Aristeidis H. Katsanos, MD, PhD
Khatri P, Kleindorfer DO, Devlin T, Sawyer Jr. RN, Starr M, Mejilla J, et al. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018
The Potential of rtPA for Ischemic Strokes With Mild Symptoms (PRISMS) trial was designed as a phase 3, randomized, double-blind clinical trial with the aim to test the safety and efficacy of intravenous thrombolysis (IVT) administered within 3 hours of symptom onset in acute ischemic stroke (AIS) patients with mild, non-disabling neurological deficits [baseline National Institutes of Health Stroke Scale (NIHSS) score equal or less than 5]. The study was prematurely terminated by the sponsor (Genentech Inc.) after recruitment of 313 patients (one third of the initially planned sample size) due to low recruitment rates. Data analysis revealed comparable 3-month favorable functional outcome [FFO, defined as modified Rankin Scale (mRS) score of 0 or 1] rates between patients receiving IVT and aspirin (78.2% vs. 81.5%; adjusted absolute risk difference: -1.1%; 95%CI: -9.4% to 7.3%) and functional improvement in the ordinal analysis of mRS scores at 3-months (OR: 0.81; 95% CI: 0.5 to 1.2). However, patients randomized to IVT had increased sICH rates within 36 hours following rtPA bolus (3.2% vs. 0%; absolute risk difference: 3.3%; 95% CI: 0.8% to 7.4%) and serious adverse events (26.0% vs. 13.1%; absolute risk difference: 12.9%, 95% CI: 4.1 to 21.7%), when compared to antiplatelet treated patients.
The definition of a non-disabling deficit as “that, if unchanged, would prevent the patient from performing basic activities of daily living…in consultation with patients and available family” leaves the primary inclusion criterion open to personal interpretations, while opening the door to selection bias and confounding by indication. The fear for these biases is further exacerbated by the lack of screening log and information on the total number of patients assessed for eligibility. Of note is also that due to the final limited sample size, there was a shift of the primary outcome during the late phase of the study from an ordinal analysis of the 3-month mRS score via a Cochran-Mantel-Haenszel hypothesis test to a linear model hypothesis on the adjusted risk difference of 3-month FFO rates. Finally, it should be highlighted that in approximately 10% of the cases, patient data on the primary outcome were imputed due to lack of three-month follow-up evaluations, while 13% of the patients were finally diagnosed as stroke mimics.
Although the PRISMS study failed to prove superiority of IVT treatment over antiplatelet therapy in AIS patients with mild, non-disabling AIS, the reported results cannot be used for the claim of clinical equipoise. Patients with mild strokes are known to be an extremely diverse population with different underlying stroke etiologies and vascular comorbidities. Taking also into account evidence from observational studies reporting that up to 15% of AIS patients with mild neurological deficit on first arrival to the emergency department may experience clinical worsening with one-third of them experiencing some degree of long-term disability, the need for prompt identification of this subgroup — which is likely to benefit the most from rtPA administration — should be the desired. However, considering that most of the patients with mild strokes are not due to large vessel occlusions and that according to current guidelines mechanical thrombectomy is strongly suggested only for patients with significant deficits on arrival (NIHSS equal or more than 6), IVT remains the only treatment that has the potential to improve disability for patients with mild neurological deficits, if administered promptly.
“Primum non nocere” is the one edge of a highly efficacious therapy, non-immune to harming, with the other edge being “remorseful regret”. Weighting potential benefit-to-risk should be the cornerstone of all available reperfusion therapies, without strict numerical cut-offs, and after individualization of neurological deficit, comorbidities and neuroimaging parameters.