A hybrid automated event adjudication system for clinical trials.

INTRODUCTION: In clinical trials, event adjudication is a process to review and confirm the accuracy of outcomes reported by site investigators. Despite efforts to automate the communication between a clinical-data-and-coordination center and an event adjudication committee, the review and confirmation of outcomes, as the core function of the process, still fully rely on human labor. To address this issue, we present an automated event adjudication system and its application in two randomized controlled trials. METHODS: Centrally executed by a clinical-data-and-coordination center, the automated event adjudication system automatedly assessed and classified outcomes in a clinical data management system. By checking clinically predefined criteria, the automated event adjudication system either confirmed or unconfirmed an outcome and automatedly updated its status in the database. It also served as a management tool to assist staff to oversee the process of event adjudication. The system has been applied in: (1) the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial and (2) the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial. The automated event adjudication system first screened outcomes reported on a case report form and confirmed those with data matched to preset definitions. For selected primary efficacy, secondary, and safety outcomes, the unconfirmed cases were referred to a human event adjudication committee for a final decision. In the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial, human adjudicators were given priority to review cases, while the automated event adjudication system took the lead in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial. RESULTS: Outcomes that were adjudicated in a hybrid model are discussed here. The COMPASS automated event adjudication system adjudicated 3283 primary efficacy outcomes and confirmed 1652 (50.3%): 132 (21.1%) strokes, 522 (53%) myocardial infarctions, and 998 (59.7%) causes of deaths. The NAVIGATE ESUS one adjudicated 737 cases of selected outcomes and confirmed 383 (52%): 219 (51.5%) strokes, 34 (42.5%) myocardial infarctions, 73 (54.9%) causes of deaths, and 57 (57.6%) major bleedings. After one deducts the time needed for migrating the system to a new study, the automated event adjudication system helped to reduce the time required for human review from approximately 1303 to 716.5 h for the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial and from 387 to 196 h for the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source trial. CONCLUSION: The automated event adjudication system in combination with human adjudicators provides a streamlined and efficient approach to event adjudication in clinical trials. To immediately apply automated event adjudication, one can first consider the automated event adjudication system and involve human assistance for cases unconfirmed by the former.

Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease.

AIMS: Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients. METHODS AND RESULTS: We analysed data of 15 400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrolment. A total of 1788 (11.6%) patients had RHD. These patients were younger (51.4±15.7 vs. 67.8±13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA2DS2-VASc score (2.1±1.7 vs. 3.7±2.2) as compared to patients without RHD (all P<0.001). Significant mitral stenosis (average mean transmitral gradient 11.5±6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, P<0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA2DS2-VASc score was modest in both groups [stroke at 1 year, c-statistics 0.69, 95% confidence interval (CI) 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively]. In the overall cohort, advanced age, female sex, prior stroke, tobacco use, and non-use of anticoagulation were predictors for stroke (all P<0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, P=0.764). CONCLUSION: The performance of the CHA2DS2-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke.

Screening for Atrial Fibrillation in the Older Population: A Randomized Clinical Trial.

