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Needle-free epinephrine products could be available in 2023
Longstanding anxiety around use of epinephrine autoinjectors has prompted research into alternative delivery routes for this life-saving medication. Several companies presented posters on their needle-free epinephrine products at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.
Intranasal formulations are under development at ARS Pharmaceuticals (San Diego) and Bryn Pharma (Raleigh, N.C.). And Aquestive Therapeutics (Warren, N.J.) is working on a sublingual film that delivers epinephrine prodrug when applied under the tongue.
Epinephrine is essential for stopping life-threatening allergic reactions, yet patients often don’t carry their autoinjectors and many hesitate to use them. “It’s needle phobia,” said ARS Pharmaceuticals CEO Richard Lowenthal in an interview with this news organization. “They’re afraid to use it. They don’t like to inject their children, so they hesitate.”
Both nasal sprays reached maximal plasma concentration in 20-30 minutes. ARS Pharmaceuticals compared its intranasal product (Neffy 1 mg) against manual intramuscular injection (0.3 mg) and two autoinjectors (EpiPen 0.3 mg and Symjepi 0.3 mg) by analyzing data from multiple randomized crossover Phase 1 studies examining pharmacokinetics and pharmacodynamics in 175 healthy adults. In this integrated analysis, EpiPen was fastest (20 minutes) at reaching maximal concentration (Tmax), followed by Symjepi and Neffy (both 30 minutes) and epinephrine 0.3 mg IM (45 minutes). In a human factors analysis, ARS Pharmaceuticals reported that untrained participants were able to administer the Neffy spray to themselves or another participant safely and effectively during a simulated emergency scenario.
Bryn Pharma compared pharmacokinetics of its nasal spray product (BRYN-NDS1C 6.6 mg) when self-administered or administered by trained professionals and found comparable profiles for each. Tmax values were also similar: 21.63 minutes (trained professional) and 19.82 minutes (self-administered).
Aquestive Therapeutics is developing a postage stamp-sized product (AQST-109) that delivers epinephrine and begins dissolving when placed under the tongue. No water or swallowing is required for administration, and its packaging is thinner and smaller than a credit card, according to CEO Keith Kendall.
Its analysis showed that the epinephrine reaches maximum plasma concentration in about 15 minutes, with a Tmax range narrower than that of the EpiPen. “The results showed dosing with AQST-109 resulted in PK concentration and Tmax values comparable to published data from autoinjectors,” said John Oppenheimer, MD, of Rutgers University School of Medicine, in a prerecorded poster summary.
Aquestive aims to move forward to the manufacture of registration batches and a pivotal pharmacokinetic study in the second half of 2022. Mr. Lowenthal said ARS Pharmaceuticals is hoping for approval and launch of its nasal spray by summer 2023.
“Having a non-needle delivery device would help many people overcome that fear and hopefully increase use in anaphylaxis,” said David Stukus, MD, an allergist-immunologist and professor of clinical pediatrics at Nationwide Children’s Hospital, Columbus, who was not involved with any of the studies on EpiPen alternatives. And “it’s not just food allergy – anaphylaxis can occur from venom stings, medications, or idiopathic causes.”
Mr. Lowenthal is the CEO of ARS Pharmaceuticals. Mr. Kendall is CEO of Aquestive Therapeutics. Dr. Oppenheimer is a consultant for Aquestive, GSK, Amgen, Sanofi, and Aimmune and sits on Aquestive’s advisory board. Dr. Stukus is a consultant for Novartis.
A version of this article first appeared on Medscape.com.
Longstanding anxiety around use of epinephrine autoinjectors has prompted research into alternative delivery routes for this life-saving medication. Several companies presented posters on their needle-free epinephrine products at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.
Intranasal formulations are under development at ARS Pharmaceuticals (San Diego) and Bryn Pharma (Raleigh, N.C.). And Aquestive Therapeutics (Warren, N.J.) is working on a sublingual film that delivers epinephrine prodrug when applied under the tongue.
Epinephrine is essential for stopping life-threatening allergic reactions, yet patients often don’t carry their autoinjectors and many hesitate to use them. “It’s needle phobia,” said ARS Pharmaceuticals CEO Richard Lowenthal in an interview with this news organization. “They’re afraid to use it. They don’t like to inject their children, so they hesitate.”
Both nasal sprays reached maximal plasma concentration in 20-30 minutes. ARS Pharmaceuticals compared its intranasal product (Neffy 1 mg) against manual intramuscular injection (0.3 mg) and two autoinjectors (EpiPen 0.3 mg and Symjepi 0.3 mg) by analyzing data from multiple randomized crossover Phase 1 studies examining pharmacokinetics and pharmacodynamics in 175 healthy adults. In this integrated analysis, EpiPen was fastest (20 minutes) at reaching maximal concentration (Tmax), followed by Symjepi and Neffy (both 30 minutes) and epinephrine 0.3 mg IM (45 minutes). In a human factors analysis, ARS Pharmaceuticals reported that untrained participants were able to administer the Neffy spray to themselves or another participant safely and effectively during a simulated emergency scenario.
Bryn Pharma compared pharmacokinetics of its nasal spray product (BRYN-NDS1C 6.6 mg) when self-administered or administered by trained professionals and found comparable profiles for each. Tmax values were also similar: 21.63 minutes (trained professional) and 19.82 minutes (self-administered).
Aquestive Therapeutics is developing a postage stamp-sized product (AQST-109) that delivers epinephrine and begins dissolving when placed under the tongue. No water or swallowing is required for administration, and its packaging is thinner and smaller than a credit card, according to CEO Keith Kendall.
Its analysis showed that the epinephrine reaches maximum plasma concentration in about 15 minutes, with a Tmax range narrower than that of the EpiPen. “The results showed dosing with AQST-109 resulted in PK concentration and Tmax values comparable to published data from autoinjectors,” said John Oppenheimer, MD, of Rutgers University School of Medicine, in a prerecorded poster summary.
Aquestive aims to move forward to the manufacture of registration batches and a pivotal pharmacokinetic study in the second half of 2022. Mr. Lowenthal said ARS Pharmaceuticals is hoping for approval and launch of its nasal spray by summer 2023.
“Having a non-needle delivery device would help many people overcome that fear and hopefully increase use in anaphylaxis,” said David Stukus, MD, an allergist-immunologist and professor of clinical pediatrics at Nationwide Children’s Hospital, Columbus, who was not involved with any of the studies on EpiPen alternatives. And “it’s not just food allergy – anaphylaxis can occur from venom stings, medications, or idiopathic causes.”
Mr. Lowenthal is the CEO of ARS Pharmaceuticals. Mr. Kendall is CEO of Aquestive Therapeutics. Dr. Oppenheimer is a consultant for Aquestive, GSK, Amgen, Sanofi, and Aimmune and sits on Aquestive’s advisory board. Dr. Stukus is a consultant for Novartis.
A version of this article first appeared on Medscape.com.
Longstanding anxiety around use of epinephrine autoinjectors has prompted research into alternative delivery routes for this life-saving medication. Several companies presented posters on their needle-free epinephrine products at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.
Intranasal formulations are under development at ARS Pharmaceuticals (San Diego) and Bryn Pharma (Raleigh, N.C.). And Aquestive Therapeutics (Warren, N.J.) is working on a sublingual film that delivers epinephrine prodrug when applied under the tongue.
Epinephrine is essential for stopping life-threatening allergic reactions, yet patients often don’t carry their autoinjectors and many hesitate to use them. “It’s needle phobia,” said ARS Pharmaceuticals CEO Richard Lowenthal in an interview with this news organization. “They’re afraid to use it. They don’t like to inject their children, so they hesitate.”
Both nasal sprays reached maximal plasma concentration in 20-30 minutes. ARS Pharmaceuticals compared its intranasal product (Neffy 1 mg) against manual intramuscular injection (0.3 mg) and two autoinjectors (EpiPen 0.3 mg and Symjepi 0.3 mg) by analyzing data from multiple randomized crossover Phase 1 studies examining pharmacokinetics and pharmacodynamics in 175 healthy adults. In this integrated analysis, EpiPen was fastest (20 minutes) at reaching maximal concentration (Tmax), followed by Symjepi and Neffy (both 30 minutes) and epinephrine 0.3 mg IM (45 minutes). In a human factors analysis, ARS Pharmaceuticals reported that untrained participants were able to administer the Neffy spray to themselves or another participant safely and effectively during a simulated emergency scenario.
Bryn Pharma compared pharmacokinetics of its nasal spray product (BRYN-NDS1C 6.6 mg) when self-administered or administered by trained professionals and found comparable profiles for each. Tmax values were also similar: 21.63 minutes (trained professional) and 19.82 minutes (self-administered).
Aquestive Therapeutics is developing a postage stamp-sized product (AQST-109) that delivers epinephrine and begins dissolving when placed under the tongue. No water or swallowing is required for administration, and its packaging is thinner and smaller than a credit card, according to CEO Keith Kendall.
Its analysis showed that the epinephrine reaches maximum plasma concentration in about 15 minutes, with a Tmax range narrower than that of the EpiPen. “The results showed dosing with AQST-109 resulted in PK concentration and Tmax values comparable to published data from autoinjectors,” said John Oppenheimer, MD, of Rutgers University School of Medicine, in a prerecorded poster summary.
Aquestive aims to move forward to the manufacture of registration batches and a pivotal pharmacokinetic study in the second half of 2022. Mr. Lowenthal said ARS Pharmaceuticals is hoping for approval and launch of its nasal spray by summer 2023.
“Having a non-needle delivery device would help many people overcome that fear and hopefully increase use in anaphylaxis,” said David Stukus, MD, an allergist-immunologist and professor of clinical pediatrics at Nationwide Children’s Hospital, Columbus, who was not involved with any of the studies on EpiPen alternatives. And “it’s not just food allergy – anaphylaxis can occur from venom stings, medications, or idiopathic causes.”
Mr. Lowenthal is the CEO of ARS Pharmaceuticals. Mr. Kendall is CEO of Aquestive Therapeutics. Dr. Oppenheimer is a consultant for Aquestive, GSK, Amgen, Sanofi, and Aimmune and sits on Aquestive’s advisory board. Dr. Stukus is a consultant for Novartis.
A version of this article first appeared on Medscape.com.
FROM AAAAI
FDA approves new CAR T-cell treatment for multiple myeloma
A new treatment option for patients with refractory/relapsed multiple myeloma who have already tried four or more therapies has been approved by the U.S. Food and Drug Administration.
There are already two other therapies on the market that target BCMA – another CAR T cell, idecabtagene vicleucel (Abecma), which was approved by the FDA in March 2021, and a drug conjugate, belantamab mafodotin (Blenrep), which was approved in August 2020.
The approval of cilta-cel was based on clinical data from the CARTITUDE-1 study, which were initially presented in December 2020 at the annual meeting of the American Society of Hematology, as reported at the time by this news organization.
The trial involved 97 patients with relapsed/refractory multiple myeloma who had already received a median of six previous treatments (range, three to 18), including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse, with fewer patients achieving a deep response as they progress through later lines of therapy,” commented Sundar Jagannath, MBBS, professor of medicine, hematology, and medical oncology at Mount Sinai, who was a principal investigator on the pivotal study.
“That is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” he said.
“Today’s approval of Carvykti helps address a great unmet need for these patients,” he commented in a press release from the manufacturer.
Like other CAR T-cell therapies, ciltacabtagene autoleucel is a one-time treatment. It involves collecting blood from the patient, extracting T cells, genetically engineering them, then transfusing them back to the patient, who in the meantime has undergone conditioning.
The results from CARTITUDE-1 show that this one-time treatment resulted in deep and durable responses.
The overall response rate was 98%, and the majority of patients (78%) achieved a stringent complete response, in which physicians are unable to observe any signs or symptoms of disease via imaging or other tests after treatment.
At a median of 18 months’ follow-up, the median duration of response was 21.8 months.
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” commented Mr. Jagannath.
“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time,” he added.
As with other CAR T-cell therapies, there were serious side effects, and these products are available only through restricted programs under a risk evaluation and mitigation strategy.
The product information for Cartykti includes a boxed warning that mentions cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
The most common adverse reactions (reported in greater than or equal to 20% of patients) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections–pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.
A version of this article first appeared on Medscape.com.
A new treatment option for patients with refractory/relapsed multiple myeloma who have already tried four or more therapies has been approved by the U.S. Food and Drug Administration.
There are already two other therapies on the market that target BCMA – another CAR T cell, idecabtagene vicleucel (Abecma), which was approved by the FDA in March 2021, and a drug conjugate, belantamab mafodotin (Blenrep), which was approved in August 2020.
The approval of cilta-cel was based on clinical data from the CARTITUDE-1 study, which were initially presented in December 2020 at the annual meeting of the American Society of Hematology, as reported at the time by this news organization.
The trial involved 97 patients with relapsed/refractory multiple myeloma who had already received a median of six previous treatments (range, three to 18), including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse, with fewer patients achieving a deep response as they progress through later lines of therapy,” commented Sundar Jagannath, MBBS, professor of medicine, hematology, and medical oncology at Mount Sinai, who was a principal investigator on the pivotal study.
“That is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” he said.
“Today’s approval of Carvykti helps address a great unmet need for these patients,” he commented in a press release from the manufacturer.
Like other CAR T-cell therapies, ciltacabtagene autoleucel is a one-time treatment. It involves collecting blood from the patient, extracting T cells, genetically engineering them, then transfusing them back to the patient, who in the meantime has undergone conditioning.
The results from CARTITUDE-1 show that this one-time treatment resulted in deep and durable responses.
The overall response rate was 98%, and the majority of patients (78%) achieved a stringent complete response, in which physicians are unable to observe any signs or symptoms of disease via imaging or other tests after treatment.
At a median of 18 months’ follow-up, the median duration of response was 21.8 months.
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” commented Mr. Jagannath.
“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time,” he added.
As with other CAR T-cell therapies, there were serious side effects, and these products are available only through restricted programs under a risk evaluation and mitigation strategy.
The product information for Cartykti includes a boxed warning that mentions cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
The most common adverse reactions (reported in greater than or equal to 20% of patients) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections–pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.
A version of this article first appeared on Medscape.com.
A new treatment option for patients with refractory/relapsed multiple myeloma who have already tried four or more therapies has been approved by the U.S. Food and Drug Administration.
There are already two other therapies on the market that target BCMA – another CAR T cell, idecabtagene vicleucel (Abecma), which was approved by the FDA in March 2021, and a drug conjugate, belantamab mafodotin (Blenrep), which was approved in August 2020.
The approval of cilta-cel was based on clinical data from the CARTITUDE-1 study, which were initially presented in December 2020 at the annual meeting of the American Society of Hematology, as reported at the time by this news organization.
The trial involved 97 patients with relapsed/refractory multiple myeloma who had already received a median of six previous treatments (range, three to 18), including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse, with fewer patients achieving a deep response as they progress through later lines of therapy,” commented Sundar Jagannath, MBBS, professor of medicine, hematology, and medical oncology at Mount Sinai, who was a principal investigator on the pivotal study.
“That is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” he said.
“Today’s approval of Carvykti helps address a great unmet need for these patients,” he commented in a press release from the manufacturer.
Like other CAR T-cell therapies, ciltacabtagene autoleucel is a one-time treatment. It involves collecting blood from the patient, extracting T cells, genetically engineering them, then transfusing them back to the patient, who in the meantime has undergone conditioning.
The results from CARTITUDE-1 show that this one-time treatment resulted in deep and durable responses.
The overall response rate was 98%, and the majority of patients (78%) achieved a stringent complete response, in which physicians are unable to observe any signs or symptoms of disease via imaging or other tests after treatment.
At a median of 18 months’ follow-up, the median duration of response was 21.8 months.
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” commented Mr. Jagannath.
“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time,” he added.
As with other CAR T-cell therapies, there were serious side effects, and these products are available only through restricted programs under a risk evaluation and mitigation strategy.
The product information for Cartykti includes a boxed warning that mentions cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
The most common adverse reactions (reported in greater than or equal to 20% of patients) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections–pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.
A version of this article first appeared on Medscape.com.
Excess sodium in soluble acetaminophen tied to CVD risk, death
a large observational study of more than 300,000 adults suggests.
“Numerous studies have reported that high sodium intake is associated with increased risks of cardiovascular disease,” Yuqing Zhang, DSc, with Massachusetts General Hospital and Harvard Medical School, Boston, told this news organization. “Given that the pain relief effect of non–sodium-containing acetaminophen is similar to that of sodium-containing acetaminophen, clinicians may prescribe non–sodium-containing acetaminophen to their patients to minimize the risk of CVD and mortality,” Dr. Zhang said.
The study was published online Feb. 24 in the European Heart Journal.
‘Compelling results’
Dr. Zhang and colleagues note that the effervescent and soluble formulations of 0.5 g acetaminophen contain 0.44 and 0.39 g of sodium, respectively.
Therefore, the intake of maximum daily dose (4 g/day) of sodium-containing acetaminophen corresponds to the ingestion of more than 3 g of sodium, a dose that alone exceeds the recommended total daily sodium intake allowance of the World Health Organization (2 g/day).
“This hidden extra sodium intake is often overlooked,” Dr. Zhang told this news organization.
Using data from the Health Improvement Network, a U.K. primary care database, the researchers examined 4,532 patients with hypertension taking sodium-containing acetaminophen and compared them with 146,866 patients with hypertension taking non–sodium-containing acetaminophen (tablet, capsule, or oral suspension formulations).
After 1 year, the risk of incident CVD (myocardial infarction, stroke, and heart failure) was 5.6% in those taking sodium-containing acetaminophen, compared with 4.6% in those taking non–sodium-containing acetaminophen (average weighted hazard ratio, 1.59; 95% confidence interval, 1.32-1.92).
A separate analysis of normotensive patients taking sodium-containing acetaminophen (n = 5,351) or non–sodium-containing acetaminophen (n = 141,948) gave similar results.
The 1-year risk of incident CVD was 4.4% in those taking sodium-containing acetaminophen vs. 3.7% among those taking non–sodium-containing acetaminophen (average weighted HR, 1.45; 95% CI, 1.18-1.79).
There was also evidence of a dose-response relationship.
In those with hypertension, CVD risk increased by roughly one-quarter (odds ratio, 1.26) for those with one prescription of sodium-containing acetaminophen and by nearly one half (OR, 1.45) for those with five or more prescriptions of sodium-containing acetaminophen. Similar findings were observed among adults without hypertension.
Mortality at 1 year was also higher in those taking sodium-containing acetaminophen than non–sodium-containing acetaminophen, in patients with hypertension (7.6% vs. 6.1%) and without hypertension (7.3% vs. 5.9%).
“The results are compelling,” write the authors of an editorial published with the study.
“The direct message from this study is clear – there are likely to be millions of people worldwide taking paracetamol on a daily basis in a ‘fast-acting’ effervescent or soluble formulation who are increasing their risks of cardiovascular disease and premature death,” say Aletta Schutte, PhD, and Bruce Neal, MBChB, PhD, of the George Institute for Global Health, Sydney.
“The weight of the evidence makes ongoing inaction on sodium-containing medications untenable. The widespread use of effervescent medication in the general population, and the enormous doses of sodium that can be consumed inadvertently by unsuspecting consumers requires urgent action,” Dr. Schutte and Dr. Neal say.
The study was supported by the National Natural Science Foundation of China, the National Key Research and Development Project, the Project Program of National Clinical Research Center for Geriatric Disorders, the Key Research and Development Program of Hunan Province, and the Science and Technology Program of Hunan Province. Dr. Zhang, Dr. Schutte, and Dr. Neal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a large observational study of more than 300,000 adults suggests.
“Numerous studies have reported that high sodium intake is associated with increased risks of cardiovascular disease,” Yuqing Zhang, DSc, with Massachusetts General Hospital and Harvard Medical School, Boston, told this news organization. “Given that the pain relief effect of non–sodium-containing acetaminophen is similar to that of sodium-containing acetaminophen, clinicians may prescribe non–sodium-containing acetaminophen to their patients to minimize the risk of CVD and mortality,” Dr. Zhang said.
The study was published online Feb. 24 in the European Heart Journal.
‘Compelling results’
Dr. Zhang and colleagues note that the effervescent and soluble formulations of 0.5 g acetaminophen contain 0.44 and 0.39 g of sodium, respectively.
Therefore, the intake of maximum daily dose (4 g/day) of sodium-containing acetaminophen corresponds to the ingestion of more than 3 g of sodium, a dose that alone exceeds the recommended total daily sodium intake allowance of the World Health Organization (2 g/day).
“This hidden extra sodium intake is often overlooked,” Dr. Zhang told this news organization.
Using data from the Health Improvement Network, a U.K. primary care database, the researchers examined 4,532 patients with hypertension taking sodium-containing acetaminophen and compared them with 146,866 patients with hypertension taking non–sodium-containing acetaminophen (tablet, capsule, or oral suspension formulations).
After 1 year, the risk of incident CVD (myocardial infarction, stroke, and heart failure) was 5.6% in those taking sodium-containing acetaminophen, compared with 4.6% in those taking non–sodium-containing acetaminophen (average weighted hazard ratio, 1.59; 95% confidence interval, 1.32-1.92).
A separate analysis of normotensive patients taking sodium-containing acetaminophen (n = 5,351) or non–sodium-containing acetaminophen (n = 141,948) gave similar results.
The 1-year risk of incident CVD was 4.4% in those taking sodium-containing acetaminophen vs. 3.7% among those taking non–sodium-containing acetaminophen (average weighted HR, 1.45; 95% CI, 1.18-1.79).
There was also evidence of a dose-response relationship.
In those with hypertension, CVD risk increased by roughly one-quarter (odds ratio, 1.26) for those with one prescription of sodium-containing acetaminophen and by nearly one half (OR, 1.45) for those with five or more prescriptions of sodium-containing acetaminophen. Similar findings were observed among adults without hypertension.
Mortality at 1 year was also higher in those taking sodium-containing acetaminophen than non–sodium-containing acetaminophen, in patients with hypertension (7.6% vs. 6.1%) and without hypertension (7.3% vs. 5.9%).
“The results are compelling,” write the authors of an editorial published with the study.
“The direct message from this study is clear – there are likely to be millions of people worldwide taking paracetamol on a daily basis in a ‘fast-acting’ effervescent or soluble formulation who are increasing their risks of cardiovascular disease and premature death,” say Aletta Schutte, PhD, and Bruce Neal, MBChB, PhD, of the George Institute for Global Health, Sydney.
“The weight of the evidence makes ongoing inaction on sodium-containing medications untenable. The widespread use of effervescent medication in the general population, and the enormous doses of sodium that can be consumed inadvertently by unsuspecting consumers requires urgent action,” Dr. Schutte and Dr. Neal say.
The study was supported by the National Natural Science Foundation of China, the National Key Research and Development Project, the Project Program of National Clinical Research Center for Geriatric Disorders, the Key Research and Development Program of Hunan Province, and the Science and Technology Program of Hunan Province. Dr. Zhang, Dr. Schutte, and Dr. Neal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a large observational study of more than 300,000 adults suggests.
“Numerous studies have reported that high sodium intake is associated with increased risks of cardiovascular disease,” Yuqing Zhang, DSc, with Massachusetts General Hospital and Harvard Medical School, Boston, told this news organization. “Given that the pain relief effect of non–sodium-containing acetaminophen is similar to that of sodium-containing acetaminophen, clinicians may prescribe non–sodium-containing acetaminophen to their patients to minimize the risk of CVD and mortality,” Dr. Zhang said.
The study was published online Feb. 24 in the European Heart Journal.
‘Compelling results’
Dr. Zhang and colleagues note that the effervescent and soluble formulations of 0.5 g acetaminophen contain 0.44 and 0.39 g of sodium, respectively.
Therefore, the intake of maximum daily dose (4 g/day) of sodium-containing acetaminophen corresponds to the ingestion of more than 3 g of sodium, a dose that alone exceeds the recommended total daily sodium intake allowance of the World Health Organization (2 g/day).
“This hidden extra sodium intake is often overlooked,” Dr. Zhang told this news organization.
Using data from the Health Improvement Network, a U.K. primary care database, the researchers examined 4,532 patients with hypertension taking sodium-containing acetaminophen and compared them with 146,866 patients with hypertension taking non–sodium-containing acetaminophen (tablet, capsule, or oral suspension formulations).
After 1 year, the risk of incident CVD (myocardial infarction, stroke, and heart failure) was 5.6% in those taking sodium-containing acetaminophen, compared with 4.6% in those taking non–sodium-containing acetaminophen (average weighted hazard ratio, 1.59; 95% confidence interval, 1.32-1.92).
A separate analysis of normotensive patients taking sodium-containing acetaminophen (n = 5,351) or non–sodium-containing acetaminophen (n = 141,948) gave similar results.
The 1-year risk of incident CVD was 4.4% in those taking sodium-containing acetaminophen vs. 3.7% among those taking non–sodium-containing acetaminophen (average weighted HR, 1.45; 95% CI, 1.18-1.79).
There was also evidence of a dose-response relationship.
In those with hypertension, CVD risk increased by roughly one-quarter (odds ratio, 1.26) for those with one prescription of sodium-containing acetaminophen and by nearly one half (OR, 1.45) for those with five or more prescriptions of sodium-containing acetaminophen. Similar findings were observed among adults without hypertension.
Mortality at 1 year was also higher in those taking sodium-containing acetaminophen than non–sodium-containing acetaminophen, in patients with hypertension (7.6% vs. 6.1%) and without hypertension (7.3% vs. 5.9%).
“The results are compelling,” write the authors of an editorial published with the study.
“The direct message from this study is clear – there are likely to be millions of people worldwide taking paracetamol on a daily basis in a ‘fast-acting’ effervescent or soluble formulation who are increasing their risks of cardiovascular disease and premature death,” say Aletta Schutte, PhD, and Bruce Neal, MBChB, PhD, of the George Institute for Global Health, Sydney.
“The weight of the evidence makes ongoing inaction on sodium-containing medications untenable. The widespread use of effervescent medication in the general population, and the enormous doses of sodium that can be consumed inadvertently by unsuspecting consumers requires urgent action,” Dr. Schutte and Dr. Neal say.
The study was supported by the National Natural Science Foundation of China, the National Key Research and Development Project, the Project Program of National Clinical Research Center for Geriatric Disorders, the Key Research and Development Program of Hunan Province, and the Science and Technology Program of Hunan Province. Dr. Zhang, Dr. Schutte, and Dr. Neal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE EUROPEAN HEART JOURNAL
In-hospital detox or not, anti-CGRPs show efficacy for medication overuse headache
, according to investigators.
Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.
“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
Inpatient or outpatient: Does it matter?
According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.
Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).
The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.
Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).
“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
Abrupt or gradual detox?
According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.
“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”
Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.
“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”
The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.
, according to investigators.
Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.
“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
Inpatient or outpatient: Does it matter?
According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.
Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).
The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.
Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).
“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
Abrupt or gradual detox?
According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.
“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”
Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.
“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”
The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.
, according to investigators.
Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.
“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
Inpatient or outpatient: Does it matter?
According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.
Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).
The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.
Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).
“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
Abrupt or gradual detox?
According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.
“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”
Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.
“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”
The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.
FROM CEPHALALGIA
FDA okays empagliflozin for HF regardless of ejection fraction
The Food and Drug Administration has approved an expanded heart failure indication for the sodium-glucose transporter 2 inhibitor empagliflozin (Jardiance) that now includes HF with mid-range or preserved left ventricular ejection fraction (LVEF), the agency announced on Feb. 24.
That means the SGLT2 inhibitor, once considered primarily an antidiabetic agent, is approved for use in patients with HF per se without regard to ventricular function. The drug received approval for HF with reduced LVEF in August 2021.
The expanded indication, specifically for reducing the risk of cardiovascular death and HF hospitalization in adults, was widely anticipated based on the landmark results from the EMPEROR-Preserved trial. The study saw a significant 21% relative reduction in that composite endpoint over about 2 years in patients with New York Heart Association class II-IV heart failure and an LVEF greater than 40% who received empagliflozin along with other standard care.
Interestingly, the drug’s expanded indication in HF resembles that approved for sacubitril/valsartan (Entresto) in February 2021 based mostly on the PARAGON-HF trial, which entered patients with HF and an LVEF at least 45%. The trial was “negative” in that it saw no significant advantage to the drug for its primary clinical outcome but did suggest benefit for some secondary endpoints.
The FDA had used more cautionary language in its expanded indication for sacubitril/valsartan, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction below normal.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved an expanded heart failure indication for the sodium-glucose transporter 2 inhibitor empagliflozin (Jardiance) that now includes HF with mid-range or preserved left ventricular ejection fraction (LVEF), the agency announced on Feb. 24.
That means the SGLT2 inhibitor, once considered primarily an antidiabetic agent, is approved for use in patients with HF per se without regard to ventricular function. The drug received approval for HF with reduced LVEF in August 2021.
The expanded indication, specifically for reducing the risk of cardiovascular death and HF hospitalization in adults, was widely anticipated based on the landmark results from the EMPEROR-Preserved trial. The study saw a significant 21% relative reduction in that composite endpoint over about 2 years in patients with New York Heart Association class II-IV heart failure and an LVEF greater than 40% who received empagliflozin along with other standard care.
Interestingly, the drug’s expanded indication in HF resembles that approved for sacubitril/valsartan (Entresto) in February 2021 based mostly on the PARAGON-HF trial, which entered patients with HF and an LVEF at least 45%. The trial was “negative” in that it saw no significant advantage to the drug for its primary clinical outcome but did suggest benefit for some secondary endpoints.
The FDA had used more cautionary language in its expanded indication for sacubitril/valsartan, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction below normal.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved an expanded heart failure indication for the sodium-glucose transporter 2 inhibitor empagliflozin (Jardiance) that now includes HF with mid-range or preserved left ventricular ejection fraction (LVEF), the agency announced on Feb. 24.
That means the SGLT2 inhibitor, once considered primarily an antidiabetic agent, is approved for use in patients with HF per se without regard to ventricular function. The drug received approval for HF with reduced LVEF in August 2021.
The expanded indication, specifically for reducing the risk of cardiovascular death and HF hospitalization in adults, was widely anticipated based on the landmark results from the EMPEROR-Preserved trial. The study saw a significant 21% relative reduction in that composite endpoint over about 2 years in patients with New York Heart Association class II-IV heart failure and an LVEF greater than 40% who received empagliflozin along with other standard care.
Interestingly, the drug’s expanded indication in HF resembles that approved for sacubitril/valsartan (Entresto) in February 2021 based mostly on the PARAGON-HF trial, which entered patients with HF and an LVEF at least 45%. The trial was “negative” in that it saw no significant advantage to the drug for its primary clinical outcome but did suggest benefit for some secondary endpoints.
The FDA had used more cautionary language in its expanded indication for sacubitril/valsartan, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction below normal.”
A version of this article first appeared on Medscape.com.
Ivermectin does not stop progression to severe COVID: randomized trial
Ivermectin treatment given to high-risk patients with mild-to-moderate COVID-19 during the first week of illness did not prevent progression to severe disease, according to results from a randomized clinical trial.
“The study findings do not support the use of ivermectin for patients with COVID-19,” researchers conclude in the paper published online in JAMA Internal Medicine.
The open-label trial was conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and Oct. 25, 2021. It was led by Steven Chee Loon Lim, MRCP, department of medicine, Raja Permaisuri Bainun Hospital, Perak, Malaysia.
Among 490 patients in the primary analysis, 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk, 1.25; 95% confidence interval, 0.87-1.80; P = .25). All major ethnic groups in Malaysia were well represented, the researchers write.
Participants (average age 62.5 and 54.5% women) were randomly assigned 1:1 to receive either a 5-day course of oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care (n = 241) or standard of care alone (n = 249). Standard of care included symptomatic therapy and monitoring for early deterioration based on clinical findings, laboratory tests, and chest imaging.
Secondary outcomes
Secondary outcomes included rates of mechanical ventilation, intensive care unit (ICU) admission, 28-day in-hospital mortality, and side effects.
In all the secondary outcomes, there were no significant differences between groups.
Mechanical ventilation occurred in four patients on the ivermectin protocol (1.7%) versus 10 patients in the control group (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17); ICU admission occurred in six (2.4%) versus eight (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79); and 28-day in-hospital death occurred in three (1.2%) versus 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09).
The most common adverse event was diarrhea, reported by 5.8% in the ivermectin group and 1.6% in the control group.
No difference by vaccine status
The researchers conducted a subgroup analysis to evaluate any differences in whether participants were vaccinated. They said that analysis was “unremarkable.”
Just more than half of participants (51.8%) were fully vaccinated, with two doses of COVID-19 vaccines. Among the fully vaccinated patients, 17.7% in the ivermectin group and 9.2% in the control group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71; P = .06).
Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19 but has not been approved by the U.S. Food and Drug Administration for that purpose. Evidence-based data for or against use has been sparse.
The authors write that “although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19, these studies had methodologic weaknesses.”
Dr. Lim and colleagues point out that their findings are consistent with those of the IVERCOR-COVID19 trial, which found ivermectin ineffective in reducing hospitalization risk.
Previous randomized trials of ivermectin for COVID-19 patients that have included at least 400 patients have focused on outpatients.
In the current study, the authors note, patients were hospitalized, which allowed investigators to observe administration of ivermectin with a high adherence rate. Additionally, the researchers used clearly defined criteria for determining progression to severe disease.
Limitations of the current study include that the open-label design might lead to under-reporting of adverse events in the control group while overestimating the drug effects of ivermectin. The study was also not designed to assess the effects of ivermectin on mortality from COVID-19.
A version of this article first appeared on Medscape.com.
Ivermectin treatment given to high-risk patients with mild-to-moderate COVID-19 during the first week of illness did not prevent progression to severe disease, according to results from a randomized clinical trial.
“The study findings do not support the use of ivermectin for patients with COVID-19,” researchers conclude in the paper published online in JAMA Internal Medicine.
The open-label trial was conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and Oct. 25, 2021. It was led by Steven Chee Loon Lim, MRCP, department of medicine, Raja Permaisuri Bainun Hospital, Perak, Malaysia.
Among 490 patients in the primary analysis, 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk, 1.25; 95% confidence interval, 0.87-1.80; P = .25). All major ethnic groups in Malaysia were well represented, the researchers write.
Participants (average age 62.5 and 54.5% women) were randomly assigned 1:1 to receive either a 5-day course of oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care (n = 241) or standard of care alone (n = 249). Standard of care included symptomatic therapy and monitoring for early deterioration based on clinical findings, laboratory tests, and chest imaging.
Secondary outcomes
Secondary outcomes included rates of mechanical ventilation, intensive care unit (ICU) admission, 28-day in-hospital mortality, and side effects.
In all the secondary outcomes, there were no significant differences between groups.
Mechanical ventilation occurred in four patients on the ivermectin protocol (1.7%) versus 10 patients in the control group (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17); ICU admission occurred in six (2.4%) versus eight (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79); and 28-day in-hospital death occurred in three (1.2%) versus 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09).
The most common adverse event was diarrhea, reported by 5.8% in the ivermectin group and 1.6% in the control group.
No difference by vaccine status
The researchers conducted a subgroup analysis to evaluate any differences in whether participants were vaccinated. They said that analysis was “unremarkable.”
Just more than half of participants (51.8%) were fully vaccinated, with two doses of COVID-19 vaccines. Among the fully vaccinated patients, 17.7% in the ivermectin group and 9.2% in the control group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71; P = .06).
Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19 but has not been approved by the U.S. Food and Drug Administration for that purpose. Evidence-based data for or against use has been sparse.
The authors write that “although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19, these studies had methodologic weaknesses.”
Dr. Lim and colleagues point out that their findings are consistent with those of the IVERCOR-COVID19 trial, which found ivermectin ineffective in reducing hospitalization risk.
Previous randomized trials of ivermectin for COVID-19 patients that have included at least 400 patients have focused on outpatients.
In the current study, the authors note, patients were hospitalized, which allowed investigators to observe administration of ivermectin with a high adherence rate. Additionally, the researchers used clearly defined criteria for determining progression to severe disease.
Limitations of the current study include that the open-label design might lead to under-reporting of adverse events in the control group while overestimating the drug effects of ivermectin. The study was also not designed to assess the effects of ivermectin on mortality from COVID-19.
A version of this article first appeared on Medscape.com.
Ivermectin treatment given to high-risk patients with mild-to-moderate COVID-19 during the first week of illness did not prevent progression to severe disease, according to results from a randomized clinical trial.
“The study findings do not support the use of ivermectin for patients with COVID-19,” researchers conclude in the paper published online in JAMA Internal Medicine.
The open-label trial was conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and Oct. 25, 2021. It was led by Steven Chee Loon Lim, MRCP, department of medicine, Raja Permaisuri Bainun Hospital, Perak, Malaysia.
Among 490 patients in the primary analysis, 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk, 1.25; 95% confidence interval, 0.87-1.80; P = .25). All major ethnic groups in Malaysia were well represented, the researchers write.
Participants (average age 62.5 and 54.5% women) were randomly assigned 1:1 to receive either a 5-day course of oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care (n = 241) or standard of care alone (n = 249). Standard of care included symptomatic therapy and monitoring for early deterioration based on clinical findings, laboratory tests, and chest imaging.
Secondary outcomes
Secondary outcomes included rates of mechanical ventilation, intensive care unit (ICU) admission, 28-day in-hospital mortality, and side effects.
In all the secondary outcomes, there were no significant differences between groups.
Mechanical ventilation occurred in four patients on the ivermectin protocol (1.7%) versus 10 patients in the control group (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17); ICU admission occurred in six (2.4%) versus eight (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79); and 28-day in-hospital death occurred in three (1.2%) versus 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09).
The most common adverse event was diarrhea, reported by 5.8% in the ivermectin group and 1.6% in the control group.
No difference by vaccine status
The researchers conducted a subgroup analysis to evaluate any differences in whether participants were vaccinated. They said that analysis was “unremarkable.”
Just more than half of participants (51.8%) were fully vaccinated, with two doses of COVID-19 vaccines. Among the fully vaccinated patients, 17.7% in the ivermectin group and 9.2% in the control group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71; P = .06).
Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19 but has not been approved by the U.S. Food and Drug Administration for that purpose. Evidence-based data for or against use has been sparse.
The authors write that “although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19, these studies had methodologic weaknesses.”
Dr. Lim and colleagues point out that their findings are consistent with those of the IVERCOR-COVID19 trial, which found ivermectin ineffective in reducing hospitalization risk.
Previous randomized trials of ivermectin for COVID-19 patients that have included at least 400 patients have focused on outpatients.
In the current study, the authors note, patients were hospitalized, which allowed investigators to observe administration of ivermectin with a high adherence rate. Additionally, the researchers used clearly defined criteria for determining progression to severe disease.
Limitations of the current study include that the open-label design might lead to under-reporting of adverse events in the control group while overestimating the drug effects of ivermectin. The study was also not designed to assess the effects of ivermectin on mortality from COVID-19.
A version of this article first appeared on Medscape.com.
FROM JAMA INTERNAL MEDICNE
DOACs comparable to warfarin in CVT
and are less likely to result in major bleeding, a retrospective study suggests.
The ACTION CVT study was presented at the International Stroke Conference (ISC) 2022 by Ekaterina Bakradze, MD, assistant professor of neurology at the University of Alabama at Birmingham.
It was also simultaneously published online in Stroke.
“This real-world data supports use of direct oral anticoagulant drugs as a reasonable alternative to warfarin in patients with cerebral venous thrombosis,” Dr. Bakradze concluded.
But she added that because this study was based on retrospective observational data, the findings should be interpreted with caution and require confirmation by larger prospective studies.
Two such studies are now underway: the Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis (DOAC-CVT) study and the randomized Study of Rivaroxaban for Cerebral Venous Thrombosis (SECRET) trial.
Dr. Bakradze explained that cerebral venous thrombosis is a less common cause of stroke and occurs more often in women and younger patients, with a median age of 37 years. Current recommended treatment consists of heparin followed by oral anticoagulation.
She noted that although randomized trials and current guidelines indicate that DOACs are a preferred alternative to warfarin for the treatment of patients with venous thromboembolism, there are limited data on their use in patients with CVT.
A small, randomized trial (RESPECT-CVT) showed no significant difference in efficacy and safety outcomes between dabigatran and warfarin in patients with cerebral venous thrombosis, but with only 120 patients, this trial was too small for definite answers to this question.
A better understanding of this issue is important, because the mechanisms underlying cerebral venous thrombosis and other thromboembolism and their subsequent risks may differ, Dr. Bakradze said.
As randomized trials in patients with cerebral venous thrombosis are difficult to perform because the condition has a low incidence and low event rates, the researchers decided to look at this question with a large retrospective multicenter study.
The ACTION-CVT study involved 845 consecutive patients with cerebral venous thrombosis over 6 years (from January 2015 and December 2020) from 27 centers in Italy, New Zealand, Switzerland, and the United States. Patients were identified from medical records with diagnostic codes and confirmed with imaging.
The primary predictor in the study was oral anticoagulant type (DOAC vs. warfarin). Study outcomes were abstracted by individual sites through review of all available medical records.
The primary outcome was recurrent venous thrombosis (venous thromboembolism or cerebral venous thrombosis) during follow-up. Imaging outcomes based on recanalization status on last venous imaging study abstracted from radiology reports were also reported.
The safety outcome was major hemorrhage, defined as new or worsening intracranial hemorrhage (ICH), or major extracranial hemorrhage. Results were adjusted for age, sex, and relevant medical conditions.
The mean age of the patients included was 44.8 years, 64.7% were women, 33% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times.
Results showed that during a median follow-up of 345 days, there were 5.68 recurrent venous thrombosis events, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years.
Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization.
When compared with warfarin, DOAC treatment was associated with similar risk for recurrent venous thrombosis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73; P = .84), death (aHR, 0.71, 95% CI, 0.24-2.08; P = .53), and rate of partial/complete recanalization (aHR, 0.92, 95% CI, 0.48-1.73; P = .79).
But patients who received a DOAC had a significantly lower rate of major hemorrhage (aHR, 0.35; 95% CI, 0.15-0.81; P = .02).
When examined separately, the occurrence of ICH per 100 patient-years was much lower among the patients prescribed DOACs than those who were prescribed warfarin (1.52 vs. 3.51), whereas the occurrence of major bleeding outside the brain was similar (0.91 vs. 1.15).
Similar efficacy, better safety
Commenting on the study at an ISC press conference, Mitchell Elkind, MD, immediate past president of the American Heart Association/American Stroke Association and professor of neurology at Columbia University, New York, said: “The community has been concerned about extending the use of these new direct-acting oral anticoagulant drugs to cerebral venous thrombosis, but this study suggests that these patients may benefit from these new agents too.”
Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey, also commented: “This study confirms what we already know from other indications about these DOAC drugs: that they have similar efficacy to warfarin but a better safety profile. These results are really spot on with that. These drugs are also much easier and more convenient to use than warfarin.”
“This is a great step forward,” he added. “Only 30% of patients in this study received DOACs, reflecting the fact that clinicians may be a little reluctant to use them in this condition. But this study now has the potential to change practice.”
In an editorial accompanying the publication in Stroke, Johnathon Gorman, MD, and Thalia Field, MD, from the Vancouver Stroke Program at the University of British Columbia, say that despite its methodological limitations, the ACTION-CVT study “provides added value to the current state of knowledge by virtue of its size and ‘real world’ setting that is reflective of how DOACs are being used to manage CVT in current clinical practice.”
They point out that although baseline characteristics between the DOAC and warfarin groups were similar, the possibility of confounding cannot be excluded, and “other characteristics not easily captured in a retrospective study may sway anticoagulation strategy.”
They acknowledge, however, that an additional propensity score analysis “provides reassurance that the groups are reasonably balanced, adjusting for variables associated with recurrent cerebral venous thrombosis, recanalization, and hemorrhage.”
The editorialists conclude that ACTION-CVT gives additional reassurance for DOACs as an alternative approach to warfarin as a treatment for cerebral venous thrombosis and for the shifts in clinical practice that are already occurring at many centers.
The study was partially supported by the Italian Ministry of Health Ricerca Corrente–IRCCS MultiMedica. Dr. Bakradze reports no disclosures. Dr. Field is the principal investigator of the SECRET trial, which received in-kind study medication from Bayer Canada. She reports honoraria from HLS Therapeutics outside the submitted work and is on the board of Destine Health. The other editorialist reports no conflicts.
A version of this article first appeared on Medscape.com.
and are less likely to result in major bleeding, a retrospective study suggests.
The ACTION CVT study was presented at the International Stroke Conference (ISC) 2022 by Ekaterina Bakradze, MD, assistant professor of neurology at the University of Alabama at Birmingham.
It was also simultaneously published online in Stroke.
“This real-world data supports use of direct oral anticoagulant drugs as a reasonable alternative to warfarin in patients with cerebral venous thrombosis,” Dr. Bakradze concluded.
But she added that because this study was based on retrospective observational data, the findings should be interpreted with caution and require confirmation by larger prospective studies.
Two such studies are now underway: the Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis (DOAC-CVT) study and the randomized Study of Rivaroxaban for Cerebral Venous Thrombosis (SECRET) trial.
Dr. Bakradze explained that cerebral venous thrombosis is a less common cause of stroke and occurs more often in women and younger patients, with a median age of 37 years. Current recommended treatment consists of heparin followed by oral anticoagulation.
She noted that although randomized trials and current guidelines indicate that DOACs are a preferred alternative to warfarin for the treatment of patients with venous thromboembolism, there are limited data on their use in patients with CVT.
A small, randomized trial (RESPECT-CVT) showed no significant difference in efficacy and safety outcomes between dabigatran and warfarin in patients with cerebral venous thrombosis, but with only 120 patients, this trial was too small for definite answers to this question.
A better understanding of this issue is important, because the mechanisms underlying cerebral venous thrombosis and other thromboembolism and their subsequent risks may differ, Dr. Bakradze said.
As randomized trials in patients with cerebral venous thrombosis are difficult to perform because the condition has a low incidence and low event rates, the researchers decided to look at this question with a large retrospective multicenter study.
The ACTION-CVT study involved 845 consecutive patients with cerebral venous thrombosis over 6 years (from January 2015 and December 2020) from 27 centers in Italy, New Zealand, Switzerland, and the United States. Patients were identified from medical records with diagnostic codes and confirmed with imaging.
The primary predictor in the study was oral anticoagulant type (DOAC vs. warfarin). Study outcomes were abstracted by individual sites through review of all available medical records.
The primary outcome was recurrent venous thrombosis (venous thromboembolism or cerebral venous thrombosis) during follow-up. Imaging outcomes based on recanalization status on last venous imaging study abstracted from radiology reports were also reported.
The safety outcome was major hemorrhage, defined as new or worsening intracranial hemorrhage (ICH), or major extracranial hemorrhage. Results were adjusted for age, sex, and relevant medical conditions.
The mean age of the patients included was 44.8 years, 64.7% were women, 33% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times.
Results showed that during a median follow-up of 345 days, there were 5.68 recurrent venous thrombosis events, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years.
Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization.
When compared with warfarin, DOAC treatment was associated with similar risk for recurrent venous thrombosis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73; P = .84), death (aHR, 0.71, 95% CI, 0.24-2.08; P = .53), and rate of partial/complete recanalization (aHR, 0.92, 95% CI, 0.48-1.73; P = .79).
But patients who received a DOAC had a significantly lower rate of major hemorrhage (aHR, 0.35; 95% CI, 0.15-0.81; P = .02).
When examined separately, the occurrence of ICH per 100 patient-years was much lower among the patients prescribed DOACs than those who were prescribed warfarin (1.52 vs. 3.51), whereas the occurrence of major bleeding outside the brain was similar (0.91 vs. 1.15).
Similar efficacy, better safety
Commenting on the study at an ISC press conference, Mitchell Elkind, MD, immediate past president of the American Heart Association/American Stroke Association and professor of neurology at Columbia University, New York, said: “The community has been concerned about extending the use of these new direct-acting oral anticoagulant drugs to cerebral venous thrombosis, but this study suggests that these patients may benefit from these new agents too.”
Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey, also commented: “This study confirms what we already know from other indications about these DOAC drugs: that they have similar efficacy to warfarin but a better safety profile. These results are really spot on with that. These drugs are also much easier and more convenient to use than warfarin.”
“This is a great step forward,” he added. “Only 30% of patients in this study received DOACs, reflecting the fact that clinicians may be a little reluctant to use them in this condition. But this study now has the potential to change practice.”
In an editorial accompanying the publication in Stroke, Johnathon Gorman, MD, and Thalia Field, MD, from the Vancouver Stroke Program at the University of British Columbia, say that despite its methodological limitations, the ACTION-CVT study “provides added value to the current state of knowledge by virtue of its size and ‘real world’ setting that is reflective of how DOACs are being used to manage CVT in current clinical practice.”
They point out that although baseline characteristics between the DOAC and warfarin groups were similar, the possibility of confounding cannot be excluded, and “other characteristics not easily captured in a retrospective study may sway anticoagulation strategy.”
They acknowledge, however, that an additional propensity score analysis “provides reassurance that the groups are reasonably balanced, adjusting for variables associated with recurrent cerebral venous thrombosis, recanalization, and hemorrhage.”
The editorialists conclude that ACTION-CVT gives additional reassurance for DOACs as an alternative approach to warfarin as a treatment for cerebral venous thrombosis and for the shifts in clinical practice that are already occurring at many centers.
The study was partially supported by the Italian Ministry of Health Ricerca Corrente–IRCCS MultiMedica. Dr. Bakradze reports no disclosures. Dr. Field is the principal investigator of the SECRET trial, which received in-kind study medication from Bayer Canada. She reports honoraria from HLS Therapeutics outside the submitted work and is on the board of Destine Health. The other editorialist reports no conflicts.
A version of this article first appeared on Medscape.com.
and are less likely to result in major bleeding, a retrospective study suggests.
The ACTION CVT study was presented at the International Stroke Conference (ISC) 2022 by Ekaterina Bakradze, MD, assistant professor of neurology at the University of Alabama at Birmingham.
It was also simultaneously published online in Stroke.
“This real-world data supports use of direct oral anticoagulant drugs as a reasonable alternative to warfarin in patients with cerebral venous thrombosis,” Dr. Bakradze concluded.
But she added that because this study was based on retrospective observational data, the findings should be interpreted with caution and require confirmation by larger prospective studies.
Two such studies are now underway: the Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis (DOAC-CVT) study and the randomized Study of Rivaroxaban for Cerebral Venous Thrombosis (SECRET) trial.
Dr. Bakradze explained that cerebral venous thrombosis is a less common cause of stroke and occurs more often in women and younger patients, with a median age of 37 years. Current recommended treatment consists of heparin followed by oral anticoagulation.
She noted that although randomized trials and current guidelines indicate that DOACs are a preferred alternative to warfarin for the treatment of patients with venous thromboembolism, there are limited data on their use in patients with CVT.
A small, randomized trial (RESPECT-CVT) showed no significant difference in efficacy and safety outcomes between dabigatran and warfarin in patients with cerebral venous thrombosis, but with only 120 patients, this trial was too small for definite answers to this question.
A better understanding of this issue is important, because the mechanisms underlying cerebral venous thrombosis and other thromboembolism and their subsequent risks may differ, Dr. Bakradze said.
As randomized trials in patients with cerebral venous thrombosis are difficult to perform because the condition has a low incidence and low event rates, the researchers decided to look at this question with a large retrospective multicenter study.
The ACTION-CVT study involved 845 consecutive patients with cerebral venous thrombosis over 6 years (from January 2015 and December 2020) from 27 centers in Italy, New Zealand, Switzerland, and the United States. Patients were identified from medical records with diagnostic codes and confirmed with imaging.
The primary predictor in the study was oral anticoagulant type (DOAC vs. warfarin). Study outcomes were abstracted by individual sites through review of all available medical records.
The primary outcome was recurrent venous thrombosis (venous thromboembolism or cerebral venous thrombosis) during follow-up. Imaging outcomes based on recanalization status on last venous imaging study abstracted from radiology reports were also reported.
The safety outcome was major hemorrhage, defined as new or worsening intracranial hemorrhage (ICH), or major extracranial hemorrhage. Results were adjusted for age, sex, and relevant medical conditions.
The mean age of the patients included was 44.8 years, 64.7% were women, 33% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times.
Results showed that during a median follow-up of 345 days, there were 5.68 recurrent venous thrombosis events, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years.
Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization.
When compared with warfarin, DOAC treatment was associated with similar risk for recurrent venous thrombosis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73; P = .84), death (aHR, 0.71, 95% CI, 0.24-2.08; P = .53), and rate of partial/complete recanalization (aHR, 0.92, 95% CI, 0.48-1.73; P = .79).
But patients who received a DOAC had a significantly lower rate of major hemorrhage (aHR, 0.35; 95% CI, 0.15-0.81; P = .02).
When examined separately, the occurrence of ICH per 100 patient-years was much lower among the patients prescribed DOACs than those who were prescribed warfarin (1.52 vs. 3.51), whereas the occurrence of major bleeding outside the brain was similar (0.91 vs. 1.15).
Similar efficacy, better safety
Commenting on the study at an ISC press conference, Mitchell Elkind, MD, immediate past president of the American Heart Association/American Stroke Association and professor of neurology at Columbia University, New York, said: “The community has been concerned about extending the use of these new direct-acting oral anticoagulant drugs to cerebral venous thrombosis, but this study suggests that these patients may benefit from these new agents too.”
Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey, also commented: “This study confirms what we already know from other indications about these DOAC drugs: that they have similar efficacy to warfarin but a better safety profile. These results are really spot on with that. These drugs are also much easier and more convenient to use than warfarin.”
“This is a great step forward,” he added. “Only 30% of patients in this study received DOACs, reflecting the fact that clinicians may be a little reluctant to use them in this condition. But this study now has the potential to change practice.”
In an editorial accompanying the publication in Stroke, Johnathon Gorman, MD, and Thalia Field, MD, from the Vancouver Stroke Program at the University of British Columbia, say that despite its methodological limitations, the ACTION-CVT study “provides added value to the current state of knowledge by virtue of its size and ‘real world’ setting that is reflective of how DOACs are being used to manage CVT in current clinical practice.”
They point out that although baseline characteristics between the DOAC and warfarin groups were similar, the possibility of confounding cannot be excluded, and “other characteristics not easily captured in a retrospective study may sway anticoagulation strategy.”
They acknowledge, however, that an additional propensity score analysis “provides reassurance that the groups are reasonably balanced, adjusting for variables associated with recurrent cerebral venous thrombosis, recanalization, and hemorrhage.”
The editorialists conclude that ACTION-CVT gives additional reassurance for DOACs as an alternative approach to warfarin as a treatment for cerebral venous thrombosis and for the shifts in clinical practice that are already occurring at many centers.
The study was partially supported by the Italian Ministry of Health Ricerca Corrente–IRCCS MultiMedica. Dr. Bakradze reports no disclosures. Dr. Field is the principal investigator of the SECRET trial, which received in-kind study medication from Bayer Canada. She reports honoraria from HLS Therapeutics outside the submitted work and is on the board of Destine Health. The other editorialist reports no conflicts.
A version of this article first appeared on Medscape.com.
From ISC 2022
High praise, condemnation for CMS Aduhelm coverage plan
Medicare has received a key endorsement of its plan to restrict payment for the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) – but also drew pleas from other groups for more generous reimbursement of the drug, as well as expected similar medications currently in development.
The Centers for Medicare & Medicaid Services received more than 9,900 comments on its plan, according to the current tally posted on its website. However, it is unclear when the final count will be available.
CMS intends to limit federal payment for monoclonal antibodies that target amyloid to clinical trials. Among supporters of this approach is the influential Medicare Payment Advisory Commission, an expert panel that helps Congress and CMS manage the federal health program.
Opponents of the CMS plan include several pharmaceutical companies. Patient and consumer groups, individuals, and lawmakers had mixed views.
CMS officials will weigh the feedback provided in the comments when setting a final coverage policy for aducanumab. It is expected the agency’s final decision will be announced on April 11.
Ongoing debate
The Food and Drug Administration’s unusual approach to clearing the drug for U.S. sales triggered a review of its management of the accelerated approval process by the Office of Inspector General for the Department of Health & Human Services.
The FDA granted an accelerated approval for aducanumab in June based on evidence that the drug clears amyloid in the brain. However, it is unclear whether clearing the protein from the brain results in clinical benefit.
Usually, accelerated approvals precede the completion of phase 3 drug trials, with the FDA allowing early access to a medicine while awaiting confirmatory trials.
