Usman, Muhammad Shariq

Abstract Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.

Abstract Aims Anticoagulants are the mainstay treatment for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), and the CHA2DS2-VASc score is widely used to guide anticoagulation therapy in this cohort. However, utility of CHA2DS2-VASc in NVAF patients is debated, primarily because it is a vascular scoring system, which does not incorporate atrial fibrillation related parameters. Therefore, we conducted a meta-analysis to estimate the discrimination ability of CHA2DS2-VASc in predicting ischaemic stroke overall, and in subgroups of patients with or without NVAF. Methods and results PubMed and Embase databases were searched till June 2020 for published articles that assessed the discrimination ability of CHA2DS2-VASc, as measured by C-statistics, during mid-term (2–5 years) and long-term (>5 years) follow-up. Summary estimates were reported as random effects C-statistics with 95% confidence intervals (CIs). Seventeen articles were included in the analysis. Nine studies (n = 453 747 patients) reported the discrimination ability of CHA2DS2-VASc in NVAF patients, and 10 studies (n = 138 262 patients) in patients without NVAF. During mid-term follow-up, CHA2DS2-VASc predicted stroke with modest discrimination in the overall cohort [0.67 (0.65–0.69)], with similar discrimination ability in patients with NVAF [0.65 (0.63–0.68)] and in those without NVAF [0.69 (0.68–0.71)] (P-interaction = 0.08). Similarly, at long-term follow-up, CHA2DS2-VASc had modest discrimination [0.66 (0.63–0.69)], which was consistent among patients with NVAF [0.63 (0.54–0.71)] and those without NVAF [0.67 (0.64–0.70)] (P-interaction = 0.39). Conclusion This meta-analysis suggests that the discrimination power of the CHA2DS2-VASc score in predicting ischaemic stroke is modest, and is similar in the presence or absence of NVAF. More accurate stroke prediction models are thus needed for the NVAF population.

Background: Efficacy of an intervention is commonly evaluated using P values, in addition to effect size measures such as absolute risk reduction, relative risk reduction, and numbers needed to treat. However, these measures are not always intuitive to clinicians. The fragility index (FI) is a more intuitive number that can facilitate interpretation but can only be used with binary outcomes. FI is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. In this retrospective analysis, we assessed the robustness of cardiovascular randomized controlled trials (RCTs), which report a positive (statistically significant) primary outcome by using the FI. Methods and Results: We searched Medline from 2007 to 2017 to identify cardiovascular RCTs published in 6 high impact journals ( The Lancet , New England Journal of Medicine , Journal of the American Medical Association , Circulation , Journal of the American College of Cardiology and European Heart Journal ). Only RCTs with sample sizes >500 and a 2-by-2 factorial design or dichotomous primary outcomes were selected. FI was calculated using a defined approach. Among the cohort of 123 RCTs that met inclusion criteria, median FI was 13 (interquartile range, 5–26). In 28 trials (22.8%), FI ranged between 1 and 4. In 37 trials (30.1%), number of patients lost to follow-up was higher than the FI. Pharmaceutical interventions had higher FI compared with other interventions, FI=19 (7–52; P =0.002). Median FI varied according to subspecialty (electrophysiology=2; heart failure=11; interventional cardiology=8; P =0.020) and multiregional RCTs had higher FI=22 (12–53.25; P =0.023). FI did not differ based on risk of bias indicators, funding, or publication year. Conclusions: Considerable variations in FI were observed among cardiovascular trials, suggesting the need for careful interpretation of results, particularly when number of patients lost to follow-up exceeds FI.

Background Data about anticoagulation in pulmonary arterial hypertension (PAH) patients are inconsistent. The objective of this study was to examine the impact of adjunctive oral anticoagulants in patients with PAH through meta-analysis, and to further assess whether response differs by PAH subtype. Methods and Results Cochrane CENTRAL, Medline, and Scopus databases were searched for randomized or nonrandomized studies that assessed the association between anticoagulation and outcomes in patients with PAH. Hazard ratios (HRs) for mortality were pooled using the random effects model. Subgroup analyses were performed for type of PAH and study design. Twelve nonrandomized studies, at moderate risk of bias, were included. These consisted of 2512 patients (1342 receiving anticoagulation and 1170 controls). Anticoagulation significantly reduced mortality in the overall PAH cohort (HR, 0.73 [0.57, 0.93]; P =0.001; I 2 =64%). On subgroup analysis, a significant mortality reduction was seen in idiopathic PAH patients (HR, 0.73 [0.56, 0.95]; P =0.02; I 2 =46%), whereas no significant difference was observed in connective tissue disease–related PAH (HR, 1.16 [0.58, 2.32]; P =0.67; I 2 =71%). Sensitivity analysis specific to scleroderma-associated PAH demonstrated a significant increase in mortality with anticoagulant use (HR, 1.58 [1.08, 2.31]; P =0.02; I 2 =9%). Conclusions This meta-analysis shows that use of anticoagulation may improve survival in idiopathic PAH patients, while increasing mortality when used in scleroderma-associated-PAH patients. Currently, no randomized clinical trials have been published, and until randomized data are available, anticoagulant use in PAH should be tailored to PAH subtype.