diabetes reported underusing insulin due to cost. Also today, methotrexate fails to cut cardiovascular events, a single-item scale is effective for assessing sleep quality, and deaths from opioid overdose for inpatients with sickle cell disease do not match those of general inpatients.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

One in four patients with type 1 or 2 diabetes reported underusing insulin due to cost. Also today, methotrexate fails to cut cardiovascular events, a single-item scale is effective for assessing sleep quality, and deaths from opioid overdose for inpatients with sickle cell disease do not match those of general inpatients.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

BARCELONA – A malfunctioning inhaler may have scotched the results of an intranasal insulin study for patients with early Alzheimer’s disease – but in an unexpected way.

Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.

A secondary analysis of the ViaNase device subgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”

The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in JAMA Neurology. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.

The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.

“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery (POD) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.

The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.

Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.

At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.

The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.

Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.

The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.

Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.

msullivan@mdedge.com

SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9, Abstract OC2.

BARCELONA – A malfunctioning inhaler may have scotched the results of an intranasal insulin study for patients with early Alzheimer’s disease – but in an unexpected way.

Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.

A secondary analysis of the ViaNase device subgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”

The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in JAMA Neurology. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.

The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.

“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery (POD) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.

The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.

Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.

At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.

The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.

Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.

The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.

Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.

msullivan@mdedge.com

SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9, Abstract OC2.

BARCELONA – A malfunctioning inhaler may have scotched the results of an intranasal insulin study for patients with early Alzheimer’s disease – but in an unexpected way.

Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.

A secondary analysis of the ViaNase device subgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”

The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in JAMA Neurology. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.

The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.

“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery (POD) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.

The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.

Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.

At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.

The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.

Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.

The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.

Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.

msullivan@mdedge.com

SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9, Abstract OC2.