Published online before print September 1, 2005, doi: 10.1161/01.STR.0000179037.82647.48
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(Stroke. 2005;36:2323.)
© 2005 American Heart Association, Inc.
Controversies in Stroke |
Use of Animal Models Has Not Contributed to Development of Acute Stroke Therapies
Pro
From the Department of Neurology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Correspondence to Markku Kaste, MD, PhD, FAHA, Professor and Chairman, Department of Neurology, Helsinki University Central Hospital, University of Helsinki, FI-00029 HUS Helsinki, Finland. E-mail markku.kaste{at}hus.fi
Section Editors: Geoffrey A. Donnan MD, FRACP Stephen M. Davis MD, FRACP
Key Words: acute stroke • animal models
In the beautiful archipelago of Stockholm, there was a satellite symposium in connection with the World Congress of Medicine in 1980. The role of calcium was then a hot topic in the cerebral ischemic cascade.1 A paper presented at the symposium demonstrated that a calcium blocker was able to decrease the size of brain infarction in rats. Already then I had a few reservations about such experimental models. In a laboratory, an investigator can modify all known confounding factors and the time from onset of ischemia to the administration of an experimental drug. The body temperature, blood pressure, blood glucose, and acid-base balance of animals can be kept constant and within normal physiological ranges. In a busy emergency room, where an elderly stroke patient is admitted with many severe concomitant diseases, ie, fragile diabetes, untreated hypertension, recent myocardial infarction, and imminent heart failure, the treating physician has major problems in balancing them while the time from onset of symptoms is, at best, an educational guess. I pointed out my doubts and asked whether the treatment would have an equal efficacy in humans as it had in rats. There was no good answer. Twenty-four years later and having been a principal investigator and a steering committee member in many acute stroke trials, I still have my doubts.
Since the early days of neuroprotecting agents in treatment of acute stroke, more than 700 drugs have been studied and more than 4000 papers describing their neuroprotective efficacy have been published,2 and yet none of those drugs has been accepted by regulatory authorities to be used for treatment of patients with acute stroke in the United States or the European Union. There are many reasons for the failures3 and we are still on the learning curve, but is this endless optimism of the Village Idiot4 fruitful? The evidence from position emission tomography studies has revealed that without early reperfusion, either spontaneously or induced by thrombolysis, the size of the final brain infarction can only marginally be reduced with neuroprotecting agents because the critically hypoperfused area accounts for the largest proportion (mean 70%) of the final infarct volume.5 Accordingly, even if neuroprotectants could prevent the maturation of the ischemic penumbra to an infarct by half, like they do in animal models, it would only reduce the size of the final infarction by 15%. It would ask for a trial with tens of thousands of stroke patients to prove such a hypothesis. My estimation is based on the assumption that thrombolysis is superior to neuroprotectant therapy and the fact that thrombolytic trials with a longer than 3-hour time window have all failed. To be positive, thrombolytic trials in which IV rtPA was initiated within a 4.5- to 6-hour time window should have enrolled 4500 patients.6
Have I learned anything else from taking part in clinical acute stroke trials based on drugs that have been found to be effective in animal models but to perceive many reasons for the failure of those trials? There is no doubt that I have gained lots of experience, which has improved the daily stroke patient care at our department. Without our participation in many neuroprotectant and thrombolytic trials, our stroke triage developed as part of these trials would certainly be less well organized. With lots of training, our present record of the door-to-needle time for rtPA is 12 minutes, which includes clinical examination, laboratory tests, computed tomography, and informed consent. Furthermore, we have enrolled more patients with stroke in the official register for rtPA-treated stroke patients, the SITS-MOST, than any other center in Europe.7
Animal models have helped us better understand the pathophysiology of ischemic brain damage, but have they otherwise contributed much to clinical practice so far? I cannot say that they have, whereas randomized, clinical trials (RCTs) have had a major impact. The need of discipline, an essential part of any RCT, has influenced ordinary patient care in many positive ways. I do not expect either that more developed animal models could contribute to emergency stroke care so that a neuroprotective agent would be able to reduce the volume of an infarct in patients with stroke by 50% as they do in rats, at least if the therapy is not combined with thrombolysis or other neuroprotective therapies.8 If, however, one means by the use of animal models studies aimed at enhancing neuronal regeneration after acute stroke, the landscape changes to a truly bright one. Here the Holy Grail of clinical stroke therapies waits for those who are worthy.9 In an innovative animal model, Lee and colleagues presented strong data for cAMP response element-binding protein (CREB) family transcription factors in recovery from experimental hypoxic ischemic brain damage and that drugs can be used to enhance neuronal recovery.10 Their observations may open a highway not only for neuronal recovery and reorganization after stroke, but also in Alzheimer disease, spinal cord injuries, and in many other neurologic diseases, which now so desperately wait for breakthroughs.9,10
Received May 10, 2005; accepted July 13, 2005.
References
1. Hass WK. The cerebral ischemic cascade. Neurol Clin. 1983; 1: 345–353.[Medline] [Order article via Infotrieve]
2. Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004; 35: 1203–1208.
3. Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol. 2003; 53: 10–20.[CrossRef][Medline] [Order article via Infotrieve]
4. Culebras A. The village idiot. Eur J Neurol. 1997; 4: 535–536.
5. Heiss W-D, Thiel A, Grond M, Graf R. Which targets are relevant for therapy of acute ischemic stroke? Stroke. 1999; 30: 1486–1489.
6. The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.[CrossRef][Medline] [Order article via Infotrieve]
7. Wahlgren NG, Fieschi C, Grond M, Hacke W, Kaste M, von Kummer R, Larrue V, Lees KR, Wardlaw J. First safety and efficacy results on broad implementation of stroke thrombolysis in the European Union after regulatory approval (SITS-MOST). Stroke. 2004; 35: 240(Abstract).
8. Kaste M. Thrombolysis in ischaemic stroke—present and future: role of combined therapy. Cerebrovasc Dis. 2001; 11 (suppl 1): 55–59.[Medline] [Order article via Infotrieve]
9. Ratan RR. cAMP response element binding protein family transcription factors: the Holy Grail of neurological therapeutics? Ann Neurol. 2004; 56: 607–609.[CrossRef][Medline] [Order article via Infotrieve]
10. Lee HT, Chang YC, Wang LY, Wang ST, Huang CC, Ho CJ. cAMP response element-binding protein activation in ligation preconditioning in neonatal brain. Ann Neurol. 2004; 56: 611–623.[CrossRef][Medline] [Order article via Infotrieve]
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