User login
FDA OKs new high-dose naloxone product for opioid overdose
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
FDA approves cell-based flu shot for ages 6 months and older
The Food and Drug Administration has approved the Flucelvax quadrivalent vaccine for use in children aged 6 months and older, according to a statement from manufacturer Seqirus.
“This approval officially allows all eligible Americans to receive a cell-based influenza vaccine, increasing the potential for greater vaccine effectiveness,” according to the company.
The Centers for Disease Control and Prevention currently recommends annual influenza vaccination for all individuals aged 6 months and older without contraindications.
Flucelvax is manufactured using a cell-based process that yields a more precise match to the WHO-selected influenza strains for a given year. This process avoids the variation associated with traditional egg-based vaccines, and offers the potential for greater vaccine effectiveness, according to the company.
The approval was based in part on data from a phase 3 randomized, controlled noninferiority study of children aged 6-47 months. The data are the first for a cell-based flu vaccine in this age group, and were presented at the Pediatric Academic Societies meeting in 2021.
In the immunogenicity study of children aged 6 months through 3 years, described in the package insert, 1,597 children received Flucelvax quadrivalent and 805 received a control quadrivalent vaccine. After 28 days, Flucelvax showed noninferiority to the control quadrivalent against four influenza strains.
The most common side effects with Flucelvax quadrivalent vaccine overall are pain, redness, swelling, or a hardened area at the injection site, headache, low energy, muscle aches, and malaise. Additional side effects reported in children include tenderness or bruising at the injection site, sleepiness, diarrhea, changes in eating habits, and irritability. The vaccine is contraindicated for individuals with allergies to any of its ingredients.
Additional efficacy data on Flucelvax for children and adolescents aged 2-18 years were recently published in The New England Journal of Medicine.
Full prescribing information for Flucelvax is available here.
The FDA approval letter is available here.pdnews@mdedge.com
The Food and Drug Administration has approved the Flucelvax quadrivalent vaccine for use in children aged 6 months and older, according to a statement from manufacturer Seqirus.
“This approval officially allows all eligible Americans to receive a cell-based influenza vaccine, increasing the potential for greater vaccine effectiveness,” according to the company.
The Centers for Disease Control and Prevention currently recommends annual influenza vaccination for all individuals aged 6 months and older without contraindications.
Flucelvax is manufactured using a cell-based process that yields a more precise match to the WHO-selected influenza strains for a given year. This process avoids the variation associated with traditional egg-based vaccines, and offers the potential for greater vaccine effectiveness, according to the company.
The approval was based in part on data from a phase 3 randomized, controlled noninferiority study of children aged 6-47 months. The data are the first for a cell-based flu vaccine in this age group, and were presented at the Pediatric Academic Societies meeting in 2021.
In the immunogenicity study of children aged 6 months through 3 years, described in the package insert, 1,597 children received Flucelvax quadrivalent and 805 received a control quadrivalent vaccine. After 28 days, Flucelvax showed noninferiority to the control quadrivalent against four influenza strains.
The most common side effects with Flucelvax quadrivalent vaccine overall are pain, redness, swelling, or a hardened area at the injection site, headache, low energy, muscle aches, and malaise. Additional side effects reported in children include tenderness or bruising at the injection site, sleepiness, diarrhea, changes in eating habits, and irritability. The vaccine is contraindicated for individuals with allergies to any of its ingredients.
Additional efficacy data on Flucelvax for children and adolescents aged 2-18 years were recently published in The New England Journal of Medicine.
Full prescribing information for Flucelvax is available here.
The FDA approval letter is available here.pdnews@mdedge.com
The Food and Drug Administration has approved the Flucelvax quadrivalent vaccine for use in children aged 6 months and older, according to a statement from manufacturer Seqirus.
“This approval officially allows all eligible Americans to receive a cell-based influenza vaccine, increasing the potential for greater vaccine effectiveness,” according to the company.
The Centers for Disease Control and Prevention currently recommends annual influenza vaccination for all individuals aged 6 months and older without contraindications.
Flucelvax is manufactured using a cell-based process that yields a more precise match to the WHO-selected influenza strains for a given year. This process avoids the variation associated with traditional egg-based vaccines, and offers the potential for greater vaccine effectiveness, according to the company.
The approval was based in part on data from a phase 3 randomized, controlled noninferiority study of children aged 6-47 months. The data are the first for a cell-based flu vaccine in this age group, and were presented at the Pediatric Academic Societies meeting in 2021.
In the immunogenicity study of children aged 6 months through 3 years, described in the package insert, 1,597 children received Flucelvax quadrivalent and 805 received a control quadrivalent vaccine. After 28 days, Flucelvax showed noninferiority to the control quadrivalent against four influenza strains.
The most common side effects with Flucelvax quadrivalent vaccine overall are pain, redness, swelling, or a hardened area at the injection site, headache, low energy, muscle aches, and malaise. Additional side effects reported in children include tenderness or bruising at the injection site, sleepiness, diarrhea, changes in eating habits, and irritability. The vaccine is contraindicated for individuals with allergies to any of its ingredients.
Additional efficacy data on Flucelvax for children and adolescents aged 2-18 years were recently published in The New England Journal of Medicine.
Full prescribing information for Flucelvax is available here.
The FDA approval letter is available here.pdnews@mdedge.com
Few JAK inhibitor users have diminished immune response to COVID-19 vaccines
Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.
The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.
To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.
Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).
Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.
Questions about antibody levels remain difficult to answer
“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”
“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”
Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.
“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”
Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”
As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”
The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.
Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.
The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.
To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.
Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).
Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.
Questions about antibody levels remain difficult to answer
“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”
“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”
Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.
“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”
Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”
As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”
The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.
Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.
The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.
To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.
Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).
Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.
Questions about antibody levels remain difficult to answer
“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”
“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”
Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.
“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”
Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”
As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”
The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.
FROM THE LANCET RHEUMATOLOGY
Adalimumab biosimilar Cyltezo gets interchangeability designation
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.
The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.
The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.
Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.
The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.
Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.
Lupin recalls irbesartan and hydrochlorothiazide/irbesartan tablets
Lupin Pharmaceuticals is recalling all batches of irbesartan tablets USP 75 mg, 150 mg, and 300 mg and irbesartan and hydrochlorothiazide (HCTZ) tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg because of the potential presence of the N-nitrosoirbesartan impurity.
“As part of Lupin’s ongoing assessment, analysis revealed that certain tested active pharmaceutical ingredient (API) batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan,” the company said in a news release posted on the U.S. Food and Drug Administration’s website. It notes that the impurity is a “probable human carcinogen.”
Lupin discontinued the marketing of irbesartan and irbesartan/HCTZ tablets on Jan. 7, 2021. It says it “has received no reports of illness that appear to relate to this issue” and is issuing the recall out of “an abundance of caution.”
The company, however, goes on to note that from Oct. 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches) to September 30 of this year, Lupin received four reports of illness from irbesartan and 0 reports from irbesartan/HCTZ.
Irbesartan is an angiotensin II receptor blocker indicated for treatment of hypertension in patients with type 2 diabetes, elevated serum creatinine, and proteinuria.
Irbesartan/HCTZ tablets include irbesartan and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lupin is notifying wholesalers, distributors, and retail outlets to immediately discontinue sales of the affected product lots and return them to the company. Specific lot numbers can be found here.
The company is advising patients to continue taking their medication and to contact their pharmacist, physician, or health care professional for advice regarding an alternative treatment.
Patients and physicians are also advised to report any adverse events or side effects related to the affected products to MedWatch, the U.S. Food and Drug Administration’s Safety Information and Adverse Event Reporting program.
A version of this article first appeared on Medscape.com.
Lupin Pharmaceuticals is recalling all batches of irbesartan tablets USP 75 mg, 150 mg, and 300 mg and irbesartan and hydrochlorothiazide (HCTZ) tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg because of the potential presence of the N-nitrosoirbesartan impurity.
“As part of Lupin’s ongoing assessment, analysis revealed that certain tested active pharmaceutical ingredient (API) batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan,” the company said in a news release posted on the U.S. Food and Drug Administration’s website. It notes that the impurity is a “probable human carcinogen.”
Lupin discontinued the marketing of irbesartan and irbesartan/HCTZ tablets on Jan. 7, 2021. It says it “has received no reports of illness that appear to relate to this issue” and is issuing the recall out of “an abundance of caution.”
The company, however, goes on to note that from Oct. 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches) to September 30 of this year, Lupin received four reports of illness from irbesartan and 0 reports from irbesartan/HCTZ.
Irbesartan is an angiotensin II receptor blocker indicated for treatment of hypertension in patients with type 2 diabetes, elevated serum creatinine, and proteinuria.
Irbesartan/HCTZ tablets include irbesartan and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lupin is notifying wholesalers, distributors, and retail outlets to immediately discontinue sales of the affected product lots and return them to the company. Specific lot numbers can be found here.
The company is advising patients to continue taking their medication and to contact their pharmacist, physician, or health care professional for advice regarding an alternative treatment.
Patients and physicians are also advised to report any adverse events or side effects related to the affected products to MedWatch, the U.S. Food and Drug Administration’s Safety Information and Adverse Event Reporting program.
A version of this article first appeared on Medscape.com.
Lupin Pharmaceuticals is recalling all batches of irbesartan tablets USP 75 mg, 150 mg, and 300 mg and irbesartan and hydrochlorothiazide (HCTZ) tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg because of the potential presence of the N-nitrosoirbesartan impurity.
“As part of Lupin’s ongoing assessment, analysis revealed that certain tested active pharmaceutical ingredient (API) batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan,” the company said in a news release posted on the U.S. Food and Drug Administration’s website. It notes that the impurity is a “probable human carcinogen.”
Lupin discontinued the marketing of irbesartan and irbesartan/HCTZ tablets on Jan. 7, 2021. It says it “has received no reports of illness that appear to relate to this issue” and is issuing the recall out of “an abundance of caution.”
The company, however, goes on to note that from Oct. 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches) to September 30 of this year, Lupin received four reports of illness from irbesartan and 0 reports from irbesartan/HCTZ.
Irbesartan is an angiotensin II receptor blocker indicated for treatment of hypertension in patients with type 2 diabetes, elevated serum creatinine, and proteinuria.
Irbesartan/HCTZ tablets include irbesartan and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lupin is notifying wholesalers, distributors, and retail outlets to immediately discontinue sales of the affected product lots and return them to the company. Specific lot numbers can be found here.
The company is advising patients to continue taking their medication and to contact their pharmacist, physician, or health care professional for advice regarding an alternative treatment.
Patients and physicians are also advised to report any adverse events or side effects related to the affected products to MedWatch, the U.S. Food and Drug Administration’s Safety Information and Adverse Event Reporting program.
A version of this article first appeared on Medscape.com.
New antimigraine drugs linked with less risk for adverse events
“[T]he lack of cardiovascular risks of these new classes of migraine-specific treatments may provide alternative treatment options for individuals for whom currently available acute treatments have failed or for those with cardiovascular contraindications,” write lead author Chun-Pai Yang, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and colleagues, in the paper, published online in JAMA Network Open.
Methods
The new study compared the outcomes for acute migraine management using the ditan, lasmiditan (a 5-hydroxytryptamine [5HT]1F–receptor agonist), and the two gepants, rimegepant, and ubrogepant (calcitonin gene–related peptide [CGRP] antagonists), with standard triptan (selective 5-HT1B/1D–receptor agonist) therapy.
The researchers evaluated 64 double-blind randomized clinical trials which included 46,442 patients, the majority of whom (74%-87%) were women with an age range of 36-43 years.
The primary outcome evaluated was the odds ratio for freedom from pain at 2 hours after a single dose and secondary outcomes were the OR for pain relief at 2 hours following a dose, as well as any adverse events.
Results
Dr. Yang and colleagues found that virtually all medications with widespread clinical use, regardless of class, were associated with higher ORs for pain freedom when compared with placebo.
Compared to ditan and gepant agents, however, triptans were associated with significantly higher ORs for pain freedom. The odds ratio ranges were 1.72-3.40 for lasmiditan, 1.58-3.13 for rimegepant, and 1.54-3.05 for ubrogepant.
With respect to pain relief at 2 hours, while all medications were more effective than placebo, triptans were associated with higher ORs when compared with the other drug classes: lasmiditan (range: OR, 1.46; 95% confidence interval, 1.09-1.96 to OR, 3.31; 95% CI, 2.41-4.55), rimegepant (range: OR, 1.33; 95% CI, 1.01-1.76 to OR, 3.01; 95% CI, 2.33-3.88), and ubrogepant (range: OR, 1.38; 95% CI, 1.02-1.88 to OR, 3.13; 95% CI, 2.35-4.15)
When assessing tolerability, the researchers found that overall, triptans were associated with the higher ORs for any adverse events (AE) with a trend of dose-response relationship. Lasmiditan (in the ditan class) was associated with the highest risk for AEs among all treatments. Most of the AEs were mild to moderate and included chest pain, tightness, heaviness, and pressure.
Dr. Yang and colleagues note that, “although these two new classes of antimigraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease.”
Balancing efficacy and tolerability
“When choosing an acute medication for a patient there is always a balance between efficacy and tolerability,” headache specialist and associate director of North Shore Headache and Spine Lauren Natbony, MD, said in an interview.
“A medication can only be effective if a patient is able to tolerate it and will actually use it,” Dr. Natbony said.
With respect to the current review, Dr. Natbony pointed out, “response to acute therapy can differ between migraine attacks and may be based on variables not controlled for, such as how early in an attack the medication was taken, associated symptoms such as nausea that may make oral medications less efficacious, etc.”
The authors acknowledge that the focus on short-term responses and AEs after a single dose is a limitation of the study. They also pointed out what they considered to be a strength of the study, which was its network meta-analysis design. According to the authors, this design allowed for “multiple direct and indirect comparisons, ranking the efficacy and safety of individual pharmacologic interventions and providing more precise estimates than those of RCTs and traditional meta-analysis.”
Funding for this study was provided through grants from the Ministry of Science and Technology, Taiwan; the Brain Research Center; and National Yang Ming Chiao Tung University.
Dr. Yang has received personal fees and grants from various pharmaceutical companies. He has also received grants from the Taiwan Ministry of Technology and Science, the Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. The other authors and Dr. Natbony disclosed no relevant financial relationships.
“[T]he lack of cardiovascular risks of these new classes of migraine-specific treatments may provide alternative treatment options for individuals for whom currently available acute treatments have failed or for those with cardiovascular contraindications,” write lead author Chun-Pai Yang, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and colleagues, in the paper, published online in JAMA Network Open.
Methods
The new study compared the outcomes for acute migraine management using the ditan, lasmiditan (a 5-hydroxytryptamine [5HT]1F–receptor agonist), and the two gepants, rimegepant, and ubrogepant (calcitonin gene–related peptide [CGRP] antagonists), with standard triptan (selective 5-HT1B/1D–receptor agonist) therapy.
The researchers evaluated 64 double-blind randomized clinical trials which included 46,442 patients, the majority of whom (74%-87%) were women with an age range of 36-43 years.
The primary outcome evaluated was the odds ratio for freedom from pain at 2 hours after a single dose and secondary outcomes were the OR for pain relief at 2 hours following a dose, as well as any adverse events.
Results
Dr. Yang and colleagues found that virtually all medications with widespread clinical use, regardless of class, were associated with higher ORs for pain freedom when compared with placebo.
Compared to ditan and gepant agents, however, triptans were associated with significantly higher ORs for pain freedom. The odds ratio ranges were 1.72-3.40 for lasmiditan, 1.58-3.13 for rimegepant, and 1.54-3.05 for ubrogepant.
With respect to pain relief at 2 hours, while all medications were more effective than placebo, triptans were associated with higher ORs when compared with the other drug classes: lasmiditan (range: OR, 1.46; 95% confidence interval, 1.09-1.96 to OR, 3.31; 95% CI, 2.41-4.55), rimegepant (range: OR, 1.33; 95% CI, 1.01-1.76 to OR, 3.01; 95% CI, 2.33-3.88), and ubrogepant (range: OR, 1.38; 95% CI, 1.02-1.88 to OR, 3.13; 95% CI, 2.35-4.15)
When assessing tolerability, the researchers found that overall, triptans were associated with the higher ORs for any adverse events (AE) with a trend of dose-response relationship. Lasmiditan (in the ditan class) was associated with the highest risk for AEs among all treatments. Most of the AEs were mild to moderate and included chest pain, tightness, heaviness, and pressure.
Dr. Yang and colleagues note that, “although these two new classes of antimigraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease.”
Balancing efficacy and tolerability
“When choosing an acute medication for a patient there is always a balance between efficacy and tolerability,” headache specialist and associate director of North Shore Headache and Spine Lauren Natbony, MD, said in an interview.
“A medication can only be effective if a patient is able to tolerate it and will actually use it,” Dr. Natbony said.
With respect to the current review, Dr. Natbony pointed out, “response to acute therapy can differ between migraine attacks and may be based on variables not controlled for, such as how early in an attack the medication was taken, associated symptoms such as nausea that may make oral medications less efficacious, etc.”
The authors acknowledge that the focus on short-term responses and AEs after a single dose is a limitation of the study. They also pointed out what they considered to be a strength of the study, which was its network meta-analysis design. According to the authors, this design allowed for “multiple direct and indirect comparisons, ranking the efficacy and safety of individual pharmacologic interventions and providing more precise estimates than those of RCTs and traditional meta-analysis.”
Funding for this study was provided through grants from the Ministry of Science and Technology, Taiwan; the Brain Research Center; and National Yang Ming Chiao Tung University.
Dr. Yang has received personal fees and grants from various pharmaceutical companies. He has also received grants from the Taiwan Ministry of Technology and Science, the Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. The other authors and Dr. Natbony disclosed no relevant financial relationships.
“[T]he lack of cardiovascular risks of these new classes of migraine-specific treatments may provide alternative treatment options for individuals for whom currently available acute treatments have failed or for those with cardiovascular contraindications,” write lead author Chun-Pai Yang, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and colleagues, in the paper, published online in JAMA Network Open.
Methods
The new study compared the outcomes for acute migraine management using the ditan, lasmiditan (a 5-hydroxytryptamine [5HT]1F–receptor agonist), and the two gepants, rimegepant, and ubrogepant (calcitonin gene–related peptide [CGRP] antagonists), with standard triptan (selective 5-HT1B/1D–receptor agonist) therapy.
The researchers evaluated 64 double-blind randomized clinical trials which included 46,442 patients, the majority of whom (74%-87%) were women with an age range of 36-43 years.
The primary outcome evaluated was the odds ratio for freedom from pain at 2 hours after a single dose and secondary outcomes were the OR for pain relief at 2 hours following a dose, as well as any adverse events.
Results
Dr. Yang and colleagues found that virtually all medications with widespread clinical use, regardless of class, were associated with higher ORs for pain freedom when compared with placebo.
Compared to ditan and gepant agents, however, triptans were associated with significantly higher ORs for pain freedom. The odds ratio ranges were 1.72-3.40 for lasmiditan, 1.58-3.13 for rimegepant, and 1.54-3.05 for ubrogepant.
With respect to pain relief at 2 hours, while all medications were more effective than placebo, triptans were associated with higher ORs when compared with the other drug classes: lasmiditan (range: OR, 1.46; 95% confidence interval, 1.09-1.96 to OR, 3.31; 95% CI, 2.41-4.55), rimegepant (range: OR, 1.33; 95% CI, 1.01-1.76 to OR, 3.01; 95% CI, 2.33-3.88), and ubrogepant (range: OR, 1.38; 95% CI, 1.02-1.88 to OR, 3.13; 95% CI, 2.35-4.15)
When assessing tolerability, the researchers found that overall, triptans were associated with the higher ORs for any adverse events (AE) with a trend of dose-response relationship. Lasmiditan (in the ditan class) was associated with the highest risk for AEs among all treatments. Most of the AEs were mild to moderate and included chest pain, tightness, heaviness, and pressure.
Dr. Yang and colleagues note that, “although these two new classes of antimigraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease.”
Balancing efficacy and tolerability
“When choosing an acute medication for a patient there is always a balance between efficacy and tolerability,” headache specialist and associate director of North Shore Headache and Spine Lauren Natbony, MD, said in an interview.
“A medication can only be effective if a patient is able to tolerate it and will actually use it,” Dr. Natbony said.
With respect to the current review, Dr. Natbony pointed out, “response to acute therapy can differ between migraine attacks and may be based on variables not controlled for, such as how early in an attack the medication was taken, associated symptoms such as nausea that may make oral medications less efficacious, etc.”
The authors acknowledge that the focus on short-term responses and AEs after a single dose is a limitation of the study. They also pointed out what they considered to be a strength of the study, which was its network meta-analysis design. According to the authors, this design allowed for “multiple direct and indirect comparisons, ranking the efficacy and safety of individual pharmacologic interventions and providing more precise estimates than those of RCTs and traditional meta-analysis.”
Funding for this study was provided through grants from the Ministry of Science and Technology, Taiwan; the Brain Research Center; and National Yang Ming Chiao Tung University.
Dr. Yang has received personal fees and grants from various pharmaceutical companies. He has also received grants from the Taiwan Ministry of Technology and Science, the Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. The other authors and Dr. Natbony disclosed no relevant financial relationships.
FROM JAMA NETWORK OPEN
Rivaroxaban’s single daily dose may lead to higher bleeding risk than other DOACs
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
FROM ANNALS OF INTERNAL MEDICINE
New reports help nail down myocarditis risk with COVID-19 vaccine
Recent literature features new descriptions of myocarditis linked to the two available mRNA vaccines against SARS-CoV-2. They tell a story largely consistent with experience to date, and support what might be its most useful public health message: The associated myocarditis is usually mild and self-limiting, and is far less likely to occur than myocarditis or death in unvaccinated people with COVID-19.
In line with previous research, the new analyses suggest the myocarditis – with onset usually a few days to a week after injection – has an overall incidence that ranges from less than 1 to perhaps 3 per 100,000 people who received at least one of the full mRNA-vaccine regimen’s two injections. Also, as in earlier studies, the incidence climbed higher – sometimes sharply – in certain groups by age and sex, particularly in young men and older male teens.
The new studies “are confirmatory, in terms of the risk being low,” but underscore that clinicians still must be wary of myocarditis as a potential complication of the mRNA vaccines, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.
Dr. Bozkurt, a leading heart failure specialist and researcher, did not contribute to any of the new reports but does study the myocarditis of COVID-19 and was lead author on a recent review of the potential vaccine complication’s features and possible mechanisms.
In the new myocarditis reports, she observed, more than 90% of the cases were mild and “resolved on their own without a major adverse outcome.” Dr. Bozkurt emphasized the need for perspective regarding the risk. For example, the myocarditis associated with SARS-CoV-2 infection is not only more likely than the vaccine-related myocarditis, but it’s also usually far more severe.
Dr. Bozkurt pointed to a recent study in which the mRNA vaccines, compared with no vaccination, appeared to escalate the myocarditis risk by a factor of 3, whereas the risk for myocarditis in SARS-CoV-2 infection was increased 18 times.
In contrast, she observed, the new myocarditis cases reported this week feature a few that are novel or are at least very rare, including the case of a patient who developed cardiogenic shock and another with fulminant myocarditis who died.
The Centers for Disease Control and Prevention in May publicly described the apparent link between myocarditis and the two available mRNA vaccines against SARS-CoV-2: BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). The next month, the Food and Drug Administration added a warning about the risk to the labeling.
Less than 1 case per 100,000
Fifteen confirmed cases of myocarditis were identified among about 2.4 million members of Kaiser Permanente Southern California aged 18 or older who received at least one injection of the Pfizer or Moderna mRNA vaccines between December 2020 and July 2021, in a report published in JAMA Internal Medicine. The study counted cases up to 10 days after the first or second injection, of which there were 2 and 13, respectively.
All eight patients who received the Pfizer BNT162b2 vaccine and the eight given the Moderna mRNA-1273 vaccine were male with a median age of 25 years (interquartile range, 20-32 years).
“The main takeaway messages from our study are that the incidence of myocarditis after COVID-19 mRNA vaccinations is very low, that this condition is primarily observed in young men within a few days after the second dose, and that most patients recover quickly,” senior author Mingsum Lee, MD, PhD, Kaiser Permanente Los Angeles Medical Center, told this news organization.
“The incidence of vaccine-related myocarditis was significantly lower than rates of COVID-19 hospitalization during the same period and population area,” she added.
The group saw a per-million incidence of 0.8 and 5.8 myocarditis cases in the 10 days after first and second injections, respectively. That made for an incidence of 0.58 per 100,000, or 1 case per 172,414 fully vaccinated adults.
The group also considered a cohort of 1,577,741 unvaccinated people with a median age of 39 years (interquartile range, 28-53 years) during the same period. Of the 75 cases of myocarditis, 52% were in men, they reported.
Comparing the vaccinated and unvaccinated cohorts, they saw a 10-day vaccine-associated myocarditis incidence rate ratio of 0.38 (95% confidence interval, 0.05-1.40; P = .15) after the first dose, and 2.7 (95% CI, 1.4-4.8; P = .004) after the second dose.
In a comparison of the vaccinated group with itself using data from a 10-day period in the previous year, the corresponding myocarditis IRRs were 1.0 (P > .99) and 3.3 (P = .03), respectively.
Dr. Lee said none of the 15 patients required admission to an intensive care unit. “All patients with myocarditis responded well to treatment and felt better quickly,” she noted.
Myocarditis after an mRNA vaccine injection is rare and, Dr. Lee said emphatically, and “the benefits of the COVID-19 vaccine greatly outweigh the risks.”