In the case of aducanumab, results of the phase 3 confirmatory trials ENGAGE and EMERGE were available at the time of FDA approval. However, interpretation of the findings is controversial.
Biogen contends that the amyloid-clearing effect of the higher dose of aducanumab shown in EMERGE indicates the drug has clinical potential. However, others argue that amyloid clearance does not indicate clinical benefit.
Limiting Medicare coverage of aducanumab for treatment of AD means “the progression of disease, for nearly all beneficiaries, would continue unabated,” Biogen wrote in its comment to CMS.
Conflicting data
Supporters of the CMS plan have a different view of the trial data. They note the failure of aducanumab in the companion ENGAGE trial, while also questioning the magnitude of benefit suggested by even the most positive data cited for the drug in the EMERGE trial.
Both studies used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, an 18-point scale measuring cognition and function.
In his comment to CMS, MedPAC chairman Michael E. Chernew, PhD, noted the change in CDR-SB score of 0.39 in EMERGE’s high-dose aducanumab group. CMS has described this as being “less than the 1-2 point change that has been suggested as a minimal clinically important difference,” Dr. Chernew wrote.
MedPAC does not normally comment on Medicare coverage decisions, but did so in this case because of its significance and because of the potential fiscal implications, he noted.
“Though there is only limited, conflicting data on Aduhelm’s clinical effectiveness, Medicare would pay a high price for the product,” Dr. Chernew wrote, pointing out the $28,200 annual U.S. price of the drug.
MedPAC thus endorsed the coverage-with-evidence-development (CED) pathway. Under this approach, Medicare would pay for these drugs when used in clinical trials that meet certain criteria.
Legal challenge?
In its comment to CMS, Biogen questioned the agency’s legal grounds for limiting coverage of aducanumab. A mandate on clinical trials as part of the CED proposal “runs afoul of the Administrative Procedure Act’s prohibition against arbitrary and capricious agency action,” Biogen said.
The drug company argued that its own planned follow-on studies would provide the kind of data Medicare officials want to see. It also argued for greater use of observational data, including real-world evidence, and of information from Medicare claims.
Roche’s Genentech, which is also developing antiamyloid drugs for AD, echoed some of Biogen’s concerns about the aducanumab plan.
CMS’ CED plan would be “unnecessarily restrictive and discouraging for patients living with this destructive disease,” David Burt, executive director for federal government affairs at Genentech, wrote in a comment to CMS.
CMS should clarify that the CED requirement would not apply to cases of FDA-approved antiamyloid therapies that have demonstrated “clinically meaningful improvement,” Mr. Burt added. He noted there are phase 3 trials of drugs in this class that could soon produce data.
CMS should “fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of antiamyloid monoclonal antibodies,” Mr. Burt wrote.
Health care inequity
In its comment to CMS, Biogen also noted the Medicare proposal would “compound the already pervasive inequities in access to treatment and will ultimately prove highly detrimental to health equity.”
There are already concerns about the access of Black and Latinx patients to clinical trials. The planned CED approach would tightly restrict access to aducanumab, as well as expected follow-ons in the amyloid-directed monoclonal antibody (mAb) drug class, the company said.
“Many of the trial sites for Aduhelm, as well as for other amyloid-directed [monoclonal antibodies] are not hospital-based outpatient settings, but include infusion centers, private practices, and medical research centers,” Biogen wrote.
Patient groups such as UsAgainstAlzheimer’s told CMS the CED approach would worsen disparities, despite the aim of Medicare officials to increase participation of Black and Latinx patients in future testing.
“CMS will be hard-pressed to achieve diversity if such hospitals are the only locations where Medicare beneficiaries are able to access mAbs,” USAgainstAlzheimer’s wrote in a Feb. 10 comment.
In contrast, the nonprofit National Center for Health Research praised CMS for what it described as an effort to address a lack of representation of Black and Latinx patients in earlier aducanumab research.
However, the NCHR also suggested CMS revise its plan to mandate that clinical trials include patients who are representative of the national population diagnosed with AD.
“Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups,” the NCHR wrote.
Patient health, Medicare at risk
On Feb. 8, a group of House Republican lawmakers asked CMS to reverse its stance. In a publicly released letter, Rep. Cathy McMorris Rodgers of Washington state, the ranking Republican on the House Energy and Commerce Committee, and colleagues urged broader coverage of aducanumab.
In the letter, the group emphasized the idea of aducanumab as a potential treatment for patients with Down syndrome who are at risk for AD.
“The link between Down Syndrome and AD is still being researched by scientists,” Rep. Rodgers and colleagues wrote.
“However, there appears to be a correlation between the additional 21st chromosome present in people with Down Syndrome and the chromosome’s gene that makes amyloid precursor proteins and can cause a build-up of the beta-amyloid plaques common amongst those with AD,” they add.
On the other hand, CMS garnered earlier support from influential Democrats. On Jan. 13, House Energy and Commerce Chairman Frank Pallone Jr (D-N.J.) and House Oversight and Reform Chairwoman Carolyn B. Maloney (D-N.Y.) released a letter praising CMS for its plan for covering aducanumab.
In addition to the HHS-OIG review of the FDA’s approval of the drug, the two House committees are in the midst of their own investigation of the agency’s decision to clear the drug.
“Any broader coverage determination before there is clarity on Aduhelm’s approval process and findings from the myriad ongoing investigations may put the health of millions of Alzheimer’s patients on the line and the financial stability of the nation’s health insurance program for American seniors at risk,” Rep. Pallone and Rep. Maloney wrote.
A version of this article first appeared on Medscape.com.
Medicare has received a key endorsement of its plan to restrict payment for the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) – but also drew pleas from other groups for more generous reimbursement of the drug, as well as expected similar medications currently in development.
The Centers for Medicare & Medicaid Services received more than 9,900 comments on its plan, according to the current tally posted on its website. However, it is unclear when the final count will be available.
CMS intends to limit federal payment for monoclonal antibodies that target amyloid to clinical trials. Among supporters of this approach is the influential Medicare Payment Advisory Commission, an expert panel that helps Congress and CMS manage the federal health program.
Opponents of the CMS plan include several pharmaceutical companies. Patient and consumer groups, individuals, and lawmakers had mixed views.
CMS officials will weigh the feedback provided in the comments when setting a final coverage policy for aducanumab. It is expected the agency’s final decision will be announced on April 11.
Ongoing debate
The Food and Drug Administration’s unusual approach to clearing the drug for U.S. sales triggered a review of its management of the accelerated approval process by the Office of Inspector General for the Department of Health & Human Services.
The FDA granted an accelerated approval for aducanumab in June based on evidence that the drug clears amyloid in the brain. However, it is unclear whether clearing the protein from the brain results in clinical benefit.
Usually, accelerated approvals precede the completion of phase 3 drug trials, with the FDA allowing early access to a medicine while awaiting confirmatory trials.
In the case of aducanumab, results of the phase 3 confirmatory trials ENGAGE and EMERGE were available at the time of FDA approval. However, interpretation of the findings is controversial.
Biogen contends that the amyloid-clearing effect of the higher dose of aducanumab shown in EMERGE indicates the drug has clinical potential. However, others argue that amyloid clearance does not indicate clinical benefit.
Limiting Medicare coverage of aducanumab for treatment of AD means “the progression of disease, for nearly all beneficiaries, would continue unabated,” Biogen wrote in its comment to CMS.
Conflicting data
Supporters of the CMS plan have a different view of the trial data. They note the failure of aducanumab in the companion ENGAGE trial, while also questioning the magnitude of benefit suggested by even the most positive data cited for the drug in the EMERGE trial.
Both studies used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, an 18-point scale measuring cognition and function.
In his comment to CMS, MedPAC chairman Michael E. Chernew, PhD, noted the change in CDR-SB score of 0.39 in EMERGE’s high-dose aducanumab group. CMS has described this as being “less than the 1-2 point change that has been suggested as a minimal clinically important difference,” Dr. Chernew wrote.
MedPAC does not normally comment on Medicare coverage decisions, but did so in this case because of its significance and because of the potential fiscal implications, he noted.
“Though there is only limited, conflicting data on Aduhelm’s clinical effectiveness, Medicare would pay a high price for the product,” Dr. Chernew wrote, pointing out the $28,200 annual U.S. price of the drug.
MedPAC thus endorsed the coverage-with-evidence-development (CED) pathway. Under this approach, Medicare would pay for these drugs when used in clinical trials that meet certain criteria.
Legal challenge?
In its comment to CMS, Biogen questioned the agency’s legal grounds for limiting coverage of aducanumab. A mandate on clinical trials as part of the CED proposal “runs afoul of the Administrative Procedure Act’s prohibition against arbitrary and capricious agency action,” Biogen said.
The drug company argued that its own planned follow-on studies would provide the kind of data Medicare officials want to see. It also argued for greater use of observational data, including real-world evidence, and of information from Medicare claims.
Roche’s Genentech, which is also developing antiamyloid drugs for AD, echoed some of Biogen’s concerns about the aducanumab plan.
CMS’ CED plan would be “unnecessarily restrictive and discouraging for patients living with this destructive disease,” David Burt, executive director for federal government affairs at Genentech, wrote in a comment to CMS.
CMS should clarify that the CED requirement would not apply to cases of FDA-approved antiamyloid therapies that have demonstrated “clinically meaningful improvement,” Mr. Burt added. He noted there are phase 3 trials of drugs in this class that could soon produce data.
CMS should “fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of antiamyloid monoclonal antibodies,” Mr. Burt wrote.
Health care inequity
In its comment to CMS, Biogen also noted the Medicare proposal would “compound the already pervasive inequities in access to treatment and will ultimately prove highly detrimental to health equity.”
There are already concerns about the access of Black and Latinx patients to clinical trials. The planned CED approach would tightly restrict access to aducanumab, as well as expected follow-ons in the amyloid-directed monoclonal antibody (mAb) drug class, the company said.
“Many of the trial sites for Aduhelm, as well as for other amyloid-directed [monoclonal antibodies] are not hospital-based outpatient settings, but include infusion centers, private practices, and medical research centers,” Biogen wrote.
Patient groups such as UsAgainstAlzheimer’s told CMS the CED approach would worsen disparities, despite the aim of Medicare officials to increase participation of Black and Latinx patients in future testing.
“CMS will be hard-pressed to achieve diversity if such hospitals are the only locations where Medicare beneficiaries are able to access mAbs,” USAgainstAlzheimer’s wrote in a Feb. 10 comment.
In contrast, the nonprofit National Center for Health Research praised CMS for what it described as an effort to address a lack of representation of Black and Latinx patients in earlier aducanumab research.
However, the NCHR also suggested CMS revise its plan to mandate that clinical trials include patients who are representative of the national population diagnosed with AD.
“Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups,” the NCHR wrote.
Patient health, Medicare at risk
On Feb. 8, a group of House Republican lawmakers asked CMS to reverse its stance. In a publicly released letter, Rep. Cathy McMorris Rodgers of Washington state, the ranking Republican on the House Energy and Commerce Committee, and colleagues urged broader coverage of aducanumab.
In the letter, the group emphasized the idea of aducanumab as a potential treatment for patients with Down syndrome who are at risk for AD.
“The link between Down Syndrome and AD is still being researched by scientists,” Rep. Rodgers and colleagues wrote.
“However, there appears to be a correlation between the additional 21st chromosome present in people with Down Syndrome and the chromosome’s gene that makes amyloid precursor proteins and can cause a build-up of the beta-amyloid plaques common amongst those with AD,” they add.
