Pharmacology

BACKGROUND

The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for Veterans nationally. Program implementation at the Madison VA began in the hematology and oncology (hem/onc) clinics. In these clinics, PHASER test results are reviewed by the hem/onc clinical pharmacist practitioner (CPP) who provides recommendations regarding therapy via an electronic health record note. The purpose of this retrospective chart review was to assess the impact of the CPP on medication management informed by pharmacogenomics.

METHODS

A retrospective chart review was completed for all Veterans enrolled in hem/onc services and offered PHASER testing between April 1, 2022 and November 1, 2022. The number and type of interventions recommended by the hem/onc CPP, acceptance of recommended interventions, and hem/onc CPP time spent were collected for all patients who accepted and completed PHASER testing. Interventions were categorized and descriptive statistics were used to summarize data.

RESULTS

Of the 98 patients reviewed by the CPP, 75 (77%) were prescribed a medication with potential pharmacogenomic implications. At least one actionable recommendation for medication therapy adjustment was identified for 40 (53%) of those patients based on their pharmacogenomic test results. The CPP spent an average of 12 minutes per patient review (range 5 to 30 minutes) and 100% of CPP recommendations were accepted.

CONCLUSIONS

The CPP efficiently reviewed pharmacogenomic test results and made meaningful recommendations for medication therapy adjustments. CPP recommendations were highly accepted in the hem/onc setting.

BACKGROUND

The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for Veterans nationally. Program implementation at the Madison VA began in the hematology and oncology (hem/onc) clinics. In these clinics, PHASER test results are reviewed by the hem/onc clinical pharmacist practitioner (CPP) who provides recommendations regarding therapy via an electronic health record note. The purpose of this retrospective chart review was to assess the impact of the CPP on medication management informed by pharmacogenomics.

METHODS

A retrospective chart review was completed for all Veterans enrolled in hem/onc services and offered PHASER testing between April 1, 2022 and November 1, 2022. The number and type of interventions recommended by the hem/onc CPP, acceptance of recommended interventions, and hem/onc CPP time spent were collected for all patients who accepted and completed PHASER testing. Interventions were categorized and descriptive statistics were used to summarize data.

RESULTS

Of the 98 patients reviewed by the CPP, 75 (77%) were prescribed a medication with potential pharmacogenomic implications. At least one actionable recommendation for medication therapy adjustment was identified for 40 (53%) of those patients based on their pharmacogenomic test results. The CPP spent an average of 12 minutes per patient review (range 5 to 30 minutes) and 100% of CPP recommendations were accepted.

CONCLUSIONS

The CPP efficiently reviewed pharmacogenomic test results and made meaningful recommendations for medication therapy adjustments. CPP recommendations were highly accepted in the hem/onc setting.

BACKGROUND

The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for Veterans nationally. Program implementation at the Madison VA began in the hematology and oncology (hem/onc) clinics. In these clinics, PHASER test results are reviewed by the hem/onc clinical pharmacist practitioner (CPP) who provides recommendations regarding therapy via an electronic health record note. The purpose of this retrospective chart review was to assess the impact of the CPP on medication management informed by pharmacogenomics.

METHODS

A retrospective chart review was completed for all Veterans enrolled in hem/onc services and offered PHASER testing between April 1, 2022 and November 1, 2022. The number and type of interventions recommended by the hem/onc CPP, acceptance of recommended interventions, and hem/onc CPP time spent were collected for all patients who accepted and completed PHASER testing. Interventions were categorized and descriptive statistics were used to summarize data.

RESULTS

Of the 98 patients reviewed by the CPP, 75 (77%) were prescribed a medication with potential pharmacogenomic implications. At least one actionable recommendation for medication therapy adjustment was identified for 40 (53%) of those patients based on their pharmacogenomic test results. The CPP spent an average of 12 minutes per patient review (range 5 to 30 minutes) and 100% of CPP recommendations were accepted.

CONCLUSIONS

The CPP efficiently reviewed pharmacogenomic test results and made meaningful recommendations for medication therapy adjustments. CPP recommendations were highly accepted in the hem/onc setting.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

PURPOSE

This quality improvement project aimed at addressing the issue of long waiting times in the hematology/ oncology clinic at Stratton VA Medical Center, aiming to improve the delivery time of infusion drugs and enhance patient care.

BACKGROUND

Patient feedback indicated that long waiting times were a significant barrier to care, with 32% of patients identifying this as an issue. Prolonged wait times in the healthcare setting can have various negative consequences, including increased patient dissatisfaction, reduced patient engagement, compromised patient safety, and increased healthcare costs.

METHODS

An interdisciplinary team comprising physicians, nurses, and pharmacists conducted a study to identify the primary contributors to extended wait times. Inadequate preparation for patients with complex infusion needs and delays in administering premedications were identified as the key factors. Wait times were measured using two variables: Go To Label Print (GTLP) and Go To First Bag Scanned (GTFS). Baseline data were collected showing a median GTLP of 8 minutes and a median GTFS of 67 minutes.

DATA ANALYSIS

The team analyzed real-time data related to wait times and the impact of interventions.

RESULTS

Two interventions were implemented: 1) redistributing patients with complex needs across the schedule and 2) adding premedications to the automated medication dispensing system. Postintervention analysis revealed a significant improvement in wait times. The median GTLP decreased to 2 minutes, and the median GTFS reduced to 53 minutes, representing a 75% improvement in GTLP and a 21% improvement in GTFS. These changes are estimated to save 303 patient hours annually.

IMPLICATIONS

This quality improvement project highlighted the significance of addressing long wait times, as they can significantly impact patient care. The team’s efforts, including the analysis of real-time data, interprofessional collaboration, and the implementation of sustainable changes through Plan-Do- Study-Act cycles, successfully improved infusion drug delivery time. These findings and interventions can serve as a model for other healthcare facilities seeking to streamline workflow in infusion centers and enhance patient care.

PURPOSE

This quality improvement project aimed at addressing the issue of long waiting times in the hematology/ oncology clinic at Stratton VA Medical Center, aiming to improve the delivery time of infusion drugs and enhance patient care.

BACKGROUND

Patient feedback indicated that long waiting times were a significant barrier to care, with 32% of patients identifying this as an issue. Prolonged wait times in the healthcare setting can have various negative consequences, including increased patient dissatisfaction, reduced patient engagement, compromised patient safety, and increased healthcare costs.

METHODS

An interdisciplinary team comprising physicians, nurses, and pharmacists conducted a study to identify the primary contributors to extended wait times. Inadequate preparation for patients with complex infusion needs and delays in administering premedications were identified as the key factors. Wait times were measured using two variables: Go To Label Print (GTLP) and Go To First Bag Scanned (GTFS). Baseline data were collected showing a median GTLP of 8 minutes and a median GTFS of 67 minutes.

DATA ANALYSIS

The team analyzed real-time data related to wait times and the impact of interventions.

RESULTS

Two interventions were implemented: 1) redistributing patients with complex needs across the schedule and 2) adding premedications to the automated medication dispensing system. Postintervention analysis revealed a significant improvement in wait times. The median GTLP decreased to 2 minutes, and the median GTFS reduced to 53 minutes, representing a 75% improvement in GTLP and a 21% improvement in GTFS. These changes are estimated to save 303 patient hours annually.

IMPLICATIONS

This quality improvement project highlighted the significance of addressing long wait times, as they can significantly impact patient care. The team’s efforts, including the analysis of real-time data, interprofessional collaboration, and the implementation of sustainable changes through Plan-Do- Study-Act cycles, successfully improved infusion drug delivery time. These findings and interventions can serve as a model for other healthcare facilities seeking to streamline workflow in infusion centers and enhance patient care.

PURPOSE

This quality improvement project aimed at addressing the issue of long waiting times in the hematology/ oncology clinic at Stratton VA Medical Center, aiming to improve the delivery time of infusion drugs and enhance patient care.

BACKGROUND

Patient feedback indicated that long waiting times were a significant barrier to care, with 32% of patients identifying this as an issue. Prolonged wait times in the healthcare setting can have various negative consequences, including increased patient dissatisfaction, reduced patient engagement, compromised patient safety, and increased healthcare costs.

METHODS

An interdisciplinary team comprising physicians, nurses, and pharmacists conducted a study to identify the primary contributors to extended wait times. Inadequate preparation for patients with complex infusion needs and delays in administering premedications were identified as the key factors. Wait times were measured using two variables: Go To Label Print (GTLP) and Go To First Bag Scanned (GTFS). Baseline data were collected showing a median GTLP of 8 minutes and a median GTFS of 67 minutes.

DATA ANALYSIS

The team analyzed real-time data related to wait times and the impact of interventions.

RESULTS

Two interventions were implemented: 1) redistributing patients with complex needs across the schedule and 2) adding premedications to the automated medication dispensing system. Postintervention analysis revealed a significant improvement in wait times. The median GTLP decreased to 2 minutes, and the median GTFS reduced to 53 minutes, representing a 75% improvement in GTLP and a 21% improvement in GTFS. These changes are estimated to save 303 patient hours annually.

IMPLICATIONS

This quality improvement project highlighted the significance of addressing long wait times, as they can significantly impact patient care. The team’s efforts, including the analysis of real-time data, interprofessional collaboration, and the implementation of sustainable changes through Plan-Do- Study-Act cycles, successfully improved infusion drug delivery time. These findings and interventions can serve as a model for other healthcare facilities seeking to streamline workflow in infusion centers and enhance patient care.

PURPOSE

To evaluate if low molecular weight iron dextran (LMWID) is a safe and effective alternative to iron sucrose for intravenous iron administration.

BACKGROUND

In recent years, intravenous iron administration has increased due to clinical indications and rapid iron repletion. Early IV iron formulations had safety concerns that precluded widespread use. High molecular weight iron dextran was removed from the US market in 2009 due to safety concerns. Since then, several new IV formulations including LMWID and iron sucrose have been approved with a favorable benefit risk profile. While recent evidence and guidelines indicate that LMWID and other iron formulations have comparable safety profiles, no head-to-head comparisons exist. Both iron sucrose and LMWID are used for the treatment of IDA in Veterans Affairs hospitals. Iron sucrose is given 200 mg weekly for 5 weeks, while LMWID is given as a single 1-gram dose over 3 hours. We conducted a retrospective crosssectional analysis to compare the safety and efficacy of IV LMWID to IV iron sucrose.

METHODS

We identified 129 patients (LMWID: n=29, iron sucrose: n=100) who received intravenous iron from 01/01/2022 to 03/03/2023. To match the sample size, we selected every 3rd patient from the iron sucrose group (n=33). We captured data on infusion-related reactions, history of asthma/inflammatory bowel disease/> 2 drug allergies, overall and ≥ 2 g/dL hemoglobin increase, and treatment cost. Descriptive statistics were used to describe the safety and efficacy parameters. An unpaired t-test was used to calculate statistical significance of the cost.

RESULTS

We found that 82.7% of the patients who received LMWID had an increase in hemoglobin vs. 60.6% in the iron sucrose group. 48.3% of patients in LMWID had ≥ 2 hemoglobin increases vs. 27.3% in the iron sucrose group. The cost for LMWID administration was $2016.10, compared to $2315.40 for administration of IV iron sucrose cost. Two-tailed p value < 0.0001 indicating the observed difference to be statistically significant. No infusion reactions were observed in both groups.

CONCLUSIONS

In this single center analysis, IV LMWID administered provided comparable safety, and improved effectiveness, and cost-effectiveness to iron sucrose.

PURPOSE

To evaluate if low molecular weight iron dextran (LMWID) is a safe and effective alternative to iron sucrose for intravenous iron administration.

BACKGROUND

In recent years, intravenous iron administration has increased due to clinical indications and rapid iron repletion. Early IV iron formulations had safety concerns that precluded widespread use. High molecular weight iron dextran was removed from the US market in 2009 due to safety concerns. Since then, several new IV formulations including LMWID and iron sucrose have been approved with a favorable benefit risk profile. While recent evidence and guidelines indicate that LMWID and other iron formulations have comparable safety profiles, no head-to-head comparisons exist. Both iron sucrose and LMWID are used for the treatment of IDA in Veterans Affairs hospitals. Iron sucrose is given 200 mg weekly for 5 weeks, while LMWID is given as a single 1-gram dose over 3 hours. We conducted a retrospective crosssectional analysis to compare the safety and efficacy of IV LMWID to IV iron sucrose.

METHODS

We identified 129 patients (LMWID: n=29, iron sucrose: n=100) who received intravenous iron from 01/01/2022 to 03/03/2023. To match the sample size, we selected every 3rd patient from the iron sucrose group (n=33). We captured data on infusion-related reactions, history of asthma/inflammatory bowel disease/> 2 drug allergies, overall and ≥ 2 g/dL hemoglobin increase, and treatment cost. Descriptive statistics were used to describe the safety and efficacy parameters. An unpaired t-test was used to calculate statistical significance of the cost.

RESULTS

We found that 82.7% of the patients who received LMWID had an increase in hemoglobin vs. 60.6% in the iron sucrose group. 48.3% of patients in LMWID had ≥ 2 hemoglobin increases vs. 27.3% in the iron sucrose group. The cost for LMWID administration was $2016.10, compared to $2315.40 for administration of IV iron sucrose cost. Two-tailed p value < 0.0001 indicating the observed difference to be statistically significant. No infusion reactions were observed in both groups.

CONCLUSIONS

In this single center analysis, IV LMWID administered provided comparable safety, and improved effectiveness, and cost-effectiveness to iron sucrose.

PURPOSE

To evaluate if low molecular weight iron dextran (LMWID) is a safe and effective alternative to iron sucrose for intravenous iron administration.

BACKGROUND

In recent years, intravenous iron administration has increased due to clinical indications and rapid iron repletion. Early IV iron formulations had safety concerns that precluded widespread use. High molecular weight iron dextran was removed from the US market in 2009 due to safety concerns. Since then, several new IV formulations including LMWID and iron sucrose have been approved with a favorable benefit risk profile. While recent evidence and guidelines indicate that LMWID and other iron formulations have comparable safety profiles, no head-to-head comparisons exist. Both iron sucrose and LMWID are used for the treatment of IDA in Veterans Affairs hospitals. Iron sucrose is given 200 mg weekly for 5 weeks, while LMWID is given as a single 1-gram dose over 3 hours. We conducted a retrospective crosssectional analysis to compare the safety and efficacy of IV LMWID to IV iron sucrose.

METHODS

We identified 129 patients (LMWID: n=29, iron sucrose: n=100) who received intravenous iron from 01/01/2022 to 03/03/2023. To match the sample size, we selected every 3rd patient from the iron sucrose group (n=33). We captured data on infusion-related reactions, history of asthma/inflammatory bowel disease/> 2 drug allergies, overall and ≥ 2 g/dL hemoglobin increase, and treatment cost. Descriptive statistics were used to describe the safety and efficacy parameters. An unpaired t-test was used to calculate statistical significance of the cost.

RESULTS

We found that 82.7% of the patients who received LMWID had an increase in hemoglobin vs. 60.6% in the iron sucrose group. 48.3% of patients in LMWID had ≥ 2 hemoglobin increases vs. 27.3% in the iron sucrose group. The cost for LMWID administration was $2016.10, compared to $2315.40 for administration of IV iron sucrose cost. Two-tailed p value < 0.0001 indicating the observed difference to be statistically significant. No infusion reactions were observed in both groups.

CONCLUSIONS

In this single center analysis, IV LMWID administered provided comparable safety, and improved effectiveness, and cost-effectiveness to iron sucrose.

BACKGROUND/PURPOSE

Tumor lysis syndrome (TLS) occurs when malignant cells rapidly break down. This may lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypocalcemia. Rasburicase reduces uric acid in cancer patients undergoing anti-cancer therapy. However, caution is required as rasburicase is contraindicated for patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency due to the increased risk of hemolysis. G6PD deficiency is more prevalent among African Americans (AA), affecting approximately 12% of this population. The FDA recommends testing for G6PD deficiency in higher risk groups before administering rasburicase.

METHODS

A retrospective analysis was conducted at the Louis Stokes Cleveland VAMC from February 1, 2018, to January 31, 2023 addressing appropriate use of rasburicase and incidence of G6PD deficiency and hemolysis. Appropriate use was defined by: TLS (2 or more: uric acid ≥ 8 or 25% increase; K+ ≥ 6.0 or 25% increase; Phos > 4.5mg/dL, or 25% increase; or calcium < 7, or 25% decrease, from baseline) or at high risk for TLS (CLL: venetoclax use w/lymph node > 10cm or WBC > 25k and elevated uric acid; AML: WBC > 100k; ALL: WBC > 100k and LDH 2x ULN; Burkitt lymphoma: LDH 2x ULN).

RESULTS

50 patients were identified who received rasburicase. 21/50 (42%) did not meet criteria for appropriate use. 44/50 (88%) underwent G6PD testing. The average time from G6PD testing order to obtaining the results was 3.4 days; 18/50 patients (36%) had G6PD resulted prior to rasburicase administration, and 26 patients (52%) received rasburicase prior to G6PD results. Overall, 13/50 (26%) were AA. Of the AA pts, 12/13 (92%) were tested for G6PD. Of these 12, 1/12 was found to be G6PD deficient and this patient experienced G6PD deficiency-induced hemolysis after rasburicase. None of the non-AA pts (0/31) tested were found to be G6PD deficient.

IMPLICATIONS

There was a high (42%) level of inappropriate use of rasburicase. G6PD deficiency was uncommon and only found in the AA population. To reduce inappropriate use, rasburicase orders will be restricted to medical oncology. G6PD testing will be limited to AA pts, with pathology to develop a rapid turnaround time for results prior to rasburicase administration to prevent hemolysis.

BACKGROUND/PURPOSE

Tumor lysis syndrome (TLS) occurs when malignant cells rapidly break down. This may lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypocalcemia. Rasburicase reduces uric acid in cancer patients undergoing anti-cancer therapy. However, caution is required as rasburicase is contraindicated for patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency due to the increased risk of hemolysis. G6PD deficiency is more prevalent among African Americans (AA), affecting approximately 12% of this population. The FDA recommends testing for G6PD deficiency in higher risk groups before administering rasburicase.

METHODS

A retrospective analysis was conducted at the Louis Stokes Cleveland VAMC from February 1, 2018, to January 31, 2023 addressing appropriate use of rasburicase and incidence of G6PD deficiency and hemolysis. Appropriate use was defined by: TLS (2 or more: uric acid ≥ 8 or 25% increase; K+ ≥ 6.0 or 25% increase; Phos > 4.5mg/dL, or 25% increase; or calcium < 7, or 25% decrease, from baseline) or at high risk for TLS (CLL: venetoclax use w/lymph node > 10cm or WBC > 25k and elevated uric acid; AML: WBC > 100k; ALL: WBC > 100k and LDH 2x ULN; Burkitt lymphoma: LDH 2x ULN).

RESULTS

50 patients were identified who received rasburicase. 21/50 (42%) did not meet criteria for appropriate use. 44/50 (88%) underwent G6PD testing. The average time from G6PD testing order to obtaining the results was 3.4 days; 18/50 patients (36%) had G6PD resulted prior to rasburicase administration, and 26 patients (52%) received rasburicase prior to G6PD results. Overall, 13/50 (26%) were AA. Of the AA pts, 12/13 (92%) were tested for G6PD. Of these 12, 1/12 was found to be G6PD deficient and this patient experienced G6PD deficiency-induced hemolysis after rasburicase. None of the non-AA pts (0/31) tested were found to be G6PD deficient.

IMPLICATIONS

There was a high (42%) level of inappropriate use of rasburicase. G6PD deficiency was uncommon and only found in the AA population. To reduce inappropriate use, rasburicase orders will be restricted to medical oncology. G6PD testing will be limited to AA pts, with pathology to develop a rapid turnaround time for results prior to rasburicase administration to prevent hemolysis.

BACKGROUND/PURPOSE

Tumor lysis syndrome (TLS) occurs when malignant cells rapidly break down. This may lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypocalcemia. Rasburicase reduces uric acid in cancer patients undergoing anti-cancer therapy. However, caution is required as rasburicase is contraindicated for patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency due to the increased risk of hemolysis. G6PD deficiency is more prevalent among African Americans (AA), affecting approximately 12% of this population. The FDA recommends testing for G6PD deficiency in higher risk groups before administering rasburicase.

METHODS

A retrospective analysis was conducted at the Louis Stokes Cleveland VAMC from February 1, 2018, to January 31, 2023 addressing appropriate use of rasburicase and incidence of G6PD deficiency and hemolysis. Appropriate use was defined by: TLS (2 or more: uric acid ≥ 8 or 25% increase; K+ ≥ 6.0 or 25% increase; Phos > 4.5mg/dL, or 25% increase; or calcium < 7, or 25% decrease, from baseline) or at high risk for TLS (CLL: venetoclax use w/lymph node > 10cm or WBC > 25k and elevated uric acid; AML: WBC > 100k; ALL: WBC > 100k and LDH 2x ULN; Burkitt lymphoma: LDH 2x ULN).

RESULTS

50 patients were identified who received rasburicase. 21/50 (42%) did not meet criteria for appropriate use. 44/50 (88%) underwent G6PD testing. The average time from G6PD testing order to obtaining the results was 3.4 days; 18/50 patients (36%) had G6PD resulted prior to rasburicase administration, and 26 patients (52%) received rasburicase prior to G6PD results. Overall, 13/50 (26%) were AA. Of the AA pts, 12/13 (92%) were tested for G6PD. Of these 12, 1/12 was found to be G6PD deficient and this patient experienced G6PD deficiency-induced hemolysis after rasburicase. None of the non-AA pts (0/31) tested were found to be G6PD deficient.

IMPLICATIONS

There was a high (42%) level of inappropriate use of rasburicase. G6PD deficiency was uncommon and only found in the AA population. To reduce inappropriate use, rasburicase orders will be restricted to medical oncology. G6PD testing will be limited to AA pts, with pathology to develop a rapid turnaround time for results prior to rasburicase administration to prevent hemolysis.

BACKGROUND

Minimal residual disease (MRD) testing in myeloma has been shown to be a strong prognostic marker for progression-free and overall survival. Limited data suggest MRD results may also be useful for therapy discontinuation decisions. The clonoSEQ Assay utilizes next generation sequencing involving a bone marrow sample, obtained at the time of diagnosis, to identify patient-specific sequence(s).

DISCUSSION

The same methodology is then applied later to assess for MRD. Although widely adopted at most US academic centers, there has been limited use of MRD across VA centers. In 2022 the Cleveland Louis Stokes VAMC partnered with Adaptive Biotechnologies to develop a process for MRD/clonoSEQ testing in myeloma pts. Hematology, Pathology, Medicine, Administration and Adaptive Biotechnologies representatives met to develop a streamlined process for ordering, sample procurement, billing and result documentation. In 5/2022 the 1st specimen was sent. EQUATE is a national cooperative group trial requiring baseline clono- SEQ testing with a positive sequence ID. Daratumumab hyaluronidase (part of standard treatment) is provided to the institution at no cost on the trial but otherwise would cost the VA $5,797.38/dose. clonoSEQ costs VA $1950/test. There have been 14 specimens sent involving 12 pts: 12 baseline marrow and 2 for MRD (posttransplant). All of the baseline specimens were found to have an identifiable sequence. Both of the MRD tracking specimens were positive. The average turnaround time for clonoSEQ results was 13.2 days (range 7 to 18 days). 4 of the 12 pts with a positive initial clonoSEQ ID qualified for the EQUATE trial but would not have been deemed eligible without the baseline clonoSEQ results. 2 of these pts have enrolled on the trial and started treatment. Costs for 14 clonoSEQ tests: $27,300. Estimated cost savings for the 2 pts enrolled onto EQUATE: $127, 542.36/pt/year= $255,084.72/year. Overall cost savings: $227,784.72.

CONCLUSIONS

An efficient process for baseline and post-treatment (MRD) clonoSEQ testing in myeloma pts was developed. Although expensive, use of this test resulted in significant overall cost savings by allowing enrollment onto a clinical trial. In addition, if studies determine that negative MRD results can guide therapeutic decisions, use of clonoSEQ testing may result in further benefits.

BACKGROUND

Minimal residual disease (MRD) testing in myeloma has been shown to be a strong prognostic marker for progression-free and overall survival. Limited data suggest MRD results may also be useful for therapy discontinuation decisions. The clonoSEQ Assay utilizes next generation sequencing involving a bone marrow sample, obtained at the time of diagnosis, to identify patient-specific sequence(s).

DISCUSSION

The same methodology is then applied later to assess for MRD. Although widely adopted at most US academic centers, there has been limited use of MRD across VA centers. In 2022 the Cleveland Louis Stokes VAMC partnered with Adaptive Biotechnologies to develop a process for MRD/clonoSEQ testing in myeloma pts. Hematology, Pathology, Medicine, Administration and Adaptive Biotechnologies representatives met to develop a streamlined process for ordering, sample procurement, billing and result documentation. In 5/2022 the 1st specimen was sent. EQUATE is a national cooperative group trial requiring baseline clono- SEQ testing with a positive sequence ID. Daratumumab hyaluronidase (part of standard treatment) is provided to the institution at no cost on the trial but otherwise would cost the VA $5,797.38/dose. clonoSEQ costs VA $1950/test. There have been 14 specimens sent involving 12 pts: 12 baseline marrow and 2 for MRD (posttransplant). All of the baseline specimens were found to have an identifiable sequence. Both of the MRD tracking specimens were positive. The average turnaround time for clonoSEQ results was 13.2 days (range 7 to 18 days). 4 of the 12 pts with a positive initial clonoSEQ ID qualified for the EQUATE trial but would not have been deemed eligible without the baseline clonoSEQ results. 2 of these pts have enrolled on the trial and started treatment. Costs for 14 clonoSEQ tests: $27,300. Estimated cost savings for the 2 pts enrolled onto EQUATE: $127, 542.36/pt/year= $255,084.72/year. Overall cost savings: $227,784.72.

CONCLUSIONS

An efficient process for baseline and post-treatment (MRD) clonoSEQ testing in myeloma pts was developed. Although expensive, use of this test resulted in significant overall cost savings by allowing enrollment onto a clinical trial. In addition, if studies determine that negative MRD results can guide therapeutic decisions, use of clonoSEQ testing may result in further benefits.

BACKGROUND

Minimal residual disease (MRD) testing in myeloma has been shown to be a strong prognostic marker for progression-free and overall survival. Limited data suggest MRD results may also be useful for therapy discontinuation decisions. The clonoSEQ Assay utilizes next generation sequencing involving a bone marrow sample, obtained at the time of diagnosis, to identify patient-specific sequence(s).

DISCUSSION

The same methodology is then applied later to assess for MRD. Although widely adopted at most US academic centers, there has been limited use of MRD across VA centers. In 2022 the Cleveland Louis Stokes VAMC partnered with Adaptive Biotechnologies to develop a process for MRD/clonoSEQ testing in myeloma pts. Hematology, Pathology, Medicine, Administration and Adaptive Biotechnologies representatives met to develop a streamlined process for ordering, sample procurement, billing and result documentation. In 5/2022 the 1st specimen was sent. EQUATE is a national cooperative group trial requiring baseline clono- SEQ testing with a positive sequence ID. Daratumumab hyaluronidase (part of standard treatment) is provided to the institution at no cost on the trial but otherwise would cost the VA $5,797.38/dose. clonoSEQ costs VA $1950/test. There have been 14 specimens sent involving 12 pts: 12 baseline marrow and 2 for MRD (posttransplant). All of the baseline specimens were found to have an identifiable sequence. Both of the MRD tracking specimens were positive. The average turnaround time for clonoSEQ results was 13.2 days (range 7 to 18 days). 4 of the 12 pts with a positive initial clonoSEQ ID qualified for the EQUATE trial but would not have been deemed eligible without the baseline clonoSEQ results. 2 of these pts have enrolled on the trial and started treatment. Costs for 14 clonoSEQ tests: $27,300. Estimated cost savings for the 2 pts enrolled onto EQUATE: $127, 542.36/pt/year= $255,084.72/year. Overall cost savings: $227,784.72.

CONCLUSIONS

An efficient process for baseline and post-treatment (MRD) clonoSEQ testing in myeloma pts was developed. Although expensive, use of this test resulted in significant overall cost savings by allowing enrollment onto a clinical trial. In addition, if studies determine that negative MRD results can guide therapeutic decisions, use of clonoSEQ testing may result in further benefits.

A single dose of an experimental psilocybin drug offered significant sustained improvement in symptoms and disability in patients with major depressive disorder (MDD) over a 6-week period, results of a study suggest.

The randomized, phase 2 trial was conducted at 11 sites across the United States and is the latest to demonstrate the psychedelic drug’s potential as a treatment for depression.

The project was funded by Usona Institute, a nonprofit medical research organization based in Madison, Wisc. The institute issued a press statement, but researchers did not comment further on the findings.

“As the largest and most rigorous study conducted across a wide spectrum of individuals with major depressive disorder, the results show promise for all people struggling with this condition,” lead author Charles Raison, MD, director of clinical and translational research at Usona, said in the statement. 

The 34 coauthors on the study are affiliated with public universities, research centers, and private companies. Eight of the investigators are identified as employees of Usona Institute.

Declining further comment, an institute spokesperson told this news organization that, “Usona has chosen the approach of no interviews, and this applies for all coauthors.”

The findings were published online in JAMA.
 

Largest study to date

Usona’s investigational psilocybin drug has been granted a breakthrough designation by the Food and Drug Administration, a process designed to speed drug development and review.

Previous smaller studies have suggested a rapid antidepressant response with psilocybin, but they have been small, unblinded, and have had short duration of follow-up, they write. This randomized, double-blind, phase 2 clinical trial is the largest study of psilocybin for depression to date, the researchers note.

It included 104 adults aged 21-65 years with MDD who had a current depressive episode of at least 60 days and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 28 or more at baseline.

Participants had to be free of psychedelic drugs for at least 5 years, have had no active suicidal ideation or suicidal behavior in the prior 12 months, no personal or first-degree family history of psychosis or mania, and no history of moderate/severe alcohol or drug use disorder.

Before the study, participants had a 7- to 35-day screening period for psychiatric medication tapering, underwent baseline assessments, and received 6-8 hours of preparation with two facilitators who would be with them during dosing.

Dosing occurred within 7 days of baseline assessments. During the 6- to 8-hour session, participants received either a single 25-mg oral dose of psilocybin or 100-mg dose of niacin. One participant randomly assigned to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin.

Participants returned the next day, the next week, and then every 2 weeks for assessments, for a follow-up of 6 weeks.
 

Psychosocial support

Participants who received psilocybin reported significantly greater improvements in MDD symptoms, compared with those who received niacin. MADRS scores – a scale from 0 to 60 where higher scores indicate more severe depression – showed greater reductions with treatment vs. placebo at 8 days (mean difference, −12.0; 95% confidence interval, −16.6 to −7.4; P < .001), and at day 43 (mean difference, −12.3; 95% CI, −17.5 to −7.2; P < .001).

More participants receiving psilocybin had sustained depressive symptom response (42% vs. 11%; P = .002) and more improvement in the Sheehan Disability Scale score, which measures functional disability, 43 days after treatment (P < .001).

The effects persisted through the end of the study, although the differences between groups were no longer significant by week 6.

“This is another exciting piece of evidence that adds to the current literature regarding the potential efficacy of psilocybin for the treatment of mental health conditions, particularly depression,” said Greg Fonzo, MD, codirector of the Center for Psychedelic Research and Therapy at the University of Texas at Austin, who commented on the findings.

Significantly more people in the psilocybin group reported at least one treatment-related adverse event (AE, 82% vs. 44%), although most were mild to moderate. Headache and nausea were the most common side effects and most resolved within 1 day of dosing.

While those numbers are high, Dr. Fonzo said they’re not out of line with AEs reported in other studies.

“Particularly with the types of adverse events reported here, like headache and nausea, those are things you would typically expect to see in this treatment,” said Dr. Fonzo, who was not part of the research.

“But it is high, and it underscores that this is not a treatment without certain risks, even though it was good that they were primarily mild in severity,” he added.
 

A ‘stepping stone’ to FDA approval?

The use of tools to measure disability in addition to symptoms of depression severity is a strength of the study, Dr. Fonzo added. The use of an active comparator and the 6-week follow-up also offer something new over previous studies.

Despite the longer follow up, questions remain about the durability of response, something only a longer study could answer, Dr. Fonzo said. The small and homogeneous sample-size are also a concern. Nearly 90% of participants were White, and more than half had an income of $75,000 a year or higher.

