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

Effect of Bedside Compared With Outside the Room Patient Case Presentation on Patients' Knowledge About Their Medical Care: A Randomized, Controlled, Multicenter Trial: Annals of Internal Medicine: Vol 174, No 9

Background: Although bedside case presentation contributes to patient-centered care through active patient participation in medical discussions, the complexity of medical information and jargon-induced confusion may cause misunderstandings and patient discomfort. Objective: To compare bedside versus outside the room patient case presentation regarding patients' knowledge about their medical care. Design: Randomized, controlled, parallel-group trial. (ClinicalTrials.gov: NCT03210987) Setting: 3 Swiss teaching hospitals. Patients: Adult medical patients who were hospitalized. Intervention: Patients were randomly assigned to bedside or outside the room case presentation. Measurements: The primary endpoint was patients' average knowledge of 3 dimensions of their medical care (each rated on a visual analogue scale from 0 to 100): understanding their disease, the therapeutic approach being used, and further plans for care. Results: Compared with patients in the outside the room group (n = 443), those in the bedside presentation group (n = 476) reported similar knowledge about their medical care (mean, 79.5 points [SD, 21.6] vs. 79.4 points [SD, 19.8]; adjusted difference, 0.09 points [95% CI, −2.58 to 2.76 points]; P = 0.95). Also, an objective rating of patient knowledge by the study team was similar for the 2 groups, but the bedside presentation group had higher ratings of confusion about medical jargon and uncertainty caused by team discussions. Bedside ward rounds were more efficient (mean, 11.89 minutes per patient [SD, 4.92] vs. 14.14 minutes per patient [SD, 5.65]; adjusted difference, −2.31 minutes [CI, −2.98 to −1.63 minutes]; P < 0.001). Limitation: Only Swiss hospitals and medical patients were included. Conclusion: Compared with outside the room case presentation, bedside case presentation was shorter and resulted in similar patient knowledge, but sensitive topics were more often avoided and patient confusion was higher. Physicians presenting at the bedside need to be skilled in the use of medical language to avoid confusion and misunderstandings. Primary Funding Source: Swiss National Foundation (10531C_ 182422).

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.

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.

Déjà Vu: Coronaviruses and Transmission in Health Care Settings

Performance Evaluation of Serial SARS-CoV-2 Rapid Antigen Testing During a Nursing Home Outbreak

Background: To address high COVID-19 burden in U.S. nursing homes, rapid SARS-CoV-2 antigen tests have been widely distributed in those facilities. However, performance data are lacking, especially in asymptomatic people. Objective: To evaluate the performance of SARS-CoV-2 antigen testing when used for facility-wide testing during a nursing home outbreak. Design: A prospective evaluation involving 3 facility-wide rounds of testing where paired respiratory specimens were collected to evaluate the performance of the BinaxNOW antigen test compared with virus culture and real-time reverse transcription polymerase chain reaction (RT-PCR). Early and late infection were defined using changes in RT-PCR cycle threshold values and prior test results. Setting: A nursing home with an ongoing SARS-CoV-2 outbreak. Participants: 532 paired specimens collected from 234 available residents and staff. Measurements: Percentage of positive agreement (PPA) and percentage of negative agreement (PNA) for BinaxNOW compared with RT-PCR and virus culture. Results: BinaxNOW PPA with virus culture, used for detection of replication-competent virus, was 95%. However, the overall PPA of antigen testing with RT-PCR was 69%, and PNA was 98%. When only the first positive test result was analyzed for each participant, PPA of antigen testing with RT-PCR was 82% among 45 symptomatic people and 52% among 343 asymptomatic people. Compared with RT-PCR and virus culture, the BinaxNOW test performed well in early infection (86% and 95%, respectively) and poorly in late infection (51% and no recovered virus, respectively). Limitation: Accurate symptom ascertainment was challenging in nursing home residents; test performance may not be representative of testing done by nonlaboratory staff. Conclusion: Despite lower positive agreement compared with RT-PCR, antigen test positivity had higher agreement with shedding of replication-competent virus. These results suggest that antigen testing could be a useful tool to rapidly identify contagious people at risk for transmitting SARS-CoV-2 during nascent outbreaks and help reduce COVID-19 burden in nursing homes. Primary Funding Source: None.

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

SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn