Pharmacology

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

Medication nonadherence is common with oral antipsychotic formulations, resulting in relapse, increased morbidity, and more frequent psychiatric hospitalization.^1-7 Psychiatric hospitalization and illness decompensation is costly to health care systems and leads to reduced quality of life for veterans and families.^6,7 Long-acting injectable antipsychotics (LAIAs) were developed to enhance antipsychotic adherence and improve patient outcomes, including reduced psychiatric hospitalization.^8-12

Little outcomes data exist comparing LAIAs, including biweekly risperidone microspheres and monthly paliperidone palmitate.^10-13 Risperidone microspheres require a 3-week oral crossover and are administered every 2 weeks, whereas paliperidone palmitate does not require an oral crossover and is administered every 4 weeks. The paliperidone palmitate loading regimen replaces an oral crossover.

The primary objective of this study was to compare the number of psychiatric hospitalizations between veterans administered risperidone microspheres and those on paliperidone palmitate pre- and post-LAIA initiation. Secondary objectives were to assess rehospitalization rates between patients taking risperidone microspheres and paliperidone palmitate, reduction in pre- and posthospitalization rates with LAIAs, and medication adherence.

Methods

This observational study with a retrospective cohort design was conducted at the Veterans Affairs Loma Linda Healthcare System (VALLHS) in California. We examined veterans who were initiated on LAIAs risperidone microspheres or paliperidone palmitate from January 01, 2016 through December 31, 2018. Veterans who were aged ≥ 18 years and received ≥ 2 injections of either risperidone microspheres or paliperidone palmitate during the study period were included. Veterans were excluded if they had received < 2 doses of either LAIA, received the LAIA outside of the review period, were nonadherent to risperidone crossover if they received risperidone microspheres, or transferred their care to another facility. At VALLHS, LAIA injections are administered by a nurse, and veterans must travel to the facility to receive the injections.

Extracted patient chart elements included participant demographics; diagnoses; comorbid alcohol, nicotine, opioid, or other substance use; duration on LAIA; psychiatric hospitalizations pre- and postinitiation of the LAIA; medication adherence; and medication discontinuation based on clinician documentation and clinic orders (Table 1).

Data Analysis

Patient demographics were analyzed using descriptive statistics and experimental comparisons between the risperidone microspheres and paliperidone palmitate groups to assess baseline differences between groups. Psychiatric hospitalizations pre- and post-LAIA were analyzed with parallel group (between veterans–independent groups) and pre-post (within veterans–dependent groups) designs. Index hospitalizations were examined for a period equivalent to the length of time veterans were on the LAIA. Psychiatric rehospitalization rates were analyzed for patients who had index hospitalizations and were rehospitalized for any period when they were receiving the LAIA. Incidences of pre- and post-LAIA hospitalizations were calculated in 100 person-years.

Parallel-group analysis was analyzed using the χ² and Mann-Whitney U tests. Pre-post analyses were analyzed using the Wilcoxon rank sum test. P was set at < .05 for statistical significance.

Results

We screened 111 veterans, and 97 were included in this study (risperidone microspheres, 44; paliperidone palmitate, 53). Mean (SD) age was 46 (13.8) years, 92% were male, 38% were White, 94% were diagnosed with schizophrenia or schizoaffective disorder, and 11% were homeless. Substance use was documented as 52% for nicotine products, 40% for alcohol, 31% for cannabis, 27% for methamphetamine, 7% for cocaine, and 3% for opioids. Cannabis, methamphetamine, cocaine, and opioid use were based on clinician documentation and listed as active diagnoses at the time of LAIA initiation. Statistical significance was found in index hospitalizations P = .009) and history of cocaine use disorder (6.8% vs 7.5%, P < .001).

Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02) and were less likely to be rehospitalized (22.7% vs 47.2%, P = .01) compared with paliperidone palmitate. However, veterans taking risperidone microspheres had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks, P = .04) compared with paliperidone palmitate, mainly because patients switched to a different LAIA or oral antipsychotic. No differences were detected in nonadherence and discontinuation between risperidone microspheres and paliperidone palmitate. All veterans in the risperidone microspheres group adhered to oral risperidone crossover with an average 87.8% days covered (Table 2).

Discussion

The main finding of this study was that initiation of LAIAs significantly reduced hospitalizations. Veterans taking risperidone microspheres had higher index hospitalizations and lower posttreatment hospitalizations compared with paliperidone palmitate. We found that patients initiated on risperidone microspheres had more hospitalizations before use of a LAIA than those initiated on paliperidone palmitate. Risperidone microspheres reduced the number of hospitalization post-LAIA significantly more than paliperidone palmitate. We also found that veterans taking risperidone microspheres were on the medication for less mean (SD) time than those on paliperidone palmitate (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04).

To our knowledge, this is one of the few studies that compared outcomes of psychiatric hospitalizations, medication adherence, and treatment discontinuation between risperidone microspheres and paliperidone palmitate, specifically in a veteran population.^16-19 Limosin and colleagues aimed to compare length of stay during the initial hospitalization, rehospitalization risk, and treatment duration between risperidone microspheres and paliperidone palmitate in patients with schizophrenia.¹⁶ These researchers detected no differences in initial hospitalization duration and time to rehospitalization between risperidone microspheres and paliperidone palmitate.¹⁶ The study revealed a more favorable trend in time to discontinuation for paliperidone palmitate, but switching between LAIAs might have confounded the data.¹⁶ The authors note that their study lacked power, and patients on paliperidone palmitate had significantly more nonpsychiatric comorbidities.¹⁶ Joshi and colleagues looked at adherence, medication discontinuation, hospitalization rates, emergency department visits, and hospitalization costs between risperidone microspheres and paliperidone palmitate in patients identified in Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases.¹⁷ The authors found paliperidone palmitate to be superior in all objectives with better adherence, lower discontinuation rates, less likelihood of hospitalization, fewer emergency department visits, and lower hospitalization costs compared with risperidone microspheres.¹⁷ Korell and colleagues aimed to establish reference ranges for plasma concentrations of risperidone and paliperidone among adherent patients.¹⁸

The results in our study are somewhat unexpected in part because of the close relationship between risperidone and paliperidone. Risperidone is converted to paliperidone (9-OH-risperidone) via hepatic cytochrome P450 2D6. Although the molecules do not have identical pharmacologic profiles, it is accepted that they are similar enough that risperidone can establish oral tolerability when transitioning therapy to paliperidone palmitate and vice versa.²⁴ Although the active moiety in risperidone microspheres and paliperidone palmitate is similar, the dosing interval for risperidone microspheres is 2 weeks compared with 4 weeks with paliperidone palmitate. One potential explanation as to why veterans started on risperidone microspheres experienced better outcomes is because they had twice as many office visits with the health care team. Facility procedures dictate veterans receive the LAIA at an on-site clinic. During the visits, a licensed vocational nurse administers the injection and monitors the patient for 15 to 30 minutes afterward.

Despite new LAIAs coming to market, high-quality data examining potential differences in treatment outcomes among agents are limited. This is problematic for clinicians who want to optimize care by understanding how administration schedules or other aspects of LAIA use could modify treatment outcomes. Our results suggest that an advantage might exist in selecting an agent with a more frequent administration schedule, at least initially. This could allow for close monitoring and regular therapeutic contact, which could improve short-term outcomes. This conclusion is supported by meta-analyses, randomized controlled trials, and conceptual articles conducted by Wehring and colleagues, Berwaerts and colleagues, and Parellada and colleagues, respectively, who examined patients on different LAIAs and contact with health care professionals as part of their research.^26-28 These researchers concluded that patients who had regular contact with a health care professional had better outcomes when initiated on a LAIA.^26-28

Limitations

There are several limitations in this study. Retrospective and observational methods introduce risks of bias and confounding variables. Sample size might have limited statistical power to detect differences. Veterans might have had undocumented pre- or posthospitalizations at other institutions, which was not accounted for and lack of rehospitalization is not conclusive of a positive outcome. Institutions could improve on our study and help to fill gaps in comparative data by conducting larger analyses over longer periods and including more LAIA agents.

Conclusions

Although veterans that were administered risperidone microspheres had a shorter treatment duration, they were less likely to be rehospitalized, had a fewer mean number of post-LAIA hospitalizations, and had a larger difference in incidence in 100 person-years compared with veterans on paliperidone palmitate. Nonadherence and discontinuation rates were comparable between risperidone microspheres and paliperidone palmitate. Future studies could aim to further clarify differences in outcomes among agents or administration schedules.

Medication nonadherence is common with oral antipsychotic formulations, resulting in relapse, increased morbidity, and more frequent psychiatric hospitalization.^1-7 Psychiatric hospitalization and illness decompensation is costly to health care systems and leads to reduced quality of life for veterans and families.^6,7 Long-acting injectable antipsychotics (LAIAs) were developed to enhance antipsychotic adherence and improve patient outcomes, including reduced psychiatric hospitalization.^8-12

Little outcomes data exist comparing LAIAs, including biweekly risperidone microspheres and monthly paliperidone palmitate.^10-13 Risperidone microspheres require a 3-week oral crossover and are administered every 2 weeks, whereas paliperidone palmitate does not require an oral crossover and is administered every 4 weeks. The paliperidone palmitate loading regimen replaces an oral crossover.

The primary objective of this study was to compare the number of psychiatric hospitalizations between veterans administered risperidone microspheres and those on paliperidone palmitate pre- and post-LAIA initiation. Secondary objectives were to assess rehospitalization rates between patients taking risperidone microspheres and paliperidone palmitate, reduction in pre- and posthospitalization rates with LAIAs, and medication adherence.

Methods

This observational study with a retrospective cohort design was conducted at the Veterans Affairs Loma Linda Healthcare System (VALLHS) in California. We examined veterans who were initiated on LAIAs risperidone microspheres or paliperidone palmitate from January 01, 2016 through December 31, 2018. Veterans who were aged ≥ 18 years and received ≥ 2 injections of either risperidone microspheres or paliperidone palmitate during the study period were included. Veterans were excluded if they had received < 2 doses of either LAIA, received the LAIA outside of the review period, were nonadherent to risperidone crossover if they received risperidone microspheres, or transferred their care to another facility. At VALLHS, LAIA injections are administered by a nurse, and veterans must travel to the facility to receive the injections.

Extracted patient chart elements included participant demographics; diagnoses; comorbid alcohol, nicotine, opioid, or other substance use; duration on LAIA; psychiatric hospitalizations pre- and postinitiation of the LAIA; medication adherence; and medication discontinuation based on clinician documentation and clinic orders (Table 1).

Data Analysis

Patient demographics were analyzed using descriptive statistics and experimental comparisons between the risperidone microspheres and paliperidone palmitate groups to assess baseline differences between groups. Psychiatric hospitalizations pre- and post-LAIA were analyzed with parallel group (between veterans–independent groups) and pre-post (within veterans–dependent groups) designs. Index hospitalizations were examined for a period equivalent to the length of time veterans were on the LAIA. Psychiatric rehospitalization rates were analyzed for patients who had index hospitalizations and were rehospitalized for any period when they were receiving the LAIA. Incidences of pre- and post-LAIA hospitalizations were calculated in 100 person-years.

Parallel-group analysis was analyzed using the χ² and Mann-Whitney U tests. Pre-post analyses were analyzed using the Wilcoxon rank sum test. P was set at < .05 for statistical significance.

Results

We screened 111 veterans, and 97 were included in this study (risperidone microspheres, 44; paliperidone palmitate, 53). Mean (SD) age was 46 (13.8) years, 92% were male, 38% were White, 94% were diagnosed with schizophrenia or schizoaffective disorder, and 11% were homeless. Substance use was documented as 52% for nicotine products, 40% for alcohol, 31% for cannabis, 27% for methamphetamine, 7% for cocaine, and 3% for opioids. Cannabis, methamphetamine, cocaine, and opioid use were based on clinician documentation and listed as active diagnoses at the time of LAIA initiation. Statistical significance was found in index hospitalizations P = .009) and history of cocaine use disorder (6.8% vs 7.5%, P < .001).

Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02) and were less likely to be rehospitalized (22.7% vs 47.2%, P = .01) compared with paliperidone palmitate. However, veterans taking risperidone microspheres had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks, P = .04) compared with paliperidone palmitate, mainly because patients switched to a different LAIA or oral antipsychotic. No differences were detected in nonadherence and discontinuation between risperidone microspheres and paliperidone palmitate. All veterans in the risperidone microspheres group adhered to oral risperidone crossover with an average 87.8% days covered (Table 2).

Discussion

The main finding of this study was that initiation of LAIAs significantly reduced hospitalizations. Veterans taking risperidone microspheres had higher index hospitalizations and lower posttreatment hospitalizations compared with paliperidone palmitate. We found that patients initiated on risperidone microspheres had more hospitalizations before use of a LAIA than those initiated on paliperidone palmitate. Risperidone microspheres reduced the number of hospitalization post-LAIA significantly more than paliperidone palmitate. We also found that veterans taking risperidone microspheres were on the medication for less mean (SD) time than those on paliperidone palmitate (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04).

