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Background: The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial randomized 2,204 patients with atrial fibrillation (AF) to catheter ablation or drug therapy. Analysis by intention-to-treat showed a nonsignificant 14% relative reduction in the primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest., Objectives: The purpose of this study was to assess recurrence of AF in the CABANA trial., Methods: The authors prospectively studied CABANA patients using a proprietary electrocardiogram recording monitor for symptom-activated and 24-h AF auto detection. The AF recurrence endpoint was any post-90-day blanking atrial tachyarrhythmias lasting 30 s or longer. Biannual 96-h Holter monitoring was used to assess AF burden. Patients who used the CABANA monitors and provided 90-day post-blanking recordings qualified for this analysis (n = 1,240; 56% of CABANA population). Treatment comparisons were performed using a modified intention-to-treat approach., Results: Median age of the 1,240 patients was 68 years, 34.4% were women, and AF was paroxysmal in 43.0%. Over 60 months of follow-up, first recurrence of any symptomatic or asymptomatic AF (hazard ratio: 0.52; 95% confidence interval: 0.45 to 0.60; p < 0.001) or first symptomatic-only AF (hazard ratio: 0.49; 95% confidence interval: 0.39 to 0.61; p < 0.001) were both significantly reduced in the catheter ablation group. Baseline Holter AF burden in both treatment groups was 48%. At 12 months, AF burden in ablation patients averaged 6.3%, and in drug-therapy patients, 14.4%. AF burden was significantly less in catheter ablation compared with drug-therapy patients across the 5-year follow-up (p < 0.001). These findings were not sensitive to the baseline pattern of AF., Conclusions: Catheter ablation was effective in reducing recurrence of any AF by 48% and symptomatic AF by 51% compared with drug therapy over 5 years of follow-up. Furthermore, AF burden was also significantly reduced in catheter ablation patients, regardless of their baseline AF type. (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial [CABANA]; NCT00911508)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Colonoscopy and fecal immunochemical testing (FIT) are considered top-tier tests for colorectal cancer (CRC) screening. Behavioral economic insights about "choice architecture" suggest that participation could be influenced by how people are presented test options., Objective: To investigate response rates for offering colonoscopy only compared with sequential choice (colonoscopy and then FIT) or active choice (colonoscopy or FIT) through mailed outreach., Design, Setting, and Participants: Three-arm pragmatic randomized clinical trial conducted between November 14, 2017, and May 14, 2018. The setting was primary care practices at an academic health system. Patients aged 50 to 74 years with at least 2 primary care visits in the 2-year preenrollment period were included if they were eligible but not up to date on CRC screening., Interventions: Eligible patients received mailed outreach about CRC screening. Equal numbers of eligible patients were randomly assigned to 3 outreach groups to receive mailings about CRC screening with the following options: (1) direct phone number to call for scheduling colonoscopy (colonoscopy only), (2) direct phone number to call for colonoscopy and a mailed FIT kit if no response within 4 weeks (sequential choice), or (3) direct phone number to call for colonoscopy and a mailed FIT kit offered at the same time (active choice)., Main Outcomes and Measures: The primary outcome was CRC screening completion (FIT or colonoscopy) within 4 months of initial outreach. The secondary outcomes were CRC screening completion within 6 months of outreach and the choice of colonoscopy as a screening test., Results: In total, 438 patients were included in the intent-to-treat analysis, with a median age of 56 years (interquartile range, 52-63 years); 55.0% were women. At 4 months, the CRC screening completion rates were 14.4% (95% CI, 8.7%-20.1%) in the colonoscopy-only arm, 17.1% (95% CI, 11.0%-23.2%) in the sequential choice arm, and 19.9% (95% CI, 13.4%-26.4%) in the active choice arm. Neither choice arm achieved a screening rate statistically greater than that in the colonoscopy-alone arm. Among those who completed CRC screening at 4 months, 90.5% (95% CI, 78.0%-103.0%) chose colonoscopy in the colonoscopy-only arm, which was significantly higher than the 52.0% (95% CI, 32.4%-71.6%; P = .005) and 37.9% (95% CI, 20.2%-55.6%; P < .001) in the sequential choice and active choice arms, respectively., Conclusions and Relevance: There was no significant increase in CRC screening when offering sequential or active choice, but there was a lower rate of colonoscopy in the choice arms than in the colonoscopy-only arm. Subtle changes in sequencing or defaults can alter patient decision making related to preventive health., Trial Registration: ClinicalTrials.gov identifier: NCT03246438.

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

The use of mobile technologies in medicine, or mHealth, holds promise to improve health worker (HW) performance, but evidence is mixed. We conducted a cluster-randomized controlled trial to evaluate the effect of text message reminders to HWs in outpatient health facilities (HFs) on quality of care for malaria, pneumonia, and diarrhea in Malawi. After a baseline HF survey (2,360 patients) in January 2015, 105 HFs were randomized to three arms: 1) text messages to HWs on malaria case management; 2) text messages to HWs on malaria, pneumonia, and diarrhea case management (latter two for children < 5 years); and 3) control arm (no messages). Messages were sent beginning April 2015 twice daily for 6 months, followed by an endline HF survey (2,536 patients) in November 2015. An intention-to-treat analysis with difference-in-differences binomial regression modeling was performed. The proportion of patients with uncomplicated malaria managed correctly increased from 42.8% to 59.6% in the control arm, from 43.7% to 55.8% in arm 1 (effect size -4.7%-points, 95% confidence interval (CI): -18.2, 8.9, P = 0.50) and from 30.2% to 50.9% in arm 2 (effect size 3.9%-points, 95% CI: -14.1, 22.0, P = 0.67). Prescription of first-line antibiotics to children < 5 years with clinically defined pneumonia increased in all arms, but decreased in arm 2 (effect size -4.1%-points, 95% CI: -42.0, 33.8, P = 0.83). Prescription of oral rehydration solution to children with diarrhea declined slightly in all arms. We found no significant improvements in malaria, pneumonia, or diarrhea treatment after HW reminders, illustrating the importance of rigorously testing new interventions before adoption.

Objective: To systematically evaluate in five orthodontic journals how many randomized controlled trials (RCTs) use intention to treat (ITT) analysis and to assess the methodological quality of the ITT analysis, and finally, to demonstrate in an academic way how outcomes can be affected when not implementing the ITT analysis., Material and Methods: A search of the database, Medline, was performed via PubMed for publication type 'randomized controlled trial' published for each journal between 1 January 2013 and 30 April 2017. The five orthodontic journals assessed were the American Journal of Orthodontics and Dentofacial Orthopedics, Angle Orthodontics, European Journal of Orthodontics, Journal of Orthodontics, and Orthodontics and Craniofacial Research. Two independent reviewers assessed each RCT to determine whether the trial reported an ITT or not or if a per-protocol analysis was accomplished., Results: The initial search generated 137 possible trials. After applying the inclusion and exclusion criteria, 90 RCTs were included and assessed. Seventeen out of 90 RCTs (18.9%) either reported an ITT analysis in the text and/or supported the ITT by flow diagrams or tables. However, six RCTs applied and reported the ITT analysis correctly, while the majority performed a per-protocol analysis instead., Conclusions: Nearly all the trials that applied the ITT analysis incorrectly analysed the results using a per-protocol analysis, and thus, overestimating the results and/or having a reduced sample size which then could produce a diminished statistical power.

In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone, and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenström macroglobulinemia (WM), most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m 2 IV on days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6 mg/m 2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m 2 ) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient had developed secondary myelodysplasia, whereas transformation to high-grade lymphoma occurred in 3 patients who had received chemoimmunotherapy after BDR. Thus, BDR is a very active, fixed-duration, chemotherapy-free regimen, inducing durable responses and with a favorable long-term toxicity profile (www.ClinicalTrials.gov #NCT00981708)., (© 2017 by The American Society of Hematology.)

Background: Binge drinking is associated with numerous negative consequences. The prevalence and intensity of binge drinking is highest among young adults. This randomized trial tested the efficacy of a 12-week interactive text message intervention to reduce binge drinking up to 6 months after intervention completion among young adults., Methods and Findings: Young adult participants (18-25 y; n = 765) drinking above the low-risk limits (AUDIT-C score >3/4 women/men), but not seeking alcohol treatment, were enrolled from 4 Emergency Departments (EDs) in Pittsburgh, PA. Participants were randomized to one of three conditions in a 2:1:1 allocation ratio: SMS Assessments + Feedback (SA+F), SMS Assessments (SA), or control. For 12 weeks, SA+F participants received texts each Thursday querying weekend drinking plans and prompting drinking limit goal commitment and each Sunday querying weekend drinking quantity. SA+F participants received tailored feedback based on their text responses. To contrast the effects of SA+F with self-monitoring, SA participants received texts on Sundays querying drinking quantity, but did not receive alcohol-specific feedback. The control arm received standard care. Follow-up outcome data collected through web-based surveys were provided by 78% of participants at 3- months, 63% at 6-months and 55% at 9-months. Multiple imputation-derived, intent-to-treat models were used for primary analysis. At 9-months, participants in the SA+F group reported greater reductions in the number of binge drinking days than participants in the control group (incident rate ratio [IRR] 0.69; 95% CI .59 to.79), lower binge drinking prevalence (odds ratio [OR] 0.52; 95% CI 0.26 to 0.98]), less drinks per drinking day (beta -.62; 95% CI -1.10 to -0.15) and lower alcohol-related injury prevalence (OR 0.42; 95% CI 0.21 to 0.88). Participants in the SA group did not reduce drinking or alcohol-related injury relative to controls. Findings were similar using complete case analyses., Conclusions: An interactive text-message intervention was more effective than self-monitoring or controls in reducing alcohol consumption and alcohol-related injury prevalence up to 6 months after intervention completion. These findings, if replicated, suggest a scalable approach to help achieve sustained reductions in binge drinking and accompanying injuries among young adults., Trial Registration: ClinicalTrials.gov NCT01688245.

Introduction: When participants drop out of randomised clinical trials, as frequently happens, the intention-to-treat (ITT) principle does not apply, potentially leading to attrition bias. Data lost from patient dropout/lack of follow-up are statistically addressed by imputing, a procedure prone to bias. Deviations from the original definition of ITT are referred to as modified intention-to-treat (mITT). As yet, the impact of the potential bias associated with mITT has not been assessed. Our objective is to investigate potential bias and disadvantages of performing mITT and evaluate possible concerns when executing different mITT approaches in meta-analyses., Methods and Analysis: Using meta-epidemiology on randomised trials considered less prone to bias (ie, good internal validity) and assessing biological or targeted agents in patients with rheumatoid arthritis, we will meta-analyse data from 10 biological and targeted drugs based on collections of trials that would correspond to 10 individual meta-analyses., Ethics and Dissemination: This study will enhance transparency for evaluating mITT treatment effects described in meta-analyses. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-review publication., Protocol Registration: In PROSPERO CRD42013006702, 11. December 2013., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)