Intraarterial Recombinant Tissue Plasminogen Activator for Ischemic Stroke: An Accelerated Dosing Regimen

Abstract

To the Editor: We read with interest the article by Qureshi et al. (3), which described an accelerated dosing regimen of intraarterial (IA) recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke that was delivered up to 8 hours after symptom onset. All patients had a National Institutes of Health (NIH) Stroke Scale (NIHSS) score greater than 10, and only one patient began treatment within 3 hours of symptom onset. The stated focus of the report was angiographic recanalization and safety of IA t-PA. Although all eight patients were reported to have at least Thrombolysis in Myocardial Infarction Phase II scale recanalization in this series, the patients had little evidence of clinical improvement. Why the authors chose a 2-point improvement in NIHSS score to define clinical improvement is unclear. We agree with the critique by Dr. Furlan that an increase of 2 or more points on the NIHSS is insufficient to define clinical improvement because variability in performance on the NIHSS alone may explain such a difference. The authors did not present the weights of the eight patients studied, so we do not know how the 40-mg maximum dose given in the series compares with the intravenous (IV) dose that they should have received had they been treated according to the National Institute of Neurological Disorders and Stroke protocol for IV rt-PA (1). They reported a 25% hemorrhage rate (all said to be asymptomatic); we assume that these were hemorrhagic conversions of existing infarctions and not frank intraparenchymal hematomas. Angiographic recanalization, without including the timing of recanalization, is a poor surrogate for clinical outcome. A table listing the times from symptom onset to recanalization for all patients would have been very helpful. These key data do not appear in the article. Also, did the authors use the start of angiography or the start of drug infusion as the time of the start of treatment? Because rt-PA requires time to affect clot lysis, the study cannot address whether recanalization would have occurred with the initial 10-mg dose of rt-PA, even if additional doses of rt-PA had not been given. The time to delivery of an effective treatment is key. It is the major focus of the nascent NIH-sponsored Interventional Management of Stroke (IMS) clinical safety pilot trial, which will incorporate IV rt-PA to accelerate clot lysis before the start of angiography and IA rt-PA administration (if needed). In this protocol, all patients will begin treatment with IV rt-PA within 3 hours of symptom onset, and some patients will start IV rt-PA within 2 hours of symptom onset. Using this paradigm for patients with an NIHSS score greater than or equal to 10, some proximal middle cerebral artery (M1 and M2) clots are nearly or completely lysed (as seen on angiograms) by the time IA rt-PA is administered (2). The IMS trial is a systematic examination of safety as well as recanalization because its ultimate long-term aim is to compare the use of IV rt-PA plus IA t-PA and other IA modalities with the use of IV t-PA alone. We agree that mechanical devices and other drugs are likely to be needed to achieve recanalization more quickly than is possible with current approaches. Yet, unless the start of therapy using these future techniques occurs within the first several hours after symptom onset, the results of angiography will continue to have a poor correlation with patients’ clinical responses. William M. Coplin Joseph Broderick Thomas T. Tomsick