Underuse of Antiviral Drugs to Prevent Progression to Severe COVID-19 - Veterans Health Administration, March-September 2022.

Antiviral drugs reduce the rate of progression to severe COVID-19 when given to patients with mild-to-moderate disease within 5 days of symptom onset. Despite being recommended for patients at high risk for progression to severe COVID-19 because of age or chronic conditions, reported antiviral use among the general adult population has been ≤35%. To ascertain reasons for underuse of antiviral medications to prevent severe COVID-19 and propose interventions accordingly, a detailed review was conducted of 110 Veterans Health Administration patients with mild-to-moderate infection at high risk for progression because of underlying conditions (organ transplantation or hematologic malignancies) who did not receive an antiviral drug. Among these 110 patients, all of whom had received COVID-19 vaccine, 22 (20.0%) were offered treatment but declined, and 88 (80.0%) were not offered treatment. Among the 88 patients not offered treatment, provider reasons included symptom duration of >5 days (22.7%), concern about possible drug interactions (5.7%), or absence of symptoms (22.7%); however, among nearly one half (43 of 88; 48.9%) of these patients, no reason other than mild symptoms was given. Among 24 (55.8%) of those 43 patients, follow-up was limited to telephone calls to report test results and inquire about symptom evolution, with no documentation of treatment being offered. These findings suggest that education of patients, providers, and medical personnel tasked with follow-up calls, combined with advance planning in the event of a positive test result, might improve the rate of recommended antiviral medication use to prevent severe COVID-19-associated illness, including death.

Risk of severe coronavirus disease 2019 despite vaccination in patients requiring treatment with immune-suppressive drugs: A nationwide cohort study of US Veterans.

BACKGROUND: Patients taking immune-suppressive drugs are at increased risk of severe coronavirus disease 2019 (COVID-19), not fully ameliorated by vaccination. We assessed the contributions of clinical and demographic factors to the risk of severe disease despite vaccination in patients taking immune-suppressive medications for solid organ transplantation (SOT), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis. METHODS: Veterans Health Administration electronic health records were used to identify patients diagnosed with RA, IBD, psoriasis, or SOT who had been vaccinated against severe acute respiratory syndrome coronavirus 2, were subsequently infected, and had received immune-suppressive drugs within 3 months before infection. The association of severe (defined as hypoxemia, mechanical ventilation, dexamethasone use, or death) versus non-severe COVID-19 with the use of immune-suppressive and antiviral drugs and clinical covariates was assessed by multivariable logistic regression. RESULTS: Severe COVID-19 was more common in patients with SOT (230/1011, 22.7%) than RA (173/1355, 12.8%), IBD (51/742, 6.9%), or psoriasis (82/1125, 7.3%). Age was strongly associated with severe COVID-19, adjusted odds ratio (aOR) of 1.04 (CI 1.03-1.05) per year. Comorbidities indicating chronic brain, heart, lung, or kidney damage were also associated with severity, aOR 1.35-2.38. The use of glucocorticoids was associated with increased risk (aOR 1.66, CI 1.39-2.18). Treatment with antivirals was associated with reduced severity, for example, aOR 0.28 (CI 0.13-0.62) for nirmatrelvir/ritonavir. CONCLUSION: The risk of severe COVID-19 despite vaccination is substantial in patients taking immune-suppressive drugs, more so in patients with SOT than in patients with inflammatory diseases. Age and severe comorbidities contribute to risk, as in the general population. Oral antivirals were very beneficial but not widely used.

Severe COVID-19 in Vaccinated Adults With Hematologic Cancers in the Veterans Health Administration.

Importance: With SARS-CoV-2 transforming into an endemic disease and with antiviral treatments available, it is important to establish which patients remain at risk of severe COVID-19 despite vaccination. Objective: To quantify the associations of clinical and demographic variables with odds of severe COVID-19 among patients with hematologic cancers. Design, Setting, and Participants: This case-control study included all patients with hematologic malignant neoplasms in the national Veterans Health Administration (VHA) who had documented SARS-CoV-2 infection after vaccination. Groups of patients with severe (cases) vs nonsevere (controls) COVID-19 were compared. Data were collected between January 1, 2020, and April 5, 2023, with data on infection collected between January 1, 2021, and September 30, 2022. All patients with diagnostic codes for hematologic malignant neoplasms who had documented vaccination followed by documented SARS-CoV-2 infection and for whom disease severity could be assessed were included. Data were analyzed from July 28 to December 30, 2023. Exposures: Clinical (comorbidities, predominant viral variant, treatment for malignant neoplasm, booster vaccination, and antiviral treatment) and demographic (age and sex) variables shown in prior studies to be associated with higher or lower rates of severe COVID-19. Comorbidities included Alzheimer disease or dementia, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, heart failure, and peripheral vascular disease. Main Outcome and Measures: The main outcome was severe COVID-19 compared with nonsevere SARS-CoV-2 infection. Severe COVID-19 was defined as death within 28 days, mechanical ventilation, or hospitalization with use of dexamethasone or evidence of hypoxemia or use of supplemental oxygen. Multivariable logistic regression was used to estimate the associations of demographic and clinical variables with the odds of severe COVID-19, expressed as adjusted odds ratios (aORs) with 95% CIs. Results: Among 6122 patients (5844 [95.5%] male, mean [SD] age, 70.89 [11.57] years), 1301 (21.3%) had severe COVID-19. Age (aOR per 1-year increase, 1.05; 95% CI, 1.04-1.06), treatment with antineoplastic or immune-suppressive drugs (eg, in combination with glucocorticoids: aOR, 2.32; 95% CI, 1.93-2.80), and comorbidities (aOR per comorbidity, 1.35; 95% CI, 1.29-1.43) were associated with higher odds of severe disease, whereas booster vaccination was associated with lower odds (aOR, 0.73; 95% CI, 0.62-0.86). After oral antiviral drugs became widely used in March 2022, 20 of 538 patients (3.7%) with SARS-CoV-2 infection during this period had progression to severe COVID-19. Conclusions and Relevance: In this case-control study of patients with hematologic cancers, odds of severe COVID-19 remained high through mid-2022 despite vaccination, especially in patients requiring treatment.

Can multisite clinical trial results change clinical practice? Use of long-acting injectable risperidone nationally in the Veterans Health Administration.

BACKGROUND: Multisite practical clinical trials evaluate treatments in real-world practice. A multisite randomized Veterans Health Administration (VHA) cooperative study (CSP#555) published in 2011 compared the first long-acting injectable (LAI) second-generation antipsychotic (SGA), Risperidone Consta®, in veterans with a diagnosis of schizophrenia or schizoaffective disorder, to oral antipsychotics, with unexpected null results for effectiveness and cost-effectiveness. Whether null results of this type could change VHA practice has not been studied. METHODS: A longitudinal observational analysis was used to evaluate the impact of the trial findings on VHA clinical practices. National administrative data compared new starts on LAI risperidone during the 4 years before the publication of CSP#555 in 2011 to new starts on LAI risperidone during the 4 years after. RESULTS: Among 119,565 Veterans with the indicated diagnoses treated with antipsychotics from 2007 to 2015, the number and proportion of new starts on LAI risperidone declined significantly following the study publication, as did the total number of annual users and drug expenditures. However, data from 2007 to 2010 showed the decline in new starts actually preceded the publication of CSP#555. This change was likely explained by the increase in new starts, total use, and expenditures on a newer medicine, LAI paliperidone, a 4-week LAI treatment, in the 2 years prior to the publication of CSP#555. CONCLUSIONS: The declining use of LAI risperidone likely primarily reflects the substitution of a longer-acting LAI SGA, paliperidone, that came to market 2 years before the study publication, a substitution that may have been reinforced by null CSP#555 study results for LAI risperidone.

Impact of multi-site clinical trial results on clinical practice: Use of risperidone to treat PTSD nationally in the veterans health administration.

