Response to Letter by Kent and Mandava
We are grateful for the interest of Drs Kent and Mandava in our article, but are somewhat surprised that they impute to us a claim that we did not advance. We concluded that the very strong association between recanalization and clinical outcome indicates that “recanalization is an appropriate biomarker of therapeutic activity in early phase trials of thrombolytic treatment in acute ischemic stroke.” We never suggested that recanalization should be used as a substitute for clinical outcome end points in pivotal, phase 3 trials.
We respectfully disagree with some of the subsidiary points advanced by Drs Kent and Mandava. Maximum permitted dose designs are more appropriate than fixed or random dose designs for pivotal trials of intra-arterial fibrinolysis.1,2 Fixed dose designs require continued infusion of lytic agent even after complete recanalization has been achieved, exposing the individual patient to needless risk, accruing needless adverse effects to the tested intervention, and deviating from the method of treatment that would be used in actual clinical practice. Also, although hyperglycemia is a poor prognostic factor in stroke patients, patients with hyperglycemia still fare better if they recanalize early than if they do not.3
Despite these quibbles, we have no quarrel with the main message of Drs Kent and Mandava. Pharmacological agents can exert pleiotropic effects not fully reflected in any single biomarker of activity. Accordingly, biomarker outcomes are useful for rapidly determining whether agents have biological activity and initial dose finding, but global functional outcomes must be used for final, pivotal phase 3 trials.
J.H.R. is a practicing vascular neurologist who administers recanalization therapies. J.L.S. has been an unfunded site subinvestigator in multicenter and single-center NIH trials in which recanalization devices or drugs were provided at no cost by Concentric Medical, Ekos, Genentech, and Talacris; is Director of an NIH Program Project which included one recanalization subproject for which devices were provided at no cost by Concentric Medical; has been an unfunded site subinvestigater in multicenter recanalization trials sponsored by Eli Lilly and Neurobiological Technologies, Inc; has served on Scientific advisory boards for Boehringer Ingelheim (secondary prevention) and Nuvelo; has served on a Speaker’s Bureau for Boehringer Ingelheim (secondary prevention); serves as Director of the UCLA Stroke Center, which provides recanalization therapies; is a practicing vascular neurologist who administers recanalization therapies.
Lewandowski CA, Frankel M, Tomsick TA, Broderick J, Frey J, Clark W, Starkman S, Grotta J, Spilker J, Khoury J, Brott T. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999; 30: 2598–2605.
Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004; 35: 904–911.
Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, Lyden PD, Broderick JP, Kwiatkowski TG, Fineberg SE. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. 2002; 59: 669–674.