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Acute lymphoblastic leukemia can be successfully treated in the frail elderly
A treatment schedule of very attenuated chemotherapy using standard drugs is feasible and effective in frail and elderly patients with acute lymphoblastic leukemia (ALL), according to a prospective study published in Clinical Lymphoma, Myeloma & Leukemia.
The study comprised 67 previously untreated patients with B- or T-lineage Philadelphia chromosome–negative ALL from 30 Spanish hospitals who were enrolled in the prospective, multicenter ALL-07FRAIL trial (NCT01358201) from the Spanish PETHEMA (Programa Español de Tratamientos en Hematologia) group from January 2008 to October 2019.
The median patient age in this analysis was 67 years and 51 patients (76%) were older than 70 years. The median Charlson Comorbidity Index was 5, with the main comorbidities being cardiovascular (47 patients), other neoplasia (24), diabetes (17), and very advanced age (>80 years; 12).
The attenuated treatment regimen consisted of a prephase with dexamethasone and intrathecal therapy with methotrexate was given for a maximum of 1 week. Then weekly induction therapy consisted of weekly vincristine (capped at 1 mg/week) and daily dexamethasone with a progressively decreasing dose along 4 weeks, as well as two additional doses of intrathecal methotrexate.
Those patients who achieved complete remission received maintenance therapy with mercaptopurine and methotrexate to complete 2 years of treatment. In addition, reinduction pulses with vincristine and dexamethasone were given every 3 months during the first year, according to Josep-Maria Ribera, MD, of the Universitat Autònoma de Barcelona, Badalona, Spain and colleagues on behalf of the PETHEMA group of the Spanish Society of Hematology.
The complete remission rate was 54% (36/67 patients). The median disease-free survival and overall survival were 6.9 months and 7.6 months, respectively.
Of the 32 patients who initiated maintenance therapy, 5 patients died of infection (2), hemorrhage (2), and acute cognitive impairment (1), and 23 relapsed, with a cumulative incidence of relapse of 74% and a median time to relapse of 12.3 months.
The most frequent toxic events reported were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases) followed by infections, metabolic (mainly hyperglycemia), and neurologic, according to the researchers.
“The lack of similar trials specifically directed to this frail population is one of the major strengths of this study, and we consider that this minimal chemotherapy approach could be used as a backbone for addition of immuno/targeted therapy in this subset of infirm patients,” the researchers concluded.
The study was supported by the CERCA Program/Generalitat de Catalunya and the Josep Carreras Leukemia Research Institute. The authors reported having no disclosures.
SOURCE: Ribera J-M et al. Clin Lymphoma Myeloma Leuk. 2020 Apr 5. doi: 10.1016/j.clml.2020.03.011.
A treatment schedule of very attenuated chemotherapy using standard drugs is feasible and effective in frail and elderly patients with acute lymphoblastic leukemia (ALL), according to a prospective study published in Clinical Lymphoma, Myeloma & Leukemia.
The study comprised 67 previously untreated patients with B- or T-lineage Philadelphia chromosome–negative ALL from 30 Spanish hospitals who were enrolled in the prospective, multicenter ALL-07FRAIL trial (NCT01358201) from the Spanish PETHEMA (Programa Español de Tratamientos en Hematologia) group from January 2008 to October 2019.
The median patient age in this analysis was 67 years and 51 patients (76%) were older than 70 years. The median Charlson Comorbidity Index was 5, with the main comorbidities being cardiovascular (47 patients), other neoplasia (24), diabetes (17), and very advanced age (>80 years; 12).
The attenuated treatment regimen consisted of a prephase with dexamethasone and intrathecal therapy with methotrexate was given for a maximum of 1 week. Then weekly induction therapy consisted of weekly vincristine (capped at 1 mg/week) and daily dexamethasone with a progressively decreasing dose along 4 weeks, as well as two additional doses of intrathecal methotrexate.
Those patients who achieved complete remission received maintenance therapy with mercaptopurine and methotrexate to complete 2 years of treatment. In addition, reinduction pulses with vincristine and dexamethasone were given every 3 months during the first year, according to Josep-Maria Ribera, MD, of the Universitat Autònoma de Barcelona, Badalona, Spain and colleagues on behalf of the PETHEMA group of the Spanish Society of Hematology.
The complete remission rate was 54% (36/67 patients). The median disease-free survival and overall survival were 6.9 months and 7.6 months, respectively.
Of the 32 patients who initiated maintenance therapy, 5 patients died of infection (2), hemorrhage (2), and acute cognitive impairment (1), and 23 relapsed, with a cumulative incidence of relapse of 74% and a median time to relapse of 12.3 months.
The most frequent toxic events reported were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases) followed by infections, metabolic (mainly hyperglycemia), and neurologic, according to the researchers.
“The lack of similar trials specifically directed to this frail population is one of the major strengths of this study, and we consider that this minimal chemotherapy approach could be used as a backbone for addition of immuno/targeted therapy in this subset of infirm patients,” the researchers concluded.
The study was supported by the CERCA Program/Generalitat de Catalunya and the Josep Carreras Leukemia Research Institute. The authors reported having no disclosures.
SOURCE: Ribera J-M et al. Clin Lymphoma Myeloma Leuk. 2020 Apr 5. doi: 10.1016/j.clml.2020.03.011.
A treatment schedule of very attenuated chemotherapy using standard drugs is feasible and effective in frail and elderly patients with acute lymphoblastic leukemia (ALL), according to a prospective study published in Clinical Lymphoma, Myeloma & Leukemia.
The study comprised 67 previously untreated patients with B- or T-lineage Philadelphia chromosome–negative ALL from 30 Spanish hospitals who were enrolled in the prospective, multicenter ALL-07FRAIL trial (NCT01358201) from the Spanish PETHEMA (Programa Español de Tratamientos en Hematologia) group from January 2008 to October 2019.
The median patient age in this analysis was 67 years and 51 patients (76%) were older than 70 years. The median Charlson Comorbidity Index was 5, with the main comorbidities being cardiovascular (47 patients), other neoplasia (24), diabetes (17), and very advanced age (>80 years; 12).
The attenuated treatment regimen consisted of a prephase with dexamethasone and intrathecal therapy with methotrexate was given for a maximum of 1 week. Then weekly induction therapy consisted of weekly vincristine (capped at 1 mg/week) and daily dexamethasone with a progressively decreasing dose along 4 weeks, as well as two additional doses of intrathecal methotrexate.
Those patients who achieved complete remission received maintenance therapy with mercaptopurine and methotrexate to complete 2 years of treatment. In addition, reinduction pulses with vincristine and dexamethasone were given every 3 months during the first year, according to Josep-Maria Ribera, MD, of the Universitat Autònoma de Barcelona, Badalona, Spain and colleagues on behalf of the PETHEMA group of the Spanish Society of Hematology.
The complete remission rate was 54% (36/67 patients). The median disease-free survival and overall survival were 6.9 months and 7.6 months, respectively.
Of the 32 patients who initiated maintenance therapy, 5 patients died of infection (2), hemorrhage (2), and acute cognitive impairment (1), and 23 relapsed, with a cumulative incidence of relapse of 74% and a median time to relapse of 12.3 months.
The most frequent toxic events reported were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases) followed by infections, metabolic (mainly hyperglycemia), and neurologic, according to the researchers.
“The lack of similar trials specifically directed to this frail population is one of the major strengths of this study, and we consider that this minimal chemotherapy approach could be used as a backbone for addition of immuno/targeted therapy in this subset of infirm patients,” the researchers concluded.
The study was supported by the CERCA Program/Generalitat de Catalunya and the Josep Carreras Leukemia Research Institute. The authors reported having no disclosures.
SOURCE: Ribera J-M et al. Clin Lymphoma Myeloma Leuk. 2020 Apr 5. doi: 10.1016/j.clml.2020.03.011.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
FDA okays emergency use for Impella RP in COVID-19 right heart failure
The Food and Drug Administration issued an emergency use authorization for use of the Impella RP heart pump system in COVID-19 patients with right heart failure or decompensation, Abiomed announced June 1.
“Based on extrapolation of data from the approved indication and reported clinical experience, FDA has concluded that the Impella RP may be effective at providing temporary right ventricular support for the treatment of acute right heart failure or decompensation caused by COVID-19 complications, including PE [pulmonary embolism],” the letter noted.
It cited, for example, use of the temporary heart pump in a 59-year-old woman suffering from COVID-19 who went into right ventricular failure and became hypotensive after an acute PE was removed. After placement of the device, the patient experienced a “dramatic and immediate” improvement in arterial pressure and the device was removed on the fifth day, according to Amir Kaki, MD, and Ted Schreiber, MD, of Ascension St. John Hospital, Detroit, whose review of the case has been posted online.
“Acute pulmonary embolism is clearly being recognized as a life-threatening manifestation of COVID-19. Impella RP is an important tool to help cardiologists save lives during this pandemic,” Dr. Kaki said in the letter. “As we have demonstrated in our series of patients, early recognition of right ventricular dysfunction and early placement of the Impella RP for patients who are hypotensive can be lifesaving.”
Other data cited in support of the Impella RP emergency use authorization (EUA) include a 2019 series of hemodynamically unstable patients with PE in Japan and a 2017 case report of a 47-year-old man with right ventricular failure, profound shock, and a massive PE.
The FDA granted premarket approval of the Impella RP system in 2017 to provide temporary right ventricular support for up to 14 days in patients with a body surface area of at least 1.5 m2 who develop acute right heart failure or decompensation following left ventricular assist device implantation, MI, heart transplant, or open-heart surgery.
The EUA indication for the Impella RP system is to provide temporary right ventricular support for up to 14 days in critical care patients with a body surface area of at least 1.5 m2 for the treatment of acute right heart failure or decompensation caused by complications related to COVID-19, including PE.
The Impella RP is authorized only for emergency use under the EUA and only for the duration of the circumstances justifying use of EUAs, the letter noted.
Last year, concerns were raised about off-indication use after interim results from a postapproval study suggested a higher risk for death than seen in premarket studies treated with the temporary heart pump.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration issued an emergency use authorization for use of the Impella RP heart pump system in COVID-19 patients with right heart failure or decompensation, Abiomed announced June 1.
“Based on extrapolation of data from the approved indication and reported clinical experience, FDA has concluded that the Impella RP may be effective at providing temporary right ventricular support for the treatment of acute right heart failure or decompensation caused by COVID-19 complications, including PE [pulmonary embolism],” the letter noted.
It cited, for example, use of the temporary heart pump in a 59-year-old woman suffering from COVID-19 who went into right ventricular failure and became hypotensive after an acute PE was removed. After placement of the device, the patient experienced a “dramatic and immediate” improvement in arterial pressure and the device was removed on the fifth day, according to Amir Kaki, MD, and Ted Schreiber, MD, of Ascension St. John Hospital, Detroit, whose review of the case has been posted online.
“Acute pulmonary embolism is clearly being recognized as a life-threatening manifestation of COVID-19. Impella RP is an important tool to help cardiologists save lives during this pandemic,” Dr. Kaki said in the letter. “As we have demonstrated in our series of patients, early recognition of right ventricular dysfunction and early placement of the Impella RP for patients who are hypotensive can be lifesaving.”
Other data cited in support of the Impella RP emergency use authorization (EUA) include a 2019 series of hemodynamically unstable patients with PE in Japan and a 2017 case report of a 47-year-old man with right ventricular failure, profound shock, and a massive PE.
The FDA granted premarket approval of the Impella RP system in 2017 to provide temporary right ventricular support for up to 14 days in patients with a body surface area of at least 1.5 m2 who develop acute right heart failure or decompensation following left ventricular assist device implantation, MI, heart transplant, or open-heart surgery.
The EUA indication for the Impella RP system is to provide temporary right ventricular support for up to 14 days in critical care patients with a body surface area of at least 1.5 m2 for the treatment of acute right heart failure or decompensation caused by complications related to COVID-19, including PE.
The Impella RP is authorized only for emergency use under the EUA and only for the duration of the circumstances justifying use of EUAs, the letter noted.