To our knowledge, this is one of the few studies that compared outcomes of psychiatric hospitalizations, medication adherence, and treatment discontinuation between risperidone microspheres and paliperidone palmitate, specifically in a veteran population.^16-19 Limosin and colleagues aimed to compare length of stay during the initial hospitalization, rehospitalization risk, and treatment duration between risperidone microspheres and paliperidone palmitate in patients with schizophrenia.¹⁶ These researchers detected no differences in initial hospitalization duration and time to rehospitalization between risperidone microspheres and paliperidone palmitate.¹⁶ The study revealed a more favorable trend in time to discontinuation for paliperidone palmitate, but switching between LAIAs might have confounded the data.¹⁶ The authors note that their study lacked power, and patients on paliperidone palmitate had significantly more nonpsychiatric comorbidities.¹⁶ Joshi and colleagues looked at adherence, medication discontinuation, hospitalization rates, emergency department visits, and hospitalization costs between risperidone microspheres and paliperidone palmitate in patients identified in Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases.¹⁷ The authors found paliperidone palmitate to be superior in all objectives with better adherence, lower discontinuation rates, less likelihood of hospitalization, fewer emergency department visits, and lower hospitalization costs compared with risperidone microspheres.¹⁷ Korell and colleagues aimed to establish reference ranges for plasma concentrations of risperidone and paliperidone among adherent patients.¹⁸

The results in our study are somewhat unexpected in part because of the close relationship between risperidone and paliperidone. Risperidone is converted to paliperidone (9-OH-risperidone) via hepatic cytochrome P450 2D6. Although the molecules do not have identical pharmacologic profiles, it is accepted that they are similar enough that risperidone can establish oral tolerability when transitioning therapy to paliperidone palmitate and vice versa.²⁴ Although the active moiety in risperidone microspheres and paliperidone palmitate is similar, the dosing interval for risperidone microspheres is 2 weeks compared with 4 weeks with paliperidone palmitate. One potential explanation as to why veterans started on risperidone microspheres experienced better outcomes is because they had twice as many office visits with the health care team. Facility procedures dictate veterans receive the LAIA at an on-site clinic. During the visits, a licensed vocational nurse administers the injection and monitors the patient for 15 to 30 minutes afterward.

Despite new LAIAs coming to market, high-quality data examining potential differences in treatment outcomes among agents are limited. This is problematic for clinicians who want to optimize care by understanding how administration schedules or other aspects of LAIA use could modify treatment outcomes. Our results suggest that an advantage might exist in selecting an agent with a more frequent administration schedule, at least initially. This could allow for close monitoring and regular therapeutic contact, which could improve short-term outcomes. This conclusion is supported by meta-analyses, randomized controlled trials, and conceptual articles conducted by Wehring and colleagues, Berwaerts and colleagues, and Parellada and colleagues, respectively, who examined patients on different LAIAs and contact with health care professionals as part of their research.^26-28 These researchers concluded that patients who had regular contact with a health care professional had better outcomes when initiated on a LAIA.^26-28

Limitations

There are several limitations in this study. Retrospective and observational methods introduce risks of bias and confounding variables. Sample size might have limited statistical power to detect differences. Veterans might have had undocumented pre- or posthospitalizations at other institutions, which was not accounted for and lack of rehospitalization is not conclusive of a positive outcome. Institutions could improve on our study and help to fill gaps in comparative data by conducting larger analyses over longer periods and including more LAIA agents.

Conclusions

Although veterans that were administered risperidone microspheres had a shorter treatment duration, they were less likely to be rehospitalized, had a fewer mean number of post-LAIA hospitalizations, and had a larger difference in incidence in 100 person-years compared with veterans on paliperidone palmitate. Nonadherence and discontinuation rates were comparable between risperidone microspheres and paliperidone palmitate. Future studies could aim to further clarify differences in outcomes among agents or administration schedules.

Medication nonadherence is common with oral antipsychotic formulations, resulting in relapse, increased morbidity, and more frequent psychiatric hospitalization.^1-7 Psychiatric hospitalization and illness decompensation is costly to health care systems and leads to reduced quality of life for veterans and families.^6,7 Long-acting injectable antipsychotics (LAIAs) were developed to enhance antipsychotic adherence and improve patient outcomes, including reduced psychiatric hospitalization.^8-12

Little outcomes data exist comparing LAIAs, including biweekly risperidone microspheres and monthly paliperidone palmitate.^10-13 Risperidone microspheres require a 3-week oral crossover and are administered every 2 weeks, whereas paliperidone palmitate does not require an oral crossover and is administered every 4 weeks. The paliperidone palmitate loading regimen replaces an oral crossover.

The primary objective of this study was to compare the number of psychiatric hospitalizations between veterans administered risperidone microspheres and those on paliperidone palmitate pre- and post-LAIA initiation. Secondary objectives were to assess rehospitalization rates between patients taking risperidone microspheres and paliperidone palmitate, reduction in pre- and posthospitalization rates with LAIAs, and medication adherence.

Methods

This observational study with a retrospective cohort design was conducted at the Veterans Affairs Loma Linda Healthcare System (VALLHS) in California. We examined veterans who were initiated on LAIAs risperidone microspheres or paliperidone palmitate from January 01, 2016 through December 31, 2018. Veterans who were aged ≥ 18 years and received ≥ 2 injections of either risperidone microspheres or paliperidone palmitate during the study period were included. Veterans were excluded if they had received < 2 doses of either LAIA, received the LAIA outside of the review period, were nonadherent to risperidone crossover if they received risperidone microspheres, or transferred their care to another facility. At VALLHS, LAIA injections are administered by a nurse, and veterans must travel to the facility to receive the injections.

Extracted patient chart elements included participant demographics; diagnoses; comorbid alcohol, nicotine, opioid, or other substance use; duration on LAIA; psychiatric hospitalizations pre- and postinitiation of the LAIA; medication adherence; and medication discontinuation based on clinician documentation and clinic orders (Table 1).

Data Analysis

Patient demographics were analyzed using descriptive statistics and experimental comparisons between the risperidone microspheres and paliperidone palmitate groups to assess baseline differences between groups. Psychiatric hospitalizations pre- and post-LAIA were analyzed with parallel group (between veterans–independent groups) and pre-post (within veterans–dependent groups) designs. Index hospitalizations were examined for a period equivalent to the length of time veterans were on the LAIA. Psychiatric rehospitalization rates were analyzed for patients who had index hospitalizations and were rehospitalized for any period when they were receiving the LAIA. Incidences of pre- and post-LAIA hospitalizations were calculated in 100 person-years.

