Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2008;39:1659-1660
Published online before print March 27, 2008, doi: 10.1161/STROKEAHA.107.505024
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
39/6/1659    most recent
STROKEAHA.107.505024v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Sacchetti, M. L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sacchetti, M. L.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Stroke
Related Collections
Right arrow Other Treatment
Right arrow Acute Cerebral Infarction
Right arrow Emergency treatment of Stroke
Right arrow Neuroprotectors
Right arrow Thrombolysis
Right arrowRelated Article

(Stroke. 2008;39:1659.)
© 2008 American Heart Association, Inc.

Editorials

Is It Time to Definitely Abandon Neuroprotection in Acute Ischemic Stroke?

Maria Luisa Sacchetti, PhD, MD

From the Department of Neurological Sciences, La Sapienza University of Rome, V. le dell’Università, Rome, Italy.

Correspondence to Maria Luisa Sacchetti, Department of Neurological Sciences, La Sapienza University of Rome, V. le dell’Università, 30 00185 Rome Italy. E-mail marialuisa.sacchetti{at}uniroma1.it


Key Words: acute care • neuroprotection • thrombolysis

See related article, pages 1751–1758.

Since the ischemic penumbra was discovered and since a therapeutic window for acute ischemic stroke has been postulated, stroke experts are looking for safe and effective drugs to treat as many acute ischemic stroke patients as possible.

Maturation of ischemic damage is a complex process, triggered by hypoperfusion at critical levels and spontaneously evolving toward cell death. It is a self-perpetuating process in which some critical steps (such as ion pumps failure and iNOS production) maintain and enhance the process.1

Reperfusion may reverse the ischemic cascade but, at the same time, induces a further damage. The risk/benefit ratio of reperfusion depends on the amount of penumbral salvageable tissue, that is "individual" and only partially predictable.2,3 Spontaneous reperfusion may occur, and symptoms may reverse, partially or totally, but the percentages of spontaneous reperfusion so far reported account for approximately the 24% of all stroke cases.4 A review of published articles about cerebral angiography in stroke reported that the percentage of spontaneous reperfusion on a population of major strokes observed within 6 to 8 hours of onset is approximately 17% of patients.5

Pharmacological reperfusion is effective and recommended in selected cases.6 This population represents a minority of all hospitalized acute ischemic strokes; the majority of patients are excluded from the treatment because they present at the hospital over the 3-hour time window7–10. In this issue of Stroke, in the SAINT I and II trials pooled analysis, only 418 of 5080 acute ischemic stroke patients observed within 6 hours of stroke onset were reperfused.11 Sophisticated technologies have been introduced in order to select cases over the 3-hour time window at lower risk of reperfusion injury, with insufficient results on the number of treatable patients.12

Neuroprotective drugs can be potentially offered to a larger percentage of patients than thrombolysis. The expectation was that they will improve neurological function by supporting vital functions of ischemic brain cells, mainly through modulation of pathological ion transport over membranes, or else trapping free-radical agents inside the penumbra. Given the complexity of the maturation of ischemic damage, it is unlikely that a neuroprotective drug can counteract all the mechanisms involved in the cascade, irrespective to reperfusion, so as to definitely stop the process. Neuroprotection might slow down the cascade for a limited period of time, possibly enhancing the positive effects of reperfusion and/or reducing the reperfusion injury; in other words, they may widen the therapeutic window of thrombolysis, not reverse the penumbra in a sufficient number of cases to show a significant clinical effectiveness.

