Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ).

OBJECTIVES: To determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs). METHODS: In a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected). RESULTS: Study enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues. CONCLUSION: Oral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection. TRIAL REGISTRATION: NCT04334148.

Design of the Healthcare Worker Exposure Response and Outcomes (HERO) research platform.

BACKGROUND: The SARS CoV-2 virus has caused one of the deadliest pandemics in recent history, resulting in over 170 million deaths and global economic disruption. There remains an urgent need for clinical trials to test therapies for treatment and prevention. DESIGN: An online research platform was created to support a registry community of healthcare workers (HCWs) to understand their experiences and conduct clinical studies to address their concerns. The first study, HERO-HCQ, was a double-blind, multicenter, randomized, pragmatic trial to evaluate the superiority of hydroxychloroquine (HCQ) vs placebo for pre-exposure prophylaxis (PrEP) of COVID-19 clinical infection in HCWs. Secondary objectives were to assess the efficacy of HCQ in preventing viral shedding of COVID-19 among HCWs and to assess the safety and tolerability of HCQ. METHODS: HCWs joined the Registry and were pre-screened for trial interest and eligibility. Trial participants were randomized 1:1 to receive HCQ or placebo. On-site baseline assessment included a COVID-19 nasopharyngeal PCR and blood serology test. Weekly follow-up was done via an online portal and included screening for symptoms of COVID-19, self-reported testing, adverse events, and quality of life assessments. The on-site visit was repeated at Day 30. DISCUSSION: The HERO research platform offers an approach to rapidly engage, screen, invite and enroll into clinical studies using a novel participant-facing online portal interface and remote data collection, enabling limited onsite procedures for conduct of a pragmatic clinical trial. This platform may be an example for future clinical trials of common conditions to enable more rapid evidence generation.

The Project Baseline Health Study: a step towards a broader mission to map human health.

The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.

BACKGROUND: Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. DESIGN: The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. SUMMARY: The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

Outcomes registry for better informed treatment of atrial fibrillation: rationale and design of ORBIT-AF.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, and death. Data on contemporary treatment patterns and outcomes associated with AF in clinical practice are limited. METHODS/DESIGN: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is a multicenter, prospective, ambulatory-based registry of incident and prevalent AF. The registry will be a nationwide collaboration of health care providers, including internists, primary care physicians, cardiologists, and electrophysiologists. Initial target enrollment is approximately 10,000 patients to be recruited from approximately 200 US outpatient practices. Enrolled patients will be observed for ≥2 years. A patient-reported outcomes substudy in ≥1,500 patients will provide serial quality-of-life assessments. The goal is to characterize treatment and outcomes of patients with AF, thereby promoting better quality of AF care and improved patient outcomes. CONCLUSION: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation will provide insights into "real-world" treatment including rate and rhythm control, stroke prevention, transitions to new therapies, and clinical and patient-centered outcomes among patients with AF in community practice settings (ClinicalTrials.gov NCT01165710).

No association between hemoglobin A1c and in-hospital mortality in patients with diabetes and acute myocardial infarction.

BACKGROUND: Patients with diabetes have increased in-hospital mortality following acute myocardial infarction (AMI), with studies suggesting higher risk with both hypoglycemia and hyperglycemia. We assessed whether a J-shaped relation exists between hemoglobin A1c (A1C) in patients with diabetes and AMI. METHODS: We assessed the associations between A1C and in-hospital mortality using data from a nationwide sample of AMI patients who had both prior diabetes and measurement of A1C (N = 15,337). RESULTS: When evaluated continuously, we observed no evidence of a J-shaped relation between A1C and in-hospital mortality in multivariable analysis (test for linearity P = .89). Patients with lowest (<5.5%) and highest A1C (≥9.5%) had a crude mortality rate of 4.6% and 2.8%, respectively, compared with 3.8% among those in the referent A1C category (6.5% to <7%). In multivariable regression, we observed no association between low A1C (<5.5%, odds ratio 0.81, 95% CI 0.47-1.39) or high A1C (A1C ≥9.5, odds ratio 1.31, 95% CI 0.94-1.83) and mortality as compared with the referent group. These findings can only be generalized to the subset of patients with diabetes who had A1C assessed during their hospitalization; these patients tended to be healthier than those in whom A1C was not assessed. CONCLUSION: In this large contemporary cohort of patients with diabetes presenting with AMI, we did not observe a J-shaped association between A1C and mortality.

Temporal trends and practice variations in clopidogrel loading doses in patients with non-ST-segment elevation myocardial infarction, from the National Cardiovascular Data Registry.

BACKGROUND: A higher loading dose of clopidogrel achieves a more rapid and consistent degree of platelet inhibition than standard dosing, although the clinical benefit of higher doses has not been clearly established. The use of the different doses in clinical practice is not known. We evaluated the patient, procedural, and hospital characteristics associated clopidogrel loading doses given to patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS: The National Cardiovascular Data Registry ACTION Get With the Guidelines Registry was queried for patients with NSTEMI admitted from 2007 to 2008. Demographic, clinical, and procedural information were collected on standardized data forms. Patients were categorized according to the clopidogrel loading dose received. Temporal trends in the use of different doses were evaluated in quarterly time intervals. RESULTS: Between January 1, 2007, and December 31, 2008, the use of a 600-mg clopidogrel loading dose increased steadily from 36.4% to 45.5%, whereas the use of 300 mg decreased slightly from 40.1% to 37.1%. Patients loaded with clopidogrel before cardiac catheterization were more likely to receive 300 mg, whereas those receiving a loading dose at the time of catheterization more often received 600 mg. The temporal increase in the use of 600 mg clopidogrel loading doses was not explained by temporal changes in periprocedural loading, use of early invasive management of patients with NSTEMI, or use of antithrombotics or glycoprotein 2b/3a inhibitors. CONCLUSIONS: Higher loading dose clopidogrel increased between 2007 and 2008. Higher-dose clopidogrel was more frequently used in lower-risk patients undergoing an early invasive strategy and receiving periprocedural loading.

Guideline implementation research: exploring the gap between evidence and practice in the CRUSADE Quality Improvement Initiative.

Translating research results into routine clinical practice remains difficult. Guidelines, such as the 2002 American College of Cardiology/American Heart Association Guidelines for the Management of Patients with Unstable Angina and non-ST-segment elevation myocardial infarction, have been developed to provide a streamlined, evidence-based approach to patient care that is of high quality and is reproducible. The Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation (CRUSADE) Quality Improvement Initiative was developed as a registry for non-ST-segment elevation acute coronary syndromes to track the use of guideline-based acute and discharge treatments for hospitalized patients, as well as outcomes associated with the use of these treatments. Care for more than 200,000 patients at more than 400 high-volume acute care hospitals in the United States was tracked in CRUSADE, with feedback provided to participating physicians and hospitals regarding their performance over time and compared with similar institutions. Such access to data has proved important in stimulating improvements in non-ST-segment elevation acute coronary syndromes care at participating hospitals for delivery of acute and discharge guideline-based therapy, as well as improving outcomes for patients. Providing quality improvement methods such as protocol order sets, continuing education programs, and a CRUSADE Quality Improvement Initiative toolbox serve to actively stimulate physician providers and institutions to improve care. The CRUSADE Initiative has also proven to be a fertile source of research in translation of treatment guidelines into routine care, resulting in more than 52 published articles and 86 abstracts presented at major emergency medicine and cardiology meetings. The cycle for research of guideline implementation demonstrated by CRUSADE includes four major steps--observation, intervention, investigation, and publication--that serve as the basis for evaluating the impact of any evidence-based guideline on patient care. Due to the success of CRUSADE, the American College of Cardiology combined the CRUSADE Initiative with the National Registry for Myocardial Infarction ST-segment elevation myocardial infarction program to form the National Cardiovascular Data Registry-Acute Coronary Treatment & Intervention Outcomes Network Registry beginning in January 2007.

Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative.

BACKGROUND: The extent to which national health quality improvement initiatives have altered reported treatment gaps among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unknown. We sought to determine recent trends in adherence to guideline-based therapies for NSTE ACS. METHODS: We evaluated the treatment of patients with high-risk (positive cardiac markers and/or ischemic ST-segment changes) NSTE ACS enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA (American College of Cardiology/American Heart Association) Guidelines (CRUSADE) Quality Improvement Initiative from 2002 through 2004 (a total of 113 595 patients over 11 calendar quarters). We analyzed adherence to guideline-recommended therapies, including medications used in the acute care period (<24 hours after presentation), invasive procedures, in-hospital outcomes, and discharge therapies and interventions. RESULTS: The use of each class I guideline recommendation, as well as overall adherence to the guidelines, improved significantly (P<.001) during the study period. In the acute care setting, the use of antiplatelet agents increased by 5% and beta-blockers by 12%; at hospital discharge, the use of antiplatelet agents increased by 3% and beta-blockers by 8%. Heparin use in the acute care period increased by 6%, largely owing to a 9% increase in the use of low-molecular-weight heparin. Use of glycoprotein IIb/IIIa inhibitors in the acute care period also increased by more than 13%. At discharge, clopidogrel use increased by 22%, lipid-lowering agents by 11%, and angiotensin-converting enzyme inhibitors by 5%. While adherence improved, many patients still failed to receive 100% indicated treatments at the end of the study period. CONCLUSIONS: During the 4 years since the initial release of the ACC/AHA guidelines for NSTE ACS, adherence to class I recommendations has significantly improved among hospitals participating in CRUSADE. Still, further improvements are needed for optimal implementation of the these guidelines.

Thrombolysis and counterpulsation to improve survival in myocardial infarction complicated by hypotension and suspected cardiogenic shock or heart failure: results of the TACTICS Trial.

BACKGROUND: Sustained hypotension, cardiogenic shock, and heart failure all imply a poor prognosis in acute myocardial infarction (MI). We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation (IABP) to standard treatment for MI, in an international trial among hospitals without primary angioplasty capabilities. METHODS: We randomized 57 patients with MI complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure to receive either fibrinolytic therapy and IABP or fibrinolysis alone. The primary end point was all-cause mortality at 6 months. RESULTS: In all, IABP was inserted in 27 of 30 assigned patients a median 30 minutes after fibrinolysis began and continued for a median 34 hours. Of the 27 patients assigned to fibrinolysis alone, 9 deteriorated such that IABP was required. The IABP group was at slightly higher risk at baseline, but the incidence of the primary end point did not differ significantly between groups (34% for combined treatment versus 43% for fibrinolysis alone; adjusted P = 0.23). Patients with Killip class III or IV showed a trend toward greater benefit from IABP (6-month mortality 39% for combined therapy versus 80% for fibrinolysis alone; P = 0.05). CONCLUSIONS: While early IABP use was not associated with a definitive survival benefit when added to fibrinolysis for patients with MI and hemodynamic compromise in this small trial, its use suggested a possible benefit for patients with the most severe heart failure or hypotension. ABBREVIATED ABSTRACT: We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation to fibrinolytic therapy among 57 patients with acute myocardial infarction complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure. The primary end point, mortality at 6 months, did not differ between groups (34% for combined treatment versus 43% for fibrinolysis alone [n = 27]; adjusted P = 0.23), although patients with Killip class III or IV did show a trend toward greater benefit from IABP (39% for combined therapy versus 80% for fibrinolysis; P = 0.05).

Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.

BACKGROUND: Sudden death from cardiac causes remains a leading cause of death among patients with congestive heart failure (CHF). Treatment with amiodarone or an implantable cardioverter-defibrillator (ICD) has been proposed to improve the prognosis in such patients. METHODS: We randomly assigned 2521 patients with New York Heart Association (NYHA) class II or III CHF and a left ventricular ejection fraction (LVEF) of 35 percent or less to conventional therapy for CHF plus placebo (847 patients), conventional therapy plus amiodarone (845 patients), or conventional therapy plus a conservatively programmed, shock-only, single-lead ICD (829 patients). Placebo and amiodarone were administered in a double-blind fashion. The primary end point was death from any cause. RESULTS: The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF. The cause of CHF was ischemic in 52 percent and nonischemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P=0.53) and ICD therapy was associated with a decreased risk of death of 23 percent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P=0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class. CONCLUSIONS: In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent.

A randomized, placebo-controlled trial of early eptifibatide for non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The acute benefits of platelet glycoprotein IIb/IIIa inhibitors for non-ST-segment elevation acute coronary syndromes (NSTE ACS) remain unclear. METHODS: In this pilot trial, 311 patients with NSTE ACS were randomly assigned in the emergency department to double-blinded therapy with eptifibatide or placebo for 12 to 24 hours before crossover to open-label eptifibatide. Serial creatine-kinase MB (CK-MB) and quantitative cardiac troponin T levels were collected during the first 24 hours to assess the impact of early platelet glycoprotein IIb/IIIa blockade on infarct size as measured by cardiac markers. RESULTS: Median peak CK-MB (10.3 vs 11.8 ng/mL; P =.71) and peak quantitative cardiac troponin T levels (0.2 vs 0.3 ng/mL; P =.95) were similar between treatment groups, respectively. Median calculated peak CK-MB values (41 vs 40 ng/mL; P =.72) and area under the CK-MB curve measurements (980 vs 764 microg/min/L; P =.68) from curve-fitting analyses that could be performed in 106 of 311 patients were also similar. CONCLUSIONS: In this pilot trial, early administration of eptifibatide in the emergency department did not modulate serologic measurements of infarct size in patients with NSTE ACS.