Pharmacology

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

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

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

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

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

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

A secondary analysis of a major study of polypill therapy for hypertension found that patients who don’t reach blood pressure targets are less likely to have their medications adjusted if they’re on fixed-dose combination therapy.

However, hypertension patients on low-dose, triple-pill combination therapy are more likely to achieve blood pressure control than are those on usual care.

The secondary analysis of Triple Pill vs. Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) was published online in JAMA Cardiology (2020 Jul 22. doi: 10.1001/jamacardio.2020.2739). The trial randomized 700 patients with hypertension in Sri Lanka to triple-pill fixed-dose combination (FDC) therapy or usual care during February 2016–May 2017, with follow-up ending in October 2017.

A greater proportion of FDC patients reached target BP by the end of the study compared with usual care, 70% vs. 55%. However, the study found that therapeutic inertia – the failure to intensify therapy in nonresponsive patients – was more common in the FDC group at 6- and 12-week follow-up: 87% vs. 64% and 90% vs. 65%, respectively; both differences were significant different at P < .001).

The once-daily FDC pill contained telmisartan 20 mg, amlodipine 2.5 mg; and chlorthalidone 12.5 mg.

“Using a triple low-dose combination blood-pressure pill reduced the need to uptitrate BP therapy as more patients are at target, but doctors were less likely to uptitrate with triple-pill therapy when it was needed,” lead author Nelson Wang, MD, a research fellow at the George Institute for Global Health in suburban Sydney, said in an interview.

“Overall, there were fewer treatment inertia episodes in the triple-pill group than in the usual care group, but this was driven by the fact that fewer triple-pill patients needed uptitration when coming to their follow-up visits,” Dr. Wang added.

The analysis found that clinicians who prescribed triple-pill FDC used 23 unique drug treatment regimens per 100 treated patients compared with 54 different regiments with usual care (P < .001). “There was a large simplification in care,” Dr. Wang said of the FDC approach.

Dr. Wang and colleagues called for greater efforts to address therapeutic inertia, particularly with FDC therapies, and suggested potential strategies consisting of patient education, incentives for appropriate treatment adjustments, and feedback mechanisms and reminders for physicians.

“There may also be a need for more dosage options with the FDC triple pill to allow physicians to intensify therapy without fear of overtreatment and adverse drug effects,” they wrote.

In an accompanying editorial (JAMA Cardiol. 2020 Jul 22. doi: 10.1001/jamacardio.2020.2693), Ann Marie Navar, MD, PhD, associate professor of cardiology at Duke Clinical Research Institute, Durham, N.C., noted that initiating treatment with FDC therapy doesn’t preclude a more personalized approach for patients who don’t achieve their BP target. “The real choice now is the choice of initial treatment,” she wrote, adding that future treatment guidelines should consider extending an FDC-first approach to patients with less severe levels of hypertension.

“The study showed there’s room for a both a population-based fixed-drug combination approach and a personalized approach to how we think about hypertension management with fixed-dose therapy,” she said in an interview. “It’s not a one-and-done situation.”

Dr. Wang has no financial relationships to disclose. Study coauthors received funding from the Australian National Health and Medical Research Council and the U.K. National Institute for Health Research. Dr. Navar has no relevant financial relationships to report.

SOURCE: Wang N et al. JAMA Cardiol. 2020. doi: 10.1001/jamacardio.2020.2739.

A secondary analysis of a major study of polypill therapy for hypertension found that patients who don’t reach blood pressure targets are less likely to have their medications adjusted if they’re on fixed-dose combination therapy.

However, hypertension patients on low-dose, triple-pill combination therapy are more likely to achieve blood pressure control than are those on usual care.

The secondary analysis of Triple Pill vs. Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) was published online in JAMA Cardiology (2020 Jul 22. doi: 10.1001/jamacardio.2020.2739). The trial randomized 700 patients with hypertension in Sri Lanka to triple-pill fixed-dose combination (FDC) therapy or usual care during February 2016–May 2017, with follow-up ending in October 2017.

A greater proportion of FDC patients reached target BP by the end of the study compared with usual care, 70% vs. 55%. However, the study found that therapeutic inertia – the failure to intensify therapy in nonresponsive patients – was more common in the FDC group at 6- and 12-week follow-up: 87% vs. 64% and 90% vs. 65%, respectively; both differences were significant different at P < .001).

The once-daily FDC pill contained telmisartan 20 mg, amlodipine 2.5 mg; and chlorthalidone 12.5 mg.

“Using a triple low-dose combination blood-pressure pill reduced the need to uptitrate BP therapy as more patients are at target, but doctors were less likely to uptitrate with triple-pill therapy when it was needed,” lead author Nelson Wang, MD, a research fellow at the George Institute for Global Health in suburban Sydney, said in an interview.

“Overall, there were fewer treatment inertia episodes in the triple-pill group than in the usual care group, but this was driven by the fact that fewer triple-pill patients needed uptitration when coming to their follow-up visits,” Dr. Wang added.

The analysis found that clinicians who prescribed triple-pill FDC used 23 unique drug treatment regimens per 100 treated patients compared with 54 different regiments with usual care (P < .001). “There was a large simplification in care,” Dr. Wang said of the FDC approach.

Dr. Wang and colleagues called for greater efforts to address therapeutic inertia, particularly with FDC therapies, and suggested potential strategies consisting of patient education, incentives for appropriate treatment adjustments, and feedback mechanisms and reminders for physicians.

“There may also be a need for more dosage options with the FDC triple pill to allow physicians to intensify therapy without fear of overtreatment and adverse drug effects,” they wrote.

In an accompanying editorial (JAMA Cardiol. 2020 Jul 22. doi: 10.1001/jamacardio.2020.2693), Ann Marie Navar, MD, PhD, associate professor of cardiology at Duke Clinical Research Institute, Durham, N.C., noted that initiating treatment with FDC therapy doesn’t preclude a more personalized approach for patients who don’t achieve their BP target. “The real choice now is the choice of initial treatment,” she wrote, adding that future treatment guidelines should consider extending an FDC-first approach to patients with less severe levels of hypertension.

“The study showed there’s room for a both a population-based fixed-drug combination approach and a personalized approach to how we think about hypertension management with fixed-dose therapy,” she said in an interview. “It’s not a one-and-done situation.”

Dr. Wang has no financial relationships to disclose. Study coauthors received funding from the Australian National Health and Medical Research Council and the U.K. National Institute for Health Research. Dr. Navar has no relevant financial relationships to report.

SOURCE: Wang N et al. JAMA Cardiol. 2020. doi: 10.1001/jamacardio.2020.2739.

A secondary analysis of a major study of polypill therapy for hypertension found that patients who don’t reach blood pressure targets are less likely to have their medications adjusted if they’re on fixed-dose combination therapy.

However, hypertension patients on low-dose, triple-pill combination therapy are more likely to achieve blood pressure control than are those on usual care.

The secondary analysis of Triple Pill vs. Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) was published online in JAMA Cardiology (2020 Jul 22. doi: 10.1001/jamacardio.2020.2739). The trial randomized 700 patients with hypertension in Sri Lanka to triple-pill fixed-dose combination (FDC) therapy or usual care during February 2016–May 2017, with follow-up ending in October 2017.

A greater proportion of FDC patients reached target BP by the end of the study compared with usual care, 70% vs. 55%. However, the study found that therapeutic inertia – the failure to intensify therapy in nonresponsive patients – was more common in the FDC group at 6- and 12-week follow-up: 87% vs. 64% and 90% vs. 65%, respectively; both differences were significant different at P < .001).

The once-daily FDC pill contained telmisartan 20 mg, amlodipine 2.5 mg; and chlorthalidone 12.5 mg.

“Using a triple low-dose combination blood-pressure pill reduced the need to uptitrate BP therapy as more patients are at target, but doctors were less likely to uptitrate with triple-pill therapy when it was needed,” lead author Nelson Wang, MD, a research fellow at the George Institute for Global Health in suburban Sydney, said in an interview.

“Overall, there were fewer treatment inertia episodes in the triple-pill group than in the usual care group, but this was driven by the fact that fewer triple-pill patients needed uptitration when coming to their follow-up visits,” Dr. Wang added.

The analysis found that clinicians who prescribed triple-pill FDC used 23 unique drug treatment regimens per 100 treated patients compared with 54 different regiments with usual care (P < .001). “There was a large simplification in care,” Dr. Wang said of the FDC approach.

Dr. Wang and colleagues called for greater efforts to address therapeutic inertia, particularly with FDC therapies, and suggested potential strategies consisting of patient education, incentives for appropriate treatment adjustments, and feedback mechanisms and reminders for physicians.

“There may also be a need for more dosage options with the FDC triple pill to allow physicians to intensify therapy without fear of overtreatment and adverse drug effects,” they wrote.

In an accompanying editorial (JAMA Cardiol. 2020 Jul 22. doi: 10.1001/jamacardio.2020.2693), Ann Marie Navar, MD, PhD, associate professor of cardiology at Duke Clinical Research Institute, Durham, N.C., noted that initiating treatment with FDC therapy doesn’t preclude a more personalized approach for patients who don’t achieve their BP target. “The real choice now is the choice of initial treatment,” she wrote, adding that future treatment guidelines should consider extending an FDC-first approach to patients with less severe levels of hypertension.

“The study showed there’s room for a both a population-based fixed-drug combination approach and a personalized approach to how we think about hypertension management with fixed-dose therapy,” she said in an interview. “It’s not a one-and-done situation.”

Dr. Wang has no financial relationships to disclose. Study coauthors received funding from the Australian National Health and Medical Research Council and the U.K. National Institute for Health Research. Dr. Navar has no relevant financial relationships to report.

SOURCE: Wang N et al. JAMA Cardiol. 2020. doi: 10.1001/jamacardio.2020.2739.

For patients with acute myocardial infarction (MI) and mild subclinical hypothyroidism (SCH), treatment with levothyroxine does not improve left ventricular function, according to results of the Thyroid in Acute Myocardial Infarction (ThyrAMI-2) trial.

“SCH is common, affecting approximately 10% of the adult population, and has been associated with worse outcomes in patients with cardiovascular disease in observational studies,” Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, said in an interview.

This study shows that levothyroxine treatment for patients with SCH and acute MI is “unlikely to be of benefit,” he said.