Sex- and age-stratified rates
In a separate analysis of 5,442,696 people given a first dose of the Pfizer BNT162b2 vaccine and 5,125,635 given a second dose, there were 142 cases of myocarditis with onset 21 days after dose 1 and 30 days after dose 2. Of those cases, 136 were documented as “definite or probable” in an Israeli Ministry of Health database that covered up to the end of May 2021.
There were also 40 cases among vaccinated people seen after the 30-day window, which were considered not related to the vaccination, and 101 cases among unvaccinated people; of the latter, 29 had confirmed diagnoses of COVID-19.
Of the 136 people with definite or probable cases, the myocarditis was “generally mild” in 129 and usually resolved on its own, notes the report on the study, published in the New England Journal of Medicine, with lead author Dror Mevorach, MD, Hadassah-Hebrew University Medical Center, Jerusalem.
The estimated myocarditis incidence after a second such vaccine dose across the entire Israeli population, based on the current study, was about one per 26,000 males and one per 218,000 females, the group writes. Those figures compare with one case per 10,857 among “the general unvaccinated population.”
Again, the risk was concentrated among younger men and male adolescents. In an analysis limited to vaccinated people aged 16-19 years, myocarditis in the 21 days after a second mRNA injection was seen in about one of 6,637 males and one of 99,853 females, the group reported.
The standardized incidence ratio of 5.34 (95% CI, 4.48-6.40) after a second injection, across all groups, “was driven mostly by the diagnosis of myocarditis in younger male recipients.” Among that male subgroup, the ratios by age group were 13.60 (95% CI, 9.30-19.20) for 16-19 years, 8.53 (95% CI, 5.57-12.50) for 20-24 years, and 6.96 (95% CI, 4.25-10.75) for 25-29 years.
Among people who received a second injection, compared with unvaccinated people, the 30-day rate ratio was 2.35 (95% CI, 1.10-5.02). Again, the effect was concentrated in males aged 16-19 years. Among them, the myocarditis rate ratios in the 30 days after a second mRNA vaccine injection were 8.96 (95% CI, 4.50-17.83) for the 16-19 years group, 6.13 (95% CI, 3.16-11.88) for the 20-24 group, and 3.58 (95% CI, 1.82-7.01) for 25-29 years.
Most of the patients with myocarditis showed “significant clinical improvement,” with a mean hospitalization time of only 3-4 days, the report notes. Treatment consisted of nonsteroidal anti-inflammatory drugs “with or without colchicine for presumed pericardial inflammation.”
However, seven patients (4.9%) developed important complications, including left-ventricular dysfunction, ventricular arrhythmias, and heart failure. Among them was a 22-year-old patient who died of fulminant myocarditis within 24 hours of diagnosis, the group wrote.
From an Israeli health care organization
Published by the same journal as the study by Dr. Menvorach and associates, an analysis of a separate database showed largely consistent findings among patients in the largest of Israel’s four health care organizations charged by the government to administer health services.
The report, with authors led by Guy Witberg, MD, Rabin Medical Center, Petah Tikva, Israel, focused on members of the health care organization aged 16 years or older who had received at least one Pfizer mRNA vaccine dose by the end of May 2021.
The cohorts from the two separate reports surely overlap substantially, as the Ministry of Health analysis from Dr. Mevorach and colleagues derived from a nationwide database, and – as Dr. Witberg and associates wrote – the health care organization providing their data covers 52% of the Israeli population.
Of 2,558,421 vaccinated people in the analysis, of whom 94% received two doses, 54 developed confirmed myocarditis in the 42 days after the first dose. Their median age was 27 years (interquartile range, 21-35 years) and all but three (94%) were male. Of those 54 cases, 41 were considered mild and 12 intermediate in severity, and one was fulminant with the patient in cardiogenic shock, the group writes. In addition, nonsustained ventricular tachycardia and atrial fibrillation developed in 5% and 3% of cases, respectively.
The estimated myocarditis incidence in the 42 days after administration of at least one mRNA vaccine dose was 2.13 per 100,000 vaccinated people. In that group, Dr. Witberg and colleagues note, the corresponding incidences per 100,000 were 4.12 and 0.23 for males and females, respectively.
Also in the current report, incidences per 100,000 vaccinated people aged 16-29 years, by sex, included 5.49 (95% CI, 3.59-7.39) overall, and 10.69 (95% CI, 6.93-14.46) for males (the highest rate in the report).
There was only one case in a female aged 16-29 years, and two cases in females 30 years or older.
Of note, some authors of the current study are also authors on the high-profile report from Noam Barda, MD, and colleagues published in the New England Journal of Medicine, that used the same database to arrive at an mRNA-vaccine-related incidence of myocarditis of 2.7 per 100,000. Eligibility criteria and follow-up time were different in that report, as were case ascertainment criteria.
The myocarditis risk associated with the two mRNA vaccines is small compared with “the morbidity and mortality of COVID-19 infection, in which up to 28% of hospitalized patients showed signs of myocardial injury,” wrote Vinay Guduguntla, MD, University of California, San Francisco, and Mitchell H. Katz, MD, NYC Health + Hospitals, New York, in an editorial accompanying the report from Dr. Lee and associates.
“Randomized clinical trials show that COVID-19 mRNA vaccines represent a safe and effective method of preventing infection,” they stated. “The identification of rare myocarditis does not change clinical decision-making.”
Dr. Bozkurt, who is immediate past president of the Heart Failure Society of America, has disclosed consulting for Bayer and scPharmaceuticals and serving on a clinical events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. Lee and the report’s other authors had no disclosures. Dr. Mevorach discloses consulting for Enlivex Therapeutics; disclosures for the other authors are available at NEJM.org. Dr. Witberg said he has no interests to disclose; disclosures for the other authors are available at NEJM.org. Dr. Guduguntla is an editorial fellow and Dr. Katz a deputy editor at JAMA Internal Medicine; neither had disclosures.
A version of this article first appeared on Medscape.com.
Recent literature features new descriptions of myocarditis linked to the two available mRNA vaccines against SARS-CoV-2. They tell a story largely consistent with experience to date, and support what might be its most useful public health message: The associated myocarditis is usually mild and self-limiting, and is far less likely to occur than myocarditis or death in unvaccinated people with COVID-19.
In line with previous research, the new analyses suggest the myocarditis – with onset usually a few days to a week after injection – has an overall incidence that ranges from less than 1 to perhaps 3 per 100,000 people who received at least one of the full mRNA-vaccine regimen’s two injections. Also, as in earlier studies, the incidence climbed higher – sometimes sharply – in certain groups by age and sex, particularly in young men and older male teens.
The new studies “are confirmatory, in terms of the risk being low,” but underscore that clinicians still must be wary of myocarditis as a potential complication of the mRNA vaccines, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.
Dr. Bozkurt, a leading heart failure specialist and researcher, did not contribute to any of the new reports but does study the myocarditis of COVID-19 and was lead author on a recent review of the potential vaccine complication’s features and possible mechanisms.
In the new myocarditis reports, she observed, more than 90% of the cases were mild and “resolved on their own without a major adverse outcome.” Dr. Bozkurt emphasized the need for perspective regarding the risk. For example, the myocarditis associated with SARS-CoV-2 infection is not only more likely than the vaccine-related myocarditis, but it’s also usually far more severe.
Dr. Bozkurt pointed to a recent study in which the mRNA vaccines, compared with no vaccination, appeared to escalate the myocarditis risk by a factor of 3, whereas the risk for myocarditis in SARS-CoV-2 infection was increased 18 times.
In contrast, she observed, the new myocarditis cases reported this week feature a few that are novel or are at least very rare, including the case of a patient who developed cardiogenic shock and another with fulminant myocarditis who died.
The Centers for Disease Control and Prevention in May publicly described the apparent link between myocarditis and the two available mRNA vaccines against SARS-CoV-2: BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). The next month, the Food and Drug Administration added a warning about the risk to the labeling.
Less than 1 case per 100,000
Fifteen confirmed cases of myocarditis were identified among about 2.4 million members of Kaiser Permanente Southern California aged 18 or older who received at least one injection of the Pfizer or Moderna mRNA vaccines between December 2020 and July 2021, in a report published in JAMA Internal Medicine. The study counted cases up to 10 days after the first or second injection, of which there were 2 and 13, respectively.
All eight patients who received the Pfizer BNT162b2 vaccine and the eight given the Moderna mRNA-1273 vaccine were male with a median age of 25 years (interquartile range, 20-32 years).
“The main takeaway messages from our study are that the incidence of myocarditis after COVID-19 mRNA vaccinations is very low, that this condition is primarily observed in young men within a few days after the second dose, and that most patients recover quickly,” senior author Mingsum Lee, MD, PhD, Kaiser Permanente Los Angeles Medical Center, told this news organization.
