Letters to the Editor
Reasons Why Stroke Trials Underestimate the Neuroprotective Effects of Drugs
To the Editor:
Despite the fact that stroke is the third highest cause of mortality and the second highest cause of morbidity, there are no effective drug treatments for acute stroke, with the possible exception of thrombolytic therapy. The persistent failure of neuroprotective agents to show benefit in acute stroke trials has absorbed immense resources for little tangible benefit or even adverse effects.1,2 More than 20 drugs have been discontinued after trials in acute stroke, and >100 000 patients may have been screened for entry into these trials without a favorable outcome being reported. Multiple mechanisms of action (antagonism of calcium and sodium channels and of N-methyl-d-aspartate [NMDA] and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] receptors, inhibition of glutamate release, scavenging free radicals) have been tried to reduce cell damage, all apparently without beneficial effects, despite remarkable efficacy in animal models. These paradoxes are discouraging pharmaceutical research in a critical area for therapeutic benefit.
I have been associated with the discovery and development of drugs for stroke and consider that experimental and clinical flaws in trial design result in drugs being tested under conditions in which they cannot show a positive outcome. Obviously not all drugs are uniformly neuroprotective, and it is important to ensure that a drug will work in a wide range of animal models, with good activity when administered several hours after damage. It is relatively easy to show apparently good effects for a neuroprotective drug by juggling the experimental conditions in one test, but criteria within the field are now established that should prevent the clinical testing of agents that are not robustly active.
Several flaws in preclinical testing have been noted. Preclinical testing is usually performed in young, healthy animals with low blood sugar. Cerebral vessels therefore have intact endothelium and low levels of circulating cytokines. In contrast, the clinical situation relates to an aged population with atherosclerotic lesions, circulating cytokines, and frequently elevated blood sugar levels. Elevated blood sugar levels can negate the protective effects of some classes of neuroprotective drugs.
Flaws in clinical testing have also been observed.3 The demonstration of a penumbra and the concept of a therapeutic time window for intervention have resulted in clinical trials being focused on rapid treatment of patients after an ischemic event, with inclusion criteria being reduced from 1 to 2 days to 6 or even 3 hours to obtain positive results. However, rapid inclusion induces a major difficulty in that peak mortality is at 3 days. Neuroprotective drugs displace insult–lesion size relationships to the right (Figure) in parallel. However, this leads to 2 problems.
First, patients with very slight strokes will have very little damage, and protective effects in this population will be difficult to measure, eliminating the benefit seen in the upper portion of the Figure.
Second, patients with very serious strokes would be expected to die during the time course of the study, but a neuroprotective drug may save some of these patients, leaving them with considerable neurological deficit (lower triangle in the Figure). However, early phase stroke trials are almost never powered to show effects on mortality, so that it is invalid to subtract the poor scores seen in the survivors. Consequently, these scores detract from the effects of the drug unless an effect on mortality is shown, which the trial is not designed to show.
Consequently, the parallel shift to the right of the insult–lesion size relationship merely results in the same score of neurological deficit, despite a powerful neuroprotective effect. The trials cannot show therapeutic benefit under these conditions.
Is this a real phenomenon? Consider the results with lifarizine, a sodium-calcium channel inhibitor, with use-dependent kinetics at sodium channels that favored ischemic conditions (time constant of 70 ms, favoring sodium channels that are depolarized for long periods of time in ischemic conditions; the drug was without effect on normal neuronal functioning or on animal behavior).4,5 The drug was active in a wide range of focal and global models of ischemia.4,5 A clinical trial was set up with rigorous inclusion criteria (maximum 6-hour delay after stroke, with CT scan; 1 in 20 patients accepted). In the control group 13 patients died, and in the treated group only 9 died, which just missed statistical significance (by 1 patient). Consequently, the neuropathology score (Barthel Index, 16% benefit at 3 months) just missed being significant, presumably because of inclusion of severely damaged patients who would have died without treatment. A powerful significant effect (35% benefit) was seen if patients who had shown a hypotensive effect were excluded (see below). Thus, this drug was classified as ineffective despite just missing positive effects on mortality in a clinical trial of only 147 patients.5 The Figure explains the reason for this.
A second issue that may cause difficulty is that elderly patients may have chronic carotid obstructions and be borderline for an ischemic event caused by hemodynamic events. Global ischemia in such patients may be caused by any prolonged fall in blood pressure1 or by ethanol consumption. Patients of this type are particularly at risk because they usually have already adapted their lifestyle to compensate for the occlusion, and the appearance of stroke damage is the end point. It is illusory to imagine that neuroprotective therapy can be applied chronically to this type of patient, and the likely outcome is that any mild hemodynamic effects of a drug will exacerbate damage.1 Stroke trials including this type of patient are liable to include exacerbated mortality or offset the benefits in mortality that may be expected in other patient populations.
Several possible solutions are worth considering. Powering studies to show beneficial effects on mortality, and then adjusting the neuropathological score to take into account severely compromised patients, is the simplest method. If appropriate inclusion criteria and trial design are used,6–11 with a Kaplan-Meier survival analysis, then this strategy may not require very large numbers of patients to show benefit. Severely compromised patients could be excluded from the trials. Methodology is also needed for the exclusion (or posttreatment reassessment) of patients with almost complete carotid obstruction. However, this approach also raises ethical issues of whether severely damaged patients should be treated. These issues are common to all neuroprotective therapies, and unless they are addressed correctly, neuroprotection will remain a preclinical curiosity, and stroke therapies based on this concept will not progress.
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