“This study says that treating the thyroid failure does not help nor harm such patients,” Terry F. Davies, MD, director, division of endocrinology, diabetes, and bone diseases, Mount Sinai Beth Israel Medical Center, New York, said in an interview. He was not involved in the study, which was published online July 21 in JAMA.

Participants included 95 adults (mean age, 63.5 years; 72 men) with persistent mild SCH who presented with acute MI at six hospitals in the United Kingdom. Most (69%) had ST-segment elevation MI.

Inclusion criteria were age older than 18 years and serum thyrotropin level >4.0 mU/L with a normal free thyroxine level on two occasions 7-10 days apart and with one thyrotropin value <10 mU/L.

Forty-six participants were randomly allocated to receive levothyroxine starting at 25 mcg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L and 49 to matching placebo capsules taken once daily for 52 weeks.

The primary outcome was left ventricular ejection fraction (LVEF) at 52 weeks, assessed via MRI, with adjustment for age, sex, acute MI type, affected coronary artery territory, and baseline LVEF.

Secondary outcomes were LV volume, infarct size, adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

The median daily dose of levothyroxine at the end of the study was 50 mcg. Adherence to study medication was 94% during the course of the study.

At week 52, mean LVEF improved from 51.3% at baseline to 53.8% in the levothyroxine group and from 54.0% to 56.1% in the placebo group.

The difference was not significant between groups, with an adjusted between-group difference of 0.76% (95% confidence interval, –0.93% to 2.46%; P = .37).

There were also no significant differences in any of the secondary outcomes. There were 15 (33.3%) cardiovascular adverse events in the levothyroxine group and 18 (36.7%) in the placebo group.

Recent clinical practice guidelines have highlighted a lack of high-quality data to make recommendations regarding the management of mild SCH, particularly for patients with cardiovascular disease, Dr. Razvi and colleagues noted in their article.

“On the basis of these findings, screening for and subsequent treatment of subclinical hypothyroidism in patients with acute myocardial infarction to preserve LV function is not justified,” they concluded.

Important caveats

The investigators noted several important caveats and limitations. The trial recruited patients with mild SCH because this group constitutes the majority of patients with SCH and for whom there is the “greatest uncertainty” regarding treatment efficacy. It’s not known whether targeting treatment for individuals with more severe disease may be beneficial.

The therapeutic benefit of levothyroxine may have been blunted, owing to the delay between coronary occlusion and the start of levothyroxine (median delay, 17 days). It’s unclear whether earlier treatment or treatment for a longer period may be beneficial.

But Dr. Davies noted that “treatment is usually avoided in the emergency situation,” and therefore he doesn’t think the treatment delay is a limitation; rather, “it would appear prudent,” he said in the interview.

“The real issues with an otherwise very careful study is the small size of the population despite the statistical assessment that this was all that was needed and, secondly, the small dose of thyroxine used,” Dr. Davies said.

The authors agree that the low dose of levothyroxine is a limitation. The median dose at the end of the study – 50 mcg daily – is “lower than that used in other trials that have demonstrated a benefit of treatment on endothelial function and lipid profiles,” they pointed out.

Dr. Davies noted that thyroid tests are “usually routine” for patients with MI. “Mild subclinical thyroid failure has been associated with worse cardiac outcomes, [but] treating such patients with thyroid hormone is very controversial since thyroid hormone can induce arrhythmias,” he said.

The study was supported in part by the National Institute for Health Research (NIHR) at the University of Leeds. Dr. Razvi received grants from the NIHR and nonfinancial support from Amdipharm Pharmaceuticals UK during the conduct of the study and personal fees from Merck and Abbott Pharmaceuticals outside the submitted work. Dr. Davies has disclosed no relevant financial relationships.
 

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

For patients with acute myocardial infarction (MI) and mild subclinical hypothyroidism (SCH), treatment with levothyroxine does not improve left ventricular function, according to results of the Thyroid in Acute Myocardial Infarction (ThyrAMI-2) trial.

“SCH is common, affecting approximately 10% of the adult population, and has been associated with worse outcomes in patients with cardiovascular disease in observational studies,” Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, said in an interview.

This study shows that levothyroxine treatment for patients with SCH and acute MI is “unlikely to be of benefit,” he said.

“This study says that treating the thyroid failure does not help nor harm such patients,” Terry F. Davies, MD, director, division of endocrinology, diabetes, and bone diseases, Mount Sinai Beth Israel Medical Center, New York, said in an interview. He was not involved in the study, which was published online July 21 in JAMA.

Participants included 95 adults (mean age, 63.5 years; 72 men) with persistent mild SCH who presented with acute MI at six hospitals in the United Kingdom. Most (69%) had ST-segment elevation MI.

Inclusion criteria were age older than 18 years and serum thyrotropin level >4.0 mU/L with a normal free thyroxine level on two occasions 7-10 days apart and with one thyrotropin value <10 mU/L.

Forty-six participants were randomly allocated to receive levothyroxine starting at 25 mcg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L and 49 to matching placebo capsules taken once daily for 52 weeks.

The primary outcome was left ventricular ejection fraction (LVEF) at 52 weeks, assessed via MRI, with adjustment for age, sex, acute MI type, affected coronary artery territory, and baseline LVEF.

Secondary outcomes were LV volume, infarct size, adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

The median daily dose of levothyroxine at the end of the study was 50 mcg. Adherence to study medication was 94% during the course of the study.

At week 52, mean LVEF improved from 51.3% at baseline to 53.8% in the levothyroxine group and from 54.0% to 56.1% in the placebo group.

The difference was not significant between groups, with an adjusted between-group difference of 0.76% (95% confidence interval, –0.93% to 2.46%; P = .37).

There were also no significant differences in any of the secondary outcomes. There were 15 (33.3%) cardiovascular adverse events in the levothyroxine group and 18 (36.7%) in the placebo group.

Recent clinical practice guidelines have highlighted a lack of high-quality data to make recommendations regarding the management of mild SCH, particularly for patients with cardiovascular disease, Dr. Razvi and colleagues noted in their article.

“On the basis of these findings, screening for and subsequent treatment of subclinical hypothyroidism in patients with acute myocardial infarction to preserve LV function is not justified,” they concluded.

Important caveats

The investigators noted several important caveats and limitations. The trial recruited patients with mild SCH because this group constitutes the majority of patients with SCH and for whom there is the “greatest uncertainty” regarding treatment efficacy. It’s not known whether targeting treatment for individuals with more severe disease may be beneficial.

The therapeutic benefit of levothyroxine may have been blunted, owing to the delay between coronary occlusion and the start of levothyroxine (median delay, 17 days). It’s unclear whether earlier treatment or treatment for a longer period may be beneficial.

But Dr. Davies noted that “treatment is usually avoided in the emergency situation,” and therefore he doesn’t think the treatment delay is a limitation; rather, “it would appear prudent,” he said in the interview.

“The real issues with an otherwise very careful study is the small size of the population despite the statistical assessment that this was all that was needed and, secondly, the small dose of thyroxine used,” Dr. Davies said.

The authors agree that the low dose of levothyroxine is a limitation. The median dose at the end of the study – 50 mcg daily – is “lower than that used in other trials that have demonstrated a benefit of treatment on endothelial function and lipid profiles,” they pointed out.

Dr. Davies noted that thyroid tests are “usually routine” for patients with MI. “Mild subclinical thyroid failure has been associated with worse cardiac outcomes, [but] treating such patients with thyroid hormone is very controversial since thyroid hormone can induce arrhythmias,” he said.

The study was supported in part by the National Institute for Health Research (NIHR) at the University of Leeds. Dr. Razvi received grants from the NIHR and nonfinancial support from Amdipharm Pharmaceuticals UK during the conduct of the study and personal fees from Merck and Abbott Pharmaceuticals outside the submitted work. Dr. Davies has disclosed no relevant financial relationships.
 

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

For patients with acute myocardial infarction (MI) and mild subclinical hypothyroidism (SCH), treatment with levothyroxine does not improve left ventricular function, according to results of the Thyroid in Acute Myocardial Infarction (ThyrAMI-2) trial.

“SCH is common, affecting approximately 10% of the adult population, and has been associated with worse outcomes in patients with cardiovascular disease in observational studies,” Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England, said in an interview.

This study shows that levothyroxine treatment for patients with SCH and acute MI is “unlikely to be of benefit,” he said.

“This study says that treating the thyroid failure does not help nor harm such patients,” Terry F. Davies, MD, director, division of endocrinology, diabetes, and bone diseases, Mount Sinai Beth Israel Medical Center, New York, said in an interview. He was not involved in the study, which was published online July 21 in JAMA.

Participants included 95 adults (mean age, 63.5 years; 72 men) with persistent mild SCH who presented with acute MI at six hospitals in the United Kingdom. Most (69%) had ST-segment elevation MI.

Inclusion criteria were age older than 18 years and serum thyrotropin level >4.0 mU/L with a normal free thyroxine level on two occasions 7-10 days apart and with one thyrotropin value <10 mU/L.

Forty-six participants were randomly allocated to receive levothyroxine starting at 25 mcg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L and 49 to matching placebo capsules taken once daily for 52 weeks.

The primary outcome was left ventricular ejection fraction (LVEF) at 52 weeks, assessed via MRI, with adjustment for age, sex, acute MI type, affected coronary artery territory, and baseline LVEF.

Secondary outcomes were LV volume, infarct size, adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

The median daily dose of levothyroxine at the end of the study was 50 mcg. Adherence to study medication was 94% during the course of the study.

At week 52, mean LVEF improved from 51.3% at baseline to 53.8% in the levothyroxine group and from 54.0% to 56.1% in the placebo group.

The difference was not significant between groups, with an adjusted between-group difference of 0.76% (95% confidence interval, –0.93% to 2.46%; P = .37).

There were also no significant differences in any of the secondary outcomes. There were 15 (33.3%) cardiovascular adverse events in the levothyroxine group and 18 (36.7%) in the placebo group.

Recent clinical practice guidelines have highlighted a lack of high-quality data to make recommendations regarding the management of mild SCH, particularly for patients with cardiovascular disease, Dr. Razvi and colleagues noted in their article.

“On the basis of these findings, screening for and subsequent treatment of subclinical hypothyroidism in patients with acute myocardial infarction to preserve LV function is not justified,” they concluded.

Important caveats

The investigators noted several important caveats and limitations. The trial recruited patients with mild SCH because this group constitutes the majority of patients with SCH and for whom there is the “greatest uncertainty” regarding treatment efficacy. It’s not known whether targeting treatment for individuals with more severe disease may be beneficial.

The therapeutic benefit of levothyroxine may have been blunted, owing to the delay between coronary occlusion and the start of levothyroxine (median delay, 17 days). It’s unclear whether earlier treatment or treatment for a longer period may be beneficial.

But Dr. Davies noted that “treatment is usually avoided in the emergency situation,” and therefore he doesn’t think the treatment delay is a limitation; rather, “it would appear prudent,” he said in the interview.

“The real issues with an otherwise very careful study is the small size of the population despite the statistical assessment that this was all that was needed and, secondly, the small dose of thyroxine used,” Dr. Davies said.

The authors agree that the low dose of levothyroxine is a limitation. The median dose at the end of the study – 50 mcg daily – is “lower than that used in other trials that have demonstrated a benefit of treatment on endothelial function and lipid profiles,” they pointed out.

Dr. Davies noted that thyroid tests are “usually routine” for patients with MI. “Mild subclinical thyroid failure has been associated with worse cardiac outcomes, [but] treating such patients with thyroid hormone is very controversial since thyroid hormone can induce arrhythmias,” he said.

The study was supported in part by the National Institute for Health Research (NIHR) at the University of Leeds. Dr. Razvi received grants from the NIHR and nonfinancial support from Amdipharm Pharmaceuticals UK during the conduct of the study and personal fees from Merck and Abbott Pharmaceuticals outside the submitted work. Dr. Davies has disclosed no relevant financial relationships.
 

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

Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
 

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.  

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
 

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
 

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
 

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
 

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
 

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

Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
 

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.  

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
 

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
 

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
 

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
 

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
 

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

Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.
 

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.  

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.
 

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).
 

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).
 

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”
 

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.
 

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

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

Patients on oral anticoagulants who experience a bleeding event may be able to discontinue therapy if certain circumstances apply, according to updated guidance from the American College of Cardiology.

The emergence of direct-acting oral anticoagulants (DOACs) to prevent venous thromboembolism and the introduction of new reversal strategies for factor Xa inhibitors prompted the creation of an Expert Consensus Decision Pathway to update the version from 2017, according to the ACC. Expert consensus decision pathways (ECDPs) are a component of the solution sets issued by the ACC to “address key questions facing care teams and attempt to provide practical guidance to be applied at the point of care.”

In an ECDP published in the Journal of the American College of Cardiology, the writing committee members developed treatment algorithms for managing bleeding in patients on DOACs and vitamin K antagonists (VKAs).

Bleeding was classified as major or nonmajor, with major defined as “bleeding that is associated with hemodynamic compromise, occurs in an anatomically critical site, requires transfusion of at least 2 units of packed red blood cells [RBCs]), or results in a hemoglobin drop greater than 2 g/dL. All other types of bleeding were classified as nonmajor.

The document includes a graphic algorithm for assessing bleed severity and managing major versus nonmajor bleeding, and a separate graphic describes considerations for reversal and use of hemostatic agents according to whether the patient is taking a VKA (warfarin and other coumarins), a direct thrombin inhibitor (dabigatran), the factor Xa inhibitors apixaban and rivaroxaban, or the factor Xa inhibitors betrixaban and edoxaban.

Another algorithm outlines whether to discontinue, delay, or restart anticoagulation. Considerations for restarting anticoagulation include whether the patient is pregnant, awaiting an invasive procedure, not able to receive medication by mouth, has a high risk of rebleeding, or is being bridged back to a vitamin K antagonist with high thrombotic risk.

In most cases of GI bleeding, for example, current data support restarting oral anticoagulants once hemostasis is achieved, but patients who experience intracranial hemorrhage should delay restarting any anticoagulation for at least 4 weeks if they are without high thrombotic risk, according to the document.

The report also recommends clinician-patient discussion before resuming anticoagulation, ideally with time allowed for patients to develop questions. Discussions should include the signs of bleeding, assessment of risk for a thromboembolic event, and the benefits of anticoagulation.

“The proliferation of oral anticoagulants (warfarin and DOACs) and growing indications for their use prompted the need for guidance on the management of these drugs,” said Gordon F. Tomaselli, MD, chair of the writing committee, in an interview. “This document provides guidance on management at the time of a bleeding complication. This includes acute management, starting and stopping drugs, and use of reversal agents,” he said. “This of course will be a dynamic document as the list of these drugs and their antidotes expand,” he noted.  

“The biggest change from the previous guidelines are twofold: an update on laboratory assessment to monitor drug levels and use of reversal agents,” while the acute management strategies have otherwise remained similar to previous documents, said Dr. Tomaselli.

Dr. Tomaselli said that he was not surprised by the biological aspects of recent research while developing the statement. However, “the extent of the use of multiple anticoagulants and antiplatelet agents was a bit surprising and complicates therapy with each of the agents,” he noted.

The way the pathways are presented may make them challenging to follow in clinical practice, said Dr. Tomaselli. “The pathways are described linearly and in practice often many things have to happen at once,” he said. “The other main issue may be limitations in the availability of some of the newer reversal agents,” he added.

“The complication of bleeding is difficult to avoid,” said Dr. Tomaselli, and for future research, “the focus needs to continue to refine the indications for anticoagulation and appropriate use with other drugs that predispose to bleeding. We also need better methods and testing to monitor drugs levels and the effect on coagulation,” he said.

In accordance with the ACC Solution Set Oversight Committee, the writing committee members, including Dr. Tomaselli, had no relevant relationships with industry to disclose.

SOURCE: Tomaselli GF et al. J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.053.

Patients on oral anticoagulants who experience a bleeding event may be able to discontinue therapy if certain circumstances apply, according to updated guidance from the American College of Cardiology.

The emergence of direct-acting oral anticoagulants (DOACs) to prevent venous thromboembolism and the introduction of new reversal strategies for factor Xa inhibitors prompted the creation of an Expert Consensus Decision Pathway to update the version from 2017, according to the ACC. Expert consensus decision pathways (ECDPs) are a component of the solution sets issued by the ACC to “address key questions facing care teams and attempt to provide practical guidance to be applied at the point of care.”

In an ECDP published in the Journal of the American College of Cardiology, the writing committee members developed treatment algorithms for managing bleeding in patients on DOACs and vitamin K antagonists (VKAs).

Bleeding was classified as major or nonmajor, with major defined as “bleeding that is associated with hemodynamic compromise, occurs in an anatomically critical site, requires transfusion of at least 2 units of packed red blood cells [RBCs]), or results in a hemoglobin drop greater than 2 g/dL. All other types of bleeding were classified as nonmajor.

The document includes a graphic algorithm for assessing bleed severity and managing major versus nonmajor bleeding, and a separate graphic describes considerations for reversal and use of hemostatic agents according to whether the patient is taking a VKA (warfarin and other coumarins), a direct thrombin inhibitor (dabigatran), the factor Xa inhibitors apixaban and rivaroxaban, or the factor Xa inhibitors betrixaban and edoxaban.

Another algorithm outlines whether to discontinue, delay, or restart anticoagulation. Considerations for restarting anticoagulation include whether the patient is pregnant, awaiting an invasive procedure, not able to receive medication by mouth, has a high risk of rebleeding, or is being bridged back to a vitamin K antagonist with high thrombotic risk.

In most cases of GI bleeding, for example, current data support restarting oral anticoagulants once hemostasis is achieved, but patients who experience intracranial hemorrhage should delay restarting any anticoagulation for at least 4 weeks if they are without high thrombotic risk, according to the document.

The report also recommends clinician-patient discussion before resuming anticoagulation, ideally with time allowed for patients to develop questions. Discussions should include the signs of bleeding, assessment of risk for a thromboembolic event, and the benefits of anticoagulation.

“The proliferation of oral anticoagulants (warfarin and DOACs) and growing indications for their use prompted the need for guidance on the management of these drugs,” said Gordon F. Tomaselli, MD, chair of the writing committee, in an interview. “This document provides guidance on management at the time of a bleeding complication. This includes acute management, starting and stopping drugs, and use of reversal agents,” he said. “This of course will be a dynamic document as the list of these drugs and their antidotes expand,” he noted.  

“The biggest change from the previous guidelines are twofold: an update on laboratory assessment to monitor drug levels and use of reversal agents,” while the acute management strategies have otherwise remained similar to previous documents, said Dr. Tomaselli.

Dr. Tomaselli said that he was not surprised by the biological aspects of recent research while developing the statement. However, “the extent of the use of multiple anticoagulants and antiplatelet agents was a bit surprising and complicates therapy with each of the agents,” he noted.

The way the pathways are presented may make them challenging to follow in clinical practice, said Dr. Tomaselli. “The pathways are described linearly and in practice often many things have to happen at once,” he said. “The other main issue may be limitations in the availability of some of the newer reversal agents,” he added.

“The complication of bleeding is difficult to avoid,” said Dr. Tomaselli, and for future research, “the focus needs to continue to refine the indications for anticoagulation and appropriate use with other drugs that predispose to bleeding. We also need better methods and testing to monitor drugs levels and the effect on coagulation,” he said.

In accordance with the ACC Solution Set Oversight Committee, the writing committee members, including Dr. Tomaselli, had no relevant relationships with industry to disclose.

SOURCE: Tomaselli GF et al. J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.053.

Patients on oral anticoagulants who experience a bleeding event may be able to discontinue therapy if certain circumstances apply, according to updated guidance from the American College of Cardiology.

The emergence of direct-acting oral anticoagulants (DOACs) to prevent venous thromboembolism and the introduction of new reversal strategies for factor Xa inhibitors prompted the creation of an Expert Consensus Decision Pathway to update the version from 2017, according to the ACC. Expert consensus decision pathways (ECDPs) are a component of the solution sets issued by the ACC to “address key questions facing care teams and attempt to provide practical guidance to be applied at the point of care.”

In an ECDP published in the Journal of the American College of Cardiology, the writing committee members developed treatment algorithms for managing bleeding in patients on DOACs and vitamin K antagonists (VKAs).

Bleeding was classified as major or nonmajor, with major defined as “bleeding that is associated with hemodynamic compromise, occurs in an anatomically critical site, requires transfusion of at least 2 units of packed red blood cells [RBCs]), or results in a hemoglobin drop greater than 2 g/dL. All other types of bleeding were classified as nonmajor.

The document includes a graphic algorithm for assessing bleed severity and managing major versus nonmajor bleeding, and a separate graphic describes considerations for reversal and use of hemostatic agents according to whether the patient is taking a VKA (warfarin and other coumarins), a direct thrombin inhibitor (dabigatran), the factor Xa inhibitors apixaban and rivaroxaban, or the factor Xa inhibitors betrixaban and edoxaban.

Another algorithm outlines whether to discontinue, delay, or restart anticoagulation. Considerations for restarting anticoagulation include whether the patient is pregnant, awaiting an invasive procedure, not able to receive medication by mouth, has a high risk of rebleeding, or is being bridged back to a vitamin K antagonist with high thrombotic risk.

In most cases of GI bleeding, for example, current data support restarting oral anticoagulants once hemostasis is achieved, but patients who experience intracranial hemorrhage should delay restarting any anticoagulation for at least 4 weeks if they are without high thrombotic risk, according to the document.

The report also recommends clinician-patient discussion before resuming anticoagulation, ideally with time allowed for patients to develop questions. Discussions should include the signs of bleeding, assessment of risk for a thromboembolic event, and the benefits of anticoagulation.

“The proliferation of oral anticoagulants (warfarin and DOACs) and growing indications for their use prompted the need for guidance on the management of these drugs,” said Gordon F. Tomaselli, MD, chair of the writing committee, in an interview. “This document provides guidance on management at the time of a bleeding complication. This includes acute management, starting and stopping drugs, and use of reversal agents,” he said. “This of course will be a dynamic document as the list of these drugs and their antidotes expand,” he noted.  

“The biggest change from the previous guidelines are twofold: an update on laboratory assessment to monitor drug levels and use of reversal agents,” while the acute management strategies have otherwise remained similar to previous documents, said Dr. Tomaselli.

Dr. Tomaselli said that he was not surprised by the biological aspects of recent research while developing the statement. However, “the extent of the use of multiple anticoagulants and antiplatelet agents was a bit surprising and complicates therapy with each of the agents,” he noted.

The way the pathways are presented may make them challenging to follow in clinical practice, said Dr. Tomaselli. “The pathways are described linearly and in practice often many things have to happen at once,” he said. “The other main issue may be limitations in the availability of some of the newer reversal agents,” he added.

“The complication of bleeding is difficult to avoid,” said Dr. Tomaselli, and for future research, “the focus needs to continue to refine the indications for anticoagulation and appropriate use with other drugs that predispose to bleeding. We also need better methods and testing to monitor drugs levels and the effect on coagulation,” he said.

In accordance with the ACC Solution Set Oversight Committee, the writing committee members, including Dr. Tomaselli, had no relevant relationships with industry to disclose.

SOURCE: Tomaselli GF et al. J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.053.

If either high sensitivity cardiac troponin (hs-cTnT) or coronary artery calcium (CAC) are elevated, the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) climbs substantially, which suggests these biomarkers yield more prognostic information when they are used together, according to a cohort study with a median 15 years of follow-up.

Among those with a double negative result, meaning hs-cTnT was less than the limit of detection (<3 ng/L) and the CAC score was zero, only 2.8% developed ASCVD within 10 years, but the rates climbed to 4.6% if hs-cTnT was detectable and to 9.8% if the CAC score exceeded zero even when the other biomarker was negative.

“The increased risk for ASCVD among those with discordant results indicate that their prognostic information is complementary, favoring their conjoined use for risk prediction,” reported a multicenter team of investigators led by Allan S. Jaffe, MD, professor of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

The study was performed with data from 6,749 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), which is a longitudinal, community-based study funded by the National Heart, Lung, and Blood Institute. Over the course of long-term follow-up in a patient population that was about half female, 39% non-Hispanic white, 28% Black, 22% Hispanic American, and 12% Asian, ASCVD events were evaluated in relation to both biomarkers measured at baseline.

At baseline, both biomarkers were negative in 22%, both positive in 40%, and discordant in 38%.

After a median follow-up of 15 years, when 1,002 ASCVD events had occurred, the crude rate of ASCVD was 2.8 per 1,000 person-years in the double-negative group. When compared with this, the adjusted hazard ratio for ASCVD among those with double positive biomarkers was 3.5 (P < .00001). Increased risk was also highly significant if just hs-cTnT was positive (HR, 1.59; P = .003) or if just CAC was positive (HR, 2.74; P < .00001).

The added value of using both biomarkers to identify individuals at very low risk of ASCVD makes sense, according to the authors of an accompanying editorial. Written by a team led by John W. McEvoy, MB, BCh, National University of Ireland, Galway, the editorial explained why the information is complementary.

“CAC indicates subclinical atherosclerosis, whereas hs-cTnT indicates myocardial ischemia or damage, not just from coronary stenosis but also due to other conditions like hypertensive heart and left ventricular hypertrophy,” the authors stated.

Although they maintained that adding N-terminal pro-brain natriuretic peptide, which could be drawn from the same blood sample as hs-cTnT, might prove to be an even better but still simple strategy to identify low-risk patients, they praised the concept of combining biomarkers.

“If one’s wish is to identify truly low-risk individuals, then it appears that it takes two negative ASCVD biomarkers to make that wish come true,” the authors of the editorial concluded.

Relative to alternative methods of ASCVD risk assessment, measurement of these biomarkers might be useful for sparing patients from interventions, such as lipid lowering with statin therapy, being considered on the basis of conventional risk factors alone.

Dr. Jaffe said in an interview that he considers the two-biomarker assessment to be a useful tool in the low-risk population that he studied, but he does not consider this strategy as a substitute for other methods, such as those outline in the 2019 ACC/AHA guidelines that address the entire spectrum of risk, although work is planned to see if this approach can be extended to this broader group.*

“The data we have presented now is a good start and suggests that these two objective measures can identify those who are at very low risk and avoid adding individuals who may not be at as low risk if only one of the two tests is used,” Dr. Jaffe explained.

“Given there are now techniques to measure coronary calcium from any chest CT study, and that high sensitivity cardiac troponin is a relatively inexpensive test, putting them together should really help risk stratify patients,” he added.

When asked whether this approach will eventually replace conventional methods of ASCVD risk assessment, such as those proposed in the 2019 American College of Cardiology/American Heart Association guidelines for the primary prevention of cardiovascular disease (Circulation. 2019;140:e596-e646), he said maybe.

“The answer is that we will probe that question in our ongoing studies using continuous data in an attempt to evaluate how to use this approach to risk stratify larger numbers of individuals,” Dr. Jaffe replied.

The senior investigator, Dr. Jaffe, has consulting relationships with many pharmaceutical companies. The editorial authors had no relevant disclosures.

SOURCE: Sandoval Y et al. J Am Coll Cardiol. 2020;76:357-370.

*Correction, 7/27/20: An earlier version of this article mischaracterized Dr. Jaffe's statement.

If either high sensitivity cardiac troponin (hs-cTnT) or coronary artery calcium (CAC) are elevated, the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) climbs substantially, which suggests these biomarkers yield more prognostic information when they are used together, according to a cohort study with a median 15 years of follow-up.

Among those with a double negative result, meaning hs-cTnT was less than the limit of detection (<3 ng/L) and the CAC score was zero, only 2.8% developed ASCVD within 10 years, but the rates climbed to 4.6% if hs-cTnT was detectable and to 9.8% if the CAC score exceeded zero even when the other biomarker was negative.

“The increased risk for ASCVD among those with discordant results indicate that their prognostic information is complementary, favoring their conjoined use for risk prediction,” reported a multicenter team of investigators led by Allan S. Jaffe, MD, professor of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

The study was performed with data from 6,749 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), which is a longitudinal, community-based study funded by the National Heart, Lung, and Blood Institute. Over the course of long-term follow-up in a patient population that was about half female, 39% non-Hispanic white, 28% Black, 22% Hispanic American, and 12% Asian, ASCVD events were evaluated in relation to both biomarkers measured at baseline.

At baseline, both biomarkers were negative in 22%, both positive in 40%, and discordant in 38%.

After a median follow-up of 15 years, when 1,002 ASCVD events had occurred, the crude rate of ASCVD was 2.8 per 1,000 person-years in the double-negative group. When compared with this, the adjusted hazard ratio for ASCVD among those with double positive biomarkers was 3.5 (P < .00001). Increased risk was also highly significant if just hs-cTnT was positive (HR, 1.59; P = .003) or if just CAC was positive (HR, 2.74; P < .00001).

The added value of using both biomarkers to identify individuals at very low risk of ASCVD makes sense, according to the authors of an accompanying editorial. Written by a team led by John W. McEvoy, MB, BCh, National University of Ireland, Galway, the editorial explained why the information is complementary.

“CAC indicates subclinical atherosclerosis, whereas hs-cTnT indicates myocardial ischemia or damage, not just from coronary stenosis but also due to other conditions like hypertensive heart and left ventricular hypertrophy,” the authors stated.

Although they maintained that adding N-terminal pro-brain natriuretic peptide, which could be drawn from the same blood sample as hs-cTnT, might prove to be an even better but still simple strategy to identify low-risk patients, they praised the concept of combining biomarkers.

“If one’s wish is to identify truly low-risk individuals, then it appears that it takes two negative ASCVD biomarkers to make that wish come true,” the authors of the editorial concluded.

Relative to alternative methods of ASCVD risk assessment, measurement of these biomarkers might be useful for sparing patients from interventions, such as lipid lowering with statin therapy, being considered on the basis of conventional risk factors alone.

Dr. Jaffe said in an interview that he considers the two-biomarker assessment to be a useful tool in the low-risk population that he studied, but he does not consider this strategy as a substitute for other methods, such as those outline in the 2019 ACC/AHA guidelines that address the entire spectrum of risk, although work is planned to see if this approach can be extended to this broader group.*

“The data we have presented now is a good start and suggests that these two objective measures can identify those who are at very low risk and avoid adding individuals who may not be at as low risk if only one of the two tests is used,” Dr. Jaffe explained.

“Given there are now techniques to measure coronary calcium from any chest CT study, and that high sensitivity cardiac troponin is a relatively inexpensive test, putting them together should really help risk stratify patients,” he added.

When asked whether this approach will eventually replace conventional methods of ASCVD risk assessment, such as those proposed in the 2019 American College of Cardiology/American Heart Association guidelines for the primary prevention of cardiovascular disease (Circulation. 2019;140:e596-e646), he said maybe.

“The answer is that we will probe that question in our ongoing studies using continuous data in an attempt to evaluate how to use this approach to risk stratify larger numbers of individuals,” Dr. Jaffe replied.

The senior investigator, Dr. Jaffe, has consulting relationships with many pharmaceutical companies. The editorial authors had no relevant disclosures.

SOURCE: Sandoval Y et al. J Am Coll Cardiol. 2020;76:357-370.

*Correction, 7/27/20: An earlier version of this article mischaracterized Dr. Jaffe's statement.

If either high sensitivity cardiac troponin (hs-cTnT) or coronary artery calcium (CAC) are elevated, the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) climbs substantially, which suggests these biomarkers yield more prognostic information when they are used together, according to a cohort study with a median 15 years of follow-up.

Among those with a double negative result, meaning hs-cTnT was less than the limit of detection (<3 ng/L) and the CAC score was zero, only 2.8% developed ASCVD within 10 years, but the rates climbed to 4.6% if hs-cTnT was detectable and to 9.8% if the CAC score exceeded zero even when the other biomarker was negative.

“The increased risk for ASCVD among those with discordant results indicate that their prognostic information is complementary, favoring their conjoined use for risk prediction,” reported a multicenter team of investigators led by Allan S. Jaffe, MD, professor of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

The study was performed with data from 6,749 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), which is a longitudinal, community-based study funded by the National Heart, Lung, and Blood Institute. Over the course of long-term follow-up in a patient population that was about half female, 39% non-Hispanic white, 28% Black, 22% Hispanic American, and 12% Asian, ASCVD events were evaluated in relation to both biomarkers measured at baseline.

At baseline, both biomarkers were negative in 22%, both positive in 40%, and discordant in 38%.

After a median follow-up of 15 years, when 1,002 ASCVD events had occurred, the crude rate of ASCVD was 2.8 per 1,000 person-years in the double-negative group. When compared with this, the adjusted hazard ratio for ASCVD among those with double positive biomarkers was 3.5 (P < .00001). Increased risk was also highly significant if just hs-cTnT was positive (HR, 1.59; P = .003) or if just CAC was positive (HR, 2.74; P < .00001).

The added value of using both biomarkers to identify individuals at very low risk of ASCVD makes sense, according to the authors of an accompanying editorial. Written by a team led by John W. McEvoy, MB, BCh, National University of Ireland, Galway, the editorial explained why the information is complementary.

“CAC indicates subclinical atherosclerosis, whereas hs-cTnT indicates myocardial ischemia or damage, not just from coronary stenosis but also due to other conditions like hypertensive heart and left ventricular hypertrophy,” the authors stated.

Although they maintained that adding N-terminal pro-brain natriuretic peptide, which could be drawn from the same blood sample as hs-cTnT, might prove to be an even better but still simple strategy to identify low-risk patients, they praised the concept of combining biomarkers.

“If one’s wish is to identify truly low-risk individuals, then it appears that it takes two negative ASCVD biomarkers to make that wish come true,” the authors of the editorial concluded.

Relative to alternative methods of ASCVD risk assessment, measurement of these biomarkers might be useful for sparing patients from interventions, such as lipid lowering with statin therapy, being considered on the basis of conventional risk factors alone.

Dr. Jaffe said in an interview that he considers the two-biomarker assessment to be a useful tool in the low-risk population that he studied, but he does not consider this strategy as a substitute for other methods, such as those outline in the 2019 ACC/AHA guidelines that address the entire spectrum of risk, although work is planned to see if this approach can be extended to this broader group.*

“The data we have presented now is a good start and suggests that these two objective measures can identify those who are at very low risk and avoid adding individuals who may not be at as low risk if only one of the two tests is used,” Dr. Jaffe explained.

“Given there are now techniques to measure coronary calcium from any chest CT study, and that high sensitivity cardiac troponin is a relatively inexpensive test, putting them together should really help risk stratify patients,” he added.

When asked whether this approach will eventually replace conventional methods of ASCVD risk assessment, such as those proposed in the 2019 American College of Cardiology/American Heart Association guidelines for the primary prevention of cardiovascular disease (Circulation. 2019;140:e596-e646), he said maybe.

“The answer is that we will probe that question in our ongoing studies using continuous data in an attempt to evaluate how to use this approach to risk stratify larger numbers of individuals,” Dr. Jaffe replied.

The senior investigator, Dr. Jaffe, has consulting relationships with many pharmaceutical companies. The editorial authors had no relevant disclosures.

SOURCE: Sandoval Y et al. J Am Coll Cardiol. 2020;76:357-370.

*Correction, 7/27/20: An earlier version of this article mischaracterized Dr. Jaffe's statement.

One of the more alarming trends that has emerged during the coronavirus crisis is the concomitant rise in the use of benzodiazepines, such as Xanax. It has been reported that at-risk individuals began seeking prescription anxiolytics as early as mid-February with a consequent peak of 34% the following month, coinciding with the World Health Organization’s declaration of a global pandemic.¹

Consistent with the available literature indicating that women are twice as likely to be affected by anxiety disorders, the prescription spikes were almost double when compared with those of their male counterparts.² The pandemic has instilled a sense of fear in people, leading to social repercussions, such as estrangement, insomnia, and paranoia for at-risk populations.^3,4

“Benzos” are commonly prescribed to help people sleep or to assist them in overcoming a host of anxiety disorders. The rapid onset of effects make Xanax a desirable and efficacious benzodiazepine.⁵ The use of these medications might not be an immediate cause for concern because patients might be taking it as intended. Nevertheless, clinicians are shying away from medical management in favor of counseling or therapy.
 

Dangerous trends

We are concerned that renewed interest in Xanax, coupled with physician reluctance to prescribe antianxiety medications, might trigger the return of an illicit drug boom. Numerous factors might contribute to this grim scenario, including patient dependence on benzodiazepines, paranoia about engaging with health care professionals because of fear tied to potential COVID-19 exposure, and/or increased access to illicit counterfeit pills from drug dealers or the dark web markets.

Lessons can be gleaned from the most extensive dark web drug busts in Britain’s history, in which a deluge of “pharmaceutical grade” Xanax pills made it to the hands of drug dealers and consumers between 2015 and 2017.⁶ A similar phenomenon emerged stateside.⁷ Virtually indistinguishable from recognized 2-mg Xanax pills, these fake pills posed a serious challenge to forensic scientists.⁸ The threat of overdose is very real for users targeted by the counterfeit Xanax trade, especially since those at risk often bypass professional health care guidelines.

In broad daylight, the drug dealers ran their operations revolving around two fake Xanax products: a primary knockoff and a limited edition – and vastly more potent “Red Devil” variant that was intentionally dyed for branding purposes. Because the “Red Devil” formulations contained 2.5 times the dose of the 2-mg pill, it had even more pronounced tolerance, dependence, and withdrawal effects (for example, panic attacks, anxiety, and/or hallucinations) – fatal consequences for users involved in consuming other drugs, such as alcohol or opioids. Preexisting drug users tend to gravitate toward benzodiazepines, such as alprazolam (Xanax), perhaps in part, because of its relatively rapid onset of action. Xanax also is known for inducing proeuphoric states at higher doses, hence the appeal of the “Red Devil” pills.

Benzodiazepines, as a class of drugs, facilitate the neurotransmitter gamma-aminobutryric acid’s (GABA) effect on the brain, producing anxiolytic, hypnotic, and/or anticonvulsant states within the user.⁹ Unbeknownst to numerous users is the fact that drugs such as alcohol and opioids, like Xanax, also serve as respiratory depressants, overriding the brain’s governance of the breathing mechanism. This, in turn, leads to unintended overdose deaths, even among seasoned drug seekers.

Overdose deaths have been steadily climbing over the years because it is common for some users to consume alcohol while being on Xanax therapy – without realizing that both substances are depressants and that taking them together can lead to side effects such as respiratory depression.

Forensic cases also have revealed that preexisting opioid consumers were drawn to Xanax; the drug’s potent mechanism of action would likely appeal to habituated users. A typical behavioral pattern has emerged among users and must be addressed. According to Australian Professor Shane Darke: “So they take their Xanax, they take their painkiller, then they get drunk, that could be enough to kill them.”

Fatalities are more likely when benzodiazepines are combined with other drug classes or if the existing supply is contaminated or laced (for example, with fentanyl).⁸

As far as deaths by accidental benzodiazepine overdose are concerned, a similar epidemic has been recorded in the United States. In 2013, almost one-third of all prescription overdose deaths can be attributed to the use of benzodiazepines (for example, Xanax, Valium, and Ativan). However, media attention has been considerably muted, especially when compared with that of narcotic abuse. This is even more puzzling when taking into account that three-quarters of benzodiazepine mortalities co-occur within the context of narcotic consumption. Substance Abuse and Mental Health Services Administration data confirm the ubiquitous nature of benzodiazepine (such as alprazolam) coprescriptions, accounting for roughly half of the 176,000 emergency department cases for 2011. The Centers for Disease Control and Prevention noted that there was a 67% increase in benzodiazepine prescriptions between 1996 and 2013, which warranted more stringent regulations for this particular class of drugs.

In 2016, the CDC issued new guidelines for opioid use acknowledging the danger of benzodiazepine coprescriptions. Food and Drug Administration “black box” warnings now grace the prescriptions of both of these drug classes.¹⁰ This trend remains on an upward trajectory, even more so during the pandemic, as there are 9.7 million prescriptions of anxiolytics/hypnotics such as Xanax, Ativan, and Klonopin in the United States as of March 2020, which represents a 10% increase over the previous year. The evolving landscape of this “new normal” may necessitate frequent patient updates and feedback via telepsychiatry, as well as the implementation of urine drug screening monitoring for drug adherence/compliance and diversion in those with suspected benzodiazepine addiction or a history of polysubstance abuse.^11,12

Clinical correlates

For patients who present acutely with Xanax toxicity in the emergency room setting, we will need to initially stabilize the vital signs and address the ongoing symptoms. It is advisable to arrange health care accommodations for patients with physical dependence to monitor and treat their withdrawal symptoms. The patient should be enrolled in a comprehensive addiction facility after undergoing formal detoxification; a tapered treatment protocol will need to be implemented because quitting “cold turkey” can lead to convulsions and, in some cases, death. Patient education, talk therapy, and alternatives to benzodiazepines should be discussed with the clinician.^13,145

However, to truly address the elephant in the room, we will need to consider institutional reforms to prevent a similar situation from arising in the future. Primary care physician shortages are compounded by changes in insurance policies. Nurses and physician assistants will need to be trained to manage benzodiazepine prescriptions. If there are community shortages in physicians, patients might turn to illegal means to secure their benzodiazepine supply, and it is imperative that we have the necessary fellowship and education programs to educate nonphysician health care clinicians with benzodiazepine management. Because physicians were prescribing benzodiazepines liberally, the Prescription Drug Monitoring Programs (PDMP) was enacted to monitor physician practices. Unfortunately, this ultimately intimidated physicians and effectively curbed reasonable physician prescribing patterns. It might be necessary to revisit existing prescription monitoring programs, encourage drug evaluations and guidelines based on evidence-based medicine and embrace telemedicine in order to facilitate patient-physician communication.

As of now, it is too early to prescribe Xanax routinely for ongoing anxiety experienced during the coronavirus crisis, and several physicians are cautious about prescribing antianxiety medications for more than a few months.¹⁷ Surprisingly, researchers in Barcelona have even explored the role of Xanax as potentially inhibiting Mpro, the primary protease of coronavirus, thereby forestalling the virus’s ability to replicate.¹⁶ However, it is worth noting that, given the preliminary nature of the results, any attempts at conclusively integrating Xanax within the context of coronavirus therapy would be premature.
 

References

1. Luhby T. Anti-anxiety medication prescriptions up 34% since coronavirus. CNN. 2020 Apr 16.

2. Women and Anxiety. Anxiety and Depression Association of America.

3. Shigemura J et al. Psychiatry Clin Neurosci. 2012 Apr 7;74(4):281-2.

4. Petersen A. More people are taking drugs for anxiety and insomnia, and doctors are worried. The Wall Street Journal. 2020 May 25.

5. Downey M. Xanax overdose and related deaths. National Drug & Alcohol Research Centre. UNSW Sydney.

6. Bryant B. Fake Xanax: The UK’s biggest ever dark net drugs bust. BBC. 2018 Mar 10.

7. Reinberg S. Fatal overdoses rising from sedatives like Valium, Xanax. HealthDay. 2016 Feb.

8. Is counterfeit Xanax dangerous? American Addiction Centers. Updated 2018 Nov 14.

9. McLaren E. Xanax history and statistics. Drugabuse.com.

10. Benzodiazepines and opioids. National Institute on Drug Abuse. 2018 Mar 15.

11. Choudhry Z et al. J Psychiatry. 2015;18(5). doi: 10.4172/2378-5756.1000319.

12. Islam FA et al. Current Psychiatry. 2018 Dec 17(12):43-4.

13. Adams M. Xanax death rate on the rise. White Sands Treatment. 2017 Sept.NEED LINK

14. Storrs C. Benzodiazepine overdose deaths soared in recent years, study finds. CNN. 2016 Feb. 18.

15. Hanscom DA. Plan A – Thrive and survive COVID-19. Back in Control. 2020.

16. Smith C. Xanax, a common anxiety medication, might actually block coronavirus. BGR. 2020 May 29.

Dr. Islam is a medical adviser for the International Maternal and Child Health Foundation (IMCHF), Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Islam disclosed no relevant financial relationships.

Mr. Choudhry is a research assistant at the IMCHF. He has no disclosures.

Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the IMCHF and is Mr. Choudhry’s father. He has no disclosures.

One of the more alarming trends that has emerged during the coronavirus crisis is the concomitant rise in the use of benzodiazepines, such as Xanax. It has been reported that at-risk individuals began seeking prescription anxiolytics as early as mid-February with a consequent peak of 34% the following month, coinciding with the World Health Organization’s declaration of a global pandemic.¹

Consistent with the available literature indicating that women are twice as likely to be affected by anxiety disorders, the prescription spikes were almost double when compared with those of their male counterparts.² The pandemic has instilled a sense of fear in people, leading to social repercussions, such as estrangement, insomnia, and paranoia for at-risk populations.^3,4

“Benzos” are commonly prescribed to help people sleep or to assist them in overcoming a host of anxiety disorders. The rapid onset of effects make Xanax a desirable and efficacious benzodiazepine.⁵ The use of these medications might not be an immediate cause for concern because patients might be taking it as intended. Nevertheless, clinicians are shying away from medical management in favor of counseling or therapy.
 

Dangerous trends

We are concerned that renewed interest in Xanax, coupled with physician reluctance to prescribe antianxiety medications, might trigger the return of an illicit drug boom. Numerous factors might contribute to this grim scenario, including patient dependence on benzodiazepines, paranoia about engaging with health care professionals because of fear tied to potential COVID-19 exposure, and/or increased access to illicit counterfeit pills from drug dealers or the dark web markets.

Lessons can be gleaned from the most extensive dark web drug busts in Britain’s history, in which a deluge of “pharmaceutical grade” Xanax pills made it to the hands of drug dealers and consumers between 2015 and 2017.⁶ A similar phenomenon emerged stateside.⁷ Virtually indistinguishable from recognized 2-mg Xanax pills, these fake pills posed a serious challenge to forensic scientists.⁸ The threat of overdose is very real for users targeted by the counterfeit Xanax trade, especially since those at risk often bypass professional health care guidelines.

In broad daylight, the drug dealers ran their operations revolving around two fake Xanax products: a primary knockoff and a limited edition – and vastly more potent “Red Devil” variant that was intentionally dyed for branding purposes. Because the “Red Devil” formulations contained 2.5 times the dose of the 2-mg pill, it had even more pronounced tolerance, dependence, and withdrawal effects (for example, panic attacks, anxiety, and/or hallucinations) – fatal consequences for users involved in consuming other drugs, such as alcohol or opioids. Preexisting drug users tend to gravitate toward benzodiazepines, such as alprazolam (Xanax), perhaps in part, because of its relatively rapid onset of action. Xanax also is known for inducing proeuphoric states at higher doses, hence the appeal of the “Red Devil” pills.

Benzodiazepines, as a class of drugs, facilitate the neurotransmitter gamma-aminobutryric acid’s (GABA) effect on the brain, producing anxiolytic, hypnotic, and/or anticonvulsant states within the user.⁹ Unbeknownst to numerous users is the fact that drugs such as alcohol and opioids, like Xanax, also serve as respiratory depressants, overriding the brain’s governance of the breathing mechanism. This, in turn, leads to unintended overdose deaths, even among seasoned drug seekers.

Overdose deaths have been steadily climbing over the years because it is common for some users to consume alcohol while being on Xanax therapy – without realizing that both substances are depressants and that taking them together can lead to side effects such as respiratory depression.

Forensic cases also have revealed that preexisting opioid consumers were drawn to Xanax; the drug’s potent mechanism of action would likely appeal to habituated users. A typical behavioral pattern has emerged among users and must be addressed. According to Australian Professor Shane Darke: “So they take their Xanax, they take their painkiller, then they get drunk, that could be enough to kill them.”

Fatalities are more likely when benzodiazepines are combined with other drug classes or if the existing supply is contaminated or laced (for example, with fentanyl).⁸

As far as deaths by accidental benzodiazepine overdose are concerned, a similar epidemic has been recorded in the United States. In 2013, almost one-third of all prescription overdose deaths can be attributed to the use of benzodiazepines (for example, Xanax, Valium, and Ativan). However, media attention has been considerably muted, especially when compared with that of narcotic abuse. This is even more puzzling when taking into account that three-quarters of benzodiazepine mortalities co-occur within the context of narcotic consumption. Substance Abuse and Mental Health Services Administration data confirm the ubiquitous nature of benzodiazepine (such as alprazolam) coprescriptions, accounting for roughly half of the 176,000 emergency department cases for 2011. The Centers for Disease Control and Prevention noted that there was a 67% increase in benzodiazepine prescriptions between 1996 and 2013, which warranted more stringent regulations for this particular class of drugs.

In 2016, the CDC issued new guidelines for opioid use acknowledging the danger of benzodiazepine coprescriptions. Food and Drug Administration “black box” warnings now grace the prescriptions of both of these drug classes.¹⁰ This trend remains on an upward trajectory, even more so during the pandemic, as there are 9.7 million prescriptions of anxiolytics/hypnotics such as Xanax, Ativan, and Klonopin in the United States as of March 2020, which represents a 10% increase over the previous year. The evolving landscape of this “new normal” may necessitate frequent patient updates and feedback via telepsychiatry, as well as the implementation of urine drug screening monitoring for drug adherence/compliance and diversion in those with suspected benzodiazepine addiction or a history of polysubstance abuse.^11,12

Clinical correlates

For patients who present acutely with Xanax toxicity in the emergency room setting, we will need to initially stabilize the vital signs and address the ongoing symptoms. It is advisable to arrange health care accommodations for patients with physical dependence to monitor and treat their withdrawal symptoms. The patient should be enrolled in a comprehensive addiction facility after undergoing formal detoxification; a tapered treatment protocol will need to be implemented because quitting “cold turkey” can lead to convulsions and, in some cases, death. Patient education, talk therapy, and alternatives to benzodiazepines should be discussed with the clinician.^13,145

However, to truly address the elephant in the room, we will need to consider institutional reforms to prevent a similar situation from arising in the future. Primary care physician shortages are compounded by changes in insurance policies. Nurses and physician assistants will need to be trained to manage benzodiazepine prescriptions. If there are community shortages in physicians, patients might turn to illegal means to secure their benzodiazepine supply, and it is imperative that we have the necessary fellowship and education programs to educate nonphysician health care clinicians with benzodiazepine management. Because physicians were prescribing benzodiazepines liberally, the Prescription Drug Monitoring Programs (PDMP) was enacted to monitor physician practices. Unfortunately, this ultimately intimidated physicians and effectively curbed reasonable physician prescribing patterns. It might be necessary to revisit existing prescription monitoring programs, encourage drug evaluations and guidelines based on evidence-based medicine and embrace telemedicine in order to facilitate patient-physician communication.

As of now, it is too early to prescribe Xanax routinely for ongoing anxiety experienced during the coronavirus crisis, and several physicians are cautious about prescribing antianxiety medications for more than a few months.¹⁷ Surprisingly, researchers in Barcelona have even explored the role of Xanax as potentially inhibiting Mpro, the primary protease of coronavirus, thereby forestalling the virus’s ability to replicate.¹⁶ However, it is worth noting that, given the preliminary nature of the results, any attempts at conclusively integrating Xanax within the context of coronavirus therapy would be premature.
 