Multi-site randomized effectiveness trials evaluate treatments under real-world conditions. Whether results change practice is under-studied. A 6-month 26-site Veterans Health Administration (VHA) cooperative study published in 2011 compared an oral second-generation antipsychotic, risperidone, to placebo for refractory PTSD with null results. National VHA administrative data compared new starts on risperidone during the 5 years before and after the year of publication. Among the 450,000-841,000 Veterans diagnosed with PTSD annually from 2006 to 2016 the proportion with new starts on risperidone declined every year before and after publication. No evidence of an effect of null study results on VHA clinical practice was observed.

Trends and practices for managing low-risk prostate cancer: a SEER-Medicare study.

BACKGROUND: Expectant management (EM) has been widely recommended for men with low-risk prostate cancers (PCa). We evaluated trends in EM and the sociodemographic and clinical factors associated with EM, initiating a National Comprehensive Cancer Network guideline-concordant active surveillance (AS) monitoring protocol, and switching from EM to active treatment (AT). METHODS: We used the SEER-Medicare database to identify men ages 66+ diagnosed with a low-risk PCa (PSA < 10 ng/mL, Gleason ≤ 6, stage ≤ T2a) in 2010-2013 with ≥1 year of follow-up. We used claims data to capture (1) PCa treatments, including surgical procedures, radiotherapy, and hormone therapy, and (2) AS monitoring procedures, including PSA tests and prostate biopsy. We defined EM as receiving no AT within 1 year of diagnosis. We used multivariable regression techniques to identify factors associated with EM, initiating AS monitoring, and switching to AT. RESULTS: During the study period, EM increased from 29.4% to 49.0%, p < 0.01. Age < 77, being married/partnered, non-Hispanic ethnicity, higher median ZIP code income, lower PSA levels, stage T1c, and more recent year of diagnosis were associated with EM. Nearly 39% of the EM cohort initiated AS monitoring; age <77, White race, being married/partnered, higher median ZIP code income, and lower PSA levels were associated with initiating AS. By three years after diagnosis, 21.3% of the EM cohort had switched to AT, usually after undergoing AS monitoring procedures. DISCUSSION: We found increasing uptake of EM over time, though over 50% still received AT. About 60% of EM patients did not initiate AS monitoring, even among those with life expectancy >10 years, implying that a substantial proportion was being managed by watchful waiting. AS monitoring was associated with switching to AT, suggesting that treatment decisions likely were based on cancer progression.

Hypertensive disorders of pregnancy among women with a history of leukemia or lymphoma.

OBJECTIVE: Hypertension during pregnancy can adversely affect maternal and fetal health. This study assessed whether diagnosis of leukemia or lymphoma prior to pregnancy is associated with hypertensive disorders of pregnancy including gestational hypertension, preeclampsia and eclampsia. STUDY DESIGN: A cross-sectional study used two statewide population-based datasets that linked birth certificates with sources of maternal medical history: hospital discharges in California and Surveillance, Epidemiology, and End Results (SEER) cancer registry data in Iowa. Birth years included 2007-2012 in California and 1989-2018 in Iowa. MAIN OUTCOME MEASURES: Primary outcome measure was hypertension in pregnancy measured from combined birth certificate and hospital diagnoses in California (for gestational hypertension, preeclampsia, or eclampsia) and birth certificate information (gestational hypertension or eclampsia) in Iowa. RESULTS: After adjusting for maternal age, race, education, smoking, and plurality, those with a history of leukemia/lymphoma were at increased risk of hypertensive disorders of pregnancy in Iowa (odds ratio (OR) = 1.86; 95% CI 1.07-3.23), but not in California (OR = 1.12; 95% CI 0.87-1.43). In sensitivity analysis restricting to more severe forms of hypertension in pregnancy (preeclampsia and eclampsia) in the California cohort, the effect estimate increased (OR = 1.29; 95% CI 0.96-1.74). CONCLUSION: In a population-based linked cancer registry-birth certificate study, an increased risk of hypertensive disorders of pregnancy was observed among leukemia or lymphoma survivors. Findings were consistent but non-significant in a second, more ethnically diverse study population with less precise cancer history data. Improved monitoring and surveillance may be warranted for leukemia or lymphoma survivors throughout their pregnancies.

The risk of preterm birth among women with a history of leukemia or lymphoma.

