Bias and Loss to Follow‐Up in Cardiovascular Randomized Trials: A Systematic Review

Abstract

Background Loss to follow‐up ( LTFU ) is common in randomized controlled trials. However, its potential impact on primary outcomes from cardiovascular randomized controlled trials is not known. Methods and Results We conducted a prospective systematic review ( PROSPERO : CRD 42019121959) for randomized controlled trials published in 8 leading journals over 5 years from January 2014 to December 2018. Extent, reporting, and handling of LTFU data were recorded, and the proportion of a trial's primary outcome results that lose statistical significance was calculated after making plausible assumptions for the intervention and control arms. These assumptions could drive differential treatment effects between the groups considering relative event incidence between LTFU participants and those included in the primary outcome. We identified 117 randomized controlled trials of which 91 (78%) trials reported LTFU , 23 (20%) reported no LTFU , and 3 (3%) trials did not report on whether LTFU occurred. The median percentage of study participants lost to follow‐up was 2% (interquartile range, 0.33%–5.3%). Only 10 trials (9%) had a low cluster of risk factors for impairment in trial quality. The percentage of trials losing statistical significance varied from 2% when the relative event incidence for LTFU between the randomized groups was 1 for the intervention arm and 1.5 for the control arm to 16% when the relative event incidence was 3 for the intervention arm and 1 for the control arm. Conclusions Almost 1 in 6 (16%) cardiovascular randomized trials published in leading journals may have a change in the primary outcome if plausible assumptions are made about differential event rates of participants lost to follow up. There is scope for improvement arising from LTFU in randomized trials in cardiovascular medicine. Registration URL : https://www.crd.york.ac.uk/prospero ; Unique identifier: CRD 42019121959.

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“…Loss to follow-up (LTFU) is a common phenomenon in clinical trials. More than threequarters of cardiovascular clinical trials have participants who are LTFU, and the statistical handling of these data varies widely [25]. In cardiovascular rehabilitation (CR) trials, dropout rates are as high as 39% [26].…”

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“…A systematic review of 117 trials found almost 80% of them showed a loss of follow-ups, and approximately one in six CVOTs may have a change in the primary outcome. 27 Thus, prevention must be prioritised; and authors should report and provide the baseline characteristics of those participants, the extent of follow‐up prior exclusion, and time of dropout and address that implication of those participants when interpreting results. More importantly, Inadequate allocation concealment may drive differential treatment effects (either overestimation or underestimation 28 ) and considered as an independent factor associated with loss of follow-ups, as allocation concealment was inadequate or unclear in more than 50% of the trials.…”

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“…1 However, high loss to follow-up (LTFU) rates are pervasive in modern RCTs and many fail to achieve complete follow-up. 2,3 Efforts to improve and standardize the reporting of LTFU have been ongoing for more than 25 years, and include the Consolidated Standards of Reporting Trials (CONSORT) statement, initially published in 1996 and updated in 2010. 4,5 This statement established recommendations for transparent reporting, including a checklist and flow diagram to facilitate accurate interpretation and critical appraisal of trial design and results.…”

“…Randomized controlled trials (RCTs) are widely accepted as the gold standard for evaluating the safety and efficacy of new interventions or therapeutic applications 1 . However, high loss to follow‐up (LTFU) rates are pervasive in modern RCTs and many fail to achieve complete follow‐up 2,3 . Efforts to improve and standardize the reporting of LTFU have been ongoing for more than 25 years, and include the Consolidated Standards of Reporting Trials (CONSORT) statement, initially published in 1996 and updated in 2010 4,5 .…”