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The NINDS Reanalysis Committee analysed the NINDS trial from the wrong perspective
- Jeffrey Mann (8 October 2004)
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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In this news report article, Jeanne Lenzer quotes Prof. O"Fallon as saying that the "imbalance did not invalidate the results of the trial." The imbalance was a marked difference in baseline stroke severity between the treated and placebo patient groups in the 91-180 minute arm of the NINDS trial. Prof. O"Fallon is correct to say that the imbalance in baseline stroke severity didn't significantly affect the positive results of the entire trial in a purely qualitative sense, but surely that is not the most pertinent issue. The more important issue is whether the stroke severity imbalance quantitatively affected the results of the 91-180 minute arm of the trial to a significant degree. The NINDS Reanalysis Committee did not specifically address the issue as to whether the imbalance in baseline stroke severity significantly affected the quantitative assessment of tPA's efficacy with particular reference to patients treated between 91-180 minutes [1]. In their original report [2], the NINDS Study Group Investigators stated that the unadjusted OR of tPA therapy for stroke patients treated between 91-180 minutes was 2.4 (using the mRS 0,1 stroke outcome scoring system), and this OR calculation was based on an estimated absolute risk difference of 21%. Those figures represent the NINDS Study Group Investigators' estimation of the "apparent" efficacy of tPA therapy in acute ischemic stroke. When I received a copy of the NINDS trial's raw data, I was able to analyse the NINDS trial in greater depth [3]. After making a "correction" for baseline stroke severity imbalances and another minor anomaly, I estimated that the absolute risk difference was only 8-11%, and not 21% as originally reported. My personal estimation suggested that approximately 50% of the estimated "apparent" efficacy of tPA (for patients treated between 91-180 minutes) is due to the baseline stroke severity imbalance, and that the "true" efficacy of tPA is therefore only ~50% of the "apparent" efficacy of tPA. Prof. David Schriger commented that "the original NINDS analysis and the reanalysis are like the two people who are standing near each other. They confirm that from that perspective it appears that the drug may be efficacious, but not necessarily effective. This is only one perspective however, and viewed from other perspectives the drug’s efficacy is not at all clear. Said another way, the reanalysis checked the math of the original analysis, but not the method." I concur with Prof. Schriger, and I believe that the NINDS Reanalysis Committee analysed the "baseline stroke severity imbalance" issue from only one perspective. They only analysed the NINDS trial's raw data to determine whether tPA was more-or-less similarly efficacious throughout the stroke severity range. They did not consider the "baseline stroke severity imbalance" problem from another perspective -- whether other factors (non-tPA influences) significantly affected the accurate estimation of tPA's "true" efficacy in patients treated between 91-180 minutes. In a critique [4] of the NINDS Reanalysis Committee's Special Report [5], I demonstrate how a marked imbalance in baseline stroke severity significantly affects the quantitative assessment of tPA's efficacy. I think that an accurate quantitative estimation of tPA's efficacy is important, because clinicians need that information in order to make an accurate estimation of the harm:benefit ratio of tPA therapy for patients treated between 91-180 minutes. The NINDS Reanalysis Committee stated in their Special Report [5] that "The Committee was charged with addressing whether eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials. Multiple exploratory analyses performed to address this question did not identify any subgroup of acute ischemic stroke patients who would be more likely either to benefit from or be harmed by receiving t-PA." I cannot fathom how the NINDS Reanalysis Committe came to this surprising conclusion. In their Special Report, the Committee stated that the OR of tPA therapy in very mild stroke patients (baseline NIHSS stroke severity 0-5 subgroup patients) was 0.8. That unadjusted OR was based on the fact that 78.6% of tPA-treated patients had a favorable stroke outcome compared to 81.3% of placebo patients. If very mild stroke patients have no prospect of added benefit from tPA therapy, but a small risk of harm due to the small risk of an iatrogenic symptomatic ICH, then the harm:benefit ratio must surely be >1.0. To accurately estimate the harm:benefit ratio of tPA therapy for moderate-severe stroke patients, who are going to be treated between 91-180 minutes, one first has to ensure that one has obtained an accurate quantitative estimation of tPA's "true" therapeutic effect from the NINDS trial. However, I believe that an accurate quantitative estimation of tPA's "true" therapeutic effect in the 91-180 minute arm of the NINDS trial can only be established if one first "corrects" for the marked imbalance in baseline stroke severity. Jeff Mann. References: 1. O’Fallon WM, Asplund K, Goldfrank LR, Hertzberg VS, Ingall TJ, Louis TA. Report of the t-PA Review Committee. National Institute of Neurologic Diseases and Stroke; 2004. Available at: http://www.ninds.nih.gov/t-PA_review_Committee 2. The National Institute of Neurological Disorders and Stroke rt -PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med 1995;333:1581-1587. 3. Mann J. A personal analysis of the NINDS trial using patient-level data. Available at http://www.homestead.com/emguidemaps/files/NINDSpersonalanalysis.html (My personal analysis is available in the soapbox section of my website at http://www.homestead.com/emguidemaps/JeffMannEMguidemaps.html -- type "Jeff Mann EM guidemaps" in the US-version of Google's search engine to locate my website if both links don't work) 4. Mann J. A Critique of the Reanalysis of the NINDS trial. Available at http://www.homestead.com/emguidemaps/files/IngallCrtitique.htm (My critique is available in the soapbox section of my website at http://www.homestead.com/emguidemaps/JeffMannEMguidemaps.html -- type "Jeff Mann EM guidemaps" in the US-version of Google's search engine to locate my website if both links don't work) 5. Ingall TJ, OFallon WM, AsplundK, Goldfrank LR, Hertzberg VS, Loius TA, Christianson TJ. Findings From the Reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic Stroke Treatment Trial. Stroke. 2004 Oct;35(10):2418-24.
Competing interests: None declared |
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