OBJECTIVE: Leukemia and lymphoma are top cancers affecting children, adolescents and young adults with high five-year survival rates. Late effects of these cancers are a concern in reproductive-age patients, including pregnancy outcomes such as preterm birth. Our study aimed to evaluate whether diagnosis of leukemia or lymphoma prior to pregnancy was associated with preterm birth (<37 weeks gestation). METHODS: We conducted a cross-sectional study using a population-based dataset from California with linked birth certificates to hospital discharge records and an Iowa-based sample that linked birth certificates to Surveillance, Epidemiology, and End Results (SEER) cancer registry data. Preterm birth was defined using birth certificates. We ascertained history of leukemia and lymphoma using discharge diagnosis data in California and SEER registry in Iowa. RESULTS: Prevalence of preterm birth in California and Iowa was 14.6% and 12.0%, respectively, in women with a history of leukemia/lymphoma compared to 7.8% and 8.2%, respectively, in women without a cancer history. After adjusting for maternal age, race, education, smoking, and plurality, Women with history of leukemia/lymphoma were at an increased risk of having a preterm birth in California (odds ratio (OR) 1.89; 95% confidence interval (CI) 1.56-2.28) and Iowa (OR 1.61; 95% CI 1.10-2.37) compared to those with no cancer history. CONCLUSION: In both California and Iowa, women with a history of leukemia or lymphoma were at increased risk for preterm birth. This suggests the importance of counseling with a history of leukemia/lymphoma prior to pregnancy and increased monitoring of women during pregnancy.

Metabolic differences among newborns born to mothers with a history of leukemia or lymphoma.

BACKGROUND: Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers. METHODS: A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program. RESULTS: A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (p < .001 - based on Bonferroni correction for multiple testing) higher compared to newborns of mothers without cancer history: C3-DC (mean difference (MD) = 0.006), C5-DC (MD = 0.009), C8:1 (MD = 0.008), C14 (MD = 0.010), and C16:1 (MD = 0.011), whereas citrulline levels were significantly lower (MD = -0.581) among newborns born to mothers with history of leukemia or lymphoma compared to newborns of mothers without a history of cancer. CONCLUSION: The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

The Relationship between Rate and Volume of Intravenous Fluid Administration and Kidney Outcomes after Angiography.

BACKGROUND AND OBJECTIVES: Contrast-associated AKI may result in higher morbidity and mortality. Intravenous fluid administration remains the mainstay for prevention. There is a lack of consensus on the optimal administration strategy. We studied the association of periprocedure fluid administration with contrast-associated AKI, defined as an increase in serum creatinine of at least 25% or 0.5 mg/dl from baseline at 3-5 days after angiography, and 90-day need for dialysis, death, or a 50% increase in serum creatinine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a secondary analysis of 4671 PRESERVE participants who underwent angiographic procedures. Although fluid type was randomized, strategy of administration was at the discretion of the clinician. We divided the study cohort into quartiles by total fluid volume. We performed multivariable logistic regression, adjusting for clinically important covariates. We tested for the interaction between fluid volume and duration of fluid administration, categorized as <6 or ≥6 hours. RESULTS: The mean (SD) age was 70 (8) years, 94% of participants were male, and median (interquartile range) eGFR was 60 (41-60) ml/min per 1.73 m2. The range of fluid administered was 89-882 ml in quartile 1 and 1258-2790 ml in quartile 4. Compared with the highest quartile (quartile 4) of fluid volume, we found a significantly higher risk of the primary outcome in quartile 1 (adjusted odds ratio, 1.58; 95% confidence interval, 1.06 to 2.38) but not in quartiles 2 and 3 compared with quartile 4. There was no difference in the incidence of contrast-associated AKI across the quartiles. The interaction between volume and duration was not significant for any of the outcomes. CONCLUSIONS: We found that administration of a total volume of 1000 ml, starting at least 1 hour before contrast injection and continuing postcontrast for a total of 6 hours, is associated with a similar risk of adverse outcomes as larger volumes of intravenous fluids administered for periods >6 hours. Mean fluid volumes <964 ml may be associated with a higher risk for the primary outcome, although residual confounding cannot be excluded.