Importance: Atrial fibrillation (AF) is a major cause of preventable strokes. Screening asymptomatic individuals for AF may increase anticoagulant use for stroke prevention. Objective: To evaluate 2 home-based AF screening interventions. Design, Setting, and Participants: This multicenter randomized clinical trial recruited individuals from primary care practices aged 75 years or older with hypertension and without known AF. From April 5, 2015, to March 26, 2019, 856 participants were enrolled from 48 practices. Interventions: The control group received standard care (routine clinical follow-up plus a pulse check and heart auscultation at baseline and 6 months). The screening group received a 2-week continuous electrocardiographic (cECG) patch monitor to wear at baseline and at 3 months, in addition to standard care. The screening group also received automated home blood pressure (BP) machines with oscillometric AF screening capability to use twice-daily during the cECG monitoring periods. Main Outcomes and Measures: With intention-to-screen analysis, the primary outcome was AF detected by cECG monitoring or clinically within 6 months. Secondary outcomes included anticoagulant use, device adherence, and AF detection by BP monitors. Results: Of the 856 participants, 487 were women (56.9%); mean (SD) age was 80.0 (4.0) years. Median cECG wear time was 27.4 of 28 days (interquartile range [IQR], 18.4-28.0 days). In the primary analysis, AF was detected in 23 of 434 participants (5.3%) in the screening group vs 2 of 422 (0.5%) in the control group (relative risk, 11.2; 95% CI, 2.7-47.1; P = .001; absolute difference, 4.8%; 95% CI, 2.6%-7.0%; P < .001; number needed to screen, 21). Of those with cECG-detected AF, median total time spent in AF was 6.3 hours (IQR, 4.2-14.0 hours; range 1.3 hours-28 days), and median duration of the longest AF episode was 5.7 hours (IQR, 2.9-12.9 hours). Anticoagulation was initiated in 15 of 20 patients (75.0%) with cECG-detected AF. By 6 months, anticoagulant therapy had been prescribed for 18 of 434 participants (4.1%) in the screening group vs 4 of 422 (0.9%) in the control group (relative risk, 4.4; 95% CI, 1.5-12.8; P = .007; absolute difference, 3.2%; 95% CI, 1.1%-5.3%; P = .003). Twice-daily AF screening using the home BP monitor had a sensitivity of 35.0% (95% CI, 15.4%-59.2%), specificity of 81.0% (95% CI, 76.7%-84.8%), positive predictive value of 8.9% (95% CI, 4.9%-15.5%), and negative predictive value of 95.9% (95% CI, 94.5%-97.0%). Adverse skin reactions requiring premature discontinuation of cECG monitoring occurred in 5 of 434 participants (1.2%). Conclusions and Relevance: In this randomized clinical trial, among older community-dwelling individuals with hypertension, AF screening with a wearable cECG monitor was well tolerated, increased AF detection 10-fold, and prompted initiation of anticoagulant therapy in most cases. Compared with continuous ECG, intermittent oscillometric screening with a BP monitor was an inferior strategy for detecting paroxysmal AF. Large trials with hard clinical outcomes are now needed to evaluate the potential benefits and harms of AF screening. Trial Registration: ClinicalTrials.gov Identifier: NCT02392754.

Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI).

BACKGROUND: The COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies) demonstrated that dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily reduced the primary major adverse cardiovascular event (MACE) outcome of cardiovascular death, myocardial infarction, or stroke, as well as, mortality, in patients with chronic coronary syndromes or peripheral arterial disease. Whether this remains true in patients with a history of percutaneous coronary intervention (PCI) is unknown. METHODS: In a prespecified subgroup analysis from COMPASS, we examined the outcomes of patients with chronic coronary syndrome with or without a previous PCI treated with DPI versus aspirin alone. Among patients with a previous PCI, we studied the effects of treatment according to the timing of the previous PCI. RESULTS: Of the 27 395 patients in COMPASS, 16 560 patients with a chronic coronary syndrome were randomly assigned to DPI or aspirin, and, of these, 9862 (59.6%) had previous PCI (mean age 68.2±7.8, female 19.4%, diabetes mellitus 35.7%, previous myocardial infarction 74.8%, multivessel PCI 38.0%). Average time from PCI to randomization was 5.4 years (SD, 4.4) and follow-up was 1.98 (SD, 0.72) years. Regardless of previous PCI, DPI versus aspirin produced consistent reductions in MACE (PCI: 4.0% versus 5.5%; hazard ratio [HR], 0.74 [95% CI, 0.61-0.88]; no PCI: 4.4% versus 5.7%; HR, 0.76 [95% CI, 0.61-0.94], P-interaction=0.85) and mortality (PCI: 2.5% versus 3.5%; HR, 0.73 [95% CI, 0.58-0.92]; no PCI: 4.1% versus 5.0%; HR, 0.80 [95% CI, 0.64-1.00], P-interaction=0.59), but increased major bleeding (PCI: 3.3% versus 2.0%; HR, 1.72 [95% CI, 1.34-2.21]; no PCI: 2.9% versus 1.8%; HR, 1.58 [95% CI, 1.15-2.17], P-interaction=0.68). In those with previous PCI, DPI compared with aspirin produced consistent (robust) reductions in MACE irrespective of time since previous PCI (as early as 1 year and as far as 10 years; P-interaction=0.65), irrespective of having a previous myocardial infarction (P-interaction=0.64). CONCLUSIONS: DPI compared with aspirin produced consistent reductions in MACE and mortality but with increased major bleeding with or without previous PCI. Among those with previous PCI 1 year and beyond, the effects on MACE and mortality were consistent irrespective of time since last PCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Rivaroxaban, Aspirin, or Both to Prevent Early Coronary Bypass Graft Occlusion: The COMPASS-CABG Study.