Parallel-group analysis was analyzed using the χ² and Mann-Whitney U tests. Pre-post analyses were analyzed using the Wilcoxon rank sum test. P was set at < .05 for statistical significance.

Results

We screened 111 veterans, and 97 were included in this study (risperidone microspheres, 44; paliperidone palmitate, 53). Mean (SD) age was 46 (13.8) years, 92% were male, 38% were White, 94% were diagnosed with schizophrenia or schizoaffective disorder, and 11% were homeless. Substance use was documented as 52% for nicotine products, 40% for alcohol, 31% for cannabis, 27% for methamphetamine, 7% for cocaine, and 3% for opioids. Cannabis, methamphetamine, cocaine, and opioid use were based on clinician documentation and listed as active diagnoses at the time of LAIA initiation. Statistical significance was found in index hospitalizations P = .009) and history of cocaine use disorder (6.8% vs 7.5%, P < .001).

Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02) and were less likely to be rehospitalized (22.7% vs 47.2%, P = .01) compared with paliperidone palmitate. However, veterans taking risperidone microspheres had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks, P = .04) compared with paliperidone palmitate, mainly because patients switched to a different LAIA or oral antipsychotic. No differences were detected in nonadherence and discontinuation between risperidone microspheres and paliperidone palmitate. All veterans in the risperidone microspheres group adhered to oral risperidone crossover with an average 87.8% days covered (Table 2).

Discussion

The main finding of this study was that initiation of LAIAs significantly reduced hospitalizations. Veterans taking risperidone microspheres had higher index hospitalizations and lower posttreatment hospitalizations compared with paliperidone palmitate. We found that patients initiated on risperidone microspheres had more hospitalizations before use of a LAIA than those initiated on paliperidone palmitate. Risperidone microspheres reduced the number of hospitalization post-LAIA significantly more than paliperidone palmitate. We also found that veterans taking risperidone microspheres were on the medication for less mean (SD) time than those on paliperidone palmitate (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04).

To our knowledge, this is one of the few studies that compared outcomes of psychiatric hospitalizations, medication adherence, and treatment discontinuation between risperidone microspheres and paliperidone palmitate, specifically in a veteran population.^16-19 Limosin and colleagues aimed to compare length of stay during the initial hospitalization, rehospitalization risk, and treatment duration between risperidone microspheres and paliperidone palmitate in patients with schizophrenia.¹⁶ These researchers detected no differences in initial hospitalization duration and time to rehospitalization between risperidone microspheres and paliperidone palmitate.¹⁶ The study revealed a more favorable trend in time to discontinuation for paliperidone palmitate, but switching between LAIAs might have confounded the data.¹⁶ The authors note that their study lacked power, and patients on paliperidone palmitate had significantly more nonpsychiatric comorbidities.¹⁶ Joshi and colleagues looked at adherence, medication discontinuation, hospitalization rates, emergency department visits, and hospitalization costs between risperidone microspheres and paliperidone palmitate in patients identified in Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases.¹⁷ The authors found paliperidone palmitate to be superior in all objectives with better adherence, lower discontinuation rates, less likelihood of hospitalization, fewer emergency department visits, and lower hospitalization costs compared with risperidone microspheres.¹⁷ Korell and colleagues aimed to establish reference ranges for plasma concentrations of risperidone and paliperidone among adherent patients.¹⁸

The results in our study are somewhat unexpected in part because of the close relationship between risperidone and paliperidone. Risperidone is converted to paliperidone (9-OH-risperidone) via hepatic cytochrome P450 2D6. Although the molecules do not have identical pharmacologic profiles, it is accepted that they are similar enough that risperidone can establish oral tolerability when transitioning therapy to paliperidone palmitate and vice versa.²⁴ Although the active moiety in risperidone microspheres and paliperidone palmitate is similar, the dosing interval for risperidone microspheres is 2 weeks compared with 4 weeks with paliperidone palmitate. One potential explanation as to why veterans started on risperidone microspheres experienced better outcomes is because they had twice as many office visits with the health care team. Facility procedures dictate veterans receive the LAIA at an on-site clinic. During the visits, a licensed vocational nurse administers the injection and monitors the patient for 15 to 30 minutes afterward.

Despite new LAIAs coming to market, high-quality data examining potential differences in treatment outcomes among agents are limited. This is problematic for clinicians who want to optimize care by understanding how administration schedules or other aspects of LAIA use could modify treatment outcomes. Our results suggest that an advantage might exist in selecting an agent with a more frequent administration schedule, at least initially. This could allow for close monitoring and regular therapeutic contact, which could improve short-term outcomes. This conclusion is supported by meta-analyses, randomized controlled trials, and conceptual articles conducted by Wehring and colleagues, Berwaerts and colleagues, and Parellada and colleagues, respectively, who examined patients on different LAIAs and contact with health care professionals as part of their research.^26-28 These researchers concluded that patients who had regular contact with a health care professional had better outcomes when initiated on a LAIA.^26-28

Limitations

There are several limitations in this study. Retrospective and observational methods introduce risks of bias and confounding variables. Sample size might have limited statistical power to detect differences. Veterans might have had undocumented pre- or posthospitalizations at other institutions, which was not accounted for and lack of rehospitalization is not conclusive of a positive outcome. Institutions could improve on our study and help to fill gaps in comparative data by conducting larger analyses over longer periods and including more LAIA agents.

Conclusions

Although veterans that were administered risperidone microspheres had a shorter treatment duration, they were less likely to be rehospitalized, had a fewer mean number of post-LAIA hospitalizations, and had a larger difference in incidence in 100 person-years compared with veterans on paliperidone palmitate. Nonadherence and discontinuation rates were comparable between risperidone microspheres and paliperidone palmitate. Future studies could aim to further clarify differences in outcomes among agents or administration schedules.

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of stage IIB and IIC melanoma after complete resection in adults and children over age 12 years. The FDA also extended the approval to those with stage III disease.

The FDA approval on Dec. 3 was based on first interim findings from the randomized, placebo-controlled KEYNOTE-716 trial, which evaluated patients with stage IIB and IIC disease. 

Since the anti-PD-1 therapy was approved in metastatic melanoma 7 years ago, “we have built on this foundation in melanoma and have expanded the use of KEYTRUDA into earlier stages of this disease,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “With today’s approval, we can now offer health care providers and patients 12 years and older the opportunity to help prevent melanoma recurrence with Keytruda across resected stage IIB, stage IIC, and stage III melanoma.”

In KEYNOTE-716, patients with completely resected stage IIB or IIC melanoma were randomly assigned to receive 200 mg of intravenous pembrolizumab, the pediatric dose 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, or placebo for up to 1 year until disease recurrence or unacceptable toxicity.

After a median follow-up of 14.4 months, investigators reported a statistically significant 35% improvement in recurrence-free survival (RFS) in those treated with pembrolizumab, compared with those who received placebo (hazard ratio, 0.65).

The most common adverse reactions reported in patients receiving pembrolizumab in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia, each occurring in at least 20% of patients.

“Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda,” according to Merck.

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

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of stage IIB and IIC melanoma after complete resection in adults and children over age 12 years. The FDA also extended the approval to those with stage III disease.

The FDA approval on Dec. 3 was based on first interim findings from the randomized, placebo-controlled KEYNOTE-716 trial, which evaluated patients with stage IIB and IIC disease. 

Since the anti-PD-1 therapy was approved in metastatic melanoma 7 years ago, “we have built on this foundation in melanoma and have expanded the use of KEYTRUDA into earlier stages of this disease,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “With today’s approval, we can now offer health care providers and patients 12 years and older the opportunity to help prevent melanoma recurrence with Keytruda across resected stage IIB, stage IIC, and stage III melanoma.”

In KEYNOTE-716, patients with completely resected stage IIB or IIC melanoma were randomly assigned to receive 200 mg of intravenous pembrolizumab, the pediatric dose 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, or placebo for up to 1 year until disease recurrence or unacceptable toxicity.

After a median follow-up of 14.4 months, investigators reported a statistically significant 35% improvement in recurrence-free survival (RFS) in those treated with pembrolizumab, compared with those who received placebo (hazard ratio, 0.65).

The most common adverse reactions reported in patients receiving pembrolizumab in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia, each occurring in at least 20% of patients.

“Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda,” according to Merck.

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

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of stage IIB and IIC melanoma after complete resection in adults and children over age 12 years. The FDA also extended the approval to those with stage III disease.

The FDA approval on Dec. 3 was based on first interim findings from the randomized, placebo-controlled KEYNOTE-716 trial, which evaluated patients with stage IIB and IIC disease. 

Since the anti-PD-1 therapy was approved in metastatic melanoma 7 years ago, “we have built on this foundation in melanoma and have expanded the use of KEYTRUDA into earlier stages of this disease,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “With today’s approval, we can now offer health care providers and patients 12 years and older the opportunity to help prevent melanoma recurrence with Keytruda across resected stage IIB, stage IIC, and stage III melanoma.”

In KEYNOTE-716, patients with completely resected stage IIB or IIC melanoma were randomly assigned to receive 200 mg of intravenous pembrolizumab, the pediatric dose 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, or placebo for up to 1 year until disease recurrence or unacceptable toxicity.

After a median follow-up of 14.4 months, investigators reported a statistically significant 35% improvement in recurrence-free survival (RFS) in those treated with pembrolizumab, compared with those who received placebo (hazard ratio, 0.65).

The most common adverse reactions reported in patients receiving pembrolizumab in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia, each occurring in at least 20% of patients.

“Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda,” according to Merck.

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

The erectile dysfunction medication Viagra could potentially be used as a treatment for Alzheimer’s disease, according to a new study published in the journal Nature Aging.

Patients who used the drug sildenafil, the generic name for Viagra, were 69% less likely to develop the disease than were nonusers.

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” Feixiong Cheng, PhD, the lead study author in the Cleveland Clinic’s Genomic Medicine Institute, said in a statement.

“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” he said.

Alzheimer’s, which is the most common form of age-related dementia, affects hundreds of millions of people worldwide. The disease is expected to affect nearly 14 million Americans by 2050. There is no approved treatment for it.

Dr. Cheng and colleagues at the Cleveland Clinic used a large gene-mapping network to analyze whether more than 1,600 Food and Drug Administration–approved drugs could work against Alzheimer’s. They gave higher scores to drugs that target both amyloid and tau proteins in the brain, which are two hallmarks of the disease. Sildenafil appeared at the top of the list.

Then the researchers used a database of health insurance claims for more than 7 million people in the U.S. to understand the relationship between sildenafil and Alzheimer’s disease outcomes. They compared sildenafil users to nonusers and found that those who used the drug were 69% less likely to have the neurodegenerative disease, even after 6 years of follow-up.

After that, the research team came up with a lab model that showed the sildenafil increased brain cell growth and targeted tau proteins. The lab model could indicate how the drug influences disease-related brain changes.

But Dr. Cheng cautioned against drawing strong conclusions. The study doesn’t demonstrate a causal relationship between sildenafil and Alzheimer’s disease. Researchers will need to conduct clinical trials with a placebo control to see how well the drug works.

Other researchers said the findings offer a new avenue for research but don’t yet provide solid answers.

“Being able to repurpose a drug already licensed for health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” Susan Kohlhaas, PhD, director of research at Alzheimer’s Research UK, told the Science Media Centre.

“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease,” she continued. “If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”

And doctors won’t likely recommend it as a treatment just yet either.

“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” Tara Spires-Jones, PhD, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, told the Science Media Centre.

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

The erectile dysfunction medication Viagra could potentially be used as a treatment for Alzheimer’s disease, according to a new study published in the journal Nature Aging.

Patients who used the drug sildenafil, the generic name for Viagra, were 69% less likely to develop the disease than were nonusers.

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” Feixiong Cheng, PhD, the lead study author in the Cleveland Clinic’s Genomic Medicine Institute, said in a statement.

“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” he said.

Alzheimer’s, which is the most common form of age-related dementia, affects hundreds of millions of people worldwide. The disease is expected to affect nearly 14 million Americans by 2050. There is no approved treatment for it.

Dr. Cheng and colleagues at the Cleveland Clinic used a large gene-mapping network to analyze whether more than 1,600 Food and Drug Administration–approved drugs could work against Alzheimer’s. They gave higher scores to drugs that target both amyloid and tau proteins in the brain, which are two hallmarks of the disease. Sildenafil appeared at the top of the list.

Then the researchers used a database of health insurance claims for more than 7 million people in the U.S. to understand the relationship between sildenafil and Alzheimer’s disease outcomes. They compared sildenafil users to nonusers and found that those who used the drug were 69% less likely to have the neurodegenerative disease, even after 6 years of follow-up.

After that, the research team came up with a lab model that showed the sildenafil increased brain cell growth and targeted tau proteins. The lab model could indicate how the drug influences disease-related brain changes.

But Dr. Cheng cautioned against drawing strong conclusions. The study doesn’t demonstrate a causal relationship between sildenafil and Alzheimer’s disease. Researchers will need to conduct clinical trials with a placebo control to see how well the drug works.

Other researchers said the findings offer a new avenue for research but don’t yet provide solid answers.

“Being able to repurpose a drug already licensed for health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” Susan Kohlhaas, PhD, director of research at Alzheimer’s Research UK, told the Science Media Centre.

“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease,” she continued. “If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”

And doctors won’t likely recommend it as a treatment just yet either.

“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” Tara Spires-Jones, PhD, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, told the Science Media Centre.

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

The erectile dysfunction medication Viagra could potentially be used as a treatment for Alzheimer’s disease, according to a new study published in the journal Nature Aging.

Patients who used the drug sildenafil, the generic name for Viagra, were 69% less likely to develop the disease than were nonusers.

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” Feixiong Cheng, PhD, the lead study author in the Cleveland Clinic’s Genomic Medicine Institute, said in a statement.

“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” he said.

Alzheimer’s, which is the most common form of age-related dementia, affects hundreds of millions of people worldwide. The disease is expected to affect nearly 14 million Americans by 2050. There is no approved treatment for it.

Dr. Cheng and colleagues at the Cleveland Clinic used a large gene-mapping network to analyze whether more than 1,600 Food and Drug Administration–approved drugs could work against Alzheimer’s. They gave higher scores to drugs that target both amyloid and tau proteins in the brain, which are two hallmarks of the disease. Sildenafil appeared at the top of the list.

Then the researchers used a database of health insurance claims for more than 7 million people in the U.S. to understand the relationship between sildenafil and Alzheimer’s disease outcomes. They compared sildenafil users to nonusers and found that those who used the drug were 69% less likely to have the neurodegenerative disease, even after 6 years of follow-up.

After that, the research team came up with a lab model that showed the sildenafil increased brain cell growth and targeted tau proteins. The lab model could indicate how the drug influences disease-related brain changes.

But Dr. Cheng cautioned against drawing strong conclusions. The study doesn’t demonstrate a causal relationship between sildenafil and Alzheimer’s disease. Researchers will need to conduct clinical trials with a placebo control to see how well the drug works.

Other researchers said the findings offer a new avenue for research but don’t yet provide solid answers.

“Being able to repurpose a drug already licensed for health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” Susan Kohlhaas, PhD, director of research at Alzheimer’s Research UK, told the Science Media Centre.

“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease,” she continued. “If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”

And doctors won’t likely recommend it as a treatment just yet either.

“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” Tara Spires-Jones, PhD, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, told the Science Media Centre.

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

Apixaban appears to be safer and more effective than rivaroxaban for reducing risk of venous thromboembolism and bleeding, based on new research.

Recurrent venous thromboembolism (VTE) – a composite of pulmonary embolism and deep vein thrombosis – was the primary effectiveness outcome in the retrospective analysis of new-user data from almost 40,000 patients, which was published in Annals of Internal Medicine. Safety was evaluated through a composite of intracranial and gastrointestinal bleeding.

After a median follow-up of 102 days in the apixaban group and 105 days in the rivaroxaban group, apixaban demonstrated superiority for both primary outcomes.

These real-world findings may guide selection of initial anticoagulant therapy, reported lead author Ghadeer K. Dawwas, PhD, MSc, MBA, of the University of Pennsylvania, Philadelphia, and colleagues.

“Randomized clinical trials comparing apixaban with rivaroxaban in patients with VTE are under way (for example, COBRRA (NCT03266783),” the investigators wrote. “Until the results from these trials become available (The estimated completion date for COBRRA is December 2023.), observational studies that use existing data can provide evidence on the effectiveness and safety of these alternatives to inform clinical practice.”

In the new research, apixaban was associated with a 23% lower rate of recurrent VTE (hazard ratio, 0.77; 95% confidence interval, 0.69-0.87), including a 15% lower rate of deep vein thrombosis and a 41% lower rate of pulmonary embolism. Apixaban was associated with 40% fewer bleeding events (HR, 0.60; 95% CI, 0.53-0.69]), including a 40% lower rate of GI bleeding and a 46% lower rate of intracranial bleeding.

The study involved 37,236 patients with VTE, all of whom were diagnosed in at least one inpatient encounter and initiated direct oral anticoagulant (DOAC) therapy within 30 days, according to Optum’s deidentified Clinformatics Data Mart Database. Patients were evenly split into apixaban and rivaroxaban groups, with 18,618 individuals in each. Propensity score matching was used to minimize differences in baseline characteristics.

Apixaban was associated with an absolute reduction in recurrent VTE of 0.6% and 1.1% over 2 and 6 months, respectively, as well as reductions in bleeding of 1.1% and 1.5% over the same respective time periods.

The investigators noted that these findings were maintained in various sensitivity and subgroup analyses, including a model in which patients with VTE who had transient risk factors were compared with VTE patients exhibiting chronic risk factors.

“These findings suggest that apixaban has superior effectiveness and safety, compared with rivaroxaban and may provide guidance to clinicians and patients regarding selection of an anticoagulant for treatment of VTE,” Dr. Dawwas and colleagues concluded.

Study may have missed some nuance in possible outcomes, according to vascular surgeon

Thomas Wakefield, MD, a vascular surgeon and a professor of surgery at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, generally agreed with the investigators’ conclusion, although he noted that DOAC selection may also be influenced by other considerations.

“The results of this study suggest that, when choosing an agent for an individual patient, apixaban does appear to have an advantage over rivaroxaban related to recurrent VTE and bleeding,” Dr. Wakefield said in an interview. “One must keep in mind that these are not the only factors that are considered when choosing an agent and these are not the only two DOACs available. For example, rivaroxaban is given once per day while apixaban is given twice per day, and rivaroxaban has been shown to be successful in the treatment of other thrombotic disorders.”

Dr. Wakefield also pointed out that the study may have missed some nuance in possible outcomes.

“The current study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to strictly outpatient treatment and less severe outcomes cannot be inferred,” he said.

Damon E. Houghton, MD, of the department of medicine and a consultant in the department of vascular medicine and hematology at Mayo Clinic, Rochester, Minn., called the study a “very nice analysis,” highlighting the large sample size.