“It’s another stepping stone in the process to FDA approval, but the next step in that process would be much larger phase 3 trials that would have much larger samples, a longer follow-up, and hopefully have a more inclusive swath of the population,” Dr. Fonzo said.

But perhaps one of the most significant limitations is the use of niacin as an active comparator, said Caleb Alexander, MD, codirector of the Center for Drug Safety and Effectiveness at Johns Hopkins University in Baltimore.

The use of an agent that doesn’t produce effects similar to those expected from a psychedelic introduced the potential for functional unblinding, Dr. Alexander said. Investigators did not ask participants to guess whether they received psilocybin or niacin, so the quality of the blinding was not assessed in the study.

“We’d like to see the use of [an] active comparator that might have a chance of obscuring to people as to whether they’ve been randomized to the treatment arm or control arm,” said Dr. Alexander, who wasn’t involved in the study. “Why not use a benzodiazepine or another drug that produces a transient euphoria that would better obscure whether or not people were receiving the psilocybin?”

The authors of an accompanying editorial shared these concerns, also noting that the study included “a significant number of patients who did not respond to therapy.”

“It is important to analyze and understand adverse outcomes in psychedelic trials and conduct longitudinal studies to determine how sustained the effects will be and what may initiate a recrudescence of symptoms,” write Rachel Yehuda, PhD, and Amy Lehrner, PhD, both of the Peters VA Medical Center and Icahn School of Medicine at Mount Sinai, New York.

“Future studies will help identify who is most likely to benefit from psychedelics, whether booster or repeated treatment is safe and beneficial, and what the optimal dose and therapeutic frameworks are.”

A long-term follow-up of the current trial was terminated last year because of low enrollment. The spokesperson with Usona Institute did not respond to questions about that study, and the institute’s statement only added that preparations are underway to launch another study that “will provide additional safety and efficacy data to support submission of a new drug application to the FDA.”

Usona published its manufacturing process that it used to synthesize psilocybin in an open-access journal and signed a statement on “open science and open praxis” with psilocybin and similar substances, which appears on their website. That statement was signed by 31 research and service organizations around the world and nearly 150 scientists, scholars, and practitioners.

The study was funded by Usona Institute. Dr. Raison reported receiving personal fees from Usona Institute and grants to Usona Institute from Dr. Bronner’s All-One, Fournier Family Foundation, Good Ventures, Steven and Alexandra Cohen Foundation, Tiny Blue Dot Foundation, Turnbull Family Foundation, and William A. Linton during the conduct of the study; and personal fees from Novartis, Sage/Biogen, Emory Healthcare, and Vail Health outside the submitted work. Dr. Fonzo and Dr. Alexander report no relevant financial relationships. Dr. Yehuda reports receiving nonfinancial support from the Multidisciplinary Association for Psychedelic Studies Public Benefit (MAPS PBC) and grants from COMPASS Pathways. Dr. Lehrner is an investigator on trials sponsored by MAPS PBC and COMPASS Pathways.

A version of this article first appeared on Medscape.com.

A single dose of an experimental psilocybin drug offered significant sustained improvement in symptoms and disability in patients with major depressive disorder (MDD) over a 6-week period, results of a study suggest.

The randomized, phase 2 trial was conducted at 11 sites across the United States and is the latest to demonstrate the psychedelic drug’s potential as a treatment for depression.

The project was funded by Usona Institute, a nonprofit medical research organization based in Madison, Wisc. The institute issued a press statement, but researchers did not comment further on the findings.

“As the largest and most rigorous study conducted across a wide spectrum of individuals with major depressive disorder, the results show promise for all people struggling with this condition,” lead author Charles Raison, MD, director of clinical and translational research at Usona, said in the statement. 

The 34 coauthors on the study are affiliated with public universities, research centers, and private companies. Eight of the investigators are identified as employees of Usona Institute.

Declining further comment, an institute spokesperson told this news organization that, “Usona has chosen the approach of no interviews, and this applies for all coauthors.”

The findings were published online in JAMA.
 

Largest study to date

Usona’s investigational psilocybin drug has been granted a breakthrough designation by the Food and Drug Administration, a process designed to speed drug development and review.

Previous smaller studies have suggested a rapid antidepressant response with psilocybin, but they have been small, unblinded, and have had short duration of follow-up, they write. This randomized, double-blind, phase 2 clinical trial is the largest study of psilocybin for depression to date, the researchers note.

It included 104 adults aged 21-65 years with MDD who had a current depressive episode of at least 60 days and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 28 or more at baseline.

Participants had to be free of psychedelic drugs for at least 5 years, have had no active suicidal ideation or suicidal behavior in the prior 12 months, no personal or first-degree family history of psychosis or mania, and no history of moderate/severe alcohol or drug use disorder.

Before the study, participants had a 7- to 35-day screening period for psychiatric medication tapering, underwent baseline assessments, and received 6-8 hours of preparation with two facilitators who would be with them during dosing.

Dosing occurred within 7 days of baseline assessments. During the 6- to 8-hour session, participants received either a single 25-mg oral dose of psilocybin or 100-mg dose of niacin. One participant randomly assigned to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin.

Participants returned the next day, the next week, and then every 2 weeks for assessments, for a follow-up of 6 weeks.
 

Psychosocial support

Participants who received psilocybin reported significantly greater improvements in MDD symptoms, compared with those who received niacin. MADRS scores – a scale from 0 to 60 where higher scores indicate more severe depression – showed greater reductions with treatment vs. placebo at 8 days (mean difference, −12.0; 95% confidence interval, −16.6 to −7.4; P < .001), and at day 43 (mean difference, −12.3; 95% CI, −17.5 to −7.2; P < .001).

More participants receiving psilocybin had sustained depressive symptom response (42% vs. 11%; P = .002) and more improvement in the Sheehan Disability Scale score, which measures functional disability, 43 days after treatment (P < .001).

The effects persisted through the end of the study, although the differences between groups were no longer significant by week 6.

“This is another exciting piece of evidence that adds to the current literature regarding the potential efficacy of psilocybin for the treatment of mental health conditions, particularly depression,” said Greg Fonzo, MD, codirector of the Center for Psychedelic Research and Therapy at the University of Texas at Austin, who commented on the findings.

Significantly more people in the psilocybin group reported at least one treatment-related adverse event (AE, 82% vs. 44%), although most were mild to moderate. Headache and nausea were the most common side effects and most resolved within 1 day of dosing.

While those numbers are high, Dr. Fonzo said they’re not out of line with AEs reported in other studies.

“Particularly with the types of adverse events reported here, like headache and nausea, those are things you would typically expect to see in this treatment,” said Dr. Fonzo, who was not part of the research.

“But it is high, and it underscores that this is not a treatment without certain risks, even though it was good that they were primarily mild in severity,” he added.
 

A ‘stepping stone’ to FDA approval?

The use of tools to measure disability in addition to symptoms of depression severity is a strength of the study, Dr. Fonzo added. The use of an active comparator and the 6-week follow-up also offer something new over previous studies.

Despite the longer follow up, questions remain about the durability of response, something only a longer study could answer, Dr. Fonzo said. The small and homogeneous sample-size are also a concern. Nearly 90% of participants were White, and more than half had an income of $75,000 a year or higher.

“It’s another stepping stone in the process to FDA approval, but the next step in that process would be much larger phase 3 trials that would have much larger samples, a longer follow-up, and hopefully have a more inclusive swath of the population,” Dr. Fonzo said.

But perhaps one of the most significant limitations is the use of niacin as an active comparator, said Caleb Alexander, MD, codirector of the Center for Drug Safety and Effectiveness at Johns Hopkins University in Baltimore.

The use of an agent that doesn’t produce effects similar to those expected from a psychedelic introduced the potential for functional unblinding, Dr. Alexander said. Investigators did not ask participants to guess whether they received psilocybin or niacin, so the quality of the blinding was not assessed in the study.

“We’d like to see the use of [an] active comparator that might have a chance of obscuring to people as to whether they’ve been randomized to the treatment arm or control arm,” said Dr. Alexander, who wasn’t involved in the study. “Why not use a benzodiazepine or another drug that produces a transient euphoria that would better obscure whether or not people were receiving the psilocybin?”

The authors of an accompanying editorial shared these concerns, also noting that the study included “a significant number of patients who did not respond to therapy.”

