Rizwan Kalani, MD
Rao NM, Levine SR, Gornbein JA, and Saver JL. Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke: Analysis of the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator Trials. Stroke. 2014

When discussing the recommendation of administering intravenous tissue plasminogen activator (IV-tPA) in acute ischemic stroke, risks and benefits are conveyed to patients and/or families. If being given within 3 hours of symptom onset, at least some of us the NINDS IV-tPA study results with its ~6% symptomatic intracerebral hemorrhage (sICH) risk. It is important to realize, that although symptomatic or radiologically extensive, some intracerebral hemorrhage (ICH) may not contribute to outcome.

Rao et al evaluated which of 4 different ICH definitions best determined clinically relevant ICH, defined as altering long term disability by modified Rankin Scale (mRS) at 3 months, as well as mortality at 3 months post-stroke from the NINDS tPA trial public data set. Only cases of ICH within 36 hours post IV-tPA were included. The definitions studied were: parenchymal hematoma (PH), and the sICH definitions of: the NINDS tPA study, ECASS 2 study, and a modified version of the Safe Implementation of Thrombolysis in Stroke Monitoring Study (mSITS-MOST). The PH definition is a pure radiologic one whereas the other three are mixed clinical and radiologic. For each definition, the authors compared the actual mRS outcomes of those who received IV-tPA and the projected 3 months outcomes of those who didn’t get tPA (based on a logistic regression model taking into account 17 variables including age, pre-existing disability, several objective markers on presentation, vascular risk factors, radiologic features, stroke location and etiology). The difference between the observed mRS with tPA and predicted mRS without tPA was compared.

Of the 312 patients treated with IV-tPA, 10.6% had any ICH by radiologic assessment. 5.4% had PH, 6.4% NINDS defined sICH, 3.8% ECASS 2 defined sICH, and 1.9% mSITS-MOST defined sICH. The ECASS 2 and mSITS-MOST definitions had the largest (and statistically significant) mRS differential between actual and predicted 3 month mRS (ECASS 2 – 1.94 mRS, mSITS-MOST – 2.18) as well as mortality analysis (ECASS 2 – 57.1%, mSITS-MOST – 48.9%).

Thus, patients meeting these definitions had the greatest and significant differences in their actual 3 month outcomes compared to what would be expected without tPA. The ECASS 2 definition identified twice as many patients as having clinically relevant sICH compared to the mSITS-MOST definition.

This report supports the idea that the NINDS study sICH definition includes patients with ICH that does not actually affect 3 month clinical outcomes. This study is the second demonstrating the ECASS 2 definition (any ICH with a decrease in NIHSS 4) may have more utility. Using this, for patients receiving IV-tPA based on the NINDS study inclusion/exclusion criteria, a clinically relevant ICH would occur in 3.8% and ICH resulting in death would in 2.5%.

I think it would be important to discuss clinically important ICH rate (not just overall sICH rate) during risk/benefit conversations with patients for IV-tPA with acute ischemic stroke. A standard definition is also going to be crucial in future, novel therapeutic clinical trials.