12-month post-trial follow-up of participants in the Australian arm of the second low-dose colchicine trial

Background In the Australian arm of the LoDoCo2 trial, colchicine 0.5mg daily compared with placebo markedly reduced the risk of cardiovascular (CV) events in patients with chronic coronary disease (2.0 vs 3.9 events per 100 person years, HR 0.51; 95% CI 0.39–0.67). The purpose of this analysis was to explore CV and non-CV outcomes in the Australian cohort out to one year after cessation of trial medication. Methods Information was collected on all potential CV events and non-CV deaths as well as a range of other co-morbidities. All CV events were blindly adjudicated. The analysis examined the primary outcome (a composite of CV death, myocardial infarction, ischemic stroke, and unscheduled revascularization) and non-CV deaths by initial randomized treatment from the beginning of the trial up until one year after cessation of trial medication. A landmark analysis was then used to examine these outcomes from the date of last contact during the trial until one year after cessation of trial medication. Results The clinical status was confirmed in 1819/1824 (99.7%) participants who were alive at the end of the trial, and in 100% of those participants still taking trial medication at the end of the trial. During post-trial follow up, 515 patients (28.2%) were taking non-study colchicine, including 278 (30.5%) originally randomized to colchicine and 237 (25.9%) randomized to placebo. Over the entire follow-up period that included the 12-month period after the trial medication was ceased, the effect of prior exposure to colchicine on the primary CV outcome was still evident (2.2 vs 3.8 events per 100 person years, HR 0.58; 95% CI 0.45–0.74), however no post-trial CV benefit were apparent in the landmark analysis (3.3 vs 3.4 events per 100 person years, HR 0.97; 95% CI 0.56–0.1.69). Over the entire course of follow-up the incidence of new cancer (7.9% vs 7.2% RR 0.91; 95% CI 0.66–1.25) and non-CV death (0.9 vs 0.6 events per 100 person years, HR 1.44; 95% CI 0.92–2.27) was no different in the treatment groups. Conclusion Although the CV benefits of colchicine treatment that emerged during the trial were still evident in the year after stopping study treatment, no additional CV benefit accrued after it was ceased. These data suggest that colchicine should be continued long-term to maximize its CV benefits. FUNDunding Acknowledgement Type of funding sources: None.

Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

How to enhance recruitment of individuals at risk of rheumatoid arthritis into trials aimed at prevention: understanding the barriers and facilitators

ObjectivesSeveral trials to test the efficacy of a pharmacological intervention aimed at primary prevention of rheumatoid arthritis (RA) are ongoing or have recently been completed. A common issue in these trials is the severe difficulty with patient recruitment. In order to enhance recruitment, this qualitative study identified barriers and facilitators of individuals at risk of RA to participate in a prevention trial.MethodsIndividuals at risk of developing RA (ie, arthralgia with anticitrullinated protein antibodies and/or rheumatoid factor without arthritis), who had previously been asked to participate in a prevention trial, participated in focus group discussions (n=18) exploring their facilitators and barriers for trial participation. Thematic analysis identified factors that were important in at-risk individuals’ decision about trial participation.ResultsThe prospect of personal benefit, the acknowledgement of one’s symptoms and the desire to contribute to society facilitated trial participation. In contrast, misconception about what it means to be at risk, or about the aim of the prevention trial, negative views on trial medication, and a low perceived urgency to act on the possibility of developing RA versus a high perceived burden of participating in a trial discouraged participation.ConclusionsTo enhance inclusion in trials aimed to prevent RA, the results suggest to use strategies such as optimising education about RA, personal risk, trial aim and trial medication, explicitly addressing misconceptions and concerns, using tools to improve information provision, limiting study burden in trial design and encouraging physicians to mention trial participation.

Placebo-Controlled Discontinuation of Long-Term Acid-Suppressant Therapy: A Randomised Trial in General Practice

Objective. To investigate whether patients on long-term antisecretory medication need to continue treatment to control symptoms. Methods. A double-blinded randomised placebo-controlled trial in general practices in Denmark. Patients aged 18–90 who were treated with antisecretory drugs on a long-term basis were randomized to esomeprazole 40 mg or identical placebo. Outcome measures were time to discontinuation with trial medication due to failed symptom control analysed as survival data. The proportion of patients stopping trial medication during the one-year follow-up was estimated. Results. A total of 171 patients were included with a median prior duration of antisecretory treatment of four years (range: 0.5 to 14.6 years). 86 patients received esomeprazole 40 mg and 85 patients received placebo. At 12 months, statistically significantly more patients in the placebo group had discontinued (73% (62/85)) compared with the esomeprazole group (21% (18/86); p < 0.001). Conclusions. Long-term users of antisecretory drugs showed a preference for the active drug compared to placebo. However, 27% of patients continued on placebo throughout the study and did not need to reinstitute usual treatment. One in five patients treated with esomeprazole discontinued trial medication due to unsatisfactory symptom control. Discontinuation of antisecretory treatment should be considered in long-term users of antisecretory drugs. This trial is registered with Trial registration ClinicalTrials.gov ID: NCT00120315.