Discussion
stroke, death
STROKE
In this study, we assessed blinding of outcome assessors in a stroke trial with PROBE design and its association with the mRS, which is a relatively subjective outcome. Our study suggests that assessors might not be truly blinded for treatment allocation in trials with PROBE design and that their guessed treatment allocation is associated with outcomes.In trials with PROBE design, patients and health care providers are not blinded, but outcome assessors are assumed to be blinded.Our finding that outcome assessors were able to guess the correct treatment allocation more often than expected based on chance could be explained by several reasons. It could be explained by the use of local assessors. Local assessors, compared to central assessors, might be more at risk for unblinding, because local assessors can (unintentionally) be informed about treatment allocation during the patient’s hospital admission and they can have access to information related to treatment allocation. Another explanation is that the assessors’ guess of treatment allocation might be influenced by outcomes (i.e. reversed causality). Although causality of our finding cannot be determined, researchers and clinicians should pay attention to the possibility of unblinding of outcome assessors in trials with PROBE design, especially since the outcome assessment method as in the IMS III trial is still used in clinical trials with PROBE design.Outcome assessors indicated that they based their guess of treatment allocation often on improvement or lack of improvement. Although this follows logic, it is important to realize that outcome assessors might associate outcomes or side effects with intervention, which can also be the case in double-blinded trials.Success of blinding of outcome assessors is often not assessed and/or reported.This study has several limitations. First, the assessors were asked to guess what treatment group the patient was assigned to, but we do not know if the patient or their proxy brought up information related to treatment during the interview, although this should have been reported to the trial coordinators as a protocol violation, and none of these reports occurred. It cannot be fully known whether assessors were truly unblinded or that the outcome affected the assessors’ guess of treatment allocation (i.e. reversed causality). For example, if raters believe strongly in the success of an intervention and that intervention proves to be successful in the trial, they will favor assessment of a good outcome in the intervention arm and will judge treatment allocation correctly significantly more often than chance. Second, patients in IMS III were randomized in a 2:1 fashion. We assumed that the assessors did not take the 2:1 randomization ratio into account when judging the patient’s treatment allocation. If the assessors took the randomization ratio into account, the expected percentage of correct indications of treatment allocation based on chance would be higher (i.e. 55.6; (intervention: ⅔ × ⅔) + (control: ⅓ × ⅓) = 5/9 = 0.556). However, it is unlikely that assessors took the 2:1 randomization rate into account as they guessed “intervention group” in 254/459 (55.3%) of the patients. If they indeed took the 2:1 randomization ratio into account, one would expect that the assessors guessed “intervention group” in 306/459 (66.7%) of the patients. Another limitation of this study is that we excluded patients who died prior to 90-day assessment and patients with missing data on guessed treatment allocation. Unblinding of patients who died before 90-day follow-up is not relevant in terms of outcome assessment as the last category on the mRS is objective (death) in contrast to the other six categories. We do not know why assessors did not guess or did not report the treatment allocation of some patients and whether there were unknown differences between this group and the included patients. Importantly, a bias associated with baseline characteristics, treatment allocation, and outcome is unlikely, because patients included in this study and patients with unknown guessed treatment allocation had similar characteristics (In conclusion, we provide evidence that assessors may not always be truly blinded for treatment allocation in clinical trials, and their guesses may be associated with outcome. Although causality between the assessors’ guess and patient outcome cannot be determined, future trials with subjective outcome should make efforts to ensure blinding and should report their blinding method and the success of blinding like the IMS III trial.