On the other hand, CMS garnered earlier support from influential Democrats. On Jan. 13, House Energy and Commerce Chairman Frank Pallone Jr (D-N.J.) and House Oversight and Reform Chairwoman Carolyn B. Maloney (D-N.Y.) released a letter praising CMS for its plan for covering aducanumab.
In addition to the HHS-OIG review of the FDA’s approval of the drug, the two House committees are in the midst of their own investigation of the agency’s decision to clear the drug.
“Any broader coverage determination before there is clarity on Aduhelm’s approval process and findings from the myriad ongoing investigations may put the health of millions of Alzheimer’s patients on the line and the financial stability of the nation’s health insurance program for American seniors at risk,” Rep. Pallone and Rep. Maloney wrote.
A version of this article first appeared on Medscape.com.
Medicare has received a key endorsement of its plan to restrict payment for the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) – but also drew pleas from other groups for more generous reimbursement of the drug, as well as expected similar medications currently in development.
The Centers for Medicare & Medicaid Services received more than 9,900 comments on its plan, according to the current tally posted on its website. However, it is unclear when the final count will be available.
CMS intends to limit federal payment for monoclonal antibodies that target amyloid to clinical trials. Among supporters of this approach is the influential Medicare Payment Advisory Commission, an expert panel that helps Congress and CMS manage the federal health program.
Opponents of the CMS plan include several pharmaceutical companies. Patient and consumer groups, individuals, and lawmakers had mixed views.
CMS officials will weigh the feedback provided in the comments when setting a final coverage policy for aducanumab. It is expected the agency’s final decision will be announced on April 11.
Ongoing debate
The Food and Drug Administration’s unusual approach to clearing the drug for U.S. sales triggered a review of its management of the accelerated approval process by the Office of Inspector General for the Department of Health & Human Services.
The FDA granted an accelerated approval for aducanumab in June based on evidence that the drug clears amyloid in the brain. However, it is unclear whether clearing the protein from the brain results in clinical benefit.
Usually, accelerated approvals precede the completion of phase 3 drug trials, with the FDA allowing early access to a medicine while awaiting confirmatory trials.
In the case of aducanumab, results of the phase 3 confirmatory trials ENGAGE and EMERGE were available at the time of FDA approval. However, interpretation of the findings is controversial.
Biogen contends that the amyloid-clearing effect of the higher dose of aducanumab shown in EMERGE indicates the drug has clinical potential. However, others argue that amyloid clearance does not indicate clinical benefit.
Limiting Medicare coverage of aducanumab for treatment of AD means “the progression of disease, for nearly all beneficiaries, would continue unabated,” Biogen wrote in its comment to CMS.
Conflicting data
Supporters of the CMS plan have a different view of the trial data. They note the failure of aducanumab in the companion ENGAGE trial, while also questioning the magnitude of benefit suggested by even the most positive data cited for the drug in the EMERGE trial.
Both studies used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, an 18-point scale measuring cognition and function.
In his comment to CMS, MedPAC chairman Michael E. Chernew, PhD, noted the change in CDR-SB score of 0.39 in EMERGE’s high-dose aducanumab group. CMS has described this as being “less than the 1-2 point change that has been suggested as a minimal clinically important difference,” Dr. Chernew wrote.
MedPAC does not normally comment on Medicare coverage decisions, but did so in this case because of its significance and because of the potential fiscal implications, he noted.
“Though there is only limited, conflicting data on Aduhelm’s clinical effectiveness, Medicare would pay a high price for the product,” Dr. Chernew wrote, pointing out the $28,200 annual U.S. price of the drug.
MedPAC thus endorsed the coverage-with-evidence-development (CED) pathway. Under this approach, Medicare would pay for these drugs when used in clinical trials that meet certain criteria.
Legal challenge?
In its comment to CMS, Biogen questioned the agency’s legal grounds for limiting coverage of aducanumab. A mandate on clinical trials as part of the CED proposal “runs afoul of the Administrative Procedure Act’s prohibition against arbitrary and capricious agency action,” Biogen said.
The drug company argued that its own planned follow-on studies would provide the kind of data Medicare officials want to see. It also argued for greater use of observational data, including real-world evidence, and of information from Medicare claims.
Roche’s Genentech, which is also developing antiamyloid drugs for AD, echoed some of Biogen’s concerns about the aducanumab plan.
CMS’ CED plan would be “unnecessarily restrictive and discouraging for patients living with this destructive disease,” David Burt, executive director for federal government affairs at Genentech, wrote in a comment to CMS.
CMS should clarify that the CED requirement would not apply to cases of FDA-approved antiamyloid therapies that have demonstrated “clinically meaningful improvement,” Mr. Burt added. He noted there are phase 3 trials of drugs in this class that could soon produce data.
CMS should “fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of antiamyloid monoclonal antibodies,” Mr. Burt wrote.
Health care inequity
In its comment to CMS, Biogen also noted the Medicare proposal would “compound the already pervasive inequities in access to treatment and will ultimately prove highly detrimental to health equity.”
There are already concerns about the access of Black and Latinx patients to clinical trials. The planned CED approach would tightly restrict access to aducanumab, as well as expected follow-ons in the amyloid-directed monoclonal antibody (mAb) drug class, the company said.
“Many of the trial sites for Aduhelm, as well as for other amyloid-directed [monoclonal antibodies] are not hospital-based outpatient settings, but include infusion centers, private practices, and medical research centers,” Biogen wrote.
Patient groups such as UsAgainstAlzheimer’s told CMS the CED approach would worsen disparities, despite the aim of Medicare officials to increase participation of Black and Latinx patients in future testing.
“CMS will be hard-pressed to achieve diversity if such hospitals are the only locations where Medicare beneficiaries are able to access mAbs,” USAgainstAlzheimer’s wrote in a Feb. 10 comment.
In contrast, the nonprofit National Center for Health Research praised CMS for what it described as an effort to address a lack of representation of Black and Latinx patients in earlier aducanumab research.
However, the NCHR also suggested CMS revise its plan to mandate that clinical trials include patients who are representative of the national population diagnosed with AD.
“Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups,” the NCHR wrote.
Patient health, Medicare at risk
On Feb. 8, a group of House Republican lawmakers asked CMS to reverse its stance. In a publicly released letter, Rep. Cathy McMorris Rodgers of Washington state, the ranking Republican on the House Energy and Commerce Committee, and colleagues urged broader coverage of aducanumab.
In the letter, the group emphasized the idea of aducanumab as a potential treatment for patients with Down syndrome who are at risk for AD.
“The link between Down Syndrome and AD is still being researched by scientists,” Rep. Rodgers and colleagues wrote.
“However, there appears to be a correlation between the additional 21st chromosome present in people with Down Syndrome and the chromosome’s gene that makes amyloid precursor proteins and can cause a build-up of the beta-amyloid plaques common amongst those with AD,” they add.
On the other hand, CMS garnered earlier support from influential Democrats. On Jan. 13, House Energy and Commerce Chairman Frank Pallone Jr (D-N.J.) and House Oversight and Reform Chairwoman Carolyn B. Maloney (D-N.Y.) released a letter praising CMS for its plan for covering aducanumab.
In addition to the HHS-OIG review of the FDA’s approval of the drug, the two House committees are in the midst of their own investigation of the agency’s decision to clear the drug.
“Any broader coverage determination before there is clarity on Aduhelm’s approval process and findings from the myriad ongoing investigations may put the health of millions of Alzheimer’s patients on the line and the financial stability of the nation’s health insurance program for American seniors at risk,” Rep. Pallone and Rep. Maloney wrote.
A version of this article first appeared on Medscape.com.
Estrogen supplementation may reduce COVID-19 death risk
Estrogen supplementation is associated with a reduced risk of death from COVID-19 among postmenopausal women, new research suggests.
The findings, from a nationwide study using data from Sweden, were published online Feb. 14 in BMJ Open by Malin Sund, MD, PhD, of Umeå (Sweden) University Faculty of Medicine and colleagues.
Among postmenopausal women aged 50-80 years with verified COVID-19, those receiving estrogen as part of hormone replacement therapy for menopausal symptoms were less than half as likely to die from it as those not receiving estrogen, even after adjustment for confounders.
“This study shows an association between estrogen levels and COVID-19 death. Consequently, drugs increasing estrogen levels may have a role in therapeutic efforts to alleviate COVID-19 severity in postmenopausal women and could be studied in randomized control trials,” the investigators write.
However, coauthor Anne-Marie Fors Connolly, MD, PhD, a resident in clinical microbiology at Umeå University, cautioned: “This is an observational study. Further clinical studies are needed to verify these results before recommending clinicians to consider estrogen supplementation.”
Stephen Evans, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, agrees.
He told the U.K. Science and Media Centre: “This is an observational study comparing three groups of women based on whether they used hormonal therapy to boost estrogen levels or who had, as a result of treatment for breast cancer ... reduced estrogen levels or neither. The findings are apparently dramatic.”
“At the very least, great caution should be exercised in thinking that menopausal hormone therapy will have substantial, or even any, benefits in dealing with COVID-19,” he warned.
Do women die less frequently from COVID-19 than men?
Studies conducted early in the pandemic suggest women may be protected from poor outcomes of SARS-CoV-2 infection, compared with men, even after adjustment for confounders.
According to more recent data from the Swedish Public Health Agency, of the 16,501 people who have died from COVID-19 since the start of the pandemic, about 45% are women and 55% are men. About 70% who have received intensive care because of COVID-19 are men, although cumulative data suggest that women are nearly as likely to die from COVID-19 as men, Dr. Connolly told this news organization.
For the current study, a total of 14,685 women aged 50-80 years were included, of whom 17.3% (2,535) had received estrogen supplementation, 81.2% (11,923) had native estrogen levels with no breast cancer or estrogen supplementation (controls), and 1.5% (227) had decreased estrogen levels because of breast cancer and antiestrogen treatment.
The group with decreased estrogen levels had a more than twofold risk of dying from COVID-19 compared with controls (odds ratio, 2.35), but this difference was no longer significant after adjustments for potential confounders including age, income, and educational level, and weighted Charlson Comorbidity Index (wCCI).
However, the group with augmented estrogen levels had a decreased risk of dying from COVID-19 before (odds ratio, 0.45) and after (OR, 0.47) adjustment.
The percentages of patients who died of COVID-19 were 4.6% of controls, 10.1% of those with decreased estrogen, and 2.1% with increased estrogen.
Not surprisingly, the risk of dying from COVID-19 also increased with age (OR of 1.15 for every year increase in age) and comorbidities (OR, 1.13 per increase in wCCI). Low income and having only a primary level education also increased the odds of dying from COVID-19.
Data on obesity, a known risk factor for COVID-19 death, weren’t reported.
“Obesity would have been a very relevant variable to include. Unfortunately, this information is not present in the nationwide registry data that we used for our study,” Dr. Connolly told this news organization.
While the data are observational and can’t be used to inform treatment, Dr. Connolly pointed to a U.S. randomized clinical trial currently recruiting patients that will investigate the effect of estradiol and progesterone therapy in 120 adults hospitalized with COVID-19.
In the meantime, she warned doctors and patients: “Please do not consider ending antiestrogen treatment following breast cancer – this is a necessary treatment for the cancer.”
Dr. Evans noted, “There are short-term benefits of menopausal hormone therapy but women should not, based on this or other observational studies, be advised to take HRT [hormone replacement therapy] for a supposed benefit on death from COVID-19.”
The study had several nonpharmaceutical industry funders, including Umeå University and the Knut and Alice Wallenberg Foundation. The authors and Dr. Evans have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Estrogen supplementation is associated with a reduced risk of death from COVID-19 among postmenopausal women, new research suggests.