“The incidence of vaccine-related myocarditis was significantly lower than rates of COVID-19 hospitalization during the same period and population area,” she added.
The group saw a per-million incidence of 0.8 and 5.8 myocarditis cases in the 10 days after first and second injections, respectively. That made for an incidence of 0.58 per 100,000, or 1 case per 172,414 fully vaccinated adults.
The group also considered a cohort of 1,577,741 unvaccinated people with a median age of 39 years (interquartile range, 28-53 years) during the same period. Of the 75 cases of myocarditis, 52% were in men, they reported.
Comparing the vaccinated and unvaccinated cohorts, they saw a 10-day vaccine-associated myocarditis incidence rate ratio of 0.38 (95% confidence interval, 0.05-1.40; P = .15) after the first dose, and 2.7 (95% CI, 1.4-4.8; P = .004) after the second dose.
In a comparison of the vaccinated group with itself using data from a 10-day period in the previous year, the corresponding myocarditis IRRs were 1.0 (P > .99) and 3.3 (P = .03), respectively.
Dr. Lee said none of the 15 patients required admission to an intensive care unit. “All patients with myocarditis responded well to treatment and felt better quickly,” she noted.
Myocarditis after an mRNA vaccine injection is rare and, Dr. Lee said emphatically, and “the benefits of the COVID-19 vaccine greatly outweigh the risks.”
Sex- and age-stratified rates
In a separate analysis of 5,442,696 people given a first dose of the Pfizer BNT162b2 vaccine and 5,125,635 given a second dose, there were 142 cases of myocarditis with onset 21 days after dose 1 and 30 days after dose 2. Of those cases, 136 were documented as “definite or probable” in an Israeli Ministry of Health database that covered up to the end of May 2021.
There were also 40 cases among vaccinated people seen after the 30-day window, which were considered not related to the vaccination, and 101 cases among unvaccinated people; of the latter, 29 had confirmed diagnoses of COVID-19.
Of the 136 people with definite or probable cases, the myocarditis was “generally mild” in 129 and usually resolved on its own, notes the report on the study, published in the New England Journal of Medicine, with lead author Dror Mevorach, MD, Hadassah-Hebrew University Medical Center, Jerusalem.
The estimated myocarditis incidence after a second such vaccine dose across the entire Israeli population, based on the current study, was about one per 26,000 males and one per 218,000 females, the group writes. Those figures compare with one case per 10,857 among “the general unvaccinated population.”
Again, the risk was concentrated among younger men and male adolescents. In an analysis limited to vaccinated people aged 16-19 years, myocarditis in the 21 days after a second mRNA injection was seen in about one of 6,637 males and one of 99,853 females, the group reported.
The standardized incidence ratio of 5.34 (95% CI, 4.48-6.40) after a second injection, across all groups, “was driven mostly by the diagnosis of myocarditis in younger male recipients.” Among that male subgroup, the ratios by age group were 13.60 (95% CI, 9.30-19.20) for 16-19 years, 8.53 (95% CI, 5.57-12.50) for 20-24 years, and 6.96 (95% CI, 4.25-10.75) for 25-29 years.
Among people who received a second injection, compared with unvaccinated people, the 30-day rate ratio was 2.35 (95% CI, 1.10-5.02). Again, the effect was concentrated in males aged 16-19 years. Among them, the myocarditis rate ratios in the 30 days after a second mRNA vaccine injection were 8.96 (95% CI, 4.50-17.83) for the 16-19 years group, 6.13 (95% CI, 3.16-11.88) for the 20-24 group, and 3.58 (95% CI, 1.82-7.01) for 25-29 years.
Most of the patients with myocarditis showed “significant clinical improvement,” with a mean hospitalization time of only 3-4 days, the report notes. Treatment consisted of nonsteroidal anti-inflammatory drugs “with or without colchicine for presumed pericardial inflammation.”
However, seven patients (4.9%) developed important complications, including left-ventricular dysfunction, ventricular arrhythmias, and heart failure. Among them was a 22-year-old patient who died of fulminant myocarditis within 24 hours of diagnosis, the group wrote.
From an Israeli health care organization
Published by the same journal as the study by Dr. Menvorach and associates, an analysis of a separate database showed largely consistent findings among patients in the largest of Israel’s four health care organizations charged by the government to administer health services.
The report, with authors led by Guy Witberg, MD, Rabin Medical Center, Petah Tikva, Israel, focused on members of the health care organization aged 16 years or older who had received at least one Pfizer mRNA vaccine dose by the end of May 2021.
The cohorts from the two separate reports surely overlap substantially, as the Ministry of Health analysis from Dr. Mevorach and colleagues derived from a nationwide database, and – as Dr. Witberg and associates wrote – the health care organization providing their data covers 52% of the Israeli population.
Of 2,558,421 vaccinated people in the analysis, of whom 94% received two doses, 54 developed confirmed myocarditis in the 42 days after the first dose. Their median age was 27 years (interquartile range, 21-35 years) and all but three (94%) were male. Of those 54 cases, 41 were considered mild and 12 intermediate in severity, and one was fulminant with the patient in cardiogenic shock, the group writes. In addition, nonsustained ventricular tachycardia and atrial fibrillation developed in 5% and 3% of cases, respectively.
The estimated myocarditis incidence in the 42 days after administration of at least one mRNA vaccine dose was 2.13 per 100,000 vaccinated people. In that group, Dr. Witberg and colleagues note, the corresponding incidences per 100,000 were 4.12 and 0.23 for males and females, respectively.
Also in the current report, incidences per 100,000 vaccinated people aged 16-29 years, by sex, included 5.49 (95% CI, 3.59-7.39) overall, and 10.69 (95% CI, 6.93-14.46) for males (the highest rate in the report).
There was only one case in a female aged 16-29 years, and two cases in females 30 years or older.
Of note, some authors of the current study are also authors on the high-profile report from Noam Barda, MD, and colleagues published in the New England Journal of Medicine, that used the same database to arrive at an mRNA-vaccine-related incidence of myocarditis of 2.7 per 100,000. Eligibility criteria and follow-up time were different in that report, as were case ascertainment criteria.
The myocarditis risk associated with the two mRNA vaccines is small compared with “the morbidity and mortality of COVID-19 infection, in which up to 28% of hospitalized patients showed signs of myocardial injury,” wrote Vinay Guduguntla, MD, University of California, San Francisco, and Mitchell H. Katz, MD, NYC Health + Hospitals, New York, in an editorial accompanying the report from Dr. Lee and associates.
“Randomized clinical trials show that COVID-19 mRNA vaccines represent a safe and effective method of preventing infection,” they stated. “The identification of rare myocarditis does not change clinical decision-making.”
Dr. Bozkurt, who is immediate past president of the Heart Failure Society of America, has disclosed consulting for Bayer and scPharmaceuticals and serving on a clinical events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. Lee and the report’s other authors had no disclosures. Dr. Mevorach discloses consulting for Enlivex Therapeutics; disclosures for the other authors are available at NEJM.org. Dr. Witberg said he has no interests to disclose; disclosures for the other authors are available at NEJM.org. Dr. Guduguntla is an editorial fellow and Dr. Katz a deputy editor at JAMA Internal Medicine; neither had disclosures.
A version of this article first appeared on Medscape.com.
Recent literature features new descriptions of myocarditis linked to the two available mRNA vaccines against SARS-CoV-2. They tell a story largely consistent with experience to date, and support what might be its most useful public health message: The associated myocarditis is usually mild and self-limiting, and is far less likely to occur than myocarditis or death in unvaccinated people with COVID-19.
In line with previous research, the new analyses suggest the myocarditis – with onset usually a few days to a week after injection – has an overall incidence that ranges from less than 1 to perhaps 3 per 100,000 people who received at least one of the full mRNA-vaccine regimen’s two injections. Also, as in earlier studies, the incidence climbed higher – sometimes sharply – in certain groups by age and sex, particularly in young men and older male teens.
The new studies “are confirmatory, in terms of the risk being low,” but underscore that clinicians still must be wary of myocarditis as a potential complication of the mRNA vaccines, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, told this news organization.
Dr. Bozkurt, a leading heart failure specialist and researcher, did not contribute to any of the new reports but does study the myocarditis of COVID-19 and was lead author on a recent review of the potential vaccine complication’s features and possible mechanisms.
In the new myocarditis reports, she observed, more than 90% of the cases were mild and “resolved on their own without a major adverse outcome.” Dr. Bozkurt emphasized the need for perspective regarding the risk. For example, the myocarditis associated with SARS-CoV-2 infection is not only more likely than the vaccine-related myocarditis, but it’s also usually far more severe.
Dr. Bozkurt pointed to a recent study in which the mRNA vaccines, compared with no vaccination, appeared to escalate the myocarditis risk by a factor of 3, whereas the risk for myocarditis in SARS-CoV-2 infection was increased 18 times.
In contrast, she observed, the new myocarditis cases reported this week feature a few that are novel or are at least very rare, including the case of a patient who developed cardiogenic shock and another with fulminant myocarditis who died.
The Centers for Disease Control and Prevention in May publicly described the apparent link between myocarditis and the two available mRNA vaccines against SARS-CoV-2: BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). The next month, the Food and Drug Administration added a warning about the risk to the labeling.
Less than 1 case per 100,000
Fifteen confirmed cases of myocarditis were identified among about 2.4 million members of Kaiser Permanente Southern California aged 18 or older who received at least one injection of the Pfizer or Moderna mRNA vaccines between December 2020 and July 2021, in a report published in JAMA Internal Medicine. The study counted cases up to 10 days after the first or second injection, of which there were 2 and 13, respectively.
All eight patients who received the Pfizer BNT162b2 vaccine and the eight given the Moderna mRNA-1273 vaccine were male with a median age of 25 years (interquartile range, 20-32 years).
“The main takeaway messages from our study are that the incidence of myocarditis after COVID-19 mRNA vaccinations is very low, that this condition is primarily observed in young men within a few days after the second dose, and that most patients recover quickly,” senior author Mingsum Lee, MD, PhD, Kaiser Permanente Los Angeles Medical Center, told this news organization.
“The incidence of vaccine-related myocarditis was significantly lower than rates of COVID-19 hospitalization during the same period and population area,” she added.
The group saw a per-million incidence of 0.8 and 5.8 myocarditis cases in the 10 days after first and second injections, respectively. That made for an incidence of 0.58 per 100,000, or 1 case per 172,414 fully vaccinated adults.
The group also considered a cohort of 1,577,741 unvaccinated people with a median age of 39 years (interquartile range, 28-53 years) during the same period. Of the 75 cases of myocarditis, 52% were in men, they reported.
Comparing the vaccinated and unvaccinated cohorts, they saw a 10-day vaccine-associated myocarditis incidence rate ratio of 0.38 (95% confidence interval, 0.05-1.40; P = .15) after the first dose, and 2.7 (95% CI, 1.4-4.8; P = .004) after the second dose.
In a comparison of the vaccinated group with itself using data from a 10-day period in the previous year, the corresponding myocarditis IRRs were 1.0 (P > .99) and 3.3 (P = .03), respectively.
Dr. Lee said none of the 15 patients required admission to an intensive care unit. “All patients with myocarditis responded well to treatment and felt better quickly,” she noted.
Myocarditis after an mRNA vaccine injection is rare and, Dr. Lee said emphatically, and “the benefits of the COVID-19 vaccine greatly outweigh the risks.”
Sex- and age-stratified rates
In a separate analysis of 5,442,696 people given a first dose of the Pfizer BNT162b2 vaccine and 5,125,635 given a second dose, there were 142 cases of myocarditis with onset 21 days after dose 1 and 30 days after dose 2. Of those cases, 136 were documented as “definite or probable” in an Israeli Ministry of Health database that covered up to the end of May 2021.
There were also 40 cases among vaccinated people seen after the 30-day window, which were considered not related to the vaccination, and 101 cases among unvaccinated people; of the latter, 29 had confirmed diagnoses of COVID-19.
Of the 136 people with definite or probable cases, the myocarditis was “generally mild” in 129 and usually resolved on its own, notes the report on the study, published in the New England Journal of Medicine, with lead author Dror Mevorach, MD, Hadassah-Hebrew University Medical Center, Jerusalem.
The estimated myocarditis incidence after a second such vaccine dose across the entire Israeli population, based on the current study, was about one per 26,000 males and one per 218,000 females, the group writes. Those figures compare with one case per 10,857 among “the general unvaccinated population.”
Again, the risk was concentrated among younger men and male adolescents. In an analysis limited to vaccinated people aged 16-19 years, myocarditis in the 21 days after a second mRNA injection was seen in about one of 6,637 males and one of 99,853 females, the group reported.
The standardized incidence ratio of 5.34 (95% CI, 4.48-6.40) after a second injection, across all groups, “was driven mostly by the diagnosis of myocarditis in younger male recipients.” Among that male subgroup, the ratios by age group were 13.60 (95% CI, 9.30-19.20) for 16-19 years, 8.53 (95% CI, 5.57-12.50) for 20-24 years, and 6.96 (95% CI, 4.25-10.75) for 25-29 years.
Among people who received a second injection, compared with unvaccinated people, the 30-day rate ratio was 2.35 (95% CI, 1.10-5.02). Again, the effect was concentrated in males aged 16-19 years. Among them, the myocarditis rate ratios in the 30 days after a second mRNA vaccine injection were 8.96 (95% CI, 4.50-17.83) for the 16-19 years group, 6.13 (95% CI, 3.16-11.88) for the 20-24 group, and 3.58 (95% CI, 1.82-7.01) for 25-29 years.
Most of the patients with myocarditis showed “significant clinical improvement,” with a mean hospitalization time of only 3-4 days, the report notes. Treatment consisted of nonsteroidal anti-inflammatory drugs “with or without colchicine for presumed pericardial inflammation.”
However, seven patients (4.9%) developed important complications, including left-ventricular dysfunction, ventricular arrhythmias, and heart failure. Among them was a 22-year-old patient who died of fulminant myocarditis within 24 hours of diagnosis, the group wrote.
From an Israeli health care organization
Published by the same journal as the study by Dr. Menvorach and associates, an analysis of a separate database showed largely consistent findings among patients in the largest of Israel’s four health care organizations charged by the government to administer health services.
The report, with authors led by Guy Witberg, MD, Rabin Medical Center, Petah Tikva, Israel, focused on members of the health care organization aged 16 years or older who had received at least one Pfizer mRNA vaccine dose by the end of May 2021.
The cohorts from the two separate reports surely overlap substantially, as the Ministry of Health analysis from Dr. Mevorach and colleagues derived from a nationwide database, and – as Dr. Witberg and associates wrote – the health care organization providing their data covers 52% of the Israeli population.
Of 2,558,421 vaccinated people in the analysis, of whom 94% received two doses, 54 developed confirmed myocarditis in the 42 days after the first dose. Their median age was 27 years (interquartile range, 21-35 years) and all but three (94%) were male. Of those 54 cases, 41 were considered mild and 12 intermediate in severity, and one was fulminant with the patient in cardiogenic shock, the group writes. In addition, nonsustained ventricular tachycardia and atrial fibrillation developed in 5% and 3% of cases, respectively.
The estimated myocarditis incidence in the 42 days after administration of at least one mRNA vaccine dose was 2.13 per 100,000 vaccinated people. In that group, Dr. Witberg and colleagues note, the corresponding incidences per 100,000 were 4.12 and 0.23 for males and females, respectively.
Also in the current report, incidences per 100,000 vaccinated people aged 16-29 years, by sex, included 5.49 (95% CI, 3.59-7.39) overall, and 10.69 (95% CI, 6.93-14.46) for males (the highest rate in the report).
There was only one case in a female aged 16-29 years, and two cases in females 30 years or older.
Of note, some authors of the current study are also authors on the high-profile report from Noam Barda, MD, and colleagues published in the New England Journal of Medicine, that used the same database to arrive at an mRNA-vaccine-related incidence of myocarditis of 2.7 per 100,000. Eligibility criteria and follow-up time were different in that report, as were case ascertainment criteria.
The myocarditis risk associated with the two mRNA vaccines is small compared with “the morbidity and mortality of COVID-19 infection, in which up to 28% of hospitalized patients showed signs of myocardial injury,” wrote Vinay Guduguntla, MD, University of California, San Francisco, and Mitchell H. Katz, MD, NYC Health + Hospitals, New York, in an editorial accompanying the report from Dr. Lee and associates.
“Randomized clinical trials show that COVID-19 mRNA vaccines represent a safe and effective method of preventing infection,” they stated. “The identification of rare myocarditis does not change clinical decision-making.”
Dr. Bozkurt, who is immediate past president of the Heart Failure Society of America, has disclosed consulting for Bayer and scPharmaceuticals and serving on a clinical events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. Lee and the report’s other authors had no disclosures. Dr. Mevorach discloses consulting for Enlivex Therapeutics; disclosures for the other authors are available at NEJM.org. Dr. Witberg said he has no interests to disclose; disclosures for the other authors are available at NEJM.org. Dr. Guduguntla is an editorial fellow and Dr. Katz a deputy editor at JAMA Internal Medicine; neither had disclosures.
A version of this article first appeared on Medscape.com.
Merck seeks FDA authorization for antiviral COVID-19 pill
, an experimental antiviral COVID-19 treatment.
If the FDA grants authorization, the drug would be the first oral antiviral treatment for COVID-19. The capsule, made by Merck and Ridgeback Biotherapeutics, is intended to treat mild to moderate COVID-19 in adults who are at risk of having severe COVID-19 or hospitalization.
“The extraordinary impact of this pandemic demands that we move with unprecedented urgency, and that is what our teams have done by submitting this application for molnupiravir to the FDA within 10 days of receiving the data,” Robert Davis, CEO and president of Merck, said in a statement. On Oct. 1, Merck and Ridgeback released interim data from its phase III clinical trial, which showed that molnupiravir reduced the risk of hospitalization or death by about 50%. About 7% of patients who received the drug were hospitalized within 30 days in the study, as compared with 14% of patients who took a placebo, the company said.
No deaths were reported in the group that received the drug, as compared with eight deaths in the group that received the placebo. None of the trial participants had been vaccinated.
“Medicines and vaccines are both essential to our collective efforts,” Mr. Davis said. “We look forward to working with the FDA on its review of our application, and to working with other regulatory agencies as we do everything we can to bring molnupiravir to patients around the world as quickly as possible.”
Merck has been producing molnupiravir in anticipation of the clinical trial results and FDA authorization. The company expects to produce 10 million courses of treatment by the end of the year, with more expected for 2022.
In June, Merck signed an agreement with the United States to supply 1.7 million courses of molnupiravir once the FDA authorizes the drug. The company has agreed to advance purchase agreements with other countries as well.
Earlier in the year, Merck also announced voluntary licensing agreements with several generics manufacturers in India to provide molnupiravir to more than 100 low- and middle-income countries after approval from local regulatory agencies.
Data from the company’s late-stage clinical trial has not yet been peer-reviewed or published.
Last week, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said the clinical trial results were “very encouraging” but noted that the FDA should closely scrutinize the drug, CNN reported.
“It is very important that this now must go through the usual process of careful examination of the data by the Food and Drug Administration, both for effectiveness but also for safety, because whenever you introduce a new compound, safety is very important,” Dr. Fauci said, adding that vaccines remain “our best tools against COVID-19.”
A version of this article firsts appeared on WebMD.com.
, an experimental antiviral COVID-19 treatment.
If the FDA grants authorization, the drug would be the first oral antiviral treatment for COVID-19. The capsule, made by Merck and Ridgeback Biotherapeutics, is intended to treat mild to moderate COVID-19 in adults who are at risk of having severe COVID-19 or hospitalization.
“The extraordinary impact of this pandemic demands that we move with unprecedented urgency, and that is what our teams have done by submitting this application for molnupiravir to the FDA within 10 days of receiving the data,” Robert Davis, CEO and president of Merck, said in a statement. On Oct. 1, Merck and Ridgeback released interim data from its phase III clinical trial, which showed that molnupiravir reduced the risk of hospitalization or death by about 50%. About 7% of patients who received the drug were hospitalized within 30 days in the study, as compared with 14% of patients who took a placebo, the company said.
No deaths were reported in the group that received the drug, as compared with eight deaths in the group that received the placebo. None of the trial participants had been vaccinated.
“Medicines and vaccines are both essential to our collective efforts,” Mr. Davis said. “We look forward to working with the FDA on its review of our application, and to working with other regulatory agencies as we do everything we can to bring molnupiravir to patients around the world as quickly as possible.”
Merck has been producing molnupiravir in anticipation of the clinical trial results and FDA authorization. The company expects to produce 10 million courses of treatment by the end of the year, with more expected for 2022.
In June, Merck signed an agreement with the United States to supply 1.7 million courses of molnupiravir once the FDA authorizes the drug. The company has agreed to advance purchase agreements with other countries as well.
Earlier in the year, Merck also announced voluntary licensing agreements with several generics manufacturers in India to provide molnupiravir to more than 100 low- and middle-income countries after approval from local regulatory agencies.
Data from the company’s late-stage clinical trial has not yet been peer-reviewed or published.
Last week, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said the clinical trial results were “very encouraging” but noted that the FDA should closely scrutinize the drug, CNN reported.
“It is very important that this now must go through the usual process of careful examination of the data by the Food and Drug Administration, both for effectiveness but also for safety, because whenever you introduce a new compound, safety is very important,” Dr. Fauci said, adding that vaccines remain “our best tools against COVID-19.”
A version of this article firsts appeared on WebMD.com.
, an experimental antiviral COVID-19 treatment.
If the FDA grants authorization, the drug would be the first oral antiviral treatment for COVID-19. The capsule, made by Merck and Ridgeback Biotherapeutics, is intended to treat mild to moderate COVID-19 in adults who are at risk of having severe COVID-19 or hospitalization.
“The extraordinary impact of this pandemic demands that we move with unprecedented urgency, and that is what our teams have done by submitting this application for molnupiravir to the FDA within 10 days of receiving the data,” Robert Davis, CEO and president of Merck, said in a statement. On Oct. 1, Merck and Ridgeback released interim data from its phase III clinical trial, which showed that molnupiravir reduced the risk of hospitalization or death by about 50%. About 7% of patients who received the drug were hospitalized within 30 days in the study, as compared with 14% of patients who took a placebo, the company said.
No deaths were reported in the group that received the drug, as compared with eight deaths in the group that received the placebo. None of the trial participants had been vaccinated.
“Medicines and vaccines are both essential to our collective efforts,” Mr. Davis said. “We look forward to working with the FDA on its review of our application, and to working with other regulatory agencies as we do everything we can to bring molnupiravir to patients around the world as quickly as possible.”
Merck has been producing molnupiravir in anticipation of the clinical trial results and FDA authorization. The company expects to produce 10 million courses of treatment by the end of the year, with more expected for 2022.
In June, Merck signed an agreement with the United States to supply 1.7 million courses of molnupiravir once the FDA authorizes the drug. The company has agreed to advance purchase agreements with other countries as well.
Earlier in the year, Merck also announced voluntary licensing agreements with several generics manufacturers in India to provide molnupiravir to more than 100 low- and middle-income countries after approval from local regulatory agencies.
Data from the company’s late-stage clinical trial has not yet been peer-reviewed or published.
Last week, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said the clinical trial results were “very encouraging” but noted that the FDA should closely scrutinize the drug, CNN reported.
“It is very important that this now must go through the usual process of careful examination of the data by the Food and Drug Administration, both for effectiveness but also for safety, because whenever you introduce a new compound, safety is very important,” Dr. Fauci said, adding that vaccines remain “our best tools against COVID-19.”
A version of this article firsts appeared on WebMD.com.
High-dose omega-3s tied to higher AFib risk
Taking high-doses of marine omega-3 fatty acids, more than 1 gram daily, may raise the risk for atrial fibrillation (AFib), according to a meta-analysis of relevant research.
However, the risk of developing AFib appears to be “relatively small” for those taking 1 gram or less of fish oil per day, Christine M. Albert, MD, chair of the department of cardiology at the Smidt Heart Institute at Cedars-Sinai, Los Angeles, told this news organization.
The study was published online Oct. 6 in the journal Circulation.
It’s estimated that 7.8% of U.S. adults – almost 19 million in all – take fish oil supplements, often unbeknownst to their health care providers, the researchers noted. Yet, the literature on the effects of omega-3 fatty acid supplementation on cardiovascular outcomes are mixed.
“Some, but not all” large-scale randomized controlled trials investigating the effects of marine omega-3 fatty acid supplements on cardiovascular outcomes have reported increased risks for AFib. The potential reasons for differing findings may be dose related, the authors note in their paper.
The goal of this meta-analysis was to “bring clarity, answers, and actionable information” to doctors and patients, said Dr. Albert. The results suggest, however, that there may not be a “straightforward answer” to whether fish oil is good or bad for AFib. Instead, the answer may depend on the dose, she added.
Pooled data
After screening 4,049 articles and abstracts, the researchers included in their analysis seven large-scale randomized controlled trials reporting cardiovascular outcomes of marine omega-3 fatty acids.
The trials reported results for AFib, either as prespecified outcome, adverse event, or a reason for hospitalization. Each had a minimum of 500 patients and a median follow-up of at least 1 year.
Trials examining the effects of omega-3 fatty acids on recurrent AFib in patients with established AFib or postoperative AFib were excluded.
The seven trials enrolled a total of 81,210 patients (mean age, 65 years; 39% women); 72.6% of participants were enrolled in clinical trials testing ≤1 gram of marine omega-3 fatty acids per day and 27.4% were enrolled in clinical trials testing >1 gram of the supplement per day. The weighted average follow-up was 4.9 years.