If it is so, the expected power of neuroproctective trial might be much lower than usually set, in particular lower than the power applied in the SAINT I and II trials.13,14

The SAINT II trial power was appropriately adjusted on the basis of SAINT I results. Why didn’t it work? The authors conclude that "The higher rate of alteplase use in SAINT I is unlikely to explain the different results in the two SAINT trials because there was no interaction between alteplase use and NXY-059 effect in either trial". Maybe. But, the other possible explanation is that if the target is to show neuroprotection clinical effectiveness on the subgroup of patients that spontaneously reperfuse, even 5.080 patients might not be enough to show the drug effectiveness. Probably the clinical program for NXY-050, as well as for other neuroprotective drugs, has reached its conclusion as single-therapy. This is probably not the case for NXY-050 combined with thrombolysis, which might be able to enlarge the number of cases safely treatable with alteplase over the 3-hour time window.15

In the 1990s, combination trials have been suggested, designed, performed, and then abandoned.16–21 In 1998 the European Community funded a Multinational Project entitled "European Multicenter Four-Arm Trial in Acute Stroke-EMFATAS" BIOMED2 program contract No. BMH4-CT98-377, aimed at designing and conducting a four-arm combination trial in order to assess the safety and estimate the efficacy of neuroprotection plus rt-PA compared with neuroprotection alone, rt-PA alone and placebo.22

Unfortunately, at that time thrombolysis was not yet definitely approved, there were no evidences on the safety of any neuroprotective drug, methodology in clinical trial design was less sophisticated than now, and therefore the project was discontinued early.

Thrombolysis is now a routine treatment; some neuroprotective drugs have been demonstrated to be safe in both cerebral ischemia and hemorrhage, and an innovative methodological trial design has been introduced.23,24 Therefore, thrombolysis plus neuroprotection combination trials seem today to be feasible.

The SAINT I and II trials pooled analysis results may be discouraging. A number of strokologists looked at the SAINT I results with hope, and we now are probably close to concluding that the potentiality of neuroprotection was unrealistic.

Is it really time to abandon neuroprotection in acute stroke clinical research, or are we just erroneously trying to reduce the number of steps needed to design an rt-PA plus neuroprotection combination trial model?

Acknowledgments

Disclosures

None.

Footnotes

The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Lo EH, Moskowitz MA, Jacobs TP. Exciting, radical, suicidal how brain cells die after stroke. Stroke. 2005; 36: 189–192.[Free Full Text]
  2. Hallenbeck JM, Duitka AJ. Background review and current concepts of reperfusion injury. Arch Neurol. 1990; 47: 1245–1254.[Abstract]
  3. Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke challenging the concept of a rigid and universal time window. Stroke. 1995; 26: 2219–2221.[Free Full Text]
  4. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007; 38: 967–973.[Abstract/Free Full Text]
  5. Moussa HK. Nonocclusion and spontaneous recanalization rates in acute ischemic stroke: a review of cerebral angiography studies. Arch Neurol. 2002; 59: 1870–1873.[Abstract/Free Full Text]
  6. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EFM. FAHA guidelines for the early management of adults with ischemic stroke. A guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke. 2007; 38: 1655–1711.[Abstract/Free Full Text]
  7. Hill MD, Buchan AM; Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. 2005; 172: 1307–1312.[Abstract/Free Full Text]
  8. Evenson KR, Rosamond WD, Morris DL. Prehospital and in-hospital delays in acute stroke care. Neuroepidemiology. 2001; 20: 65–76.[CrossRef][Medline] [Order article via Infotrieve]
  9. Pittock SJ, Meldrum D, Hardiman O, Deane C, Dunne P, Hussey A, Gorman M, Moroney JT. Patient and hospital delays in acute ischaemic stroke in a Dublin teaching hospital. Ir Med. 2003; 96: 167–168, 170–171.
  10. Lacy CR, Suh DC, Bueno M, Kostis JB. Delay in presentation and evaluation for acute stroke: Stroke Time Registry for Outcomes Knowledge and Epidemiology (S.T.R.O.K.E.). Stroke. 2001; 32: 63–69.[Abstract/Free Full Text]
  11. Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Shuaib A, Ashwood T, Wasiewski W, Alderfer V, Hårdemark HG, Rodichok L; for the SAINT I and II Investigators. NXY-059 for the treatment of Acute Stroke: pooled Analysis of the SAINT I and II trials. Stroke. 2008; 39: 1751–1758.
  12. Guadagno JV, Donnan GA, Markus R, Gillardb JH, Baron J-C. Imaging the ischaemic penumbra. Curr Opin Neurol. 2004; 17: 61–67.[CrossRef][Medline] [Order article via Infotrieve]
  13. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener H-C, Grotta J, Lyden P, Shuaib A, Hardemark H-G, Wasiewski W; for the Stroke–Acute Ischemic NXY Treatment (SAINT I) Trial Investigators NXY-059 for Acute Ischemic Stroke. N Engl J Med. 2006; 354: 588–600.[Abstract/Free Full Text]
  14. Shuaib A, Lees KR, Lyden P, Grotta JC, Davalos A, Davis SM, Diener HC, Ashwood T, Wasiewski W, Emeribe U; for the SAINT II Trial Investigators NXY-059 for the Treatment of Acute Ischemic Stroke. N Engl J Med. 2007; 357: 562–571.[Abstract/Free Full Text]
  15. Grotta JC. Neuroprotection is unlikely to be effective in human using current trial design. Stroke. 2002; 33: 306–307.[Free Full Text]
  16. Sacchetti ML, Falcou A, Fieschi C. Experimental basis for combined treatment in acute ischemic stroke. In: Castillo J, Davalos A, Toni D, eds. Management of Acute Ischemic Stroke. Barcelona, Spain: Springer Verlag; 1997: 253–262.
  17. Sacchetti ML, Toni D, Fiorelli M, Argentino C, Fieschi C. The concept of combination therapy in acute ischemic stroke. Neurology. 1997; 49 (Suppl. 4): S70–S74.
  18. Steiner T, Hacke W. Combination therapy with neuroprotectants and thrombolytics in acute ischemic stroke. Eur Neurol. 1998; 401–408.
  19. The European Ad Hoc Consensus Group. Neuroprotection as initial therapy in Acute Stroke. Third Report of an Ad Hoc Consensus Group Meeting. Cerebrovasc Dis. 1998; 8: 59–72.[CrossRef][Medline] [Order article via Infotrieve]
  20. Davis M, Barer D. Neuroprotection in acute ischemic stroke II: Clinical potential. Vascular Medicine. 1999; 4: 149–163.[Abstract/Free Full Text]
  21. Grotta JC. Combination therapy stroke trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis. 2001; 12: 258–263.[CrossRef][Medline] [Order article via Infotrieve]
  22. Toni D, Sacchetti ML, Chamorro A. Acute stroke trials: the problems of local investigators? Eur Neurol. 2003; 49: 109–114.[CrossRef][Medline] [Order article via Infotrieve]
  23. Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener H-C, Grotta JC, Ashwood TJ, Hardemark H-G, Svensson HH, Rodichok L, Wasiewski WW, Åhlberg G; for the CHANT Trial Investigators. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT trial. Stroke. 2007; 38: 2262–2269.[Abstract/Free Full Text]
  24. Fisher M, Hanley DF, Howard G, Jauch EC, Warach W; for the STAIR Group. Recommendations from the STAIR V meeting on acute stroke trials, technology and outcomes. Stroke. 2007; 38: 245–248.[Free Full Text]

Related Article:

NXY-059 for the Treatment of Acute Stroke: Pooled Analysis of the SAINT I and II Trials
Hans-Christoph Diener, Kennedy R. Lees, Patrick Lyden, Jim Grotta, Antoni Davalos, Stephen M. Davis, Ashfaq Shuaib, Tim Ashwood, Warren Wasiewski, Vivian Alderfer, Hans-Goran Hårdemark, Larry Rodichok for the SAINT I and II Investigators
Stroke 2008 39: 1751-1758. [Abstract] [Full Text] [PDF]




This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
39/6/1659    most recent
STROKEAHA.107.505024v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Sacchetti, M. L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sacchetti, M. L.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Stroke
Related Collections
Right arrow Other Treatment
Right arrow Acute Cerebral Infarction
Right arrow Emergency treatment of Stroke
Right arrow Neuroprotectors
Right arrow Thrombolysis
Right arrowRelated Article

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2008 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.