Excess deaths from COVID-19 among Medicare beneficiaries with psychiatric diagnoses: community versus nursing home.

BACKGROUND: Psychiatric illness may pose an additional risk of death for older adults during the COVID-19 pandemic. Older adults in the community versus institutions might be influenced by the pandemic differently. This study examines excess deaths during the COVID-19 pandemic among Medicare beneficiaries with and without psychiatric diagnoses (depression, anxiety, bipolar disorder, and schizophrenia) in the community versus nursing homes. METHODS: This is a retrospective cohort study of a 20% random sample of 15,229,713 fee-for-service Medicare beneficiaries, from January 2019 through December 2021. Unadjusted monthly mortality risks, COVID-19 infection rates, and case-fatality rates after COVID-19 diagnosis were calculated. Excess deaths in 2020, compared to 2019 were estimated from multivariable logistic regressions. RESULTS: Of all included Medicare beneficiaries in 2020 (N = 5,140,619), 28.9% had a psychiatric diagnosis; 1.7% lived in nursing homes. In 2020, there were 246,422 observed deaths, compared to 215,264 expected, representing a 14.5% increase over expected. Patients with psychiatric diagnoses had more excess deaths than those without psychiatric diagnoses (1,107 vs. 403 excess deaths per 100,000 beneficiaries, p < 0.01). The largest increases in mortality risks were observed among patients with schizophrenia (32.4% increase) and bipolar disorder (25.4% increase). The pandemic-associated increase in deaths with psychiatric diagnoses was only found in the community, not in nursing homes. The increased mortality for patients with psychiatric diagnoses was limited to those with medical comorbidities. The increase in mortality for psychiatric diagnoses was associated with higher COVID-19 infection rates (1-year infection rate = 7.9% vs. 4.2% in 2020), rather than excess case fatality. CONCLUSIONS: Excess deaths during the COVID-19 pandemic were disproportionally greater in beneficiaries with psychiatric diagnoses, at least in part due to higher infection rates. Policy interventions should focus on preventing COVID-19 infections and deaths among community-dwelling patients with major psychiatric disorders in addition to those living the nursing homes.

Thromboprophylaxis in people hospitalized with COVID-19: Assessing intermediate or standard doses in a retrospective cohort study.

Background and Objectives: Current clinical guidelines recommend thromboprophylaxis for adults hospitalized with coronavirus disease 2019 (COVID-19), yet it is unknown whether higher doses of thromboprophylaxis offer benefits beyond standard doses. Methods: We studied electronic health records from 50 091 adults hospitalized with COVID-19 in the United States between February 2020 and February 2021. We compared standard (enoxaparin 30 or 40 mg/day, fondaparinux 2.5 mg, or heparin 5000 units twice or thrice per day) versus intermediate (enoxaparin 30 or 40 mg twice daily, or up to 1.2 mg/kg of body weight daily, heparin 7500 units thrice per day or heparin 10 000 units twice or thrice per day) thromboprophylaxis. We separately examined risk of escalation to therapeutic anticoagulation, severe disease (first occurrence of high-flow nasal cannula, noninvasive positive pressure ventilation or invasive mechanical ventilation), and death. To summarize risk, we present hazard ratios (HRs) with 95% confidence intervals (CIs) using adjusted time-dependent Cox proportional hazards regression models. Results: People whose first dose was high intensity were younger, more often obese, and had greater oxygen support requirements. Intermediate dose thromboprophylaxis was associated with increased risk of therapeutic anticoagulation (HR, 3.39; 95% CI, 3.22-3.57), severe disease (HR, 1.22; 95% CI, 1.17-1.28), and death (HR, 1.37; 95% CI, 1.21-1.55). Increased risks associated with intermediate-dose thromboprophylaxis persisted in subgroup and sensitivity analyses varying populations and definitions of exposures, outcomes, and covariates. Conclusions: Our findings do not support routine use of intermediate-dose thromboprophylaxis to prevent clinical worsening, severe disease, or death among adults hospitalized with COVID-19.