Last year, concerns were raised about off-indication use after interim results from a postapproval study suggested a higher risk for death than seen in premarket studies treated with the temporary heart pump.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration issued an emergency use authorization for use of the Impella RP heart pump system in COVID-19 patients with right heart failure or decompensation, Abiomed announced June 1.
“Based on extrapolation of data from the approved indication and reported clinical experience, FDA has concluded that the Impella RP may be effective at providing temporary right ventricular support for the treatment of acute right heart failure or decompensation caused by COVID-19 complications, including PE [pulmonary embolism],” the letter noted.
It cited, for example, use of the temporary heart pump in a 59-year-old woman suffering from COVID-19 who went into right ventricular failure and became hypotensive after an acute PE was removed. After placement of the device, the patient experienced a “dramatic and immediate” improvement in arterial pressure and the device was removed on the fifth day, according to Amir Kaki, MD, and Ted Schreiber, MD, of Ascension St. John Hospital, Detroit, whose review of the case has been posted online.
“Acute pulmonary embolism is clearly being recognized as a life-threatening manifestation of COVID-19. Impella RP is an important tool to help cardiologists save lives during this pandemic,” Dr. Kaki said in the letter. “As we have demonstrated in our series of patients, early recognition of right ventricular dysfunction and early placement of the Impella RP for patients who are hypotensive can be lifesaving.”
Other data cited in support of the Impella RP emergency use authorization (EUA) include a 2019 series of hemodynamically unstable patients with PE in Japan and a 2017 case report of a 47-year-old man with right ventricular failure, profound shock, and a massive PE.
The FDA granted premarket approval of the Impella RP system in 2017 to provide temporary right ventricular support for up to 14 days in patients with a body surface area of at least 1.5 m2 who develop acute right heart failure or decompensation following left ventricular assist device implantation, MI, heart transplant, or open-heart surgery.
The EUA indication for the Impella RP system is to provide temporary right ventricular support for up to 14 days in critical care patients with a body surface area of at least 1.5 m2 for the treatment of acute right heart failure or decompensation caused by complications related to COVID-19, including PE.
The Impella RP is authorized only for emergency use under the EUA and only for the duration of the circumstances justifying use of EUAs, the letter noted.
Last year, concerns were raised about off-indication use after interim results from a postapproval study suggested a higher risk for death than seen in premarket studies treated with the temporary heart pump.
A version of this article originally appeared on Medscape.com.
More evidence hydroxychloroquine is ineffective, harmful in COVID-19
Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycin, offer no benefit in treating patients with COVID-19 and, instead, are associated with ventricular arrhythmias and higher rates of mortality, according to a major new international study.
In the largest observational study of its kind, including close to 100,000 people in 671 hospitals on six continents, investigators compared outcomes in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with a macrolide with 80,000 control patients with COVID-19 not receiving these agents.
Treatment with any of these medications, either alone or in combination, was associated with increased death during hospitalization; compared with about 10% in control group patients, mortality rates ranged from more than 16% to almost 24% in the treated groups.
Patients treated with hydroxychloroquine plus a macrolide showed the highest rates of serious cardiac arrhythmias, and, even after accounting for demographic factors and comorbidities, this combination was found to be associated with a more than 5-fold increase in the risk of developing a serious arrhythmia while in the hospital.
“In this real-world study, the biggest yet, we looked at 100,000 patients [with COVID-19] across six continents and found not the slightest hint of benefits and only risks, and the data is pretty straightforward,” study coauthor Frank Ruschitzka, MD, director of the Heart Center at University Hospital, Zürich, said in an interview. The study was published online May 22 in The Lancet.
‘Inconclusive’ evidence
The absence of an effective treatment for COVID-19 has led to the “repurposing” of the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for treating autoimmune disease, but this approach is based on anecdotal evidence or open-label randomized trials that have been “largely inconclusive,” the authors wrote.
Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk for ventricular arrhythmias, the authors noted.
“Our primary question was whether there was any associated benefits of the use of hydroxychloroquine, chloroquine, or a combined regimen with macrolides in treating COVID-19, and — if there was no benefit — would there be harm?” lead author Mandeep R. Mehra, MD, MSc, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, said in an interview.
The investigators used data from a multinational registry comprising 671 hospitals that included patients (n = 96,032; mean age 53.8 years; 46.3% female) who had been hospitalized between Dec. 20, 2019, and April 14, 2020, with confirmed COVID-19 infection.
They also collected data about demographics, underlying comorbidities, and medical history, and medications that patients were taking at baseline.
Patients receiving treatment (n = 14,888) were divided into four groups: those receiving chloroquine alone (n = 1,868), those receiving chloroquine with a macrolide (n = 3,783), those receiving hydroxychloroquine alone (n = 3,016) and those receiving hydroxychloroquine with a macrolide (n = 6,221).
The remaining patients not treated with these regimens (n = 81,144) were regarded as the control group.
Most patients (65.9%) came from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients of Asian origin (14.1%), black patients (9.4%), and Hispanic patients (6.2%).
Comorbidities and underlying conditions included obesity, hyperlipidemia, and hypertension in about 30%.
Comorbidities and underlying conditions
The investigators conducted multiple analyses to control for confounding variables, including Cox proportional hazards regression and propensity score matching analyses.
“In an observational study, there is always a chance of residual confounding, which is why we did propensity score based matched analyses,” Dr. Ruschitzka explained.
No significant differences were found in distribution of demographics and comorbidities between the groups.
As good as it gets
“We found no benefit in any of the four treatment regimens for hospitalized patients with COVID-19, but we did notice higher rates of death and serious ventricular arrhythmias in these patients, compared to the controls,” Dr. Mehra reported.
Of the patients in the control group, roughly 9.3% died during their hospitalization, compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and a macrolide, and 23.8% of those treated with hydroxychloroquine and a macrolide.
After accounting for confounding variables, the researchers estimated that the excess mortality risk attributable to use of the drug regimen ranged from 34% to 45%.
Patients treated with any of the four regimens sustained more serious arrhythmias, compared with those in the control group (0.35), with the biggest increase seen in the group treated with the combination of hydroxychloroquine plus a macrolide (8.1%), followed by chloroquine with a macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).
“We were fairly reassured that, although the study was observational, the signals were robust and consistent across all regions of the world in diverse populations, and we did not see any muting of that signal, depending on region,” Dr. Mehra said.
“Two months ago, we were all scratching our heads about how to treat patients with COVID-19, and then came a drug [hydroxychloroquine] with some anecdotal evidence, but now we have 2 months more experience, and we looked to science to provide some answer,” Dr. Ruschitzka said.
“Although this was not a randomized, controlled trial, so we do not have a definite answer, the data provided in this [large, multinational] real-world study is as good as it gets and the best data we have,” he concluded.
“Let the science speak for itself”
Commenting on the study in an interview, Christian Funck-Brentano, MD, from the Hospital Pitié-Salpêtrière and Sorbonne University, both in Paris, said that, although the study is observational and therefore not as reliable as a randomized controlled trial, it is “nevertheless well-documented, studied a huge amount of people, and utilized several sensitivity methods, all of which showed the same results.”
Dr. Funck-Brentano, who is the coauthor of an accompanying editorial in The Lancet and was not involved with the study, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with a macrolide do any good and we have potential evidence that they do harm and kill people.”
Also commenting on the study in an interview, David Holtgrave, PhD, dean of the School of Public Health at the State University of New York at Albany, said that, “while no one observational study alone would lead to a firm clinical recommendation, I think it is helpful for physicians and public health officials to be aware of the findings of the peer-reviewed observational studies to date and the National Institutes of Health COVID-19 treatment guidelines and the Food and Drug Administration’s statement of drug safety concern about hydroxychloroquine to inform their decision-making as we await the results of randomized clinical trials of these drugs for the treatment of COVID-19,” said Dr. Holtgrave, who was not involved with the study.
He added that, to his knowledge, there are “still no published studies of prophylactic use of these drugs to prevent COVID-19.”
Dr. Mehra emphasized that a cardinal principle of practicing medicine is “first do no harm” and “even in situations where you believe a desperate disease calls for desperate measures, responsible physicians should take a step back and ask if we are doing harm, and until we can say we aren’t, I don’t think it’s wise to push something like this in the absence of good efficacy data.”
Dr. Ruschitzka added that those who are encouraging the use of these agents “should review their decision based on today’s data and let the science speak for itself.”
The study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Dr. Mehra reported personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. Dr. Ruschitzka was paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zürich and no personal payments were received in relation to these trials or other activities. Dr. Funck-Brentano, his coauthor, and Dr. Holtgrave declared no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycin, offer no benefit in treating patients with COVID-19 and, instead, are associated with ventricular arrhythmias and higher rates of mortality, according to a major new international study.
In the largest observational study of its kind, including close to 100,000 people in 671 hospitals on six continents, investigators compared outcomes in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with a macrolide with 80,000 control patients with COVID-19 not receiving these agents.
Treatment with any of these medications, either alone or in combination, was associated with increased death during hospitalization; compared with about 10% in control group patients, mortality rates ranged from more than 16% to almost 24% in the treated groups.
Patients treated with hydroxychloroquine plus a macrolide showed the highest rates of serious cardiac arrhythmias, and, even after accounting for demographic factors and comorbidities, this combination was found to be associated with a more than 5-fold increase in the risk of developing a serious arrhythmia while in the hospital.
“In this real-world study, the biggest yet, we looked at 100,000 patients [with COVID-19] across six continents and found not the slightest hint of benefits and only risks, and the data is pretty straightforward,” study coauthor Frank Ruschitzka, MD, director of the Heart Center at University Hospital, Zürich, said in an interview. The study was published online May 22 in The Lancet.
‘Inconclusive’ evidence
The absence of an effective treatment for COVID-19 has led to the “repurposing” of the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for treating autoimmune disease, but this approach is based on anecdotal evidence or open-label randomized trials that have been “largely inconclusive,” the authors wrote.
Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk for ventricular arrhythmias, the authors noted.
“Our primary question was whether there was any associated benefits of the use of hydroxychloroquine, chloroquine, or a combined regimen with macrolides in treating COVID-19, and — if there was no benefit — would there be harm?” lead author Mandeep R. Mehra, MD, MSc, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, said in an interview.
The investigators used data from a multinational registry comprising 671 hospitals that included patients (n = 96,032; mean age 53.8 years; 46.3% female) who had been hospitalized between Dec. 20, 2019, and April 14, 2020, with confirmed COVID-19 infection.
They also collected data about demographics, underlying comorbidities, and medical history, and medications that patients were taking at baseline.
Patients receiving treatment (n = 14,888) were divided into four groups: those receiving chloroquine alone (n = 1,868), those receiving chloroquine with a macrolide (n = 3,783), those receiving hydroxychloroquine alone (n = 3,016) and those receiving hydroxychloroquine with a macrolide (n = 6,221).
The remaining patients not treated with these regimens (n = 81,144) were regarded as the control group.
Most patients (65.9%) came from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients of Asian origin (14.1%), black patients (9.4%), and Hispanic patients (6.2%).
Comorbidities and underlying conditions included obesity, hyperlipidemia, and hypertension in about 30%.
Comorbidities and underlying conditions
The investigators conducted multiple analyses to control for confounding variables, including Cox proportional hazards regression and propensity score matching analyses.
“In an observational study, there is always a chance of residual confounding, which is why we did propensity score based matched analyses,” Dr. Ruschitzka explained.
No significant differences were found in distribution of demographics and comorbidities between the groups.
As good as it gets
“We found no benefit in any of the four treatment regimens for hospitalized patients with COVID-19, but we did notice higher rates of death and serious ventricular arrhythmias in these patients, compared to the controls,” Dr. Mehra reported.
Of the patients in the control group, roughly 9.3% died during their hospitalization, compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and a macrolide, and 23.8% of those treated with hydroxychloroquine and a macrolide.
After accounting for confounding variables, the researchers estimated that the excess mortality risk attributable to use of the drug regimen ranged from 34% to 45%.
Patients treated with any of the four regimens sustained more serious arrhythmias, compared with those in the control group (0.35), with the biggest increase seen in the group treated with the combination of hydroxychloroquine plus a macrolide (8.1%), followed by chloroquine with a macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).
“We were fairly reassured that, although the study was observational, the signals were robust and consistent across all regions of the world in diverse populations, and we did not see any muting of that signal, depending on region,” Dr. Mehra said.
“Two months ago, we were all scratching our heads about how to treat patients with COVID-19, and then came a drug [hydroxychloroquine] with some anecdotal evidence, but now we have 2 months more experience, and we looked to science to provide some answer,” Dr. Ruschitzka said.
“Although this was not a randomized, controlled trial, so we do not have a definite answer, the data provided in this [large, multinational] real-world study is as good as it gets and the best data we have,” he concluded.
“Let the science speak for itself”
Commenting on the study in an interview, Christian Funck-Brentano, MD, from the Hospital Pitié-Salpêtrière and Sorbonne University, both in Paris, said that, although the study is observational and therefore not as reliable as a randomized controlled trial, it is “nevertheless well-documented, studied a huge amount of people, and utilized several sensitivity methods, all of which showed the same results.”
Dr. Funck-Brentano, who is the coauthor of an accompanying editorial in The Lancet and was not involved with the study, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with a macrolide do any good and we have potential evidence that they do harm and kill people.”
Also commenting on the study in an interview, David Holtgrave, PhD, dean of the School of Public Health at the State University of New York at Albany, said that, “while no one observational study alone would lead to a firm clinical recommendation, I think it is helpful for physicians and public health officials to be aware of the findings of the peer-reviewed observational studies to date and the National Institutes of Health COVID-19 treatment guidelines and the Food and Drug Administration’s statement of drug safety concern about hydroxychloroquine to inform their decision-making as we await the results of randomized clinical trials of these drugs for the treatment of COVID-19,” said Dr. Holtgrave, who was not involved with the study.
He added that, to his knowledge, there are “still no published studies of prophylactic use of these drugs to prevent COVID-19.”
Dr. Mehra emphasized that a cardinal principle of practicing medicine is “first do no harm” and “even in situations where you believe a desperate disease calls for desperate measures, responsible physicians should take a step back and ask if we are doing harm, and until we can say we aren’t, I don’t think it’s wise to push something like this in the absence of good efficacy data.”
Dr. Ruschitzka added that those who are encouraging the use of these agents “should review their decision based on today’s data and let the science speak for itself.”
The study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Dr. Mehra reported personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. Dr. Ruschitzka was paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zürich and no personal payments were received in relation to these trials or other activities. Dr. Funck-Brentano, his coauthor, and Dr. Holtgrave declared no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycin, offer no benefit in treating patients with COVID-19 and, instead, are associated with ventricular arrhythmias and higher rates of mortality, according to a major new international study.
In the largest observational study of its kind, including close to 100,000 people in 671 hospitals on six continents, investigators compared outcomes in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with a macrolide with 80,000 control patients with COVID-19 not receiving these agents.
Treatment with any of these medications, either alone or in combination, was associated with increased death during hospitalization; compared with about 10% in control group patients, mortality rates ranged from more than 16% to almost 24% in the treated groups.
Patients treated with hydroxychloroquine plus a macrolide showed the highest rates of serious cardiac arrhythmias, and, even after accounting for demographic factors and comorbidities, this combination was found to be associated with a more than 5-fold increase in the risk of developing a serious arrhythmia while in the hospital.
“In this real-world study, the biggest yet, we looked at 100,000 patients [with COVID-19] across six continents and found not the slightest hint of benefits and only risks, and the data is pretty straightforward,” study coauthor Frank Ruschitzka, MD, director of the Heart Center at University Hospital, Zürich, said in an interview. The study was published online May 22 in The Lancet.
‘Inconclusive’ evidence
The absence of an effective treatment for COVID-19 has led to the “repurposing” of the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for treating autoimmune disease, but this approach is based on anecdotal evidence or open-label randomized trials that have been “largely inconclusive,” the authors wrote.
Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk for ventricular arrhythmias, the authors noted.
“Our primary question was whether there was any associated benefits of the use of hydroxychloroquine, chloroquine, or a combined regimen with macrolides in treating COVID-19, and — if there was no benefit — would there be harm?” lead author Mandeep R. Mehra, MD, MSc, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, said in an interview.
The investigators used data from a multinational registry comprising 671 hospitals that included patients (n = 96,032; mean age 53.8 years; 46.3% female) who had been hospitalized between Dec. 20, 2019, and April 14, 2020, with confirmed COVID-19 infection.
They also collected data about demographics, underlying comorbidities, and medical history, and medications that patients were taking at baseline.
Patients receiving treatment (n = 14,888) were divided into four groups: those receiving chloroquine alone (n = 1,868), those receiving chloroquine with a macrolide (n = 3,783), those receiving hydroxychloroquine alone (n = 3,016) and those receiving hydroxychloroquine with a macrolide (n = 6,221).
The remaining patients not treated with these regimens (n = 81,144) were regarded as the control group.
Most patients (65.9%) came from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients of Asian origin (14.1%), black patients (9.4%), and Hispanic patients (6.2%).
Comorbidities and underlying conditions included obesity, hyperlipidemia, and hypertension in about 30%.
Comorbidities and underlying conditions
The investigators conducted multiple analyses to control for confounding variables, including Cox proportional hazards regression and propensity score matching analyses.
“In an observational study, there is always a chance of residual confounding, which is why we did propensity score based matched analyses,” Dr. Ruschitzka explained.
No significant differences were found in distribution of demographics and comorbidities between the groups.
As good as it gets
“We found no benefit in any of the four treatment regimens for hospitalized patients with COVID-19, but we did notice higher rates of death and serious ventricular arrhythmias in these patients, compared to the controls,” Dr. Mehra reported.
Of the patients in the control group, roughly 9.3% died during their hospitalization, compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and a macrolide, and 23.8% of those treated with hydroxychloroquine and a macrolide.
After accounting for confounding variables, the researchers estimated that the excess mortality risk attributable to use of the drug regimen ranged from 34% to 45%.
Patients treated with any of the four regimens sustained more serious arrhythmias, compared with those in the control group (0.35), with the biggest increase seen in the group treated with the combination of hydroxychloroquine plus a macrolide (8.1%), followed by chloroquine with a macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).
“We were fairly reassured that, although the study was observational, the signals were robust and consistent across all regions of the world in diverse populations, and we did not see any muting of that signal, depending on region,” Dr. Mehra said.
“Two months ago, we were all scratching our heads about how to treat patients with COVID-19, and then came a drug [hydroxychloroquine] with some anecdotal evidence, but now we have 2 months more experience, and we looked to science to provide some answer,” Dr. Ruschitzka said.
“Although this was not a randomized, controlled trial, so we do not have a definite answer, the data provided in this [large, multinational] real-world study is as good as it gets and the best data we have,” he concluded.
“Let the science speak for itself”
Commenting on the study in an interview, Christian Funck-Brentano, MD, from the Hospital Pitié-Salpêtrière and Sorbonne University, both in Paris, said that, although the study is observational and therefore not as reliable as a randomized controlled trial, it is “nevertheless well-documented, studied a huge amount of people, and utilized several sensitivity methods, all of which showed the same results.”
Dr. Funck-Brentano, who is the coauthor of an accompanying editorial in The Lancet and was not involved with the study, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with a macrolide do any good and we have potential evidence that they do harm and kill people.”
Also commenting on the study in an interview, David Holtgrave, PhD, dean of the School of Public Health at the State University of New York at Albany, said that, “while no one observational study alone would lead to a firm clinical recommendation, I think it is helpful for physicians and public health officials to be aware of the findings of the peer-reviewed observational studies to date and the National Institutes of Health COVID-19 treatment guidelines and the Food and Drug Administration’s statement of drug safety concern about hydroxychloroquine to inform their decision-making as we await the results of randomized clinical trials of these drugs for the treatment of COVID-19,” said Dr. Holtgrave, who was not involved with the study.
He added that, to his knowledge, there are “still no published studies of prophylactic use of these drugs to prevent COVID-19.”
Dr. Mehra emphasized that a cardinal principle of practicing medicine is “first do no harm” and “even in situations where you believe a desperate disease calls for desperate measures, responsible physicians should take a step back and ask if we are doing harm, and until we can say we aren’t, I don’t think it’s wise to push something like this in the absence of good efficacy data.”
Dr. Ruschitzka added that those who are encouraging the use of these agents “should review their decision based on today’s data and let the science speak for itself.”
The study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Dr. Mehra reported personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. Dr. Ruschitzka was paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zürich and no personal payments were received in relation to these trials or other activities. Dr. Funck-Brentano, his coauthor, and Dr. Holtgrave declared no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Low-dose erlotinib seems feasible for frail, elderly patients with NSCLC
, according to researchers.
They conducted a phase 2 trial to investigate whether one-third of the maximum tolerated dose of erlotinib could maintain sufficient plasma concentration of the drug while avoiding the adverse effects of higher doses. The results were published in JAMA Oncology.
Erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in elderly patients with EGFR-positive NSCLC, according to study author Shingo Miyamoto, MD, of Japanese Red Cross Medical Center in Tokyo, and colleagues.
“With the increasing number of elderly patients with cancer, many of whom also have significant comorbidities, there is a considerable value in investigating whether EGFR-TKIs are effective for the frail population,” the authors wrote. They also noted that it is “difficult to identify the appropriate dose of molecular-targeted drugs.”
With this in mind, Dr. Miyamoto and colleagues conducted a single-arm, phase 2 trial of low-dose erlotinib in 80 chemotherapy-naive frail or elderly patients with EGFR-positive NSCLC. Frailty was defined by age and the Charlson Comorbidity Index. The patients’ median age was 80 years (range, 49-90 years).
Patients received erlotinib at 50 mg per day, which is one-third of the established maximum tolerated dose, for 4 weeks. Then, they were evaluated with radiologic imaging. Treatment continued until disease progression or unacceptable adverse events. Dosing was modified by treatment response or by adverse events.
Results
At last follow-up, 7 of the 80 patients were still receiving low-dose erlotinib. Reasons for discontinuation were disease progression (n = 60), patient request (n = 6), adverse events (n = 4), and death (n = 3).
The overall response rate was 60%, and the disease control rate was 90%. The researchers measured plasma erlotinib concentration in 48 patients and found it did not correlate with response.
The median progression-free survival was 9.3 months, and the median overall survival was 26.2 months.
Ten patients had erlotinib temporarily suspended because of adverse events. Five patients had their dose reduced to 25 mg because of adverse events, including oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia.
Two patients discontinued treatment because of adverse events. One patient had a cutaneous ulcer and bone infection. The other had oral mucositis.
Dr. Miyamoto and colleagues concluded that, “low-dose erlotinib was associated with efficacy and safety in frail patients with EGFR mutation–positive lung cancer. More research on the dosing strategy of target-based drugs is warranted, especially in frail patients in the real-world setting.”
Less is more
Sometimes, less can be more, said Mellar P. Davis, MD, an oncologist and section head of the palliative care department at Geisinger Medical System in Danville, Penn., who was not involved in this study.
“Why do patients benefit from small doses? It may be that there are fewer drug interruptions over time and patients are able to stay on schedule,” Dr. Davis said. “It may also be that erlotinib clearance is reduced in the elderly and comorbid patient. The reduced dose may, in fact, be the ‘therapeutic’ dose in this special population.”
Plasma levels were frequently in therapeutic ranges in this study, but patients who had subtherapeutic plasma levels also responded to therapy, Dr. Davis pointed out. The lower dose was shown to maintain sufficient concentrations of the treatment while reducing adverse effects.
However, Dr. Davis noted, this was not a randomized trial. “It is always a risk hedging bets on single-arm trials,” he said. “Randomized trials often prove phase 2 single-arm trials wrong.”