“It is important to analyze and understand adverse outcomes in psychedelic trials and conduct longitudinal studies to determine how sustained the effects will be and what may initiate a recrudescence of symptoms,” write Rachel Yehuda, PhD, and Amy Lehrner, PhD, both of the Peters VA Medical Center and Icahn School of Medicine at Mount Sinai, New York.

“Future studies will help identify who is most likely to benefit from psychedelics, whether booster or repeated treatment is safe and beneficial, and what the optimal dose and therapeutic frameworks are.”

A long-term follow-up of the current trial was terminated last year because of low enrollment. The spokesperson with Usona Institute did not respond to questions about that study, and the institute’s statement only added that preparations are underway to launch another study that “will provide additional safety and efficacy data to support submission of a new drug application to the FDA.”

Usona published its manufacturing process that it used to synthesize psilocybin in an open-access journal and signed a statement on “open science and open praxis” with psilocybin and similar substances, which appears on their website. That statement was signed by 31 research and service organizations around the world and nearly 150 scientists, scholars, and practitioners.

The study was funded by Usona Institute. Dr. Raison reported receiving personal fees from Usona Institute and grants to Usona Institute from Dr. Bronner’s All-One, Fournier Family Foundation, Good Ventures, Steven and Alexandra Cohen Foundation, Tiny Blue Dot Foundation, Turnbull Family Foundation, and William A. Linton during the conduct of the study; and personal fees from Novartis, Sage/Biogen, Emory Healthcare, and Vail Health outside the submitted work. Dr. Fonzo and Dr. Alexander report no relevant financial relationships. Dr. Yehuda reports receiving nonfinancial support from the Multidisciplinary Association for Psychedelic Studies Public Benefit (MAPS PBC) and grants from COMPASS Pathways. Dr. Lehrner is an investigator on trials sponsored by MAPS PBC and COMPASS Pathways.

A version of this article first appeared on Medscape.com.

A single dose of an experimental psilocybin drug offered significant sustained improvement in symptoms and disability in patients with major depressive disorder (MDD) over a 6-week period, results of a study suggest.

The randomized, phase 2 trial was conducted at 11 sites across the United States and is the latest to demonstrate the psychedelic drug’s potential as a treatment for depression.

The project was funded by Usona Institute, a nonprofit medical research organization based in Madison, Wisc. The institute issued a press statement, but researchers did not comment further on the findings.

“As the largest and most rigorous study conducted across a wide spectrum of individuals with major depressive disorder, the results show promise for all people struggling with this condition,” lead author Charles Raison, MD, director of clinical and translational research at Usona, said in the statement. 

The 34 coauthors on the study are affiliated with public universities, research centers, and private companies. Eight of the investigators are identified as employees of Usona Institute.

Declining further comment, an institute spokesperson told this news organization that, “Usona has chosen the approach of no interviews, and this applies for all coauthors.”

The findings were published online in JAMA.
 

Largest study to date

Usona’s investigational psilocybin drug has been granted a breakthrough designation by the Food and Drug Administration, a process designed to speed drug development and review.

Previous smaller studies have suggested a rapid antidepressant response with psilocybin, but they have been small, unblinded, and have had short duration of follow-up, they write. This randomized, double-blind, phase 2 clinical trial is the largest study of psilocybin for depression to date, the researchers note.

It included 104 adults aged 21-65 years with MDD who had a current depressive episode of at least 60 days and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 28 or more at baseline.

Participants had to be free of psychedelic drugs for at least 5 years, have had no active suicidal ideation or suicidal behavior in the prior 12 months, no personal or first-degree family history of psychosis or mania, and no history of moderate/severe alcohol or drug use disorder.

Before the study, participants had a 7- to 35-day screening period for psychiatric medication tapering, underwent baseline assessments, and received 6-8 hours of preparation with two facilitators who would be with them during dosing.

Dosing occurred within 7 days of baseline assessments. During the 6- to 8-hour session, participants received either a single 25-mg oral dose of psilocybin or 100-mg dose of niacin. One participant randomly assigned to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin.

Participants returned the next day, the next week, and then every 2 weeks for assessments, for a follow-up of 6 weeks.
 

Psychosocial support

Participants who received psilocybin reported significantly greater improvements in MDD symptoms, compared with those who received niacin. MADRS scores – a scale from 0 to 60 where higher scores indicate more severe depression – showed greater reductions with treatment vs. placebo at 8 days (mean difference, −12.0; 95% confidence interval, −16.6 to −7.4; P < .001), and at day 43 (mean difference, −12.3; 95% CI, −17.5 to −7.2; P < .001).

More participants receiving psilocybin had sustained depressive symptom response (42% vs. 11%; P = .002) and more improvement in the Sheehan Disability Scale score, which measures functional disability, 43 days after treatment (P < .001).

The effects persisted through the end of the study, although the differences between groups were no longer significant by week 6.

“This is another exciting piece of evidence that adds to the current literature regarding the potential efficacy of psilocybin for the treatment of mental health conditions, particularly depression,” said Greg Fonzo, MD, codirector of the Center for Psychedelic Research and Therapy at the University of Texas at Austin, who commented on the findings.

Significantly more people in the psilocybin group reported at least one treatment-related adverse event (AE, 82% vs. 44%), although most were mild to moderate. Headache and nausea were the most common side effects and most resolved within 1 day of dosing.

While those numbers are high, Dr. Fonzo said they’re not out of line with AEs reported in other studies.

“Particularly with the types of adverse events reported here, like headache and nausea, those are things you would typically expect to see in this treatment,” said Dr. Fonzo, who was not part of the research.

“But it is high, and it underscores that this is not a treatment without certain risks, even though it was good that they were primarily mild in severity,” he added.
 

A ‘stepping stone’ to FDA approval?

The use of tools to measure disability in addition to symptoms of depression severity is a strength of the study, Dr. Fonzo added. The use of an active comparator and the 6-week follow-up also offer something new over previous studies.

Despite the longer follow up, questions remain about the durability of response, something only a longer study could answer, Dr. Fonzo said. The small and homogeneous sample-size are also a concern. Nearly 90% of participants were White, and more than half had an income of $75,000 a year or higher.

“It’s another stepping stone in the process to FDA approval, but the next step in that process would be much larger phase 3 trials that would have much larger samples, a longer follow-up, and hopefully have a more inclusive swath of the population,” Dr. Fonzo said.

But perhaps one of the most significant limitations is the use of niacin as an active comparator, said Caleb Alexander, MD, codirector of the Center for Drug Safety and Effectiveness at Johns Hopkins University in Baltimore.

The use of an agent that doesn’t produce effects similar to those expected from a psychedelic introduced the potential for functional unblinding, Dr. Alexander said. Investigators did not ask participants to guess whether they received psilocybin or niacin, so the quality of the blinding was not assessed in the study.

“We’d like to see the use of [an] active comparator that might have a chance of obscuring to people as to whether they’ve been randomized to the treatment arm or control arm,” said Dr. Alexander, who wasn’t involved in the study. “Why not use a benzodiazepine or another drug that produces a transient euphoria that would better obscure whether or not people were receiving the psilocybin?”

The authors of an accompanying editorial shared these concerns, also noting that the study included “a significant number of patients who did not respond to therapy.”

“It is important to analyze and understand adverse outcomes in psychedelic trials and conduct longitudinal studies to determine how sustained the effects will be and what may initiate a recrudescence of symptoms,” write Rachel Yehuda, PhD, and Amy Lehrner, PhD, both of the Peters VA Medical Center and Icahn School of Medicine at Mount Sinai, New York.

“Future studies will help identify who is most likely to benefit from psychedelics, whether booster or repeated treatment is safe and beneficial, and what the optimal dose and therapeutic frameworks are.”

A long-term follow-up of the current trial was terminated last year because of low enrollment. The spokesperson with Usona Institute did not respond to questions about that study, and the institute’s statement only added that preparations are underway to launch another study that “will provide additional safety and efficacy data to support submission of a new drug application to the FDA.”

Usona published its manufacturing process that it used to synthesize psilocybin in an open-access journal and signed a statement on “open science and open praxis” with psilocybin and similar substances, which appears on their website. That statement was signed by 31 research and service organizations around the world and nearly 150 scientists, scholars, and practitioners.