Effectiveness of COVID-19 Booster on the Risk of Hospitalization Among Medicare Beneficiaries.

OBJECTIVE: To determine the effectiveness of booster vaccinations on the risk of hospitalization with coronavirus disease 2019 (COVID-19) and how it varies by enrollee characteristics and interval from the initial vaccination to receipt of a booster. PATIENTS AND METHODS: This cohort study used 100% Medicare claims from January 1, 2020, through December 31, 2021, and matched 3,940,475 individuals who received boosters to 3,940,475 controls based on week and type of original COVID-19 vaccine and demographic and clinical characteristics. We compared the association of booster vs no booster with COVID-19 hospitalization using Cox proportional hazards regression models controlling for patient characteristics. We also determined the association of time from original vaccine to booster with COVID-19 hospitalization. RESULTS: Over a maximum of 130 days of follow-up, boosted enrollees had 8.20 (95% CI, 7.81 to 8.60) COVID-19 hospitalizations per million days vs 43.70 (95% CI, 42.79 to 44.64) for controls (81% effectiveness). Effectiveness varied by race, prior hospitalizations, and certain comorbidities, for example, leukemia/lymphoma (53% effectiveness), autoimmune disease (73%), and dementia (73%). Boosters received between 6 and 9 months after original vaccination varied between 81% and 85% effectiveness, while boosters received at 5 to 6 months (62%) or less than 5 months (58%) were less effective. CONCLUSION: Boosters are highly effective in the Medicare population. Approximately 69,225 hospitalizations would be prevented by boosters in the 15 million individuals aged 65 years or older currently not boosted in a period similar to the September 2020 through January 2021 period studied. Boosters provided the greatest benefits if they were received between 6 and 9 months following original vaccinations. However, boosters were associated with substantial decreases in COVID-19 hospitalizations in all categories of enrollees.

Real-World Effectiveness of Remdesivir in Adults Hospitalized With Coronavirus Disease 2019 (COVID-19): A Retrospective, Multicenter Comparative Effectiveness Study.

BACKGROUND: There is an urgent need to understand the real-world effectiveness of remdesivir in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This was a retrospective comparative effectiveness study. Individuals hospitalized in a large private healthcare network in the United States from 23 February 2020 through 11 February 2021 with a positive test for SARS-CoV-2 and ICD-10 diagnosis codes consistent with symptomatic coronavirus disease 2019 (COVID-19) were included. Remdesivir recipients were matched to controls using time-dependent propensity scores. The primary outcome was time to improvement with a secondary outcome of time to death. RESULTS: Of 96 859 COVID-19 patients, 42 473 (43.9%) received at least 1 remdesivir dose. The median age of remdesivir recipients was 65 years, 23 701 (55.8%) were male, and 22 819 (53.7%) were non-White. Matches were found for 18 328 patients (43.2%). Remdesivir recipients were significantly more likely to achieve clinical improvement by 28 days (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI], 1.16-1.22). Remdesivir patients on no oxygen (aHR 1.30, 95% CI, 1.22-1.38) or low-flow oxygen (aHR 1.23, 95% CI, 1.19-1.27) were significantly more likely to achieve clinical improvement by 28 days. There was no significant impact on the likelihood of mortality overall (aHR 1.02, 95% CI, .97-1.08). Remdesivir recipients on low-flow oxygen were significantly less likely to die than controls (aHR 0.85, 95% CI, .77-.92; 28-day mortality 8.4% [865 deaths] for remdesivir patients, 12.5% [1334 deaths] for controls). CONCLUSIONS: These results support the use of remdesivir for hospitalized COVID-19 patients on no or low-flow oxygen. Routine initiation of remdesivir in more severely ill patients is unlikely to be beneficial.

Hospitalizations and Mortality From Non-SARS-CoV-2 Causes Among Medicare Beneficiaries at US Hospitals During the SARS-CoV-2 Pandemic.

Importance: The increased hospital mortality rates from non-SARS-CoV-2 causes during the SARS-CoV-2 pandemic are incompletely characterized. Objective: To describe changes in mortality rates after hospitalization for non-SARS-CoV-2 conditions during the COVID-19 pandemic and how mortality varies by characteristics of the admission and hospital. Design, Setting, and Participants: Retrospective cohort study from January 2019 through September 2021 using 100% of national Medicare claims, including 4626 US hospitals. Participants included 8 448 758 individuals with non-COVID-19 medical admissions with fee-for-service Medicare insurance. Main Outcomes and Measures: Outcome was mortality in the 30 days after admission with adjusted odds generated from a 3-level (admission, hospital, and county) logistic regression model that included diagnosis, demographic variables, comorbidities, hospital characteristics, and hospital prevalence of SARS-CoV-2. Results: There were 8 448 758 non-SARS-CoV-2 medical admissions in 2019 and from April 2020 to September 2021 (mean [SD] age, 73.66 [12.88] years; 52.82% women; 821 569 [11.87%] Black, 438 453 [6.34%] Hispanic, 5 351 956 [77.35%] White, and 307 218 [4.44%] categorized as other). Mortality in the 30 days after admission increased from 9.43% in 2019 to 11.48% from April 1, 2020, to March 31, 2021 (odds ratio [OR], 1.20; 95% CI, 1.19-1.21) in multilevel logistic regression analyses including admission and hospital characteristics. The increase in mortality was maintained throughout the first 18 months of the pandemic and varied by race and ethnicity (OR, 1.27; 95% CI, 1.23-1.30 for Black enrollees; OR, 1.25; 95% CI, 1.23-1.27 for Hispanic enrollees; and OR, 1.18; 95% CI, 1.17-1.19 for White enrollees); Medicaid eligibility (OR, 1.25; 95% CI, 1.24-1.27 for Medicaid eligible vs OR, 1.18; 95% CI, 1.16-1.18 for noneligible); and hospital quality score, measured on a scale of 1 to 5 stars with 1 being the worst and 5 being the best (OR, 1.27; 95% CI, 1.22-1.31 for 1 star vs OR, 1.11; 95% CI, 1.08-1.15 for 5 stars). Greater hospital prevalence of SARS-CoV-2 was associated with greater increases in odds of death from the prepandemic period to the pandemic period; for example, comparing mortality in October through December 2020 with October through December 2019, the OR was 1.44 (95% CI, 1.39-1.49) for hospitals in the top quartile of SARS-CoV-2 admissions vs an OR of 1.19 (95% CI, 1.16-1.22) for admissions to hospitals in the lowest quartile. This association was mostly limited to admissions with high-severity diagnoses. Conclusions and Relevance: The prolonged elevation in mortality rates after hospital admission in 2020 and 2021 for non-SARS-CoV-2 diagnoses contrasts with reports of improvement in hospital mortality during 2020 for SARS-CoV-2. The results of this cohort study suggest that, with the continued impact of SARS-CoV-2, it is important to implement interventions to improve access to high-quality hospital care for those with non-SARS-CoV-2 diseases.

Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: a retrospective cohort study using data from the National COVID Cohort Collaborative.

BACKGROUND: Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals. METHODS: We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray's proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology. FINDINGS: Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83-0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10-2·69) and for cancer (2·57, 1·86-3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions. INTERPRETATION: Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined. FUNDING: None.

Use of Hydroxychloroquine, Remdesivir, and Dexamethasone Among Adults Hospitalized With COVID-19 in the United States : A Retrospective Cohort Study.

BACKGROUND: Relatively little is known about the use patterns of potential pharmacologic treatments of COVID-19 in the United States. OBJECTIVE: To use the National COVID Cohort Collaborative (N3C), a large, multicenter, longitudinal cohort, to characterize the use of hydroxychloroquine, remdesivir, and dexamethasone, overall as well as across individuals, health systems, and time. DESIGN: Retrospective cohort study. SETTING: 43 health systems in the United States. PARTICIPANTS: 137 870 adults hospitalized with COVID-19 between 1 February 2020 and 28 February 2021. MEASUREMENTS: Inpatient use of hydroxychloroquine, remdesivir, or dexamethasone. RESULTS: Among 137 870 persons hospitalized with confirmed or suspected COVID-19, 8754 (6.3%) received hydroxychloroquine, 29 272 (21.2%) remdesivir, and 53 909 (39.1%) dexamethasone during the study period. Since the release of results from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in mid-June, approximately 78% to 84% of people who have had invasive mechanical ventilation have received dexamethasone or other glucocorticoids. The use of hydroxychloroquine increased during March 2020, peaking at 42%, and started declining by April 2020. By contrast, remdesivir and dexamethasone use gradually increased over the study period. Dexamethasone and remdesivir use varied substantially across health centers (intraclass correlation coefficient, 14.2% for dexamethasone and 84.6% for remdesivir). LIMITATION: Because most N3C data contributors are academic medical centers, findings may not reflect the experience of community hospitals. CONCLUSION: Dexamethasone, an evidence-based treatment of COVID-19, may be underused among persons who are mechanically ventilated. The use of remdesivir and dexamethasone varied across health systems, suggesting variation in patient case mix, drug access, treatment protocols, and quality of care. PRIMARY FUNDING SOURCE: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; and National Institute on Aging.

Risk Factors Associated With SARS-CoV-2 Infections, Hospitalization, and Mortality Among US Nursing Home Residents.

Importance: Nursing home residents account for approximately 40% of deaths from SARS-CoV-2. Objective: To identify risk factors for SARS-CoV-2 incidence, hospitalization, and mortality among nursing home residents in the US. Design, Setting, and Participants: This retrospective longitudinal cohort study was conducted in long-stay residents aged 65 years or older with fee-for-service Medicare residing in 15 038 US nursing homes from April 1, 2020, to September 30, 2020. Data were analyzed from November 22, 2020, to February 10, 2021. Main Outcomes and Measures: The main outcome was risk of diagnosis with SARS-CoV-2 (per International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes) by September 30 and hospitalization or death within 30 days after diagnosis. Three-level (resident, facility, and county) logistic regression models and competing risk models conditioned on nursing home facility were used to determine association of patient characteristics with outcomes. Results: Among 482 323 long-stay residents included, the mean (SD) age was 82.7 (9.2) years, with 326 861 (67.8%) women, and 383 838 residents (79.6%) identifying as White. Among 137 119 residents (28.4%) diagnosed with SARS-CoV-2 during follow up, 29 204 residents (21.3%) were hospitalized, and 26 384 residents (19.2%) died within 30 days. Nursing homes explained 37.2% of the variation in risk of infection, while county explained 23.4%. Risk of infection increased with increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) (eg, BMI>45 vs BMI 18.5-25: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.15-1.24) but varied little by other resident characteristics. Risk of hospitalization after SARS-CoV-2 increased with increasing BMI (eg, BMI>45 vs BMI 18.5-25: aHR, 1.40; 95% CI, 1.28-1.52); male sex (aHR, 1.32; 95% CI, 1.29-1.35); Black (aHR, 1.28; 95% CI, 1.24-1.32), Hispanic (aHR, 1.20; 95% CI, 1.15-1.26), or Asian (aHR, 1.46; 95% CI, 1.36-1.57) race/ethnicity; impaired functional status (eg, severely impaired vs not impaired: aHR, 1.15; 95% CI, 1.10-1.22); and increasing comorbidities, such as renal disease (aHR, 1.21; 95% CI, 1.18-1.24) and diabetes (aHR, 1.16; 95% CI, 1.13-1.18). Risk of mortality increased with age (eg, age >90 years vs 65-70 years: aHR, 2.55; 95% CI, 2.44-2.67), impaired cognition (eg, severely impaired vs not impaired: aHR, 1.79; 95% CI, 1.71-1.86), and functional impairment (eg, severely impaired vs not impaired: aHR, 1.94; 1.83-2.05). Conclusions and Relevance: These findings suggest that among long-stay nursing home residents, risk of SARS-CoV-2 infection was associated with county and facility of residence, while risk of hospitalization and death after SARS-CoV-2 infection was associated with facility and individual resident characteristics. For many resident characteristics, there were substantial differences in risk of hospitalization vs mortality. This may represent resident preferences, triaging decisions, or inadequate recognition of risk of death.