He added that quality-of-life measures are absent from the study. Erlotinib is a palliative drug with side effects, Dr. Davis noted.
“Control of cancer and cancer regression should improve symptoms and quality of life when balanced against treatment toxicity,” he said. “In this study, I would have thought that symptom improvement, performance score, and quality of life would have been the primary outcome or the co-primary outcome with disease control.”
Should a randomized, controlled trial of low-dose erlotinib be conducted in the frail/elderly population? “If one believes trials should be quantitatively based, the answer would be no,” Dr. Davis said. “Responses may be the same, and it would be expensive to prove that low-dose erlotinib is the same as standard doses when comparing survival.”
However, if one is interested in quality of life, particularly in this growing population, a trial that incorporated quality-of-life measures would make more sense, according to Dr. Davis. “For if one can achieve less toxicity and treat more patients and get the same duration of clinical benefit, then less will be more,” he concluded.
Dr. Davis reported having no conflicts of interest. Study authors disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and many other companies. Erlotinib is manufactured for OSI Pharmaceuticals, an affiliate of Astellas Pharma, and distributed by Genentech, a member of the Roche Group.
The study was supported by the Japan Agency for Medical Research and Development.
SOURCE: Miyamoto S et al. JAMA Oncol. 2020 May 14; e201250. doi: 10.1001/jamaoncol.2020.1250.
, according to researchers.
They conducted a phase 2 trial to investigate whether one-third of the maximum tolerated dose of erlotinib could maintain sufficient plasma concentration of the drug while avoiding the adverse effects of higher doses. The results were published in JAMA Oncology.
Erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in elderly patients with EGFR-positive NSCLC, according to study author Shingo Miyamoto, MD, of Japanese Red Cross Medical Center in Tokyo, and colleagues.
“With the increasing number of elderly patients with cancer, many of whom also have significant comorbidities, there is a considerable value in investigating whether EGFR-TKIs are effective for the frail population,” the authors wrote. They also noted that it is “difficult to identify the appropriate dose of molecular-targeted drugs.”
With this in mind, Dr. Miyamoto and colleagues conducted a single-arm, phase 2 trial of low-dose erlotinib in 80 chemotherapy-naive frail or elderly patients with EGFR-positive NSCLC. Frailty was defined by age and the Charlson Comorbidity Index. The patients’ median age was 80 years (range, 49-90 years).
Patients received erlotinib at 50 mg per day, which is one-third of the established maximum tolerated dose, for 4 weeks. Then, they were evaluated with radiologic imaging. Treatment continued until disease progression or unacceptable adverse events. Dosing was modified by treatment response or by adverse events.
Results
At last follow-up, 7 of the 80 patients were still receiving low-dose erlotinib. Reasons for discontinuation were disease progression (n = 60), patient request (n = 6), adverse events (n = 4), and death (n = 3).
The overall response rate was 60%, and the disease control rate was 90%. The researchers measured plasma erlotinib concentration in 48 patients and found it did not correlate with response.
The median progression-free survival was 9.3 months, and the median overall survival was 26.2 months.
Ten patients had erlotinib temporarily suspended because of adverse events. Five patients had their dose reduced to 25 mg because of adverse events, including oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia.
Two patients discontinued treatment because of adverse events. One patient had a cutaneous ulcer and bone infection. The other had oral mucositis.
Dr. Miyamoto and colleagues concluded that, “low-dose erlotinib was associated with efficacy and safety in frail patients with EGFR mutation–positive lung cancer. More research on the dosing strategy of target-based drugs is warranted, especially in frail patients in the real-world setting.”
Less is more
Sometimes, less can be more, said Mellar P. Davis, MD, an oncologist and section head of the palliative care department at Geisinger Medical System in Danville, Penn., who was not involved in this study.
“Why do patients benefit from small doses? It may be that there are fewer drug interruptions over time and patients are able to stay on schedule,” Dr. Davis said. “It may also be that erlotinib clearance is reduced in the elderly and comorbid patient. The reduced dose may, in fact, be the ‘therapeutic’ dose in this special population.”
Plasma levels were frequently in therapeutic ranges in this study, but patients who had subtherapeutic plasma levels also responded to therapy, Dr. Davis pointed out. The lower dose was shown to maintain sufficient concentrations of the treatment while reducing adverse effects.
However, Dr. Davis noted, this was not a randomized trial. “It is always a risk hedging bets on single-arm trials,” he said. “Randomized trials often prove phase 2 single-arm trials wrong.”
He added that quality-of-life measures are absent from the study. Erlotinib is a palliative drug with side effects, Dr. Davis noted.
“Control of cancer and cancer regression should improve symptoms and quality of life when balanced against treatment toxicity,” he said. “In this study, I would have thought that symptom improvement, performance score, and quality of life would have been the primary outcome or the co-primary outcome with disease control.”
Should a randomized, controlled trial of low-dose erlotinib be conducted in the frail/elderly population? “If one believes trials should be quantitatively based, the answer would be no,” Dr. Davis said. “Responses may be the same, and it would be expensive to prove that low-dose erlotinib is the same as standard doses when comparing survival.”
However, if one is interested in quality of life, particularly in this growing population, a trial that incorporated quality-of-life measures would make more sense, according to Dr. Davis. “For if one can achieve less toxicity and treat more patients and get the same duration of clinical benefit, then less will be more,” he concluded.
Dr. Davis reported having no conflicts of interest. Study authors disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and many other companies. Erlotinib is manufactured for OSI Pharmaceuticals, an affiliate of Astellas Pharma, and distributed by Genentech, a member of the Roche Group.
The study was supported by the Japan Agency for Medical Research and Development.
SOURCE: Miyamoto S et al. JAMA Oncol. 2020 May 14; e201250. doi: 10.1001/jamaoncol.2020.1250.
, according to researchers.
They conducted a phase 2 trial to investigate whether one-third of the maximum tolerated dose of erlotinib could maintain sufficient plasma concentration of the drug while avoiding the adverse effects of higher doses. The results were published in JAMA Oncology.
Erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in elderly patients with EGFR-positive NSCLC, according to study author Shingo Miyamoto, MD, of Japanese Red Cross Medical Center in Tokyo, and colleagues.
“With the increasing number of elderly patients with cancer, many of whom also have significant comorbidities, there is a considerable value in investigating whether EGFR-TKIs are effective for the frail population,” the authors wrote. They also noted that it is “difficult to identify the appropriate dose of molecular-targeted drugs.”
With this in mind, Dr. Miyamoto and colleagues conducted a single-arm, phase 2 trial of low-dose erlotinib in 80 chemotherapy-naive frail or elderly patients with EGFR-positive NSCLC. Frailty was defined by age and the Charlson Comorbidity Index. The patients’ median age was 80 years (range, 49-90 years).
Patients received erlotinib at 50 mg per day, which is one-third of the established maximum tolerated dose, for 4 weeks. Then, they were evaluated with radiologic imaging. Treatment continued until disease progression or unacceptable adverse events. Dosing was modified by treatment response or by adverse events.
Results
At last follow-up, 7 of the 80 patients were still receiving low-dose erlotinib. Reasons for discontinuation were disease progression (n = 60), patient request (n = 6), adverse events (n = 4), and death (n = 3).
The overall response rate was 60%, and the disease control rate was 90%. The researchers measured plasma erlotinib concentration in 48 patients and found it did not correlate with response.
The median progression-free survival was 9.3 months, and the median overall survival was 26.2 months.
Ten patients had erlotinib temporarily suspended because of adverse events. Five patients had their dose reduced to 25 mg because of adverse events, including oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia.
Two patients discontinued treatment because of adverse events. One patient had a cutaneous ulcer and bone infection. The other had oral mucositis.
Dr. Miyamoto and colleagues concluded that, “low-dose erlotinib was associated with efficacy and safety in frail patients with EGFR mutation–positive lung cancer. More research on the dosing strategy of target-based drugs is warranted, especially in frail patients in the real-world setting.”
Less is more
Sometimes, less can be more, said Mellar P. Davis, MD, an oncologist and section head of the palliative care department at Geisinger Medical System in Danville, Penn., who was not involved in this study.
“Why do patients benefit from small doses? It may be that there are fewer drug interruptions over time and patients are able to stay on schedule,” Dr. Davis said. “It may also be that erlotinib clearance is reduced in the elderly and comorbid patient. The reduced dose may, in fact, be the ‘therapeutic’ dose in this special population.”
Plasma levels were frequently in therapeutic ranges in this study, but patients who had subtherapeutic plasma levels also responded to therapy, Dr. Davis pointed out. The lower dose was shown to maintain sufficient concentrations of the treatment while reducing adverse effects.
However, Dr. Davis noted, this was not a randomized trial. “It is always a risk hedging bets on single-arm trials,” he said. “Randomized trials often prove phase 2 single-arm trials wrong.”
He added that quality-of-life measures are absent from the study. Erlotinib is a palliative drug with side effects, Dr. Davis noted.
“Control of cancer and cancer regression should improve symptoms and quality of life when balanced against treatment toxicity,” he said. “In this study, I would have thought that symptom improvement, performance score, and quality of life would have been the primary outcome or the co-primary outcome with disease control.”
Should a randomized, controlled trial of low-dose erlotinib be conducted in the frail/elderly population? “If one believes trials should be quantitatively based, the answer would be no,” Dr. Davis said. “Responses may be the same, and it would be expensive to prove that low-dose erlotinib is the same as standard doses when comparing survival.”
However, if one is interested in quality of life, particularly in this growing population, a trial that incorporated quality-of-life measures would make more sense, according to Dr. Davis. “For if one can achieve less toxicity and treat more patients and get the same duration of clinical benefit, then less will be more,” he concluded.
Dr. Davis reported having no conflicts of interest. Study authors disclosed relationships with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, and many other companies. Erlotinib is manufactured for OSI Pharmaceuticals, an affiliate of Astellas Pharma, and distributed by Genentech, a member of the Roche Group.
The study was supported by the Japan Agency for Medical Research and Development.
SOURCE: Miyamoto S et al. JAMA Oncol. 2020 May 14; e201250. doi: 10.1001/jamaoncol.2020.1250.
FDA approves olaparib for certain metastatic prostate cancers
The Food and Drug Administration approved olaparib (Lynparza, AstraZeneca) for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
The drug is limited to use in men who have progressed following prior treatment with enzalutamide or abiraterone.
Olaparib becomes the second PARP inhibitor approved by the FDA for use in prostate cancer this week. Earlier, rucaparib (Rubraca, Clovis Oncology) was approved for use in patients with mCRPC that harbor deleterious BRCA mutations (germline and/or somatic).
Olaparib is also indicated for use in ovarian, breast, and pancreatic cancers.
The FDA also approved two companion diagnostic devices for treatment with olaparib: the FoundationOne CDx test (Foundation Medicine) for the selection of patients carrying HRR gene alterations and the BRACAnalysis CDx test (Myriad Genetic Laboratories) for the selection of patients carrying germline BRCA1/2 alterations.
The approval was based on results from the open-label, multicenter PROfound trial, which randomly assigned 387 patients to olaparib 300 mg twice daily and to investigator’s choice of enzalutamide or abiraterone acetate. All patients received a GnRH analogue or had prior bilateral orchiectomy.
The study involved two cohorts. Patients with mutations in either BRCA1, BRCA2, or ATM were randomly assigned in cohort A (n = 245); patients with mutations among 12 other genes involved in the HRR pathway were randomly assigned in cohort B (n = 142); those with co-mutations were assigned to cohort A.
The major efficacy outcome of the trial was radiological progression-free survival (rPFS) (cohort A).
In cohort A, patients receiving olaparib had a median rPFS of 7.4 months vs 3.6 months among patients receiving investigator’s choice (hazard ratio [HR], 0.34; P < .0001). Median overall survival was 19.1 months vs 14.7 months (HR, 0.69; P = .0175) and the overall response rate was 33% vs 2% (P < .0001).
In cohort A+B, patients receiving olaparib had a median rPFS of 5.8 months vs 3.5 months among patients receiving investigator’s choice (HR, 0.49; P < .0001).
The study results were first presented at the 2019 annual meeting of the European Society for Medical Oncology. At that time, study investigator Maha Hussain, MD, Northwestern University, Chicago, said the rPFS result and other outcomes were a “remarkable achievement” in such heavily pretreated patients with prostate cancer.
Patients with prostate cancer should now undergo genetic testing of tumor tissue to identify the roughly 30% of patients who can benefit – as is already routinely being done for breast, ovarian, and lung cancer, said experts at ESMO.
The most common adverse reactions with olaparib (≥10% of patients) were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough, and dyspnea. Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients randomly assigned to olaparib, compared with 3.1% of those receiving investigator’s choice of enzalutamide or abiraterone.
Olaparib carries the warning that myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) occurred in <1.5% of patients exposed to it as a monotherapy, and that the majority of events had a fatal outcome.
The recommended olaparib dose is 300 mg taken orally twice daily, with or without food.
This article first appeared on Medscape.com.
The Food and Drug Administration approved olaparib (Lynparza, AstraZeneca) for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
The drug is limited to use in men who have progressed following prior treatment with enzalutamide or abiraterone.
Olaparib becomes the second PARP inhibitor approved by the FDA for use in prostate cancer this week. Earlier, rucaparib (Rubraca, Clovis Oncology) was approved for use in patients with mCRPC that harbor deleterious BRCA mutations (germline and/or somatic).
Olaparib is also indicated for use in ovarian, breast, and pancreatic cancers.
The FDA also approved two companion diagnostic devices for treatment with olaparib: the FoundationOne CDx test (Foundation Medicine) for the selection of patients carrying HRR gene alterations and the BRACAnalysis CDx test (Myriad Genetic Laboratories) for the selection of patients carrying germline BRCA1/2 alterations.
The approval was based on results from the open-label, multicenter PROfound trial, which randomly assigned 387 patients to olaparib 300 mg twice daily and to investigator’s choice of enzalutamide or abiraterone acetate. All patients received a GnRH analogue or had prior bilateral orchiectomy.
The study involved two cohorts. Patients with mutations in either BRCA1, BRCA2, or ATM were randomly assigned in cohort A (n = 245); patients with mutations among 12 other genes involved in the HRR pathway were randomly assigned in cohort B (n = 142); those with co-mutations were assigned to cohort A.
The major efficacy outcome of the trial was radiological progression-free survival (rPFS) (cohort A).
In cohort A, patients receiving olaparib had a median rPFS of 7.4 months vs 3.6 months among patients receiving investigator’s choice (hazard ratio [HR], 0.34; P < .0001). Median overall survival was 19.1 months vs 14.7 months (HR, 0.69; P = .0175) and the overall response rate was 33% vs 2% (P < .0001).
In cohort A+B, patients receiving olaparib had a median rPFS of 5.8 months vs 3.5 months among patients receiving investigator’s choice (HR, 0.49; P < .0001).
The study results were first presented at the 2019 annual meeting of the European Society for Medical Oncology. At that time, study investigator Maha Hussain, MD, Northwestern University, Chicago, said the rPFS result and other outcomes were a “remarkable achievement” in such heavily pretreated patients with prostate cancer.
Patients with prostate cancer should now undergo genetic testing of tumor tissue to identify the roughly 30% of patients who can benefit – as is already routinely being done for breast, ovarian, and lung cancer, said experts at ESMO.
The most common adverse reactions with olaparib (≥10% of patients) were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough, and dyspnea. Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients randomly assigned to olaparib, compared with 3.1% of those receiving investigator’s choice of enzalutamide or abiraterone.
Olaparib carries the warning that myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) occurred in <1.5% of patients exposed to it as a monotherapy, and that the majority of events had a fatal outcome.
The recommended olaparib dose is 300 mg taken orally twice daily, with or without food.
This article first appeared on Medscape.com.
The Food and Drug Administration approved olaparib (Lynparza, AstraZeneca) for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
The drug is limited to use in men who have progressed following prior treatment with enzalutamide or abiraterone.
Olaparib becomes the second PARP inhibitor approved by the FDA for use in prostate cancer this week. Earlier, rucaparib (Rubraca, Clovis Oncology) was approved for use in patients with mCRPC that harbor deleterious BRCA mutations (germline and/or somatic).
Olaparib is also indicated for use in ovarian, breast, and pancreatic cancers.
The FDA also approved two companion diagnostic devices for treatment with olaparib: the FoundationOne CDx test (Foundation Medicine) for the selection of patients carrying HRR gene alterations and the BRACAnalysis CDx test (Myriad Genetic Laboratories) for the selection of patients carrying germline BRCA1/2 alterations.
The approval was based on results from the open-label, multicenter PROfound trial, which randomly assigned 387 patients to olaparib 300 mg twice daily and to investigator’s choice of enzalutamide or abiraterone acetate. All patients received a GnRH analogue or had prior bilateral orchiectomy.
The study involved two cohorts. Patients with mutations in either BRCA1, BRCA2, or ATM were randomly assigned in cohort A (n = 245); patients with mutations among 12 other genes involved in the HRR pathway were randomly assigned in cohort B (n = 142); those with co-mutations were assigned to cohort A.
The major efficacy outcome of the trial was radiological progression-free survival (rPFS) (cohort A).
In cohort A, patients receiving olaparib had a median rPFS of 7.4 months vs 3.6 months among patients receiving investigator’s choice (hazard ratio [HR], 0.34; P < .0001). Median overall survival was 19.1 months vs 14.7 months (HR, 0.69; P = .0175) and the overall response rate was 33% vs 2% (P < .0001).
In cohort A+B, patients receiving olaparib had a median rPFS of 5.8 months vs 3.5 months among patients receiving investigator’s choice (HR, 0.49; P < .0001).
The study results were first presented at the 2019 annual meeting of the European Society for Medical Oncology. At that time, study investigator Maha Hussain, MD, Northwestern University, Chicago, said the rPFS result and other outcomes were a “remarkable achievement” in such heavily pretreated patients with prostate cancer.
Patients with prostate cancer should now undergo genetic testing of tumor tissue to identify the roughly 30% of patients who can benefit – as is already routinely being done for breast, ovarian, and lung cancer, said experts at ESMO.
The most common adverse reactions with olaparib (≥10% of patients) were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough, and dyspnea. Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients randomly assigned to olaparib, compared with 3.1% of those receiving investigator’s choice of enzalutamide or abiraterone.
Olaparib carries the warning that myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) occurred in <1.5% of patients exposed to it as a monotherapy, and that the majority of events had a fatal outcome.
The recommended olaparib dose is 300 mg taken orally twice daily, with or without food.
This article first appeared on Medscape.com.
FDA expands approval of atezolizumab in NSCLC
The Food and Drug Administration has expanded the approved indication for atezolizumab (Tecentriq) in patients with non–small cell lung cancer (NSCLC).
Atezolizumab is now approved as first-line monotherapy for adults with metastatic NSCLC whose tumors are EGFR and ALK wild-type but have high PD-L1 expression (PD-L1 stained ≥50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥10% of the tumor area).
The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic to identify patients with NSCLC who are eligible for treatment with atezolizumab.
The drug was evaluated in the IMpower110 trial (NCT02409342), which enrolled patients with stage IV, PD-L1–positive (tumor cells [TC] ≥1% or immune cells [IC] ≥1%) NSCLC who had received no prior chemotherapy for metastatic disease.
The patients were randomized to receive atezolizumab at 1,200 mg every 3 weeks (n = 286) or platinum-based chemotherapy (n = 263), which consisted of carboplatin or cisplatin with either pemetrexed or gemcitabine, until disease progression or unacceptable toxicity.
Overall survival was superior in the atezolizumab arm, but only among patients with high PD-L1 expression (TC ≥50% or IC ≥10%). The median overall survival was 20.2 months among PD-L1–high patients in the atezolizumab arm and 13.1 months among PD-L1–high patients in the chemotherapy arm (hazard ratio, 0.59; P = .0106). There was no significant difference in overall survival between the treatment arms for patients in the other two PD-L1 subgroups – TC ≥5% or IC ≥5% and TC ≥1% or IC ≥1%.
Serious adverse events occurred in 28% of patients receiving atezolizumab. The most frequent of these were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%), and pneumonitis (2.1%). Fatal adverse events in the atezolizumab arm included unexplained death, aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infraction, and device occlusion (one patient each).
For more details on atezolizumab, see the full prescribing information.
The FDA has granted the approval of atezolizumab to Genentech and the approval of the VENTANA PD-L1 (SP142) Assay to Ventana Medical Systems.
The Food and Drug Administration has expanded the approved indication for atezolizumab (Tecentriq) in patients with non–small cell lung cancer (NSCLC).
Atezolizumab is now approved as first-line monotherapy for adults with metastatic NSCLC whose tumors are EGFR and ALK wild-type but have high PD-L1 expression (PD-L1 stained ≥50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥10% of the tumor area).
The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic to identify patients with NSCLC who are eligible for treatment with atezolizumab.
The drug was evaluated in the IMpower110 trial (NCT02409342), which enrolled patients with stage IV, PD-L1–positive (tumor cells [TC] ≥1% or immune cells [IC] ≥1%) NSCLC who had received no prior chemotherapy for metastatic disease.
The patients were randomized to receive atezolizumab at 1,200 mg every 3 weeks (n = 286) or platinum-based chemotherapy (n = 263), which consisted of carboplatin or cisplatin with either pemetrexed or gemcitabine, until disease progression or unacceptable toxicity.
Overall survival was superior in the atezolizumab arm, but only among patients with high PD-L1 expression (TC ≥50% or IC ≥10%). The median overall survival was 20.2 months among PD-L1–high patients in the atezolizumab arm and 13.1 months among PD-L1–high patients in the chemotherapy arm (hazard ratio, 0.59; P = .0106). There was no significant difference in overall survival between the treatment arms for patients in the other two PD-L1 subgroups – TC ≥5% or IC ≥5% and TC ≥1% or IC ≥1%.
Serious adverse events occurred in 28% of patients receiving atezolizumab. The most frequent of these were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%), and pneumonitis (2.1%). Fatal adverse events in the atezolizumab arm included unexplained death, aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infraction, and device occlusion (one patient each).
For more details on atezolizumab, see the full prescribing information.
The FDA has granted the approval of atezolizumab to Genentech and the approval of the VENTANA PD-L1 (SP142) Assay to Ventana Medical Systems.
The Food and Drug Administration has expanded the approved indication for atezolizumab (Tecentriq) in patients with non–small cell lung cancer (NSCLC).
Atezolizumab is now approved as first-line monotherapy for adults with metastatic NSCLC whose tumors are EGFR and ALK wild-type but have high PD-L1 expression (PD-L1 stained ≥50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥10% of the tumor area).
The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic to identify patients with NSCLC who are eligible for treatment with atezolizumab.
The drug was evaluated in the IMpower110 trial (NCT02409342), which enrolled patients with stage IV, PD-L1–positive (tumor cells [TC] ≥1% or immune cells [IC] ≥1%) NSCLC who had received no prior chemotherapy for metastatic disease.
The patients were randomized to receive atezolizumab at 1,200 mg every 3 weeks (n = 286) or platinum-based chemotherapy (n = 263), which consisted of carboplatin or cisplatin with either pemetrexed or gemcitabine, until disease progression or unacceptable toxicity.
Overall survival was superior in the atezolizumab arm, but only among patients with high PD-L1 expression (TC ≥50% or IC ≥10%). The median overall survival was 20.2 months among PD-L1–high patients in the atezolizumab arm and 13.1 months among PD-L1–high patients in the chemotherapy arm (hazard ratio, 0.59; P = .0106). There was no significant difference in overall survival between the treatment arms for patients in the other two PD-L1 subgroups – TC ≥5% or IC ≥5% and TC ≥1% or IC ≥1%.
