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.

Effect of the STAMP (Sharing and Talking About My Preferences) Intervention on Completing Multiple Advance Care Planning Activities in Ambulatory Care: A Cluster Randomized Controlled Trial: Annals of Internal Medicine: Vol 174, No 11

Background: Interventions with the potential for broad reach in ambulatory settings are necessary to achieve a life course approach to advance care planning. Objective: To examine the effect of a computer-tailored, behavioral health model–based intervention on the engagement of adults in advance care planning recruited from ambulatory care settings. Design: Cluster randomized controlled trial with participant-level analysis. (ClinicalTrials.gov: NCT03137459) Setting: 10 pairs of primary and selected specialty care practices matched on patient sociodemographic information. Participants: English-speaking adults aged 55 years or older; 454 adults at practices randomly assigned to usual care and 455 at practices randomly assigned to intervention. Intervention: Brief telephone or web-based assessment generating a mailed, individually tailored feedback report with a stage-matched brochure at baseline, 2 months, and 4 months. Measurements: The primary outcome was completion of the following 4 advance care planning activities at 6 months: identifying and communicating with a trusted person about views on quality versus quantity of life, assignment of a health care agent, completion of a living will, and ensuring that the documents are in the medical record—assessed by a blinded interviewer. Secondary outcomes were completion of individual advance care planning activities. Results: Participants were 64% women and 76% White. The mean age was 68.3 years (SD, 8.3). The predicted probability of completing all advance care planning activities in usual care sites was 8.2% (95% CI, 4.9% to 11.4%) versus 14.1% (CI, 11.0% to 17.2%) in intervention sites (adjusted risk difference, 5.2 percentage points [CI, 1.6 to 8.8 percentage points]). Prespecified subgroup analysis found no statistically significant interactions between the intervention and age, education, or race. Limitations: The study was done in a single region and excluded non–English speaking participants. No information was collected about nonparticipants. Conclusion: A brief, easily delivered, tailored print intervention increased participation in advance care planning in ambulatory care settings. Primary Funding Source: National Institute of Nursing Research and National Institute of Aging.

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

Prevalence of Symptoms More Than Seven Months After Diagnosis of Symptomatic COVID-19 in an Outpatient Setting

Background: With millions of SARS-CoV-2 infections worldwide, increasing numbers of patients are coming forward with long-term clinical effects of the disease lasting several weeks to months. Objective: To characterize symptoms 7 to 9 months after diagnosis of COVID-19. Design: Self-reported surveys and semistructured telephone interviews at enrollment and 30 to 45 days and 7 to 9 months from diagnosis. Setting: From 18 March to 15 May 2020, symptomatic persons who tested positive for SARS-CoV-2 at the Geneva University Hospitals were followed by CoviCare, a virtual, clinical, outpatient follow-up program. Persons were contacted again at 30 to 45 days and 7 to 9 months from diagnosis. Participants: Persons who were a part of the CoviCare program from 18 March to 15 May 2020. Measurements: A standardized interview of symptoms consistent with COVID-19, with grading of intensity. Results: Of the 629 participants in the study who completed the baseline interviews, 410 completed follow-up at 7 to 9 months after COVID-19 diagnosis; 39.0% reported residual symptoms. Fatigue (20.7%) was the most common symptom reported, followed by loss of taste or smell (16.8%), dyspnea (11.7%), and headache (10.0%). Limitation: Limitations include generalizability and missing data for 34.8% of participants. Conclusion: Residual symptoms after SARS-CoV-2 infection are common among otherwise young and healthy persons followed in an outpatient setting. These findings contribute to the recognition of long-term effects in a disease mostly counted by its death toll to date by promoting communication on postacute sequelae of SARS-CoV-2 and encouraging physicians to continue long-term monitoring of their patients. Primary Funding Source: None.

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.

Management of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice Guideline

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline. Methods: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020. Recommendations: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.

Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement: How Would You Manage This Patient With Severe Aortic Stenosis?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 174, No 4

Aortic stenosis (AS) is common, especially among the elderly. Left untreated, severe symptomatic AS is typically fatal. Surgical aortic valve replacement (SAVR) was the standard of care until transcatheter aortic valve replacement (TAVR) was shown to have lower mortality rates in patients at the highest surgical risk and was recommended for this group in the 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines. In the 2017 AHA/ACC focused update, evidence of benefit and noninferiority extended the use of TAVR to intermediate-risk patients. More recent studies suggest potential benefit to low-risk patients, although no published guidelines yet recommend the use of TAVR for this population. An advantage of SAVR is a 30-year experience with valve durability, but SAVR may have higher rates of perioperative death and a slower return of quality of life. Although TAVR has less than 10-year experience with valve durability, it has lower or noninferior primary end points, such as mortality and stroke, and fewer periprocedural complications among anatomically permissive patients. Here, a cardiologist and a cardiothoracic surgeon debate the risks and benefits of TAVR versus SAVR for a patient with severe symptomatic AS who is at low risk for surgical death.

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.

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