Association Between Chronic Use of Immunosuppresive Drugs and Clinical Outcomes From Coronavirus Disease 2019 (COVID-19) Hospitalization: A Retrospective Cohort Study in a Large US Health System.

BACKGROUND: It is unclear whether chronic use of immunosuppressive drugs worsens or improves the severity of coronavirus disease 2019 (COVID-19), with plausible mechanisms for both. METHODS: Retrospective cohort study in 2121 consecutive adults with acute inpatient hospital admission between 4 March and 29 August 2020 with confirmed or suspected COVID-19 in a large academic health system, with adjustment for confounding with propensity score-derived stabilized inverse probability of treatment weights. Chronic immunosuppression was defined as prescriptions for immunosuppressive drugs current at the time of admission. Outcomes included mechanical ventilation, in-hospital mortality, and length of stay. RESULTS: There were 2121 patients admitted with laboratory-confirmed (1967, 93%) or suspected (154, 7%) COVID-19 during the study period, with a median age of 55 years (interquartile range, 40-67). Of these, 108 (5%) were classified as immunosuppressed before COVID-19, primarily with prednisone (>7.5 mg/day), tacrolimus, or mycophenolate mofetil. Among the entire cohort, 311 (15%) received mechanical ventilation; the median (interquartile range) length of stay was 5.2 (2.5-10.6) days, and 1927 (91%) survived to discharge. After adjustment, there were no significant differences in the risk of mechanical ventilation (hazard ratio [HR], .79; 95% confidence interval [CI], .46-1.35), in-hospital mortality (HR, .66; 95% CI, .28-1.55), or length of stay (HR, 1.16; 95% CI, .92-1.47) among individuals with immunosuppression and counterparts. CONCLUSIONS: Chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes among adults hospitalized with COVID-19 in one US health system.

Projected Utility of Pharmacogenomic Testing Among Individuals Hospitalized With COVID-19: A Retrospective Multicenter Study in the United States.

Many academic institutions are collecting blood samples from patients seeking treatment for coronavirus disease 2019 (COVID-19) to build research biorepositories. It may be feasible to extract pharmacogenomic (PGx) information from biorepositories for clinical use. We sought to characterize the potential value of multigene PGx testing among individuals hospitalized with COVID-19 in the United States. We performed a cross-sectional analysis of electronic health records from consecutive individuals hospitalized with COVID-19 at a large, urban academic health system. We characterized medication orders, focusing on medications with actionable PGx guidance related to 14 commonly assayed genes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, G6PD, HLA-A, HLA-B, IFNL3, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1). A simulation analysis combined medication data with population phenotype frequencies to estimate how many treatment modifications would be enabled if multigene PGx results were available. Sixty-four unique medications with PGx guidance were ordered at least once in the cohort (n = 1,852, mean age 60.1 years). Nearly nine in 10 individuals (89.7%) had at least one order for a medication with PGx guidance and 427 patients (23.1%) had orders for 4 or more actionable medications. Using a simulation, we estimated that 17 treatment modifications per 100 patients would be enabled if PGx results were available. The genes CYP2D6 and CYP2C19 were responsible for the majority of treatment modifications, and the medications most often affected were ondansetron, oxycodone, and clopidogrel. PGx results would be relevant for nearly all individuals hospitalized with COVID-19 and would provide the opportunity to improve clinical care.

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.