Serious adverse events occurred in 28% of patients receiving atezolizumab. The most frequent of these were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%), and pneumonitis (2.1%). Fatal adverse events in the atezolizumab arm included unexplained death, aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infraction, and device occlusion (one patient each).
For more details on atezolizumab, see the full prescribing information.
The FDA has granted the approval of atezolizumab to Genentech and the approval of the VENTANA PD-L1 (SP142) Assay to Ventana Medical Systems.
DOACs linked to lower fracture risk versus warfarin in AFib patients
results of a recent population-based cohort study show.
The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.
This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.
“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.
The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.
Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.
“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.
There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.
“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.
The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.
In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.
DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.
Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.
“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”
The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.
The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.
“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.
Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).
Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.
SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.
results of a recent population-based cohort study show.
The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.
This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.
“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.
The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.
Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.
“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.
There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.
“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.
The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.
In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.
DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.
Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.
“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”
The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.
The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.
“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.
Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).
Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.
SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.
results of a recent population-based cohort study show.
The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.
This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.
“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.
The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.
Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.
“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.
There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.
“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.
The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.
In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.
DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.
Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.
“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”
The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.
The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.
“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.
Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).
Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.
SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.
FROM ANNALS OF INTERNAL MEDICINE
Vitamin D: A low-hanging fruit in COVID-19?
Mainstream media outlets have been flooded recently with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.
as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.
But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.
And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic – in particular frontline health care workers – most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.
This is especially important given the fact that, during “lockdown” scenarios, many people are spending more time than usual indoors.
Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.
“There’s no randomized, controlled trial for sure, and that’s the gold standard,” he said in an interview, and “the observational data are so confounded, it’s difficult to know.”
Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he said. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of “therapy” for the infection, are currently lacking.
Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.
“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] – a low-hanging fruit – is a contributory factor and we can do something about it now,” she said in an interview.
Dr. Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the United Kingdom, also has not yet made this recommendation, she said.
Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”
Dr. Bajaj said – as did Dr. Rosen and Dr. Kenny – that randomized, controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.
“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”
What is the role of vitamin D fortification?
In their study in the Irish Medical Journal, Dr. Kenny and colleagues noted that, in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.
But these countries do not formally fortify foods or recommend supplementation with vitamin D.
Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.
Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators reported.
“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have ... potential benefits for COVID-19,” they concluded.
“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Dr. Kenny said.
Dr. Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.
Dr. Rosen has doubts on this issue, too.
“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.
“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”
Does vitamin D have a role to play in immune modulation?
One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.
In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom, and the United States.
Specifically, the risk of severe COVID-19 cases among patients with severe vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal vitamin D levels was 14.6% (a reduction of 15.6%).
“This potential effect may be attributed to vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” said the researchers.
Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.
“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.
Dr. Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.
“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he said.
“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”
Ethnic minorities disproportionately affected
It is also well recognized that COVID-19 disproportionately affects black and Asian minority ethnic individuals.
But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.
“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals, and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, of the University of Glasgow and colleagues concluded.
But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.
The black and Asian minority ethnic population, “especially frontline staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” said Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, England, and David C. Anderson, a retired endocrinologist, said in a letter to BAPIO members.
Indeed, they suggested a booster dose of 100,000 IU as a one-off for black and Asian minority ethnic health care staff that should raise vitamin D levels for 2-3 months. They referred to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status ... for up to 3 months”.
Commenting on the idea, Dr. Rosen remarked that, in general, the high-dose 50,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1,000 IU per day, except that the blood levels go up quicker and higher.
“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if health care workers suspect vitamin D deficiency, daily doses of 1,000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”
On the specific question of vitamin D needs in ethnic minorities, Dr. Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.
“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than [whites],” he pointed out.
Testing and governmental recommendations during COVID-19
The U.S. National Institutes of Health in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people. There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.
And Dr. Rosen pointed out that there is no evidence for mass screening of vitamin D levels among the U.S. population.
“U.S. public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels; for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.
“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU per day],” he suggested. “It won’t harm.”
The U.K.’s Public Health England (PHE) clarified its advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”
However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.
Dr. Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has ties with Amgen, AstraZeneca Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, Eli Lilly,Valeant, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, LMC Healthcare,mdBriefCase,Medscape, andMeducom. Dr. Kenny, Dr. Rosen, and Dr. Singhal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Mainstream media outlets have been flooded recently with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.
as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.
But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.
And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic – in particular frontline health care workers – most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.
This is especially important given the fact that, during “lockdown” scenarios, many people are spending more time than usual indoors.
Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.
“There’s no randomized, controlled trial for sure, and that’s the gold standard,” he said in an interview, and “the observational data are so confounded, it’s difficult to know.”
Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he said. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of “therapy” for the infection, are currently lacking.
Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.
“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] – a low-hanging fruit – is a contributory factor and we can do something about it now,” she said in an interview.
Dr. Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the United Kingdom, also has not yet made this recommendation, she said.
Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”
Dr. Bajaj said – as did Dr. Rosen and Dr. Kenny – that randomized, controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.
“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”
What is the role of vitamin D fortification?
In their study in the Irish Medical Journal, Dr. Kenny and colleagues noted that, in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.
But these countries do not formally fortify foods or recommend supplementation with vitamin D.
Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.
Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators reported.
“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have ... potential benefits for COVID-19,” they concluded.
“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Dr. Kenny said.
Dr. Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.
Dr. Rosen has doubts on this issue, too.
“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.
“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”
Does vitamin D have a role to play in immune modulation?
One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.
In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom, and the United States.
Specifically, the risk of severe COVID-19 cases among patients with severe vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal vitamin D levels was 14.6% (a reduction of 15.6%).
“This potential effect may be attributed to vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” said the researchers.
Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.
“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.
Dr. Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.
“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he said.
“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”
Ethnic minorities disproportionately affected
It is also well recognized that COVID-19 disproportionately affects black and Asian minority ethnic individuals.
But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.
“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals, and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, of the University of Glasgow and colleagues concluded.
But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.
The black and Asian minority ethnic population, “especially frontline staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” said Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, England, and David C. Anderson, a retired endocrinologist, said in a letter to BAPIO members.
Indeed, they suggested a booster dose of 100,000 IU as a one-off for black and Asian minority ethnic health care staff that should raise vitamin D levels for 2-3 months. They referred to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status ... for up to 3 months”.
Commenting on the idea, Dr. Rosen remarked that, in general, the high-dose 50,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1,000 IU per day, except that the blood levels go up quicker and higher.
“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if health care workers suspect vitamin D deficiency, daily doses of 1,000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”
On the specific question of vitamin D needs in ethnic minorities, Dr. Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.
“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than [whites],” he pointed out.
Testing and governmental recommendations during COVID-19
The U.S. National Institutes of Health in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people. There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.
And Dr. Rosen pointed out that there is no evidence for mass screening of vitamin D levels among the U.S. population.
“U.S. public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels; for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.
“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU per day],” he suggested. “It won’t harm.”
The U.K.’s Public Health England (PHE) clarified its advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”
However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.
Dr. Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has ties with Amgen, AstraZeneca Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, Eli Lilly,Valeant, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, LMC Healthcare,mdBriefCase,Medscape, andMeducom. Dr. Kenny, Dr. Rosen, and Dr. Singhal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Mainstream media outlets have been flooded recently with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.
as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.
But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.
And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic – in particular frontline health care workers – most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.
This is especially important given the fact that, during “lockdown” scenarios, many people are spending more time than usual indoors.
Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.
“There’s no randomized, controlled trial for sure, and that’s the gold standard,” he said in an interview, and “the observational data are so confounded, it’s difficult to know.”
Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he said. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of “therapy” for the infection, are currently lacking.
Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.
“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] – a low-hanging fruit – is a contributory factor and we can do something about it now,” she said in an interview.
Dr. Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the United Kingdom, also has not yet made this recommendation, she said.
Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”
Dr. Bajaj said – as did Dr. Rosen and Dr. Kenny – that randomized, controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.
“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”
What is the role of vitamin D fortification?
In their study in the Irish Medical Journal, Dr. Kenny and colleagues noted that, in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.
But these countries do not formally fortify foods or recommend supplementation with vitamin D.
Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.
Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators reported.
“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have ... potential benefits for COVID-19,” they concluded.
“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Dr. Kenny said.
Dr. Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.
Dr. Rosen has doubts on this issue, too.
“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.
“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”
Does vitamin D have a role to play in immune modulation?
One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.
In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom, and the United States.
Specifically, the risk of severe COVID-19 cases among patients with severe vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal vitamin D levels was 14.6% (a reduction of 15.6%).
“This potential effect may be attributed to vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” said the researchers.
Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.
“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.
Dr. Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.
“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he said.
“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”
Ethnic minorities disproportionately affected
It is also well recognized that COVID-19 disproportionately affects black and Asian minority ethnic individuals.
But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.
“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals, and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, of the University of Glasgow and colleagues concluded.
But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.
The black and Asian minority ethnic population, “especially frontline staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” said Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, England, and David C. Anderson, a retired endocrinologist, said in a letter to BAPIO members.
Indeed, they suggested a booster dose of 100,000 IU as a one-off for black and Asian minority ethnic health care staff that should raise vitamin D levels for 2-3 months. They referred to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status ... for up to 3 months”.
Commenting on the idea, Dr. Rosen remarked that, in general, the high-dose 50,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1,000 IU per day, except that the blood levels go up quicker and higher.
“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if health care workers suspect vitamin D deficiency, daily doses of 1,000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”
On the specific question of vitamin D needs in ethnic minorities, Dr. Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.
“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than [whites],” he pointed out.
Testing and governmental recommendations during COVID-19
The U.S. National Institutes of Health in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people. There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.
And Dr. Rosen pointed out that there is no evidence for mass screening of vitamin D levels among the U.S. population.
“U.S. public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels; for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.
“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU per day],” he suggested. “It won’t harm.”
The U.K.’s Public Health England (PHE) clarified its advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”
However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.
Dr. Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has ties with Amgen, AstraZeneca Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, Eli Lilly,Valeant, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, LMC Healthcare,mdBriefCase,Medscape, andMeducom. Dr. Kenny, Dr. Rosen, and Dr. Singhal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TNF inhibitors may dampen COVID-19 severity
Patients on a tumor necrosis factor inhibitor for their rheumatic disease when they became infected with COVID-19 were markedly less likely to subsequently require hospitalization, according to intriguing early evidence from the COVID-19 Global Rheumatology Alliance Registry.
On the other hand, those registry patients who were on 10 mg of prednisone or more daily when they got infected were more than twice as likely to be hospitalized than were those who were not on corticosteroids, even after controlling for the severity of their rheumatic disease and other potential confounders, Jinoos Yazdany, MD, reported at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
“We saw a signal with moderate to high-dose steroids. I think it’s something we’re going to have to keep an eye out on as more data come in,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.
The global registry launched on March 24, 2020, and was quickly embraced by rheumatologists from around the world. By May 12, the registry included more than 1,300 patients with a range of rheumatic diseases, all with confirmed COVID-19 infection as a requisite for enrollment; the cases were submitted by more than 300 rheumatologists in 40 countries. The registry is supported by the ACR and European League Against Rheumatism.
Dr. Yazdany, a member of the registry steering committee, described the project’s two main goals: To learn the outcomes of COVID-19–infected patients with various rheumatic diseases and to make inferences regarding the impact of the immunosuppressive and antimalarial medications widely prescribed by rheumatologists.
She presented soon-to-be-published data on the characteristics and disposition of the first 600 patients, 46% of whom were hospitalized and 9% died. A caveat regarding the registry, she noted, is that these are observational data and thus potentially subject to unrecognized confounders. Also, the registry population is skewed toward the sicker end of the COVID-19 disease spectrum because while all participants have confirmed infection, testing for the infection has been notoriously uneven. Many people are infected asymptomatically and thus may not undergo testing even where readily available.
Early key findings from registry
The risk factors for more severe infection resulting in hospitalization in patients with rheumatic diseases are by and large the same drivers described in the general population: older age and comorbid conditions including diabetes, hypertension, cardiovascular disease, obesity, chronic kidney disease, and lung disease. Notably, however, patients on the equivalent of 10 mg/day of prednisone or more were at a 105% increased risk for hospitalization, compared with those not on corticosteroids after adjustment for age, comorbid conditions, and rheumatic disease severity.