“The results are not a reason to abandon rivaroxaban altogether, but do suggest that, when otherwise appropriate for a patient, apixaban should be the first choice,” Dr. Houghton said in a written comment. “Hopefully this analysis will encourage more payers to create financial incentives that facilitate the use of apixaban in more patients.”

Randomized trial needed, says hematologist

Colleen Edwards, MD, of the departments of medicine, hematology, and medical oncology, at the Icahn School of Medicine at Mount Sinai, New York, had a more guarded view of the findings than Dr. Wakefield and Dr. Houghton.

“[The investigators] certainly seem to be doing a lot of statistical gymnastics in this paper,” Dr. Edwards said in an interview. “They used all kinds of surrogates in place of real data that you would get from a randomized trial.”

For example, Dr. Edwards noted the use of prescription refills as a surrogate for medication adherence, and emphasized that inpatient observational data may not reflect outpatient therapy.

“Inpatients are constantly missing their medicines all the time,” she said. “They’re holding it for procedures, they’re NPO, they’re off the floor, so they missed their medicine. So it’s just a very different patient population than the outpatient population, which is where venous thromboembolism is treated now, by and large.”

Although Dr. Edwards suggested that the findings might guide treatment selection “a little bit,” she noted that insurance constraints and costs play a greater role, and ultimately concluded that a randomized trial is needed to materially alter clinical decision-making.

“I think we really have to wait for randomized trial before we abandon our other choices,” she said.

The investigators disclosed relationships with Merck, Celgene, UCB, and others. Dr. Wakefield reported awaiting disclosures. Dr. Houghton and Dr. Edwards reported no relevant conflicts of interest.

Apixaban appears to be safer and more effective than rivaroxaban for reducing risk of venous thromboembolism and bleeding, based on new research.

Recurrent venous thromboembolism (VTE) – a composite of pulmonary embolism and deep vein thrombosis – was the primary effectiveness outcome in the retrospective analysis of new-user data from almost 40,000 patients, which was published in Annals of Internal Medicine. Safety was evaluated through a composite of intracranial and gastrointestinal bleeding.

After a median follow-up of 102 days in the apixaban group and 105 days in the rivaroxaban group, apixaban demonstrated superiority for both primary outcomes.

These real-world findings may guide selection of initial anticoagulant therapy, reported lead author Ghadeer K. Dawwas, PhD, MSc, MBA, of the University of Pennsylvania, Philadelphia, and colleagues.

“Randomized clinical trials comparing apixaban with rivaroxaban in patients with VTE are under way (for example, COBRRA (NCT03266783),” the investigators wrote. “Until the results from these trials become available (The estimated completion date for COBRRA is December 2023.), observational studies that use existing data can provide evidence on the effectiveness and safety of these alternatives to inform clinical practice.”

In the new research, apixaban was associated with a 23% lower rate of recurrent VTE (hazard ratio, 0.77; 95% confidence interval, 0.69-0.87), including a 15% lower rate of deep vein thrombosis and a 41% lower rate of pulmonary embolism. Apixaban was associated with 40% fewer bleeding events (HR, 0.60; 95% CI, 0.53-0.69]), including a 40% lower rate of GI bleeding and a 46% lower rate of intracranial bleeding.

The study involved 37,236 patients with VTE, all of whom were diagnosed in at least one inpatient encounter and initiated direct oral anticoagulant (DOAC) therapy within 30 days, according to Optum’s deidentified Clinformatics Data Mart Database. Patients were evenly split into apixaban and rivaroxaban groups, with 18,618 individuals in each. Propensity score matching was used to minimize differences in baseline characteristics.

Apixaban was associated with an absolute reduction in recurrent VTE of 0.6% and 1.1% over 2 and 6 months, respectively, as well as reductions in bleeding of 1.1% and 1.5% over the same respective time periods.

The investigators noted that these findings were maintained in various sensitivity and subgroup analyses, including a model in which patients with VTE who had transient risk factors were compared with VTE patients exhibiting chronic risk factors.

“These findings suggest that apixaban has superior effectiveness and safety, compared with rivaroxaban and may provide guidance to clinicians and patients regarding selection of an anticoagulant for treatment of VTE,” Dr. Dawwas and colleagues concluded.

Study may have missed some nuance in possible outcomes, according to vascular surgeon

Thomas Wakefield, MD, a vascular surgeon and a professor of surgery at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, generally agreed with the investigators’ conclusion, although he noted that DOAC selection may also be influenced by other considerations.

“The results of this study suggest that, when choosing an agent for an individual patient, apixaban does appear to have an advantage over rivaroxaban related to recurrent VTE and bleeding,” Dr. Wakefield said in an interview. “One must keep in mind that these are not the only factors that are considered when choosing an agent and these are not the only two DOACs available. For example, rivaroxaban is given once per day while apixaban is given twice per day, and rivaroxaban has been shown to be successful in the treatment of other thrombotic disorders.”

Dr. Wakefield also pointed out that the study may have missed some nuance in possible outcomes.

“The current study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to strictly outpatient treatment and less severe outcomes cannot be inferred,” he said.

Damon E. Houghton, MD, of the department of medicine and a consultant in the department of vascular medicine and hematology at Mayo Clinic, Rochester, Minn., called the study a “very nice analysis,” highlighting the large sample size.

“The results are not a reason to abandon rivaroxaban altogether, but do suggest that, when otherwise appropriate for a patient, apixaban should be the first choice,” Dr. Houghton said in a written comment. “Hopefully this analysis will encourage more payers to create financial incentives that facilitate the use of apixaban in more patients.”

Randomized trial needed, says hematologist

Colleen Edwards, MD, of the departments of medicine, hematology, and medical oncology, at the Icahn School of Medicine at Mount Sinai, New York, had a more guarded view of the findings than Dr. Wakefield and Dr. Houghton.

“[The investigators] certainly seem to be doing a lot of statistical gymnastics in this paper,” Dr. Edwards said in an interview. “They used all kinds of surrogates in place of real data that you would get from a randomized trial.”

For example, Dr. Edwards noted the use of prescription refills as a surrogate for medication adherence, and emphasized that inpatient observational data may not reflect outpatient therapy.

“Inpatients are constantly missing their medicines all the time,” she said. “They’re holding it for procedures, they’re NPO, they’re off the floor, so they missed their medicine. So it’s just a very different patient population than the outpatient population, which is where venous thromboembolism is treated now, by and large.”

Although Dr. Edwards suggested that the findings might guide treatment selection “a little bit,” she noted that insurance constraints and costs play a greater role, and ultimately concluded that a randomized trial is needed to materially alter clinical decision-making.

