Clinical trials for cytoprotection in stroke

Abstract

To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-to-treat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

FIG. 1.

Meta-analysis of 22 calcium antagonist acute stroke trials. Rx = treatment group; P = placebo group. From Horn and Limburg. Calcium antagonists for ischemic stroke: a systematic review. Stroke 32:570–576. Copyright © 2001, Lippincott Williams and Wilkins. All rights reserved.

FIG. 2.

Barthel Index Score results of the GAIN Americas trial of Gavestinel vs. placebo in acute stroke patients. From JAMA 285:1719. Copyright © 2001, American Medical Association. All rights reserved.

FIG. 3.

Barthel Index Score results of the GAIN Americas trial of Gavestinel vs. placebo in acute stroke patients. Reprinted with permission from Elsevier (The Lancet, 355:1949–1954, 2000).

FIG. 4.

Time course of bladder temperature in normothermia and hypothermia patient groups. From the Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:557–563. Copyright © 2002, Massachusetts Medical Society. All rights reserved.