A couple months back, this little report – MaRISS – was published with minimal fanfare in Stroke. Considering the effort necessary to fund and conduct a prospective study, it’s rather remarkable these data are so uninformative.
The stated purpose of this study:
“The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population.”
Reading between the lines – and considering the study and virtually every author here are sponsored by Genentech – the hoped-for outcome was likely some observational support for the pervasive practice of treating mild stroke with alteplase. Considering all the bias of their study design, it’s actually rather surprising they were unable to do so.
To be included in MaRISS, patients with mild stroke were approached after initial treatment, within 24 hours of hospital admission. However, it is grossly obvious the vast majority of patients meeting eligibility criteria were not even approached. Their “CONSORT diagram” doesn’t actually describe their study population prior to the “consented” step of the process – meaning it only describes those patients dropping out or excluded subsequent to consent. How many patients with mild stroke were admitted to participating hospitals during the study period? How many patients were approached, but declined participation? This information is conspicuously and irresponsibly absent.
The resulting convenience sample, then, ultimately reflects the selection biases of those enrolling. For example, out of 1,765 patients included, only 3 (0.3%) developed symptomatic intracranial hemorrhage. This clearly indicates these data are flawed, as the PRISMS trial demonstrated a 3.3% rate of sICH, and even the Get With the Guidelines-Stroke registry of minor stroke shows a 1.8% rate of sICH. The authors provide the understated: “it is possible that individuals with early complication from thrombolytic treatment were not enrolled.”
Sometimes, possibilities are near certainties – and this is one of those cases.
Regardless, the authors then attempt to discern a beneficial effect of alteplase by comparing their treated (57%) and untreated (43%) final study population. Again, the bias of these authors is quite clear because they create eight different adjustment models and use mRS, Barthel Index, European Quality of Life 5 Dimensions, a Visual Analogue Scale version of stroke assessment, and the Stroke Impact Scale to create an 8 x 5 grid of tests for alteplase to display its superiority. In only one of these boxes was their model able to shake out a benefit for alteplase – and, of course, this chance finding gets escalated into the abstract with “a suggestion of efficacy was noted in the NIHSS 3–5 subgroup.” Nor was any effect on outcomes from time-to-treatment with alteplase identified.
So, an observational trial unable to obtain a representative sample nor describe a hoped-for treatment effect. What little remains is a page and a half of mostly previously-described associations of clinical features with poor functional outcomes, fractionally moving the science forward. If anything, these data ought to enhance calls for better prospective clinical trials versus placebo in minor stroke – if anyone weren’t already entrenched in their clinical opinions.
“Predictors of Outcomes in Patients With Mild Ischemic Stroke Symptoms”
https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032809
OMG thank you. I couldn’t believe what I was reading. And kid you not, multiple colleagues thought this was an RCT based on the way it was written/presented.
It seemed that this was Genentech’s attempt at countering the findings of PRISM (also funded by Genentech)…but this was not even remotely the same patient population. An “NIH 0-5 with non-disabling symptoms”, where I think the median NIH was actually 2 and mostly comprised of sensory deficits (ie PRISMS) is a lot different than just “NIH 0-5” which can include very severe disabling deficits. An NIH of 5 could be made up of a 3 for a leg and 2 for an arm for example, and could easily include LVO patients. And I would expect the latter group to have more benefit from tPA. I don’t think anyone ever questioned giving tPA to someone with severe disabling deficits and NIH 5.
It’s still just totally wild 57% of this study population received alteplase – with a mean NIHSS of 2.9 in that alteplase group. I haven’t yet seen a GWTG analysis showing the distribution of current NIHSS treatment practices, but I’m guessing these minor stroke patients are the largest and fastest-growing segment.
PRISMS actually showed a statistically significant in adverse events with tPA in NIH<5. Not ever reported on.