It is, sadly, negative by the primary outcome of 90-day Rankin score (mRS 0-2), adding another tick mark to the list of failed contemporary trials for systemic thrombolysis. Safety outcomes, mercifully for the patients involved, were similar, with low rates of neurologic worsening associated with intracranial hemorrhage in each cohort.
The authors, as before, find and focus on a single positive subgroup: patients with ischemic injury volume of less than 25mL on MRI. There was, interestingly, no positive effect noted for patients whose ischemic injury volume was less than 25mL on CT – and the authors had no specific explanation for the discrepancy. However, given the recent successful endovascular trials, it is quite reasonable to suggest an imaging-based, tissue-salvage model is more appropriate than the simplistic time-based model suggested by NINDS. Unfortunately, tissue salvage is dependent upon recanalization – and rates were not significantly different between cohorts, 49% with desmoteplase vs. 42% with placebo. This is the persistent elephant neurologists fail to acknowledge – that systemic thrombolysis simply rarely works as advertised – greatly diminishing any possible beneficial effect.
The conflict-of-interest statement falls on what probably would have once been considered the extreme side, but now is tragically routine:
The funder was involved in the study design, data collection, data analysis, and data interpretation. Two employees of the funder provided medical writing assistance in the editing of the report. The corresponding author had full access to all study data; all other authors without funder affiliation had access to study data via the corresponding author and authors with funder affiliation had full access to all study data.Interestingly, review of the ClinicalTrials.gov registration indicates the study was initially planned in 2008 to enroll 320 patients, with an end date in 2010. In 2010, the planned enrollment was increased to 400, and the study ultimately enrolled 492. Given the COI involved, it reasonable to suggest the funder was involved in ongoing analysis of the results with the intention of stopping the study at the precise moment a positive outcome – or ultimate futility – was detected. Despite the best efforts of Jeff Drazen and the NEJM to downplay potential distortions secondary to funding sources, clearly, our vigilance for such likely scientific misconduct should not be diminished.
“Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial”