National Institutes of Health Stroke Scale
Authors: Chalos Vicky , van der Ende Nadinda A.M. , Lingsma Hester F. , Mulder Maxim J.H.L. , Venema Esmee , Dijkland Simone A. , Berkhemer Olvert A. , Yoo Albert J. , Broderick Joseph P. , Palesch Yuko Y. , Yeatts Sharon D. , Roos Yvo B.W.E.M. , van Oostenbrugge Robert J. , van Zwam Wim H. , Majoie Charles B.L.M. , van der Lugt Aad , Roozenbeek Bob , Dippel Diederik W.J. ,   on behalf of the MR CLEAN Investigators*, Berkhemer Olvert A. , Fransen Puck S.S. , Beumer Debbie , van den Berg Lucie A. , Lingsma Hester F. , Yoo Albert J. , Schonewille Wouter J. , Albert Vos Jan , Nederkoorn Paul J. , Wermer Marieke J.H. , van Walderveen Marianne A.A. , Staals Julie , Hofmeijer Jeannette , van Oostayen Jacques A. , Lycklama a Nijeholt Geert J. , Boiten Jelis , Brouwer Patrick A. , Emmer Bart J. , de Bruijn Sebastiaan F. , van Dijk Lukas C. , Kappelle L. Jaap , Lo Rob H. , van Dijk Ewoud J. , de Vries Joost , de Kort Paul L.M. , van Rooij Willem Jan J. , van den Berg Jan S.P. , van Hasselt Boudewijn A.A.M. , Aerden Leo A.M. , Dallinga Rene J. , Visser Marieke C. , Bot Joseph C.J. , Vroomen Patrick C. , Eshghi Omid , Schreuder Tobien H.C.M.L. , Heijboer Roel J.J. , Keizer Koos , Tielbeek Alexander V. , den Hertog Heleen M. , Gerrits Dick G. , van den Berg-Vos Renske M. , Karas Giorgos B. , Steyerberg Ewout W. , Flach H. Zwenneke , Marquering Henk A. , Sprengers Marieke E.S. , Jenniskens Sjoerd F.M. , Beenen Ludo F.M. , van den Berg Rene , Koudstaal Peter J. , van Zwam Wim H. , Roos Yvo B.W.E.M. , van der Lugt Aad , van Oostenbrugge Robert J. , Majoie Charles B.L.M. , Dippel Diederik W.J. 
Published: December 2019

Background and Purpose—
The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke.

Methods—
We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed.

Results—
In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22–2.32) to respectively 1.36 (95% CI, 0.97–1.91) and 1.24 (95% CI, 0.87–1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS.

Conclusions—
The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties.

Clinical Trial Registration—

URL:
http://www.isrctn.com
. Unique identifier: ISRCTN10888758;
https://www.clinicaltrials.gov
. Unique identifier: NCT00359424.