Patients on a background tumor necrosis factor (TNF) inhibitor had an adjusted 60% reduction in risk of hospitalization. This apparent protective effect against more severe COVID-19 disease is mechanistically plausible: In animal studies, being on a TNF inhibitor has been associated with less severe infection following exposure to influenza virus, Dr. Yazdany observed.
COVID-infected patients on any biologic disease-modifying antirheumatic drug had a 54% decreased risk of hospitalization. However, in this early analysis, the study was sufficiently powered only to specifically assess the impact of TNF inhibitors, since those agents were by far the most commonly used biologics. As the registry grows, it will be possible to analyze the impact of other antirheumatic medications.
Being on hydroxychloroquine or other antimalarials at the time of COVID-19 infection had no impact on hospitalization.
The only rheumatic disease diagnosis with an odds of hospitalization significantly different from that of RA patients was systemic lupus erythematosus (SLE). Lupus patients were at 80% increased risk of hospitalization. Although this was a statistically significant difference, Dr. Yazdany cautioned against making too much of it because of the strong potential for unmeasured confounding. In particular, lupus patients as a group are known to rate on the lower end of measures of social determinants of health, a status that is an established major risk factor for COVID-19 disease.
“A strength of the global registry has been that it provides timely data that’s been very helpful for rheumatologists to rapidly dispel misinformation that has been spread about hydroxychloroquine, especially statements about lupus patients not getting COVID-19. We know from these data that’s not true,” she said.
Being on background NSAIDs at the time of SARS-CoV-2 infection was not associated with increased risk of hospitalization; in fact, NSAID users were 36% less likely to be hospitalized for their COVID-19 disease, although this difference didn’t reach statistical significance.
Dr. Yazdany urged her fellow rheumatologists to enter their cases on the registry website: rheum-covid.org. There they can also join the registry mailing list and receive weekly updates.
Other recent insights on COVID-19 in rheumatology
An as-yet unpublished U.K. observational study involving electronic health record data on 17 million people included 885,000 individuals with RA, SLE, or psoriasis. After extensive statistical controlling for the known risk factors for severe COVID-19 infection, including a measure of socioeconomic deprivation, the group with one of these autoimmune diseases had an adjusted, statistically significant 23% increased risk of hospital death because of COVID-19 infection.
“This is the largest study of its kind to date. There’s potential for unmeasured confounding and selection bias here due to who gets tested. We’ll have to see where this study lands, but I think it does suggest there’s a slightly higher mortality risk in COVID-infected patients with rheumatic disease,” according to Dr. Yazdany.
On the other hand, there have been at least eight recently published patient surveys and case series of patients with rheumatic diseases in areas of the world hardest hit by the pandemic, and they paint a consistent picture.
“What we’ve learned from these studies was the infection rate was generally in the ballpark of people in the region. It doesn’t seem like there’s a dramatically higher infection rate in people with rheumatic disease in these surveys. The hospitalized rheumatology patients had many of the familiar comorbidities. This is the first glance at how likely people are to become infected and how they fared, and I think overall the data have been quite reassuring,” she said.
Dr. Yazdany reported serving as a consultant to AstraZeneca and Eli Lilly and receiving research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Centers for Disease Control and Prevention.
Patients on a tumor necrosis factor inhibitor for their rheumatic disease when they became infected with COVID-19 were markedly less likely to subsequently require hospitalization, according to intriguing early evidence from the COVID-19 Global Rheumatology Alliance Registry.
On the other hand, those registry patients who were on 10 mg of prednisone or more daily when they got infected were more than twice as likely to be hospitalized than were those who were not on corticosteroids, even after controlling for the severity of their rheumatic disease and other potential confounders, Jinoos Yazdany, MD, reported at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
“We saw a signal with moderate to high-dose steroids. I think it’s something we’re going to have to keep an eye out on as more data come in,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.
The global registry launched on March 24, 2020, and was quickly embraced by rheumatologists from around the world. By May 12, the registry included more than 1,300 patients with a range of rheumatic diseases, all with confirmed COVID-19 infection as a requisite for enrollment; the cases were submitted by more than 300 rheumatologists in 40 countries. The registry is supported by the ACR and European League Against Rheumatism.
Dr. Yazdany, a member of the registry steering committee, described the project’s two main goals: To learn the outcomes of COVID-19–infected patients with various rheumatic diseases and to make inferences regarding the impact of the immunosuppressive and antimalarial medications widely prescribed by rheumatologists.
She presented soon-to-be-published data on the characteristics and disposition of the first 600 patients, 46% of whom were hospitalized and 9% died. A caveat regarding the registry, she noted, is that these are observational data and thus potentially subject to unrecognized confounders. Also, the registry population is skewed toward the sicker end of the COVID-19 disease spectrum because while all participants have confirmed infection, testing for the infection has been notoriously uneven. Many people are infected asymptomatically and thus may not undergo testing even where readily available.
Early key findings from registry
The risk factors for more severe infection resulting in hospitalization in patients with rheumatic diseases are by and large the same drivers described in the general population: older age and comorbid conditions including diabetes, hypertension, cardiovascular disease, obesity, chronic kidney disease, and lung disease. Notably, however, patients on the equivalent of 10 mg/day of prednisone or more were at a 105% increased risk for hospitalization, compared with those not on corticosteroids after adjustment for age, comorbid conditions, and rheumatic disease severity.
Patients on a background tumor necrosis factor (TNF) inhibitor had an adjusted 60% reduction in risk of hospitalization. This apparent protective effect against more severe COVID-19 disease is mechanistically plausible: In animal studies, being on a TNF inhibitor has been associated with less severe infection following exposure to influenza virus, Dr. Yazdany observed.
COVID-infected patients on any biologic disease-modifying antirheumatic drug had a 54% decreased risk of hospitalization. However, in this early analysis, the study was sufficiently powered only to specifically assess the impact of TNF inhibitors, since those agents were by far the most commonly used biologics. As the registry grows, it will be possible to analyze the impact of other antirheumatic medications.
Being on hydroxychloroquine or other antimalarials at the time of COVID-19 infection had no impact on hospitalization.
The only rheumatic disease diagnosis with an odds of hospitalization significantly different from that of RA patients was systemic lupus erythematosus (SLE). Lupus patients were at 80% increased risk of hospitalization. Although this was a statistically significant difference, Dr. Yazdany cautioned against making too much of it because of the strong potential for unmeasured confounding. In particular, lupus patients as a group are known to rate on the lower end of measures of social determinants of health, a status that is an established major risk factor for COVID-19 disease.
“A strength of the global registry has been that it provides timely data that’s been very helpful for rheumatologists to rapidly dispel misinformation that has been spread about hydroxychloroquine, especially statements about lupus patients not getting COVID-19. We know from these data that’s not true,” she said.
Being on background NSAIDs at the time of SARS-CoV-2 infection was not associated with increased risk of hospitalization; in fact, NSAID users were 36% less likely to be hospitalized for their COVID-19 disease, although this difference didn’t reach statistical significance.
Dr. Yazdany urged her fellow rheumatologists to enter their cases on the registry website: rheum-covid.org. There they can also join the registry mailing list and receive weekly updates.
Other recent insights on COVID-19 in rheumatology
An as-yet unpublished U.K. observational study involving electronic health record data on 17 million people included 885,000 individuals with RA, SLE, or psoriasis. After extensive statistical controlling for the known risk factors for severe COVID-19 infection, including a measure of socioeconomic deprivation, the group with one of these autoimmune diseases had an adjusted, statistically significant 23% increased risk of hospital death because of COVID-19 infection.
“This is the largest study of its kind to date. There’s potential for unmeasured confounding and selection bias here due to who gets tested. We’ll have to see where this study lands, but I think it does suggest there’s a slightly higher mortality risk in COVID-infected patients with rheumatic disease,” according to Dr. Yazdany.
On the other hand, there have been at least eight recently published patient surveys and case series of patients with rheumatic diseases in areas of the world hardest hit by the pandemic, and they paint a consistent picture.
“What we’ve learned from these studies was the infection rate was generally in the ballpark of people in the region. It doesn’t seem like there’s a dramatically higher infection rate in people with rheumatic disease in these surveys. The hospitalized rheumatology patients had many of the familiar comorbidities. This is the first glance at how likely people are to become infected and how they fared, and I think overall the data have been quite reassuring,” she said.
Dr. Yazdany reported serving as a consultant to AstraZeneca and Eli Lilly and receiving research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Centers for Disease Control and Prevention.
Patients on a tumor necrosis factor inhibitor for their rheumatic disease when they became infected with COVID-19 were markedly less likely to subsequently require hospitalization, according to intriguing early evidence from the COVID-19 Global Rheumatology Alliance Registry.
On the other hand, those registry patients who were on 10 mg of prednisone or more daily when they got infected were more than twice as likely to be hospitalized than were those who were not on corticosteroids, even after controlling for the severity of their rheumatic disease and other potential confounders, Jinoos Yazdany, MD, reported at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
“We saw a signal with moderate to high-dose steroids. I think it’s something we’re going to have to keep an eye out on as more data come in,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.
The global registry launched on March 24, 2020, and was quickly embraced by rheumatologists from around the world. By May 12, the registry included more than 1,300 patients with a range of rheumatic diseases, all with confirmed COVID-19 infection as a requisite for enrollment; the cases were submitted by more than 300 rheumatologists in 40 countries. The registry is supported by the ACR and European League Against Rheumatism.
Dr. Yazdany, a member of the registry steering committee, described the project’s two main goals: To learn the outcomes of COVID-19–infected patients with various rheumatic diseases and to make inferences regarding the impact of the immunosuppressive and antimalarial medications widely prescribed by rheumatologists.
She presented soon-to-be-published data on the characteristics and disposition of the first 600 patients, 46% of whom were hospitalized and 9% died. A caveat regarding the registry, she noted, is that these are observational data and thus potentially subject to unrecognized confounders. Also, the registry population is skewed toward the sicker end of the COVID-19 disease spectrum because while all participants have confirmed infection, testing for the infection has been notoriously uneven. Many people are infected asymptomatically and thus may not undergo testing even where readily available.
Early key findings from registry
The risk factors for more severe infection resulting in hospitalization in patients with rheumatic diseases are by and large the same drivers described in the general population: older age and comorbid conditions including diabetes, hypertension, cardiovascular disease, obesity, chronic kidney disease, and lung disease. Notably, however, patients on the equivalent of 10 mg/day of prednisone or more were at a 105% increased risk for hospitalization, compared with those not on corticosteroids after adjustment for age, comorbid conditions, and rheumatic disease severity.
Patients on a background tumor necrosis factor (TNF) inhibitor had an adjusted 60% reduction in risk of hospitalization. This apparent protective effect against more severe COVID-19 disease is mechanistically plausible: In animal studies, being on a TNF inhibitor has been associated with less severe infection following exposure to influenza virus, Dr. Yazdany observed.
COVID-infected patients on any biologic disease-modifying antirheumatic drug had a 54% decreased risk of hospitalization. However, in this early analysis, the study was sufficiently powered only to specifically assess the impact of TNF inhibitors, since those agents were by far the most commonly used biologics. As the registry grows, it will be possible to analyze the impact of other antirheumatic medications.
Being on hydroxychloroquine or other antimalarials at the time of COVID-19 infection had no impact on hospitalization.
The only rheumatic disease diagnosis with an odds of hospitalization significantly different from that of RA patients was systemic lupus erythematosus (SLE). Lupus patients were at 80% increased risk of hospitalization. Although this was a statistically significant difference, Dr. Yazdany cautioned against making too much of it because of the strong potential for unmeasured confounding. In particular, lupus patients as a group are known to rate on the lower end of measures of social determinants of health, a status that is an established major risk factor for COVID-19 disease.