The findings, from a nationwide study using data from Sweden, were published online Feb. 14 in BMJ Open by Malin Sund, MD, PhD, of Umeå (Sweden) University Faculty of Medicine and colleagues.
Among postmenopausal women aged 50-80 years with verified COVID-19, those receiving estrogen as part of hormone replacement therapy for menopausal symptoms were less than half as likely to die from it as those not receiving estrogen, even after adjustment for confounders.
“This study shows an association between estrogen levels and COVID-19 death. Consequently, drugs increasing estrogen levels may have a role in therapeutic efforts to alleviate COVID-19 severity in postmenopausal women and could be studied in randomized control trials,” the investigators write.
However, coauthor Anne-Marie Fors Connolly, MD, PhD, a resident in clinical microbiology at Umeå University, cautioned: “This is an observational study. Further clinical studies are needed to verify these results before recommending clinicians to consider estrogen supplementation.”
Stephen Evans, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, agrees.
He told the U.K. Science and Media Centre: “This is an observational study comparing three groups of women based on whether they used hormonal therapy to boost estrogen levels or who had, as a result of treatment for breast cancer ... reduced estrogen levels or neither. The findings are apparently dramatic.”
“At the very least, great caution should be exercised in thinking that menopausal hormone therapy will have substantial, or even any, benefits in dealing with COVID-19,” he warned.
Do women die less frequently from COVID-19 than men?
Studies conducted early in the pandemic suggest women may be protected from poor outcomes of SARS-CoV-2 infection, compared with men, even after adjustment for confounders.
According to more recent data from the Swedish Public Health Agency, of the 16,501 people who have died from COVID-19 since the start of the pandemic, about 45% are women and 55% are men. About 70% who have received intensive care because of COVID-19 are men, although cumulative data suggest that women are nearly as likely to die from COVID-19 as men, Dr. Connolly told this news organization.
For the current study, a total of 14,685 women aged 50-80 years were included, of whom 17.3% (2,535) had received estrogen supplementation, 81.2% (11,923) had native estrogen levels with no breast cancer or estrogen supplementation (controls), and 1.5% (227) had decreased estrogen levels because of breast cancer and antiestrogen treatment.
The group with decreased estrogen levels had a more than twofold risk of dying from COVID-19 compared with controls (odds ratio, 2.35), but this difference was no longer significant after adjustments for potential confounders including age, income, and educational level, and weighted Charlson Comorbidity Index (wCCI).
However, the group with augmented estrogen levels had a decreased risk of dying from COVID-19 before (odds ratio, 0.45) and after (OR, 0.47) adjustment.
The percentages of patients who died of COVID-19 were 4.6% of controls, 10.1% of those with decreased estrogen, and 2.1% with increased estrogen.
Not surprisingly, the risk of dying from COVID-19 also increased with age (OR of 1.15 for every year increase in age) and comorbidities (OR, 1.13 per increase in wCCI). Low income and having only a primary level education also increased the odds of dying from COVID-19.
Data on obesity, a known risk factor for COVID-19 death, weren’t reported.
“Obesity would have been a very relevant variable to include. Unfortunately, this information is not present in the nationwide registry data that we used for our study,” Dr. Connolly told this news organization.
While the data are observational and can’t be used to inform treatment, Dr. Connolly pointed to a U.S. randomized clinical trial currently recruiting patients that will investigate the effect of estradiol and progesterone therapy in 120 adults hospitalized with COVID-19.
In the meantime, she warned doctors and patients: “Please do not consider ending antiestrogen treatment following breast cancer – this is a necessary treatment for the cancer.”
Dr. Evans noted, “There are short-term benefits of menopausal hormone therapy but women should not, based on this or other observational studies, be advised to take HRT [hormone replacement therapy] for a supposed benefit on death from COVID-19.”
The study had several nonpharmaceutical industry funders, including Umeå University and the Knut and Alice Wallenberg Foundation. The authors and Dr. Evans have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Estrogen supplementation is associated with a reduced risk of death from COVID-19 among postmenopausal women, new research suggests.
The findings, from a nationwide study using data from Sweden, were published online Feb. 14 in BMJ Open by Malin Sund, MD, PhD, of Umeå (Sweden) University Faculty of Medicine and colleagues.
Among postmenopausal women aged 50-80 years with verified COVID-19, those receiving estrogen as part of hormone replacement therapy for menopausal symptoms were less than half as likely to die from it as those not receiving estrogen, even after adjustment for confounders.
“This study shows an association between estrogen levels and COVID-19 death. Consequently, drugs increasing estrogen levels may have a role in therapeutic efforts to alleviate COVID-19 severity in postmenopausal women and could be studied in randomized control trials,” the investigators write.
However, coauthor Anne-Marie Fors Connolly, MD, PhD, a resident in clinical microbiology at Umeå University, cautioned: “This is an observational study. Further clinical studies are needed to verify these results before recommending clinicians to consider estrogen supplementation.”
Stephen Evans, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, agrees.
He told the U.K. Science and Media Centre: “This is an observational study comparing three groups of women based on whether they used hormonal therapy to boost estrogen levels or who had, as a result of treatment for breast cancer ... reduced estrogen levels or neither. The findings are apparently dramatic.”
“At the very least, great caution should be exercised in thinking that menopausal hormone therapy will have substantial, or even any, benefits in dealing with COVID-19,” he warned.
Do women die less frequently from COVID-19 than men?
Studies conducted early in the pandemic suggest women may be protected from poor outcomes of SARS-CoV-2 infection, compared with men, even after adjustment for confounders.
According to more recent data from the Swedish Public Health Agency, of the 16,501 people who have died from COVID-19 since the start of the pandemic, about 45% are women and 55% are men. About 70% who have received intensive care because of COVID-19 are men, although cumulative data suggest that women are nearly as likely to die from COVID-19 as men, Dr. Connolly told this news organization.
For the current study, a total of 14,685 women aged 50-80 years were included, of whom 17.3% (2,535) had received estrogen supplementation, 81.2% (11,923) had native estrogen levels with no breast cancer or estrogen supplementation (controls), and 1.5% (227) had decreased estrogen levels because of breast cancer and antiestrogen treatment.
The group with decreased estrogen levels had a more than twofold risk of dying from COVID-19 compared with controls (odds ratio, 2.35), but this difference was no longer significant after adjustments for potential confounders including age, income, and educational level, and weighted Charlson Comorbidity Index (wCCI).
However, the group with augmented estrogen levels had a decreased risk of dying from COVID-19 before (odds ratio, 0.45) and after (OR, 0.47) adjustment.
The percentages of patients who died of COVID-19 were 4.6% of controls, 10.1% of those with decreased estrogen, and 2.1% with increased estrogen.
Not surprisingly, the risk of dying from COVID-19 also increased with age (OR of 1.15 for every year increase in age) and comorbidities (OR, 1.13 per increase in wCCI). Low income and having only a primary level education also increased the odds of dying from COVID-19.
Data on obesity, a known risk factor for COVID-19 death, weren’t reported.
“Obesity would have been a very relevant variable to include. Unfortunately, this information is not present in the nationwide registry data that we used for our study,” Dr. Connolly told this news organization.
While the data are observational and can’t be used to inform treatment, Dr. Connolly pointed to a U.S. randomized clinical trial currently recruiting patients that will investigate the effect of estradiol and progesterone therapy in 120 adults hospitalized with COVID-19.
In the meantime, she warned doctors and patients: “Please do not consider ending antiestrogen treatment following breast cancer – this is a necessary treatment for the cancer.”
Dr. Evans noted, “There are short-term benefits of menopausal hormone therapy but women should not, based on this or other observational studies, be advised to take HRT [hormone replacement therapy] for a supposed benefit on death from COVID-19.”
The study had several nonpharmaceutical industry funders, including Umeå University and the Knut and Alice Wallenberg Foundation. The authors and Dr. Evans have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
Ketamine fast, effective for suicidal crises
In addition, a strong effect of ketamine was observed in patients with bipolar disorder, “whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was nonsignificant in those with major depressive disorders,” the researchers wrote.
“We assessed for the first time in the same study the effect of ketamine on three a priori–defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses,” study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, said in an interview.
“This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder,” Dr. Jollant added.
The study was published online Feb. 2, 2022, in the BMJ.
Swift, full remission
The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.
They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.
The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0-2 (maximum score, 38).
“We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear,” said Dr. Jollant.
They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs. 32%; odds ratio, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0-92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3-5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9-17.3; P = .07).
At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.
“Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain,” they wrote.
Ketamine’s side effects were “limited” with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.
The investigators acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.
A new perspective on ketamine
In an accompanying editorial, Riccardo De Giorgi, MD, Wellcome Trust doctoral training fellow, department of psychiatry, University of Oxford (England), said the study challenges current thinking about ketamine.
The “unexpected” outcome (no benefit) in the depressive group “perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine,” Dr. De Giorgi wrote.
“In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder,” Dr. De Giorgi pointed out.
“While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine,” Dr. De Giorgi wrote.
“Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts,” he concluded.
Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Dr. Jollant and Dr. De Giorgi disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In addition, a strong effect of ketamine was observed in patients with bipolar disorder, “whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was nonsignificant in those with major depressive disorders,” the researchers wrote.
“We assessed for the first time in the same study the effect of ketamine on three a priori–defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses,” study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, said in an interview.
“This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder,” Dr. Jollant added.
The study was published online Feb. 2, 2022, in the BMJ.
Swift, full remission
The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.
They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.
The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0-2 (maximum score, 38).
“We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear,” said Dr. Jollant.
They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs. 32%; odds ratio, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0-92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3-5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9-17.3; P = .07).
At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.
“Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain,” they wrote.
Ketamine’s side effects were “limited” with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.
The investigators acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.
A new perspective on ketamine
In an accompanying editorial, Riccardo De Giorgi, MD, Wellcome Trust doctoral training fellow, department of psychiatry, University of Oxford (England), said the study challenges current thinking about ketamine.
The “unexpected” outcome (no benefit) in the depressive group “perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine,” Dr. De Giorgi wrote.
“In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder,” Dr. De Giorgi pointed out.
“While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine,” Dr. De Giorgi wrote.
“Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts,” he concluded.
Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Dr. Jollant and Dr. De Giorgi disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In addition, a strong effect of ketamine was observed in patients with bipolar disorder, “whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was nonsignificant in those with major depressive disorders,” the researchers wrote.
“We assessed for the first time in the same study the effect of ketamine on three a priori–defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses,” study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, said in an interview.
“This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder,” Dr. Jollant added.
The study was published online Feb. 2, 2022, in the BMJ.
Swift, full remission
The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.
They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.
The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0-2 (maximum score, 38).
“We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear,” said Dr. Jollant.
They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs. 32%; odds ratio, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0-92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3-5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9-17.3; P = .07).
At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.
“Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain,” they wrote.
Ketamine’s side effects were “limited” with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.
The investigators acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.
A new perspective on ketamine
In an accompanying editorial, Riccardo De Giorgi, MD, Wellcome Trust doctoral training fellow, department of psychiatry, University of Oxford (England), said the study challenges current thinking about ketamine.
The “unexpected” outcome (no benefit) in the depressive group “perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine,” Dr. De Giorgi wrote.
“In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder,” Dr. De Giorgi pointed out.
“While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine,” Dr. De Giorgi wrote.
“Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts,” he concluded.
Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Dr. Jollant and Dr. De Giorgi disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE BMJ