“I think we really have to wait for randomized trial before we abandon our other choices,” she said.

The investigators disclosed relationships with Merck, Celgene, UCB, and others. Dr. Wakefield reported awaiting disclosures. Dr. Houghton and Dr. Edwards reported no relevant conflicts of interest.

Apixaban appears to be safer and more effective than rivaroxaban for reducing risk of venous thromboembolism and bleeding, based on new research.

Recurrent venous thromboembolism (VTE) – a composite of pulmonary embolism and deep vein thrombosis – was the primary effectiveness outcome in the retrospective analysis of new-user data from almost 40,000 patients, which was published in Annals of Internal Medicine. Safety was evaluated through a composite of intracranial and gastrointestinal bleeding.

After a median follow-up of 102 days in the apixaban group and 105 days in the rivaroxaban group, apixaban demonstrated superiority for both primary outcomes.

These real-world findings may guide selection of initial anticoagulant therapy, reported lead author Ghadeer K. Dawwas, PhD, MSc, MBA, of the University of Pennsylvania, Philadelphia, and colleagues.

“Randomized clinical trials comparing apixaban with rivaroxaban in patients with VTE are under way (for example, COBRRA (NCT03266783),” the investigators wrote. “Until the results from these trials become available (The estimated completion date for COBRRA is December 2023.), observational studies that use existing data can provide evidence on the effectiveness and safety of these alternatives to inform clinical practice.”

In the new research, apixaban was associated with a 23% lower rate of recurrent VTE (hazard ratio, 0.77; 95% confidence interval, 0.69-0.87), including a 15% lower rate of deep vein thrombosis and a 41% lower rate of pulmonary embolism. Apixaban was associated with 40% fewer bleeding events (HR, 0.60; 95% CI, 0.53-0.69]), including a 40% lower rate of GI bleeding and a 46% lower rate of intracranial bleeding.

The study involved 37,236 patients with VTE, all of whom were diagnosed in at least one inpatient encounter and initiated direct oral anticoagulant (DOAC) therapy within 30 days, according to Optum’s deidentified Clinformatics Data Mart Database. Patients were evenly split into apixaban and rivaroxaban groups, with 18,618 individuals in each. Propensity score matching was used to minimize differences in baseline characteristics.

Apixaban was associated with an absolute reduction in recurrent VTE of 0.6% and 1.1% over 2 and 6 months, respectively, as well as reductions in bleeding of 1.1% and 1.5% over the same respective time periods.

The investigators noted that these findings were maintained in various sensitivity and subgroup analyses, including a model in which patients with VTE who had transient risk factors were compared with VTE patients exhibiting chronic risk factors.

“These findings suggest that apixaban has superior effectiveness and safety, compared with rivaroxaban and may provide guidance to clinicians and patients regarding selection of an anticoagulant for treatment of VTE,” Dr. Dawwas and colleagues concluded.

Study may have missed some nuance in possible outcomes, according to vascular surgeon

Thomas Wakefield, MD, a vascular surgeon and a professor of surgery at the University of Michigan Health Frankel Cardiovascular Center, Ann Arbor, generally agreed with the investigators’ conclusion, although he noted that DOAC selection may also be influenced by other considerations.

“The results of this study suggest that, when choosing an agent for an individual patient, apixaban does appear to have an advantage over rivaroxaban related to recurrent VTE and bleeding,” Dr. Wakefield said in an interview. “One must keep in mind that these are not the only factors that are considered when choosing an agent and these are not the only two DOACs available. For example, rivaroxaban is given once per day while apixaban is given twice per day, and rivaroxaban has been shown to be successful in the treatment of other thrombotic disorders.”

Dr. Wakefield also pointed out that the study may have missed some nuance in possible outcomes.

“The current study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to strictly outpatient treatment and less severe outcomes cannot be inferred,” he said.

Damon E. Houghton, MD, of the department of medicine and a consultant in the department of vascular medicine and hematology at Mayo Clinic, Rochester, Minn., called the study a “very nice analysis,” highlighting the large sample size.

“The results are not a reason to abandon rivaroxaban altogether, but do suggest that, when otherwise appropriate for a patient, apixaban should be the first choice,” Dr. Houghton said in a written comment. “Hopefully this analysis will encourage more payers to create financial incentives that facilitate the use of apixaban in more patients.”

Randomized trial needed, says hematologist

Colleen Edwards, MD, of the departments of medicine, hematology, and medical oncology, at the Icahn School of Medicine at Mount Sinai, New York, had a more guarded view of the findings than Dr. Wakefield and Dr. Houghton.

“[The investigators] certainly seem to be doing a lot of statistical gymnastics in this paper,” Dr. Edwards said in an interview. “They used all kinds of surrogates in place of real data that you would get from a randomized trial.”

For example, Dr. Edwards noted the use of prescription refills as a surrogate for medication adherence, and emphasized that inpatient observational data may not reflect outpatient therapy.

“Inpatients are constantly missing their medicines all the time,” she said. “They’re holding it for procedures, they’re NPO, they’re off the floor, so they missed their medicine. So it’s just a very different patient population than the outpatient population, which is where venous thromboembolism is treated now, by and large.”

Although Dr. Edwards suggested that the findings might guide treatment selection “a little bit,” she noted that insurance constraints and costs play a greater role, and ultimately concluded that a randomized trial is needed to materially alter clinical decision-making.

“I think we really have to wait for randomized trial before we abandon our other choices,” she said.

The investigators disclosed relationships with Merck, Celgene, UCB, and others. Dr. Wakefield reported awaiting disclosures. Dr. Houghton and Dr. Edwards reported no relevant conflicts of interest.

The U.S. Food and Drug Administration (FDA) has approved daratumumab + hyaluronidase-fihj (Darzalex Faspro) and carfilzomib (Kyprolis) plus dexamethasone (Kd) for patients with relapsed or refractory multiple myeloma who have had one to three prior lines of therapy.

Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.

“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.

Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.

The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

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

The U.S. Food and Drug Administration (FDA) has approved daratumumab + hyaluronidase-fihj (Darzalex Faspro) and carfilzomib (Kyprolis) plus dexamethasone (Kd) for patients with relapsed or refractory multiple myeloma who have had one to three prior lines of therapy.

Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.

“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.

Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.

The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

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

The U.S. Food and Drug Administration (FDA) has approved daratumumab + hyaluronidase-fihj (Darzalex Faspro) and carfilzomib (Kyprolis) plus dexamethasone (Kd) for patients with relapsed or refractory multiple myeloma who have had one to three prior lines of therapy.

Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.

“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.

Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.

The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

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

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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