References

1. Luhby T. Anti-anxiety medication prescriptions up 34% since coronavirus. CNN. 2020 Apr 16.

2. Women and Anxiety. Anxiety and Depression Association of America.

3. Shigemura J et al. Psychiatry Clin Neurosci. 2012 Apr 7;74(4):281-2.

4. Petersen A. More people are taking drugs for anxiety and insomnia, and doctors are worried. The Wall Street Journal. 2020 May 25.

5. Downey M. Xanax overdose and related deaths. National Drug & Alcohol Research Centre. UNSW Sydney.

6. Bryant B. Fake Xanax: The UK’s biggest ever dark net drugs bust. BBC. 2018 Mar 10.

7. Reinberg S. Fatal overdoses rising from sedatives like Valium, Xanax. HealthDay. 2016 Feb.

8. Is counterfeit Xanax dangerous? American Addiction Centers. Updated 2018 Nov 14.

9. McLaren E. Xanax history and statistics. Drugabuse.com.

10. Benzodiazepines and opioids. National Institute on Drug Abuse. 2018 Mar 15.

11. Choudhry Z et al. J Psychiatry. 2015;18(5). doi: 10.4172/2378-5756.1000319.

12. Islam FA et al. Current Psychiatry. 2018 Dec 17(12):43-4.

13. Adams M. Xanax death rate on the rise. White Sands Treatment. 2017 Sept.NEED LINK

14. Storrs C. Benzodiazepine overdose deaths soared in recent years, study finds. CNN. 2016 Feb. 18.

15. Hanscom DA. Plan A – Thrive and survive COVID-19. Back in Control. 2020.

16. Smith C. Xanax, a common anxiety medication, might actually block coronavirus. BGR. 2020 May 29.

Dr. Islam is a medical adviser for the International Maternal and Child Health Foundation (IMCHF), Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Islam disclosed no relevant financial relationships.

Mr. Choudhry is a research assistant at the IMCHF. He has no disclosures.

Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the IMCHF and is Mr. Choudhry’s father. He has no disclosures.

One of the more alarming trends that has emerged during the coronavirus crisis is the concomitant rise in the use of benzodiazepines, such as Xanax. It has been reported that at-risk individuals began seeking prescription anxiolytics as early as mid-February with a consequent peak of 34% the following month, coinciding with the World Health Organization’s declaration of a global pandemic.¹

Consistent with the available literature indicating that women are twice as likely to be affected by anxiety disorders, the prescription spikes were almost double when compared with those of their male counterparts.² The pandemic has instilled a sense of fear in people, leading to social repercussions, such as estrangement, insomnia, and paranoia for at-risk populations.^3,4

“Benzos” are commonly prescribed to help people sleep or to assist them in overcoming a host of anxiety disorders. The rapid onset of effects make Xanax a desirable and efficacious benzodiazepine.⁵ The use of these medications might not be an immediate cause for concern because patients might be taking it as intended. Nevertheless, clinicians are shying away from medical management in favor of counseling or therapy.
 

Dangerous trends

We are concerned that renewed interest in Xanax, coupled with physician reluctance to prescribe antianxiety medications, might trigger the return of an illicit drug boom. Numerous factors might contribute to this grim scenario, including patient dependence on benzodiazepines, paranoia about engaging with health care professionals because of fear tied to potential COVID-19 exposure, and/or increased access to illicit counterfeit pills from drug dealers or the dark web markets.

Lessons can be gleaned from the most extensive dark web drug busts in Britain’s history, in which a deluge of “pharmaceutical grade” Xanax pills made it to the hands of drug dealers and consumers between 2015 and 2017.⁶ A similar phenomenon emerged stateside.⁷ Virtually indistinguishable from recognized 2-mg Xanax pills, these fake pills posed a serious challenge to forensic scientists.⁸ The threat of overdose is very real for users targeted by the counterfeit Xanax trade, especially since those at risk often bypass professional health care guidelines.

In broad daylight, the drug dealers ran their operations revolving around two fake Xanax products: a primary knockoff and a limited edition – and vastly more potent “Red Devil” variant that was intentionally dyed for branding purposes. Because the “Red Devil” formulations contained 2.5 times the dose of the 2-mg pill, it had even more pronounced tolerance, dependence, and withdrawal effects (for example, panic attacks, anxiety, and/or hallucinations) – fatal consequences for users involved in consuming other drugs, such as alcohol or opioids. Preexisting drug users tend to gravitate toward benzodiazepines, such as alprazolam (Xanax), perhaps in part, because of its relatively rapid onset of action. Xanax also is known for inducing proeuphoric states at higher doses, hence the appeal of the “Red Devil” pills.

Benzodiazepines, as a class of drugs, facilitate the neurotransmitter gamma-aminobutryric acid’s (GABA) effect on the brain, producing anxiolytic, hypnotic, and/or anticonvulsant states within the user.⁹ Unbeknownst to numerous users is the fact that drugs such as alcohol and opioids, like Xanax, also serve as respiratory depressants, overriding the brain’s governance of the breathing mechanism. This, in turn, leads to unintended overdose deaths, even among seasoned drug seekers.

Overdose deaths have been steadily climbing over the years because it is common for some users to consume alcohol while being on Xanax therapy – without realizing that both substances are depressants and that taking them together can lead to side effects such as respiratory depression.

Forensic cases also have revealed that preexisting opioid consumers were drawn to Xanax; the drug’s potent mechanism of action would likely appeal to habituated users. A typical behavioral pattern has emerged among users and must be addressed. According to Australian Professor Shane Darke: “So they take their Xanax, they take their painkiller, then they get drunk, that could be enough to kill them.”

Fatalities are more likely when benzodiazepines are combined with other drug classes or if the existing supply is contaminated or laced (for example, with fentanyl).⁸

As far as deaths by accidental benzodiazepine overdose are concerned, a similar epidemic has been recorded in the United States. In 2013, almost one-third of all prescription overdose deaths can be attributed to the use of benzodiazepines (for example, Xanax, Valium, and Ativan). However, media attention has been considerably muted, especially when compared with that of narcotic abuse. This is even more puzzling when taking into account that three-quarters of benzodiazepine mortalities co-occur within the context of narcotic consumption. Substance Abuse and Mental Health Services Administration data confirm the ubiquitous nature of benzodiazepine (such as alprazolam) coprescriptions, accounting for roughly half of the 176,000 emergency department cases for 2011. The Centers for Disease Control and Prevention noted that there was a 67% increase in benzodiazepine prescriptions between 1996 and 2013, which warranted more stringent regulations for this particular class of drugs.

In 2016, the CDC issued new guidelines for opioid use acknowledging the danger of benzodiazepine coprescriptions. Food and Drug Administration “black box” warnings now grace the prescriptions of both of these drug classes.¹⁰ This trend remains on an upward trajectory, even more so during the pandemic, as there are 9.7 million prescriptions of anxiolytics/hypnotics such as Xanax, Ativan, and Klonopin in the United States as of March 2020, which represents a 10% increase over the previous year. The evolving landscape of this “new normal” may necessitate frequent patient updates and feedback via telepsychiatry, as well as the implementation of urine drug screening monitoring for drug adherence/compliance and diversion in those with suspected benzodiazepine addiction or a history of polysubstance abuse.^11,12

Clinical correlates

For patients who present acutely with Xanax toxicity in the emergency room setting, we will need to initially stabilize the vital signs and address the ongoing symptoms. It is advisable to arrange health care accommodations for patients with physical dependence to monitor and treat their withdrawal symptoms. The patient should be enrolled in a comprehensive addiction facility after undergoing formal detoxification; a tapered treatment protocol will need to be implemented because quitting “cold turkey” can lead to convulsions and, in some cases, death. Patient education, talk therapy, and alternatives to benzodiazepines should be discussed with the clinician.^13,145

However, to truly address the elephant in the room, we will need to consider institutional reforms to prevent a similar situation from arising in the future. Primary care physician shortages are compounded by changes in insurance policies. Nurses and physician assistants will need to be trained to manage benzodiazepine prescriptions. If there are community shortages in physicians, patients might turn to illegal means to secure their benzodiazepine supply, and it is imperative that we have the necessary fellowship and education programs to educate nonphysician health care clinicians with benzodiazepine management. Because physicians were prescribing benzodiazepines liberally, the Prescription Drug Monitoring Programs (PDMP) was enacted to monitor physician practices. Unfortunately, this ultimately intimidated physicians and effectively curbed reasonable physician prescribing patterns. It might be necessary to revisit existing prescription monitoring programs, encourage drug evaluations and guidelines based on evidence-based medicine and embrace telemedicine in order to facilitate patient-physician communication.

As of now, it is too early to prescribe Xanax routinely for ongoing anxiety experienced during the coronavirus crisis, and several physicians are cautious about prescribing antianxiety medications for more than a few months.¹⁷ Surprisingly, researchers in Barcelona have even explored the role of Xanax as potentially inhibiting Mpro, the primary protease of coronavirus, thereby forestalling the virus’s ability to replicate.¹⁶ However, it is worth noting that, given the preliminary nature of the results, any attempts at conclusively integrating Xanax within the context of coronavirus therapy would be premature.
 

References

1. Luhby T. Anti-anxiety medication prescriptions up 34% since coronavirus. CNN. 2020 Apr 16.

2. Women and Anxiety. Anxiety and Depression Association of America.

3. Shigemura J et al. Psychiatry Clin Neurosci. 2012 Apr 7;74(4):281-2.

4. Petersen A. More people are taking drugs for anxiety and insomnia, and doctors are worried. The Wall Street Journal. 2020 May 25.

5. Downey M. Xanax overdose and related deaths. National Drug & Alcohol Research Centre. UNSW Sydney.

6. Bryant B. Fake Xanax: The UK’s biggest ever dark net drugs bust. BBC. 2018 Mar 10.

7. Reinberg S. Fatal overdoses rising from sedatives like Valium, Xanax. HealthDay. 2016 Feb.

8. Is counterfeit Xanax dangerous? American Addiction Centers. Updated 2018 Nov 14.

9. McLaren E. Xanax history and statistics. Drugabuse.com.

10. Benzodiazepines and opioids. National Institute on Drug Abuse. 2018 Mar 15.

11. Choudhry Z et al. J Psychiatry. 2015;18(5). doi: 10.4172/2378-5756.1000319.

12. Islam FA et al. Current Psychiatry. 2018 Dec 17(12):43-4.

13. Adams M. Xanax death rate on the rise. White Sands Treatment. 2017 Sept.NEED LINK

14. Storrs C. Benzodiazepine overdose deaths soared in recent years, study finds. CNN. 2016 Feb. 18.

15. Hanscom DA. Plan A – Thrive and survive COVID-19. Back in Control. 2020.

16. Smith C. Xanax, a common anxiety medication, might actually block coronavirus. BGR. 2020 May 29.

Dr. Islam is a medical adviser for the International Maternal and Child Health Foundation (IMCHF), Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Islam disclosed no relevant financial relationships.

Mr. Choudhry is a research assistant at the IMCHF. He has no disclosures.

Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the IMCHF and is Mr. Choudhry’s father. He has no disclosures.

Swapping out intravenous fentanyl in favor of IV acetaminophen in patients with ST-elevation MI (STEMI) provides comparable pain relief but with desirably higher blood levels of ticagrelor both immediately after primary percutaneous intervention and 1 hour post procedure.

Bruce Jancin/Frontline Medical News

That’s according to results of the Dutch ON-TIME 3 trial, presented by Anne H. Tavenier, MD, at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Our trial results have implications for the prehospital treatment of STEMI patients,” said Dr. Tavenier, a cardiologist at the Isala Clinic in Zwolle, the Netherlands.

The explanation for the success of this novel STEMI pain management strategy? The synthetic opioid fentanyl impairs gastrointestinal absorption of oral P2Y12 receptor antagonists such as ticagrelor. Opiates do so as well, whereas acetaminophen does not, she explained.

The potent platelet inhibition provided by oral P2Y12 inhibitors is crucial to successful primary PCI for STEMI. But these platelet inhibitory effects are inherently slowed in STEMI patients owing to hemodynamic changes and delayed GI absorption. And even though both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of opioids for pain control in STEMI patients, the fact is that these medications further delay the absorption of oral P2Y12 inhibitors. And this delay is further exacerbated by the nausea and vomiting which are common side effects of IV fentanyl, she continued.

The impetus for the ON-TIME 3 trial was straightforward, the cardiologist said: “For years, STEMI patients have been treated with morphine or morphinelike drugs like fentanyl because of pain or sympathetic stress. To date, trials investigating alternative analgesics to opioids have been scarce.”

ON-TIME 3 was a multicenter, open-label, phase 4 clinical trial in which 195 STEMI patients with a self-reported pain score of at least 4 on a 0-10 scale received crushed ticagrelor in the ambulance along with either 1,000 mg of IV acetaminophen or fentanyl at 1-2 mcg/kg.

Ticagrelor blood levels were significantly higher in the IV acetaminophen group when measured just prior to primary PCI (151 ng/mL versus 60 ng/mL in the IV fentanyl group; immediately after PCI (326 versus 115 ng/mL), and 1 hour post PCI (488 versus 372 ng/mL).

However, there was no significant between-group difference in levels of platelet reactivity units measured immediately after primary PCI, Dr. Tavenier added.

Discussant Christoph K. Naber, MD, PhD, confessed that prior to ON-TIME 3 he was unaware that administering opioids to STEMI patients results in delayed absorption of oral P2Y12 inhibitors. Upon delving into the literature, however, he found that this is indeed a well-documented problem.

“The open question I have about this very elegant trial is whether the increased P2Y12 levels will translate into a measurable difference in clinical outcomes,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.

The answer to that question would require a larger, longer-term trial. And he’s disinclined to wait around for that to happen.

“I think when we look at the risk balance, the risk of switching from an opioid to acetaminophen, if it works for the patient, is rather low. So this might be something to introduce in my practice,” the cardiologist said.

Dr. Tavenier and Dr. Naber reported having no financial conflicts of interest.

bjancin@mdedge.com

SOURCE: Tavenier AH. EuroPCR 2020.

Swapping out intravenous fentanyl in favor of IV acetaminophen in patients with ST-elevation MI (STEMI) provides comparable pain relief but with desirably higher blood levels of ticagrelor both immediately after primary percutaneous intervention and 1 hour post procedure.

Bruce Jancin/Frontline Medical News

That’s according to results of the Dutch ON-TIME 3 trial, presented by Anne H. Tavenier, MD, at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Our trial results have implications for the prehospital treatment of STEMI patients,” said Dr. Tavenier, a cardiologist at the Isala Clinic in Zwolle, the Netherlands.

The explanation for the success of this novel STEMI pain management strategy? The synthetic opioid fentanyl impairs gastrointestinal absorption of oral P2Y12 receptor antagonists such as ticagrelor. Opiates do so as well, whereas acetaminophen does not, she explained.

The potent platelet inhibition provided by oral P2Y12 inhibitors is crucial to successful primary PCI for STEMI. But these platelet inhibitory effects are inherently slowed in STEMI patients owing to hemodynamic changes and delayed GI absorption. And even though both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of opioids for pain control in STEMI patients, the fact is that these medications further delay the absorption of oral P2Y12 inhibitors. And this delay is further exacerbated by the nausea and vomiting which are common side effects of IV fentanyl, she continued.

The impetus for the ON-TIME 3 trial was straightforward, the cardiologist said: “For years, STEMI patients have been treated with morphine or morphinelike drugs like fentanyl because of pain or sympathetic stress. To date, trials investigating alternative analgesics to opioids have been scarce.”

ON-TIME 3 was a multicenter, open-label, phase 4 clinical trial in which 195 STEMI patients with a self-reported pain score of at least 4 on a 0-10 scale received crushed ticagrelor in the ambulance along with either 1,000 mg of IV acetaminophen or fentanyl at 1-2 mcg/kg.

Ticagrelor blood levels were significantly higher in the IV acetaminophen group when measured just prior to primary PCI (151 ng/mL versus 60 ng/mL in the IV fentanyl group; immediately after PCI (326 versus 115 ng/mL), and 1 hour post PCI (488 versus 372 ng/mL).

However, there was no significant between-group difference in levels of platelet reactivity units measured immediately after primary PCI, Dr. Tavenier added.

Discussant Christoph K. Naber, MD, PhD, confessed that prior to ON-TIME 3 he was unaware that administering opioids to STEMI patients results in delayed absorption of oral P2Y12 inhibitors. Upon delving into the literature, however, he found that this is indeed a well-documented problem.

“The open question I have about this very elegant trial is whether the increased P2Y12 levels will translate into a measurable difference in clinical outcomes,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.

The answer to that question would require a larger, longer-term trial. And he’s disinclined to wait around for that to happen.

“I think when we look at the risk balance, the risk of switching from an opioid to acetaminophen, if it works for the patient, is rather low. So this might be something to introduce in my practice,” the cardiologist said.

Dr. Tavenier and Dr. Naber reported having no financial conflicts of interest.

bjancin@mdedge.com

SOURCE: Tavenier AH. EuroPCR 2020.

Swapping out intravenous fentanyl in favor of IV acetaminophen in patients with ST-elevation MI (STEMI) provides comparable pain relief but with desirably higher blood levels of ticagrelor both immediately after primary percutaneous intervention and 1 hour post procedure.

Bruce Jancin/Frontline Medical News

That’s according to results of the Dutch ON-TIME 3 trial, presented by Anne H. Tavenier, MD, at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Our trial results have implications for the prehospital treatment of STEMI patients,” said Dr. Tavenier, a cardiologist at the Isala Clinic in Zwolle, the Netherlands.

The explanation for the success of this novel STEMI pain management strategy? The synthetic opioid fentanyl impairs gastrointestinal absorption of oral P2Y12 receptor antagonists such as ticagrelor. Opiates do so as well, whereas acetaminophen does not, she explained.

The potent platelet inhibition provided by oral P2Y12 inhibitors is crucial to successful primary PCI for STEMI. But these platelet inhibitory effects are inherently slowed in STEMI patients owing to hemodynamic changes and delayed GI absorption. And even though both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of opioids for pain control in STEMI patients, the fact is that these medications further delay the absorption of oral P2Y12 inhibitors. And this delay is further exacerbated by the nausea and vomiting which are common side effects of IV fentanyl, she continued.

The impetus for the ON-TIME 3 trial was straightforward, the cardiologist said: “For years, STEMI patients have been treated with morphine or morphinelike drugs like fentanyl because of pain or sympathetic stress. To date, trials investigating alternative analgesics to opioids have been scarce.”

ON-TIME 3 was a multicenter, open-label, phase 4 clinical trial in which 195 STEMI patients with a self-reported pain score of at least 4 on a 0-10 scale received crushed ticagrelor in the ambulance along with either 1,000 mg of IV acetaminophen or fentanyl at 1-2 mcg/kg.

Ticagrelor blood levels were significantly higher in the IV acetaminophen group when measured just prior to primary PCI (151 ng/mL versus 60 ng/mL in the IV fentanyl group; immediately after PCI (326 versus 115 ng/mL), and 1 hour post PCI (488 versus 372 ng/mL).

However, there was no significant between-group difference in levels of platelet reactivity units measured immediately after primary PCI, Dr. Tavenier added.

Discussant Christoph K. Naber, MD, PhD, confessed that prior to ON-TIME 3 he was unaware that administering opioids to STEMI patients results in delayed absorption of oral P2Y12 inhibitors. Upon delving into the literature, however, he found that this is indeed a well-documented problem.

“The open question I have about this very elegant trial is whether the increased P2Y12 levels will translate into a measurable difference in clinical outcomes,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.

The answer to that question would require a larger, longer-term trial. And he’s disinclined to wait around for that to happen.

“I think when we look at the risk balance, the risk of switching from an opioid to acetaminophen, if it works for the patient, is rather low. So this might be something to introduce in my practice,” the cardiologist said.

Dr. Tavenier and Dr. Naber reported having no financial conflicts of interest.

bjancin@mdedge.com

SOURCE: Tavenier AH. EuroPCR 2020.

The Food and Drug Administration has approved expanded use of Dysport to treat upper- and lower-limb spasticity – including that caused by cerebral palsy – for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.

When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.

“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.

The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.

The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.

Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The Food and Drug Administration has approved expanded use of Dysport to treat upper- and lower-limb spasticity – including that caused by cerebral palsy – for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.

When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.

“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.

The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.

The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.

Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The Food and Drug Administration has approved expanded use of Dysport to treat upper- and lower-limb spasticity – including that caused by cerebral palsy – for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.

When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.

“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.

The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.

The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.

Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.