Sickle Cell Disorders and Severe COVID-19 Outcomes: A Cohort Study

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics

Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients. To facilitate the execution of these studies and minimize start-up time, ACTIV selected several existing networks to launch the master protocols. The master protocols were also designed to test several agent classes prioritized by ACTIV that covered the spectrum of the disease pathophysiology. Each protocol, either adaptive or pragmatic, was designed to efficiently select those treatments that provide benefit to patients while rapidly eliminating those that were either ineffective or unsafe. The ACTIV Therapeutics-Clinical Working Group members describe the process by which these master protocols were designed, developed, and launched. Lessons learned that may be useful in meeting the challenges of a future pandemic are also described.

Patient Characteristics and Costs Associated With COVID-19–Related Medical Care Among Medicare Fee-for-Service Beneficiaries

Background: New cases of COVID-19 continue to occur daily in the United States, and the need for medical treatments continues to grow. Knowledge of the direct medical costs of COVID-19 treatments is limited. Objective: To examine the characteristics of older adults with COVID-19 and their costs for COVID-19–related medical care. Design: Retrospective observational study. Setting: Medical claims for Medicare fee-for-service (FFS) beneficiaries. Patients: Medicare FFS beneficiaries aged 65 years or older who had a COVID-19–related medical encounter during April through December 2020. Measurements: Patient characteristics and direct medical costs of COVID-19–related hospitalizations and outpatient visits. Results: Among 28.1 million Medicare FFS beneficiaries, 1 181 127 (4.2%) sought COVID-19–related medical care. Among these patients, 23.0% had an inpatient stay and 4.2% died during hospitalization. The majority of the patients were female (57.0%), non-Hispanic White (79.6%), and residents of an urban county (77.2%). Medicare FFS costs for COVID-19–related medical care were $6.3 billion; 92.6% of costs were for hospitalizations. The mean hospitalization cost was $21 752, and the mean length of stay was 9.2 days; hospitalization cost and length of stay were higher if the patient needed a ventilator ($49 441 and 17.1 days) or died ($32 015 and 11.3 days). The mean cost per outpatient visit was $164. Patients aged 75 years or older were more likely to be hospitalized, but their hospitalizations were associated with lower costs than for younger patients. Male sex and non-White race/ethnicity were associated with higher probability of being hospitalized and higher medical costs. Limitation: Results are based on Medicare FFS patients. Conclusion: The COVID-19 pandemic has resulted in substantial disease and economic burden among older Americans, particularly those of non-White race/ethnicity. Primary Funding Source: None.

In-Hospital Mortality in a Cohort of Hospitalized Pregnant and Nonpregnant Patients With COVID-19

Use of Hydroxychloroquine, Remdesivir, and Dexamethasone Among Adults Hospitalized With COVID-19 in the United States: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 174, No 10

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 for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data

Background: Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited. Objective: To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE. Design: Retrospective new-user cohort study. Setting: U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020. Participants: Adults with VTE who were newly prescribed apixaban or rivaroxaban. Measurements: The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding. Results: Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation. Limitation: Short follow-up. Conclusion: In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban. Primary Funding Source: None.

Effect of Sotagliflozin on Total Hospitalizations in Patients With Type 2 Diabetes and Worsening Heart Failure: A Randomized Trial: Annals of Internal Medicine: Vol 174, No 8

Background: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium–glucose cotransporter-1 and sodium–glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%. Objective: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial. Design: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934) Setting: 306 sites in 32 countries. Participants: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure. Intervention: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo. Measurements: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models. Results: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days). Limitation: Other than heart failure, the primary reason for each hospitalization was unspecified. Conclusion: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life. Primary Funding Source: Sanofi at initiation and Lexicon Pharmaceuticals at completion.

Associations of Serum Testosterone and Sex Hormone–Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men

Background: The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. Objective: To analyze associations of serum total testosterone and sex hormone–binding globulin (SHBG) with incident cardiovascular events in men. Design: Cohort study. Setting: UK Biobank prospective cohort. Participants: Community-dwelling men aged 40 to 69 years. Measurements: Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. Results: Of 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). Limitation: Observational study; single baseline measurement of testosterone and SHBG. Conclusion: Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. Primary Funding Source: Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

Fantasies of a Wounded Healer

Factors Associated With Risk for Care Escalation Among Patients With COVID-19 Receiving Home-Based Hospital Care