BACKGROUND: Patients with recent coronary artery bypass graft (CABG) surgery are at risk for early graft failure, which is associated with a risk of myocardial infarction and death. In the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) trial, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the primary major adverse cardiovascular events (MACE) outcome of cardiovascular death, stroke, or myocardial infarction. Rivaroxaban 5 mg twice daily alone did not significantly reduce MACE. OBJECTIVES: This pre-planned substudy sought to determine whether the COMPASS treatments are more effective than aspirin alone for preventing graft failure and MACE after CABG surgery. METHODS: The substudy randomized 1,448 COMPASS trial patients 4 to 14 days after CABG surgery to receive the combination of rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone. The primary outcome was graft failure, diagnosed by computed tomography angiogram 1 year after surgery. RESULTS: The combination of rivaroxaban and aspirin and the regimen of rivaroxaban alone did not reduce the graft failure rates compared with aspirin alone (combination vs. aspirin: 113 [9.1%] vs. 91 [8.0%] failed grafts; odds ratio [OR]: 1.13; 95% confidence interval [CI]: 0.82 to 1.57; p = 0.45; rivaroxaban alone vs. aspirin: 92 [7.8%] vs. 92 [8.0%] failed grafts; OR: 0.95; 95% CI: 0.67 to 1.33; p = 0.75). Compared with aspirin, the combination was associated with fewer MACE (12 [2.4%] vs. 16 [3.5%]; hazard ratio [HR]: 0.69; 95% CI: 0.33 to 1.47; p = 0.34), whereas rivaroxaban alone was not (16 [3.3%] vs. 16 [3.5%]; HR: 0.99, CI: 0.50 to 1.99; p = 0.98). There was no fatal bleeding or tamponade within 30 days of randomization. CONCLUSIONS: The combination of rivaroxaban 2.5 mg twice daily plus aspirin or rivaroxaban 5 mg twice daily alone compared with aspirin alone did not reduce graft failure in patients with recent CABG surgery, but the combination of rivaroxaban 2.5 mg twice daily plus aspirin was associated with similar reductions in MACE, as observed in the larger COMPASS trial. (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS [COMPASS]; NCT01776424).

Randomized Controlled Trial of Radiation Protection With a Patient Lead Shield and a Novel, Nonlead Surgical Cap for Operators Performing Coronary Angiography or Intervention.

BACKGROUND: Interventional cardiologists receive one of the highest levels of annual occupational radiation exposure. Further measures to protect healthcare workers are needed. METHODS AND RESULTS: We evaluated the efficacy of a pelvic lead shield and a novel surgical cap in reducing operators' radiation exposure. Patients undergoing coronary angiography or percutaneous coronary intervention (n=230) were randomized to have their procedure with or without a lead shield (Ultraray Medical, Oakville, Canada) placed over the patient. During all procedures, operators wore the No Brainer surgical cap (Worldwide Innovations and Technology, Kansas City, KS) designed to protect the head from radiation exposure. The coprimary outcomes for the lead shield comparison were (1) operator dose (µSv) and (2) operator dose indexed for air kerma (µSv/mGy). For the cap comparison, the primary outcome was the difference between total radiation dose (µSv; internal and external to cap). The lead shield use resulted in a 76% reduction in operator dose (mean dose, 3.07; 95% confidence interval [CI], 2.00-4.71 µSv lead shield group versus 12.57; 95% CI, 8.14-19.40 µSv control group; P<0.001). The mean dose indexed for air kerma was reduced by 72% (0.004; 95% CI, 0.003-0.005 µSv/mGy lead shield group versus 0.015; 95% CI, 0.012-0.019 µSv/mGy control group; P<0.001). The cap use resulted in a significant reduction in operator head radiation exposure (mean left temporal difference [external-internal] radiation dose was 4.79 [95% CI, 3.30-6.68] µSv; P<0.001). CONCLUSIONS: The use of a pelvic lead shield and the cap reduced significantly the operator radiation exposure and can be easily incorporated into clinical practice. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02128035.