The study was funded by Usona Institute. Dr. Raison reported receiving personal fees from Usona Institute and grants to Usona Institute from Dr. Bronner’s All-One, Fournier Family Foundation, Good Ventures, Steven and Alexandra Cohen Foundation, Tiny Blue Dot Foundation, Turnbull Family Foundation, and William A. Linton during the conduct of the study; and personal fees from Novartis, Sage/Biogen, Emory Healthcare, and Vail Health outside the submitted work. Dr. Fonzo and Dr. Alexander report no relevant financial relationships. Dr. Yehuda reports receiving nonfinancial support from the Multidisciplinary Association for Psychedelic Studies Public Benefit (MAPS PBC) and grants from COMPASS Pathways. Dr. Lehrner is an investigator on trials sponsored by MAPS PBC and COMPASS Pathways.

A version of this article first appeared on Medscape.com.

AMSTERDAM – Dropping aspirin and using low-dose prasugrel (Effient) alone in the initial month of treatment after percutaneous coronary intervention (PCI) failed to lower bleeding risk, compared with dual antiplatelet therapy (DAPT), and there was a signal of possible harm in terms of increased subacute stent thrombosis, in the STOPDAPT-3 trial.

“Therefore, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should still remain the standard strategy at least for 1 month after PCI,” said the trial’s lead investigator Masahiro Natsuaki, MD, Saga (Japan) University.

The STOPDAPT-3 trial was presented at the recent annual congress of the European Society of Cardiology.

Designated discussant Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, explained that the current wisdom before this study was that aspirin withdrawal in the postacute phase after PCI (after 1 month of DAPT onwards) is associated with lower bleeding risk without affecting ischemic risk, but this STOPDAPT-3 trial is the first to look at the idea of not giving aspirin at all.

“This study is a well-designed, well-conducted trial, and the results are very clear: there is no benefit of dropping aspirin in this early period with respect to major bleeding, and at the same time there was some signal for possible harm,” Dr. Valgimigli said.

He pointed out that the possible harm was not related to the coprimary cardiovascular composite endpoint, which did fulfill noninferiority, although he acknowledged the “generous” noninferiority margin.

Rather, the possible harm was related to an increase in subacute stent thrombosis, which was three times higher in the nonaspirin group (0.58% vs. 0.17%). 

“While these absolute event rates are extremely low, they are unquestionably higher in the nonaspirin group,” he added.

In his presentation, Dr. Natsuaki explained that very short durations (1-3 months) of DAPT followed by P2Y12 inhibitor monotherapy has been shown to reduce bleeding events without increasing cardiovascular events, compared with longer durations of DAPT after PCI using drug-eluting stents.

However, the incidence of major bleeding events within the 1-month mandatory DAPT period after PCI remains high in clinical practice, particularly in patients with ACS or high bleeding risk.

In single-arm studies, use of prasugrel or ticagrelor (Brilinta) alone following new-generation drug-eluting stent implantation was not associated with any stent thrombosis in selected low-risk patients with or without ACS, and it is thought that removing aspirin from the DAPT regimen might reduce bleeding events early after PCI without compromising the risk of cardiovascular events. However, the efficacy and safety of this strategy has not been proven in randomized trials.
 

STOPDAPT-3 trial

STOPDAPT-3 investigated the efficacy and safety of prasugrel monotherapy compared with 1-month DAPT with aspirin and prasugrel in Japanese patients with ACS or high bleeding risk undergoing PCI with cobalt-chromium everolimus-eluting stents.

The study enrolled 6,002 patients with ACS or high bleeding risk who were randomly assigned to prasugrel monotherapy (3.75 mg/day; the licensed dose in Japan) or to DAPT with aspirin (81-100 mg/day) and prasugrel after a loading dose of prasugrel 20 mg in both groups.

There were two primary endpoints: major bleeding events (defined as BARC type 3 or 5) at 1 month for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month for noninferiority.

The major secondary endpoint was a composite of the coprimary bleeding and cardiovascular endpoints (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding) at 1 month representing net clinical benefit.

Results showed that, at 1 month, the no-aspirin strategy was not superior to DAPT for the coprimary bleeding endpoint, with major bleeding events occurring in 4.47% of the prasugrel monotherapy group versus 4.71% of those on DAPT (hazard ratio, 0.95; 95% confidence interval, 0.75-1.20).

The prasugrel monotherapy strategy was noninferior to DAPT, although there was a relative 50% margin for the coprimary cardiovascular endpoint. Cardiovascular endpoints occurred in 4.12% of prasugrel monotherapy group versus 3.69% of the DAPT patients (HR, 1.12; 95% CI, 0.87-1.45; P for noninferiority = .01).

The major secondary net clinical benefit endpoint occurred in 7.14% patients in the prasugrel monotherapy group and 7.38% patients in the DAPT group, with no between-group difference, indicating a similar effect on net clinical benefit for both groups.

However, there was an excess of any coronary revascularization (1.15% vs. 0.57%) and definite or probable stent thrombosis (0.71% vs. 0.44%) in the prasugrel monotherapy group compared with the DAPT group, while definite stent thrombosis was not different between the two groups (0.47% vs. 0.37%).

In a subgroup analysis stratified by ACS and non-ACS, the excess risk for cardiovascular events in the no-aspirin group, compared with the DAPT group, was seen in patients with ACS, but not in those without ACS.
 

Future: Focus on dose and timing

In his discussion, Dr. Valgimigli said the implications of this trial for clinical practice were very clear: “Aspirin remains a cornerstone treatment in the periprocedural and acute phase of PCI in patients without indications for oral anticoagulation.” 

However, he added that the study opens several important points for subsequent discussion.

These include the role of type and dose of P2Y12 inhibitor therapy used; specifically, he questioned whether the 3.75-mg dose of prasugrel was enough.

Dr. Valgimigli also pointed out that this study did not include a purely high bleeding risk population, and he said there was still potential to investigate periprocedure versus postprocedure aspirin administration.

The STOPDAPT-3 trial was funded by Abbott Medical Japan. Dr. Natsuaki reported receiving honoraria from Abbott Medical Japan, Daiichi Sankyo, and Bayer.

A version of this article first appeared on Medscape.com.

AMSTERDAM – Dropping aspirin and using low-dose prasugrel (Effient) alone in the initial month of treatment after percutaneous coronary intervention (PCI) failed to lower bleeding risk, compared with dual antiplatelet therapy (DAPT), and there was a signal of possible harm in terms of increased subacute stent thrombosis, in the STOPDAPT-3 trial.

“Therefore, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should still remain the standard strategy at least for 1 month after PCI,” said the trial’s lead investigator Masahiro Natsuaki, MD, Saga (Japan) University.

The STOPDAPT-3 trial was presented at the recent annual congress of the European Society of Cardiology.

Designated discussant Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, explained that the current wisdom before this study was that aspirin withdrawal in the postacute phase after PCI (after 1 month of DAPT onwards) is associated with lower bleeding risk without affecting ischemic risk, but this STOPDAPT-3 trial is the first to look at the idea of not giving aspirin at all.

“This study is a well-designed, well-conducted trial, and the results are very clear: there is no benefit of dropping aspirin in this early period with respect to major bleeding, and at the same time there was some signal for possible harm,” Dr. Valgimigli said.

He pointed out that the possible harm was not related to the coprimary cardiovascular composite endpoint, which did fulfill noninferiority, although he acknowledged the “generous” noninferiority margin.

Rather, the possible harm was related to an increase in subacute stent thrombosis, which was three times higher in the nonaspirin group (0.58% vs. 0.17%). 

“While these absolute event rates are extremely low, they are unquestionably higher in the nonaspirin group,” he added.

In his presentation, Dr. Natsuaki explained that very short durations (1-3 months) of DAPT followed by P2Y12 inhibitor monotherapy has been shown to reduce bleeding events without increasing cardiovascular events, compared with longer durations of DAPT after PCI using drug-eluting stents.

However, the incidence of major bleeding events within the 1-month mandatory DAPT period after PCI remains high in clinical practice, particularly in patients with ACS or high bleeding risk.

In single-arm studies, use of prasugrel or ticagrelor (Brilinta) alone following new-generation drug-eluting stent implantation was not associated with any stent thrombosis in selected low-risk patients with or without ACS, and it is thought that removing aspirin from the DAPT regimen might reduce bleeding events early after PCI without compromising the risk of cardiovascular events. However, the efficacy and safety of this strategy has not been proven in randomized trials.
 

STOPDAPT-3 trial

STOPDAPT-3 investigated the efficacy and safety of prasugrel monotherapy compared with 1-month DAPT with aspirin and prasugrel in Japanese patients with ACS or high bleeding risk undergoing PCI with cobalt-chromium everolimus-eluting stents.

The study enrolled 6,002 patients with ACS or high bleeding risk who were randomly assigned to prasugrel monotherapy (3.75 mg/day; the licensed dose in Japan) or to DAPT with aspirin (81-100 mg/day) and prasugrel after a loading dose of prasugrel 20 mg in both groups.

There were two primary endpoints: major bleeding events (defined as BARC type 3 or 5) at 1 month for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month for noninferiority.

The major secondary endpoint was a composite of the coprimary bleeding and cardiovascular endpoints (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding) at 1 month representing net clinical benefit.

Results showed that, at 1 month, the no-aspirin strategy was not superior to DAPT for the coprimary bleeding endpoint, with major bleeding events occurring in 4.47% of the prasugrel monotherapy group versus 4.71% of those on DAPT (hazard ratio, 0.95; 95% confidence interval, 0.75-1.20).

The prasugrel monotherapy strategy was noninferior to DAPT, although there was a relative 50% margin for the coprimary cardiovascular endpoint. Cardiovascular endpoints occurred in 4.12% of prasugrel monotherapy group versus 3.69% of the DAPT patients (HR, 1.12; 95% CI, 0.87-1.45; P for noninferiority = .01).

The major secondary net clinical benefit endpoint occurred in 7.14% patients in the prasugrel monotherapy group and 7.38% patients in the DAPT group, with no between-group difference, indicating a similar effect on net clinical benefit for both groups.

However, there was an excess of any coronary revascularization (1.15% vs. 0.57%) and definite or probable stent thrombosis (0.71% vs. 0.44%) in the prasugrel monotherapy group compared with the DAPT group, while definite stent thrombosis was not different between the two groups (0.47% vs. 0.37%).

In a subgroup analysis stratified by ACS and non-ACS, the excess risk for cardiovascular events in the no-aspirin group, compared with the DAPT group, was seen in patients with ACS, but not in those without ACS.
 

Future: Focus on dose and timing

In his discussion, Dr. Valgimigli said the implications of this trial for clinical practice were very clear: “Aspirin remains a cornerstone treatment in the periprocedural and acute phase of PCI in patients without indications for oral anticoagulation.” 

However, he added that the study opens several important points for subsequent discussion.

These include the role of type and dose of P2Y12 inhibitor therapy used; specifically, he questioned whether the 3.75-mg dose of prasugrel was enough.

Dr. Valgimigli also pointed out that this study did not include a purely high bleeding risk population, and he said there was still potential to investigate periprocedure versus postprocedure aspirin administration.

The STOPDAPT-3 trial was funded by Abbott Medical Japan. Dr. Natsuaki reported receiving honoraria from Abbott Medical Japan, Daiichi Sankyo, and Bayer.

A version of this article first appeared on Medscape.com.

AMSTERDAM – Dropping aspirin and using low-dose prasugrel (Effient) alone in the initial month of treatment after percutaneous coronary intervention (PCI) failed to lower bleeding risk, compared with dual antiplatelet therapy (DAPT), and there was a signal of possible harm in terms of increased subacute stent thrombosis, in the STOPDAPT-3 trial.

“Therefore, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should still remain the standard strategy at least for 1 month after PCI,” said the trial’s lead investigator Masahiro Natsuaki, MD, Saga (Japan) University.

The STOPDAPT-3 trial was presented at the recent annual congress of the European Society of Cardiology.

Designated discussant Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, explained that the current wisdom before this study was that aspirin withdrawal in the postacute phase after PCI (after 1 month of DAPT onwards) is associated with lower bleeding risk without affecting ischemic risk, but this STOPDAPT-3 trial is the first to look at the idea of not giving aspirin at all.

“This study is a well-designed, well-conducted trial, and the results are very clear: there is no benefit of dropping aspirin in this early period with respect to major bleeding, and at the same time there was some signal for possible harm,” Dr. Valgimigli said.

He pointed out that the possible harm was not related to the coprimary cardiovascular composite endpoint, which did fulfill noninferiority, although he acknowledged the “generous” noninferiority margin.

Rather, the possible harm was related to an increase in subacute stent thrombosis, which was three times higher in the nonaspirin group (0.58% vs. 0.17%). 

“While these absolute event rates are extremely low, they are unquestionably higher in the nonaspirin group,” he added.

In his presentation, Dr. Natsuaki explained that very short durations (1-3 months) of DAPT followed by P2Y12 inhibitor monotherapy has been shown to reduce bleeding events without increasing cardiovascular events, compared with longer durations of DAPT after PCI using drug-eluting stents.

However, the incidence of major bleeding events within the 1-month mandatory DAPT period after PCI remains high in clinical practice, particularly in patients with ACS or high bleeding risk.

In single-arm studies, use of prasugrel or ticagrelor (Brilinta) alone following new-generation drug-eluting stent implantation was not associated with any stent thrombosis in selected low-risk patients with or without ACS, and it is thought that removing aspirin from the DAPT regimen might reduce bleeding events early after PCI without compromising the risk of cardiovascular events. However, the efficacy and safety of this strategy has not been proven in randomized trials.
 

STOPDAPT-3 trial

STOPDAPT-3 investigated the efficacy and safety of prasugrel monotherapy compared with 1-month DAPT with aspirin and prasugrel in Japanese patients with ACS or high bleeding risk undergoing PCI with cobalt-chromium everolimus-eluting stents.

The study enrolled 6,002 patients with ACS or high bleeding risk who were randomly assigned to prasugrel monotherapy (3.75 mg/day; the licensed dose in Japan) or to DAPT with aspirin (81-100 mg/day) and prasugrel after a loading dose of prasugrel 20 mg in both groups.

There were two primary endpoints: major bleeding events (defined as BARC type 3 or 5) at 1 month for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month for noninferiority.

The major secondary endpoint was a composite of the coprimary bleeding and cardiovascular endpoints (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding) at 1 month representing net clinical benefit.

Results showed that, at 1 month, the no-aspirin strategy was not superior to DAPT for the coprimary bleeding endpoint, with major bleeding events occurring in 4.47% of the prasugrel monotherapy group versus 4.71% of those on DAPT (hazard ratio, 0.95; 95% confidence interval, 0.75-1.20).

The prasugrel monotherapy strategy was noninferior to DAPT, although there was a relative 50% margin for the coprimary cardiovascular endpoint. Cardiovascular endpoints occurred in 4.12% of prasugrel monotherapy group versus 3.69% of the DAPT patients (HR, 1.12; 95% CI, 0.87-1.45; P for noninferiority = .01).

The major secondary net clinical benefit endpoint occurred in 7.14% patients in the prasugrel monotherapy group and 7.38% patients in the DAPT group, with no between-group difference, indicating a similar effect on net clinical benefit for both groups.

However, there was an excess of any coronary revascularization (1.15% vs. 0.57%) and definite or probable stent thrombosis (0.71% vs. 0.44%) in the prasugrel monotherapy group compared with the DAPT group, while definite stent thrombosis was not different between the two groups (0.47% vs. 0.37%).

In a subgroup analysis stratified by ACS and non-ACS, the excess risk for cardiovascular events in the no-aspirin group, compared with the DAPT group, was seen in patients with ACS, but not in those without ACS.
 

Future: Focus on dose and timing

In his discussion, Dr. Valgimigli said the implications of this trial for clinical practice were very clear: “Aspirin remains a cornerstone treatment in the periprocedural and acute phase of PCI in patients without indications for oral anticoagulation.” 

However, he added that the study opens several important points for subsequent discussion.

These include the role of type and dose of P2Y12 inhibitor therapy used; specifically, he questioned whether the 3.75-mg dose of prasugrel was enough.

Dr. Valgimigli also pointed out that this study did not include a purely high bleeding risk population, and he said there was still potential to investigate periprocedure versus postprocedure aspirin administration.

The STOPDAPT-3 trial was funded by Abbott Medical Japan. Dr. Natsuaki reported receiving honoraria from Abbott Medical Japan, Daiichi Sankyo, and Bayer.

A version of this article first appeared on Medscape.com.

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

A version of this article first appeared on Medscape.com.

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

A version of this article first appeared on Medscape.com.

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

A version of this article first appeared on Medscape.com.