doi: 10.1161/01.STROKEAHA.107.502153
(Stroke. 2007;38:e128.)
© 2007 American Heart Association, Inc.
Letters to the Editor |
Response to Letter by Fisher et al
Department of Neurology, University of Miami Miller School of Medicine, Miami, Fla
See Editor-in-Chief’s Note, page 3116.
Response:
The authors correctly point out that Dr Lees was not section coeditor when the Hess critique1 and the Fisher Editorial2 appeared in the section of Stroke in which Dr Lees subsequently served in that capacity. As noted, Dr Hachinski, the Editor-in-Chief, indeed published a clarification of this matter.3 The point is well taken and duly acknowledged.
For the rest, Dr Fisher and colleagues, perhaps in an effort to add gravitas to their comments, have seriously confused fact and opinion.4 What they characterize as "statements that are clearly incorrect" and "allegations and mis-statements" are, in actuality, merely opinions that differ from their own and which were set forth to stimulate close consideration of relevant issues. Incidentally, "impugn" is defined as "to assail by words or arguments ... [to] call in question ... "5—a term appropriate to the present exercise.
Thus, the doubt I cast on the wisdom of carrying SAINT II to completion given the findings of SAINT I6 is clearly an opinion, not "another mis-statement."4 The SAINT publications themselves explicitly indicate that patients were enrolled in SAINT I between May 2003 and November 2004,7 and that enrollment in SAINT II occurred between May 2003 and June 2006.8 Thus, although the 2 studies may have been "designed as concurrent trials" (italics inserted for emphasis),4 their execution was, in fact, partially sequential. The very fact that the results of SAINT I were used as the basis for increasing the study population of SAINT II from 1700 to 3200 subjects8 attests to this. It also leads one to question, given the weakly positive outcome of SAINT I,7 as to whether SAINT II incorporated interim analyses for futility. Given the strongly negative outcome of SAINT II (ie, virtually identical primary outcomes in the treatment and control groups),8 it is quite likely that interim analyses would have revealed futility, thereby allowing the study to be prematurely terminated and resulting in potentially great savings of funds and effort. Unfortunately, the recent definitive SAINT-II report8 does not reveal whether an interim futility-analysis, in fact, was performed.
As to whether the Editorial by Dr Fisher2 and the critique by Dr Hess1 express optimism or not, I have carefully reread these reports and stand firmly by my initial impression that the overall tone of both pieces is strongly and unmistakably optimistic, notwithstanding the disclaimers retrospectively posited in the authors’ letter.4 The problem is certainly not one of "convenient out-of-context quotations."4 The individual reader is encouraged to read these pieces and decide this matter for him/herself.
I am not alone in raising questions of serious concern regarding the SAINT-I and -II trials.9–14 The interested reader is referred, in particular, to the recent critical review of Savitz,13 which soberly analyzes the preclinical and clinical shortcomings of the NXY-059 program, and the recent commentary of Feuerstein et al,14 which offers key ideas for strengthening translational drug development in the future.
Everyone is, of course, entitled to be optimistic, but there is a palpable downside (particularly in the field of neuroprotection) whenever premature, overly optimistic pronouncements are followed by disappointingly negative outcomes. In my opinion, the failure of NXY-059 in the SAINT-II clinical trial,8 when coupled with the degree to which the SAINT-I results were over-enthusiastically eulogized, has given rise to an unfortunate backlash of nihilism as to neuroprotection in general. In such an intellectual climate, the pharmaceutical industry is currently loathe to attempt further incursions into this area15—a highly regrettable state-of-affairs. This mindset ignores the huge corpus of laboratory work that, taken together, provides incontrovertible proof-of-principle that protecting the ischemic brain is possible. It is vital not to quash enthusiasm on the part of academia, the pharmaceutical and biotech industries, and federal funding agencies for this challenging area of medical therapeutics, in which advances are so desperately needed.
Acknowledgments
Disclosures
None.
References
1. Hess DC. NXY-059: a hopeful sign in the treatment of stroke. Stroke. 2006; 37: 2649–2650.
2. Fisher M. NXY-059 for acute ischemic stroke: the promise of neuroprotection is finally realized? Stroke. 2006; 37: 2651–2652.
3. Hachinski V. Clarification. Stroke. 2006; 37: 2648.
4. Fisher M, Hess DC, Lees KR. Issues pertaining to the critiques of the SAINT-I trial. Stroke. 2007; 38: e126–e127.
5. American College Dictionary. New York, NY: Random House; 1956.
6. Ginsberg MD. Life after Cerovive: a personal perspective on ischemic neuroprotection in the post-NXY-059 era. Stroke. 2007; 38: 1967–1972.
7. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, Grotta J, Lyden P, Shuaib A, Hardemark HG, Wasiewski WW. NXY-059 for acute ischemic stroke. N Engl J Med. 2006; 354: 588–600.
8. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T, Wasiewski WW, Emeribe U. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007; 357: 562–571.
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10. Serebruany V. NXY-059 for acute ischemic stroke. N Engl J Med. 2006; 354: 2075–2076.
11. Koziol JA, Feng AC. On the analysis and interpretation of outcome measures in stroke clinical trials: lessons from the SAINT I study of NXY-059 for acute ischemic stroke. Stroke. 2006; 37: 2644–2647.
12. Serebruany VL. Hypokalemia, cardiac failure, and reporting NXY-059 safety for acute stroke. J Cardiovasc Pharmacol Ther. 2006; 11: 229–231.
13. Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol. 2007; 205: 20–25.[CrossRef][Medline] [Order article via Infotrieve]
14. Feuerstein GZ, Zaleska MM, Krams M, Wang X, Day M, Rutkowski JL, Finklestein SP, Pangalos MN, Poole M, Stiles GL, Ruffolo RR, Walsh FL. Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J Cereb Blood Flow Metab. 2007; June 20: 1–3. Epub ahead of print.[CrossRef]
15. Garber K. Stroke treatment-light at the end of the tunnel? Nat Biotechnol. 2007; 25: 838–840.[CrossRef][Medline] [Order article via Infotrieve]
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