Overall, use of omega-3 fatty acids was associated with a 25% increased risk for AFib (hazard ratio, 1.25; 95% confidence interval, 1.07-1.46; P = .013).
In analyses stratified by dose, the risk for AFib was “significantly more pronounced” in trials testing high doses of marine omega-3 fatty acid supplements (>1 gram per day: HR, 1.49; 95% CI, 1.04-2.15; P = .042) compared with those testing lower doses (≤1 gram per day: HR, 1.12; 95% CI, 1.03-1.22; P = .024; P for interaction < .001).
In meta-regression, the HR for AFib increased per 1 gram increase in daily omega-3 fatty acid dose (HR. 1.11; 95% CI, 1.06-1.15; P = .001).
Risk-benefit balance
“This meta-analysis adds new evidence regarding the risk of AFib in patients taking marine omega-3 fatty acid supplements,” wrote Dr. Albert and colleagues.
“Since the benefit of omega-3 fatty acids also appears to be dose dependent, the associated risk of AFib should be balanced against the benefit on atherosclerotic cardiovascular outcomes,” they suggested.
They cautioned that the meta-analysis pooled aggregate-level trial data, not individual patient data. Therefore, subgroup analyses by age or other patient level characteristics were not possible.
The risk of developing AFib increases with advancing age and is more common in men than in women. Additional risk factors include elevated blood pressure, coronary artery disease, heart failure, heart valve defects, obesity, and diabetes.
The authors said the potential risk of developing AFib with high doses of omega-3 fatty acid supplements should be discussed with patients and they should know the signs and symptoms of the condition.
The study had no specific funding. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
Taking high-doses of marine omega-3 fatty acids, more than 1 gram daily, may raise the risk for atrial fibrillation (AFib), according to a meta-analysis of relevant research.
However, the risk of developing AFib appears to be “relatively small” for those taking 1 gram or less of fish oil per day, Christine M. Albert, MD, chair of the department of cardiology at the Smidt Heart Institute at Cedars-Sinai, Los Angeles, told this news organization.
The study was published online Oct. 6 in the journal Circulation.
It’s estimated that 7.8% of U.S. adults – almost 19 million in all – take fish oil supplements, often unbeknownst to their health care providers, the researchers noted. Yet, the literature on the effects of omega-3 fatty acid supplementation on cardiovascular outcomes are mixed.
“Some, but not all” large-scale randomized controlled trials investigating the effects of marine omega-3 fatty acid supplements on cardiovascular outcomes have reported increased risks for AFib. The potential reasons for differing findings may be dose related, the authors note in their paper.
The goal of this meta-analysis was to “bring clarity, answers, and actionable information” to doctors and patients, said Dr. Albert. The results suggest, however, that there may not be a “straightforward answer” to whether fish oil is good or bad for AFib. Instead, the answer may depend on the dose, she added.
Pooled data
After screening 4,049 articles and abstracts, the researchers included in their analysis seven large-scale randomized controlled trials reporting cardiovascular outcomes of marine omega-3 fatty acids.
The trials reported results for AFib, either as prespecified outcome, adverse event, or a reason for hospitalization. Each had a minimum of 500 patients and a median follow-up of at least 1 year.
Trials examining the effects of omega-3 fatty acids on recurrent AFib in patients with established AFib or postoperative AFib were excluded.
The seven trials enrolled a total of 81,210 patients (mean age, 65 years; 39% women); 72.6% of participants were enrolled in clinical trials testing ≤1 gram of marine omega-3 fatty acids per day and 27.4% were enrolled in clinical trials testing >1 gram of the supplement per day. The weighted average follow-up was 4.9 years.
Overall, use of omega-3 fatty acids was associated with a 25% increased risk for AFib (hazard ratio, 1.25; 95% confidence interval, 1.07-1.46; P = .013).
In analyses stratified by dose, the risk for AFib was “significantly more pronounced” in trials testing high doses of marine omega-3 fatty acid supplements (>1 gram per day: HR, 1.49; 95% CI, 1.04-2.15; P = .042) compared with those testing lower doses (≤1 gram per day: HR, 1.12; 95% CI, 1.03-1.22; P = .024; P for interaction < .001).
In meta-regression, the HR for AFib increased per 1 gram increase in daily omega-3 fatty acid dose (HR. 1.11; 95% CI, 1.06-1.15; P = .001).
Risk-benefit balance
“This meta-analysis adds new evidence regarding the risk of AFib in patients taking marine omega-3 fatty acid supplements,” wrote Dr. Albert and colleagues.
“Since the benefit of omega-3 fatty acids also appears to be dose dependent, the associated risk of AFib should be balanced against the benefit on atherosclerotic cardiovascular outcomes,” they suggested.
They cautioned that the meta-analysis pooled aggregate-level trial data, not individual patient data. Therefore, subgroup analyses by age or other patient level characteristics were not possible.
The risk of developing AFib increases with advancing age and is more common in men than in women. Additional risk factors include elevated blood pressure, coronary artery disease, heart failure, heart valve defects, obesity, and diabetes.
The authors said the potential risk of developing AFib with high doses of omega-3 fatty acid supplements should be discussed with patients and they should know the signs and symptoms of the condition.
The study had no specific funding. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
Taking high-doses of marine omega-3 fatty acids, more than 1 gram daily, may raise the risk for atrial fibrillation (AFib), according to a meta-analysis of relevant research.
However, the risk of developing AFib appears to be “relatively small” for those taking 1 gram or less of fish oil per day, Christine M. Albert, MD, chair of the department of cardiology at the Smidt Heart Institute at Cedars-Sinai, Los Angeles, told this news organization.
The study was published online Oct. 6 in the journal Circulation.
It’s estimated that 7.8% of U.S. adults – almost 19 million in all – take fish oil supplements, often unbeknownst to their health care providers, the researchers noted. Yet, the literature on the effects of omega-3 fatty acid supplementation on cardiovascular outcomes are mixed.
“Some, but not all” large-scale randomized controlled trials investigating the effects of marine omega-3 fatty acid supplements on cardiovascular outcomes have reported increased risks for AFib. The potential reasons for differing findings may be dose related, the authors note in their paper.
The goal of this meta-analysis was to “bring clarity, answers, and actionable information” to doctors and patients, said Dr. Albert. The results suggest, however, that there may not be a “straightforward answer” to whether fish oil is good or bad for AFib. Instead, the answer may depend on the dose, she added.
Pooled data
After screening 4,049 articles and abstracts, the researchers included in their analysis seven large-scale randomized controlled trials reporting cardiovascular outcomes of marine omega-3 fatty acids.
The trials reported results for AFib, either as prespecified outcome, adverse event, or a reason for hospitalization. Each had a minimum of 500 patients and a median follow-up of at least 1 year.
Trials examining the effects of omega-3 fatty acids on recurrent AFib in patients with established AFib or postoperative AFib were excluded.
The seven trials enrolled a total of 81,210 patients (mean age, 65 years; 39% women); 72.6% of participants were enrolled in clinical trials testing ≤1 gram of marine omega-3 fatty acids per day and 27.4% were enrolled in clinical trials testing >1 gram of the supplement per day. The weighted average follow-up was 4.9 years.
Overall, use of omega-3 fatty acids was associated with a 25% increased risk for AFib (hazard ratio, 1.25; 95% confidence interval, 1.07-1.46; P = .013).
In analyses stratified by dose, the risk for AFib was “significantly more pronounced” in trials testing high doses of marine omega-3 fatty acid supplements (>1 gram per day: HR, 1.49; 95% CI, 1.04-2.15; P = .042) compared with those testing lower doses (≤1 gram per day: HR, 1.12; 95% CI, 1.03-1.22; P = .024; P for interaction < .001).
In meta-regression, the HR for AFib increased per 1 gram increase in daily omega-3 fatty acid dose (HR. 1.11; 95% CI, 1.06-1.15; P = .001).
Risk-benefit balance
“This meta-analysis adds new evidence regarding the risk of AFib in patients taking marine omega-3 fatty acid supplements,” wrote Dr. Albert and colleagues.
“Since the benefit of omega-3 fatty acids also appears to be dose dependent, the associated risk of AFib should be balanced against the benefit on atherosclerotic cardiovascular outcomes,” they suggested.
They cautioned that the meta-analysis pooled aggregate-level trial data, not individual patient data. Therefore, subgroup analyses by age or other patient level characteristics were not possible.
The risk of developing AFib increases with advancing age and is more common in men than in women. Additional risk factors include elevated blood pressure, coronary artery disease, heart failure, heart valve defects, obesity, and diabetes.
The authors said the potential risk of developing AFib with high doses of omega-3 fatty acid supplements should be discussed with patients and they should know the signs and symptoms of the condition.
The study had no specific funding. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.