“A strength of the global registry has been that it provides timely data that’s been very helpful for rheumatologists to rapidly dispel misinformation that has been spread about hydroxychloroquine, especially statements about lupus patients not getting COVID-19. We know from these data that’s not true,” she said.
Being on background NSAIDs at the time of SARS-CoV-2 infection was not associated with increased risk of hospitalization; in fact, NSAID users were 36% less likely to be hospitalized for their COVID-19 disease, although this difference didn’t reach statistical significance.
Dr. Yazdany urged her fellow rheumatologists to enter their cases on the registry website: rheum-covid.org. There they can also join the registry mailing list and receive weekly updates.
Other recent insights on COVID-19 in rheumatology
An as-yet unpublished U.K. observational study involving electronic health record data on 17 million people included 885,000 individuals with RA, SLE, or psoriasis. After extensive statistical controlling for the known risk factors for severe COVID-19 infection, including a measure of socioeconomic deprivation, the group with one of these autoimmune diseases had an adjusted, statistically significant 23% increased risk of hospital death because of COVID-19 infection.
“This is the largest study of its kind to date. There’s potential for unmeasured confounding and selection bias here due to who gets tested. We’ll have to see where this study lands, but I think it does suggest there’s a slightly higher mortality risk in COVID-infected patients with rheumatic disease,” according to Dr. Yazdany.
On the other hand, there have been at least eight recently published patient surveys and case series of patients with rheumatic diseases in areas of the world hardest hit by the pandemic, and they paint a consistent picture.
“What we’ve learned from these studies was the infection rate was generally in the ballpark of people in the region. It doesn’t seem like there’s a dramatically higher infection rate in people with rheumatic disease in these surveys. The hospitalized rheumatology patients had many of the familiar comorbidities. This is the first glance at how likely people are to become infected and how they fared, and I think overall the data have been quite reassuring,” she said.
Dr. Yazdany reported serving as a consultant to AstraZeneca and Eli Lilly and receiving research funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Centers for Disease Control and Prevention.
REPORTING FROM SOTA 2020
First PARP inhibitor approved for metastatic prostate cancer
A completely new approach to the treatment of prostate cancer is now available to clinicians through the approval of the first PARP inhibitor for use in certain patients with this disease.
Rucaparib (Rubraca, Clovis Oncology) is the first PARP inhibitor approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) that harbors deleterious BRCA mutations (germline and/or somatic). The drug is indicated for use in patients who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.
The drug is already marketed for use in ovarian cancer.
The new prostate cancer indication was granted an accelerated approval by the US Food and Drug Administration (FDA) on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial. A confirmatory phase 3 trial, TRITON3, is currently underway.
“Standard treatment options for men with mCRPC have been limited to androgen receptor–targeting therapies, taxane chemotherapy, radium-223, and sipuleucel-T,” said Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, in a statement.
“Rucaparib is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation,” said Abida, who is also the principal investigator of the TRITON2 study. “Given the level and duration of responses observed with rucaparib in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population.”
Other indications, another PARP inhibitor
Rucaparib is already approved for the treatment of women with advanced BRCA mutation–positive ovarian cancer who have received two or more prior chemotherapies. It is also approved as maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who demonstrate a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
Another PARP inhibitor, olaparib (Lynparza, AstraZeneca), is awaiting approval for use in prostate cancer in men with BRCA mutations. That pending approval is based on results from the phase 3 PROfound trial, which was hailed as a “landmark trial” when it was presented last year. The results showed a significant improved in disease-free progression. The company recently announced that there was also a significant improvement in overall survival.
Olaparib is already approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status and as first-line maintenance treatment in BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy and for the maintenance treatment of germline BRCA-mutated advanced pancreatic cancer following first-line platinum-based chemotherapy.
Details of the TRITON2 study
The accelerated approval for use of rucaparib in BRCA prostate cancer was based on efficacy data from the multicenter, single-arm TRITON2 clinical trial. The cohort included 62 patients with a BRCA (germline and/or somatic) mutation and measurable disease; 115 patients with a BRCA (germline and/or somatic) mutation and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency (HRD)–positive mCRPC.
The major efficacy outcomes were objective response rate (ORR) and duration of response. Confirmed PSA response rate was also a prespecified endpoint. Data were assessed by independent radiologic review.
For the patients with measurable disease and a BRCA mutation, the ORR was 44%. The ORR was similar for patients with a germline BRCA mutation.
Median duration of response was not evaluable at data cutoff but ranged from 1.7 to 24+ months. Of the 27 patients with a confirmed objective response, 15 (56%) patients showed a response that lasted 6 months or longer.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%.
The safety evaluation was based on an analysis of the 209 patients with HRD-positive mCRPC and included 115 with deleterious BRCA mutations. The most common adverse events (≥20%; grade 1-4) in the patients with BRCA mutations were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).
Rucaparib has been associated with hematologic toxicity, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, MDS/AML was not observed in the TRITON2 study, regardless of HRD mutation.
Confirmation with TRITON3
A phase 3, randomized, open-label study, TRITON3, is currently underway and is expected to serve as the confirmatory study for the accelerated approval in mCRPC. TRITON3 is comparing rucaparib with physician’s choice of therapy in patients with mCRPC who have specific gene alterations, including BRCA and ATM alterations, and who have experienced disease progression after androgen receptor–directed therapy but have not yet received chemotherapy. The primary endpoint for TRITON3 is radiographic progression-free survival.
This article first appeared on Medscape.com.
A completely new approach to the treatment of prostate cancer is now available to clinicians through the approval of the first PARP inhibitor for use in certain patients with this disease.
Rucaparib (Rubraca, Clovis Oncology) is the first PARP inhibitor approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) that harbors deleterious BRCA mutations (germline and/or somatic). The drug is indicated for use in patients who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.
The drug is already marketed for use in ovarian cancer.
The new prostate cancer indication was granted an accelerated approval by the US Food and Drug Administration (FDA) on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial. A confirmatory phase 3 trial, TRITON3, is currently underway.
“Standard treatment options for men with mCRPC have been limited to androgen receptor–targeting therapies, taxane chemotherapy, radium-223, and sipuleucel-T,” said Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, in a statement.
“Rucaparib is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation,” said Abida, who is also the principal investigator of the TRITON2 study. “Given the level and duration of responses observed with rucaparib in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population.”
Other indications, another PARP inhibitor
Rucaparib is already approved for the treatment of women with advanced BRCA mutation–positive ovarian cancer who have received two or more prior chemotherapies. It is also approved as maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who demonstrate a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
Another PARP inhibitor, olaparib (Lynparza, AstraZeneca), is awaiting approval for use in prostate cancer in men with BRCA mutations. That pending approval is based on results from the phase 3 PROfound trial, which was hailed as a “landmark trial” when it was presented last year. The results showed a significant improved in disease-free progression. The company recently announced that there was also a significant improvement in overall survival.
Olaparib is already approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status and as first-line maintenance treatment in BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy and for the maintenance treatment of germline BRCA-mutated advanced pancreatic cancer following first-line platinum-based chemotherapy.
Details of the TRITON2 study
The accelerated approval for use of rucaparib in BRCA prostate cancer was based on efficacy data from the multicenter, single-arm TRITON2 clinical trial. The cohort included 62 patients with a BRCA (germline and/or somatic) mutation and measurable disease; 115 patients with a BRCA (germline and/or somatic) mutation and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency (HRD)–positive mCRPC.
The major efficacy outcomes were objective response rate (ORR) and duration of response. Confirmed PSA response rate was also a prespecified endpoint. Data were assessed by independent radiologic review.
For the patients with measurable disease and a BRCA mutation, the ORR was 44%. The ORR was similar for patients with a germline BRCA mutation.
Median duration of response was not evaluable at data cutoff but ranged from 1.7 to 24+ months. Of the 27 patients with a confirmed objective response, 15 (56%) patients showed a response that lasted 6 months or longer.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%.
The safety evaluation was based on an analysis of the 209 patients with HRD-positive mCRPC and included 115 with deleterious BRCA mutations. The most common adverse events (≥20%; grade 1-4) in the patients with BRCA mutations were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).
Rucaparib has been associated with hematologic toxicity, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, MDS/AML was not observed in the TRITON2 study, regardless of HRD mutation.
Confirmation with TRITON3
A phase 3, randomized, open-label study, TRITON3, is currently underway and is expected to serve as the confirmatory study for the accelerated approval in mCRPC. TRITON3 is comparing rucaparib with physician’s choice of therapy in patients with mCRPC who have specific gene alterations, including BRCA and ATM alterations, and who have experienced disease progression after androgen receptor–directed therapy but have not yet received chemotherapy. The primary endpoint for TRITON3 is radiographic progression-free survival.
This article first appeared on Medscape.com.
A completely new approach to the treatment of prostate cancer is now available to clinicians through the approval of the first PARP inhibitor for use in certain patients with this disease.
Rucaparib (Rubraca, Clovis Oncology) is the first PARP inhibitor approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) that harbors deleterious BRCA mutations (germline and/or somatic). The drug is indicated for use in patients who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.
The drug is already marketed for use in ovarian cancer.
The new prostate cancer indication was granted an accelerated approval by the US Food and Drug Administration (FDA) on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial. A confirmatory phase 3 trial, TRITON3, is currently underway.
“Standard treatment options for men with mCRPC have been limited to androgen receptor–targeting therapies, taxane chemotherapy, radium-223, and sipuleucel-T,” said Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, in a statement.
“Rucaparib is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation,” said Abida, who is also the principal investigator of the TRITON2 study. “Given the level and duration of responses observed with rucaparib in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population.”
Other indications, another PARP inhibitor
Rucaparib is already approved for the treatment of women with advanced BRCA mutation–positive ovarian cancer who have received two or more prior chemotherapies. It is also approved as maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who demonstrate a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
Another PARP inhibitor, olaparib (Lynparza, AstraZeneca), is awaiting approval for use in prostate cancer in men with BRCA mutations. That pending approval is based on results from the phase 3 PROfound trial, which was hailed as a “landmark trial” when it was presented last year. The results showed a significant improved in disease-free progression. The company recently announced that there was also a significant improvement in overall survival.
Olaparib is already approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status and as first-line maintenance treatment in BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy and for the maintenance treatment of germline BRCA-mutated advanced pancreatic cancer following first-line platinum-based chemotherapy.
Details of the TRITON2 study
The accelerated approval for use of rucaparib in BRCA prostate cancer was based on efficacy data from the multicenter, single-arm TRITON2 clinical trial. The cohort included 62 patients with a BRCA (germline and/or somatic) mutation and measurable disease; 115 patients with a BRCA (germline and/or somatic) mutation and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency (HRD)–positive mCRPC.
The major efficacy outcomes were objective response rate (ORR) and duration of response. Confirmed PSA response rate was also a prespecified endpoint. Data were assessed by independent radiologic review.
For the patients with measurable disease and a BRCA mutation, the ORR was 44%. The ORR was similar for patients with a germline BRCA mutation.
Median duration of response was not evaluable at data cutoff but ranged from 1.7 to 24+ months. Of the 27 patients with a confirmed objective response, 15 (56%) patients showed a response that lasted 6 months or longer.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%.
The safety evaluation was based on an analysis of the 209 patients with HRD-positive mCRPC and included 115 with deleterious BRCA mutations. The most common adverse events (≥20%; grade 1-4) in the patients with BRCA mutations were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).
Rucaparib has been associated with hematologic toxicity, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, MDS/AML was not observed in the TRITON2 study, regardless of HRD mutation.
Confirmation with TRITON3
A phase 3, randomized, open-label study, TRITON3, is currently underway and is expected to serve as the confirmatory study for the accelerated approval in mCRPC. TRITON3 is comparing rucaparib with physician’s choice of therapy in patients with mCRPC who have specific gene alterations, including BRCA and ATM alterations, and who have experienced disease progression after androgen receptor–directed therapy but have not yet received chemotherapy. The primary endpoint for TRITON3 is radiographic progression-free survival.
This article first appeared on Medscape.com.