Abstract
Most early phase trials in stroke and brain trauma have failed in phase 3, including efforts to improve acute ischemic stroke outcomes beyond that achieved by intravenous recombinant tissue plasminogen activator (t-PA) (IVT). With the exception of more recent stent retriever trials, most subsequent phase 3 trials failed. We previously showed that baseline imbalances, non-linear relationships of these factors to outcome, and unrepresentative control populations invalidate traditional statistical analysis in early trials of heterogeneous diseases such as stroke. We developed an alternative approach using a pooled outcome model derived from control arms of randomized clinical trial (RCTs). This model then permits comparing treatment trials to an expected outcome of a pooled population. Here, we hypothesized we could develop such a model for IVT and tested it against outcomes without IVT. We surveyed literature for all trials involving one arm with IVT reporting baseline National Institute Stroke Scale (NIHSS), age, and outcome. A non-linear fit was performed including multi-dimensional statistical intervals (±95 %) permitting visual comparison of outcomes at their own baselines. We compared models derived from non-IVT control arms. Models from 24 IVT RCTs representing 3195 subjects were successfully generated for functional outcome, modified Rankin Scale (mRS) 0–2 (r 2 = 0. 83, p < 0.001), and mortality (r 2 = 0.54; p = 0.001). We confirmed better outcomes compared to no IVT and mixed use IVT models across the range of baseline factors. It was possible to generate an expected outcome model for IVT from existing literature. We confirmed benefit compared to placebo. This model should be useful to compare to new agents without the need for statistical manipulation.
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Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20. Epub 2014/12/18.
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18. Epub 2015/02/12.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30. Epub 2015/02/12.
Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–95. Epub 2015/04/18.
Fugate JE, Rabinstein AA. Update on intravenous recombinant tissue plasminogen activator for acute ischemic stroke. Mayo Clin Proc. 2014. Epub 2014/04/30.
Kent TA, Shah SD, Mandava P. Improving early clinical trial phase identification of promising therapeutics. Neurology. 2015;85(3):274–83.
Lapchak PA. Fast neuroprotection (fast-NPRX) for acute ischemic stroke victims: the time for treatment is now. Transl Stroke Res. 2013;4(6):704–9. Epub 2013/12/11.
Lapchak PA, Zhang JH. Resolving the negative data publication dilemma in translational stroke research. Transl Stroke Res. 2011;2(1):1–6. Epub 2011/06/15.
Mandava P, Kent TA. A method to determine stroke trial success using multidimensional pooled control functions. Stroke. 2009;40(5):1803–10. Epub 2009/03/17.
Uchino K, Billheimer D, Cramer SC. Entry criteria and baseline characteristics predict outcome in acute stroke trials. Stroke. 2001;32(4):909–16. Epub 2001/04/03.
Crager MR. Analysis of covariance in parallel-group clinical trials with pretreatment baselines. Biometrics. 1987;43(4):895–901. Epub 1987/12/01.
Koch GG, Tangen CM, Jung JW, Amara IA. Issues for covariance analysis of dichotomous and ordered categorical data from randomized clinical trials and non-parametric strategies for addressing them. Stat Med. 1998;17(15–16):1863–92. Epub 1998/09/28.
Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, et al. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354(6):588–600. Epub 2006/02/10.
Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562–71. Epub 2007/08/10.
Davalos A, Alvarez-Sabin J, Castillo J, Diez-Tejedor E, Ferro J, Martinez-Vila E, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380(9839):349–57. Epub 2012/06/14.
Mandava P, Kent TA. Intra-arterial therapies for acute ischemic stroke. Neurology. 2007;68(24):2132–9. Epub 2007/06/15.
Mandava P, Suarez JI, Kent TA. Intravenous rt-PA versus endovascular therapy for acute ischemic stroke. Curr Atheroscler Rep. 2008;10(4):332–8. Epub 2008/07/09.
Dolan KD, Yang L, Trampel CP. Nonlinear regression technique to estimate kinetic parameters and confidence intervals in unsteady-state conduction-heated foods. J Food Eng. 2007;80:581–93.
Mandava P, Krumpelman CS, Shah JN, White DL, Kent TA. Quantification of errors in ordinal outcome scales using Shannon entropy: effect on sample size calculations. PLoS One. 2013;8(7):e67754. Epub 2013/07/19.
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(24):1581–7. Epub 1995/12/14.
Using the F-test to compare two models. Non-linear regression. Stat Topic Files. 2013; Available from: https://sakai.duke.edu/access/content/group/25e08a3d-9fc4-41b0-a7e9-815732c1c4ba/New%20folder/Stat%20Topic%20Files/Non-Linear%20Regression/FTestTutorial.pdf.
Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351(21):2170–8. Epub 2004/11/19.
Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893–903. Epub 2013/02/09.
Ciccone A, Valvassori L, Ponzio M, Ballabio E, Gasparotti R, Sessa M, et al. Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial. J Neurointervent Surg. 2010;2(1):74–9. Epub 2010/03/01.
Haley Jr EC, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707–11. Epub 2010/02/27.
Hill MD, Martin RH, Palesch YY, Tamariz D, Waldman BD, Ryckborst KJ, et al. The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis. Stroke. 2011;42(6):1621–5. Epub 2011/05/07.
Lang W, Stadler CH, Poljakovic Z, Fleet D. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. Int J Stroke. 2013;8(2):95–104. Epub 2012/09/27.
Lyden P, Jacoby M, Schim J, Albers G, Mazzeo P, Ashwood T, et al. The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurology. 2001;57(7):1199–205. Epub 2001/10/10.
Molina CA, Barreto AD, Tsivgoulis G, Sierzenski P, Malkoff MD, Rubiera M, et al. Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol. 2009;66(1):28–38. Epub 2009/08/12.
Pancioli AM, Adeoye O, Schmit PA, Khoury J, Levine SR, Tomsick TA, et al. Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke. 2013;44(9):2381–7. Epub 2013/07/28.
Pancioli AM, Broderick J, Brott T, Tomsick T, Khoury J, Bean J, et al. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial. Stroke. 2008;39(12):3268–76. Epub 2008/09/06.
Piironen K, Tiainen M, Mustanoja S, Kaukonen KM, Meretoja A, Tatlisumak T, et al. Mild hypothermia after intravenous thrombolysis in patients with acute stroke: a randomized controlled trial. Stroke. 2014;45(2):486–91. Epub 2014/01/18.
Zinkstok SM, Roos YB. Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial. Lancet. 2012;380(9843):731–7. Epub 2012/07/04.
Chamorro A, Amaro S, Castellanos M, Segura T, Arenillas J, Marti-Fabregas J, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol. 2014;13(5):453–60. Epub 2014/04/08.
Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(10):904–13. Epub 2013/02/08.
Huang X, Cheripelli BK, Lloyd SM, Kalladka D, Moreton FC, Siddiqui A, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14(4):368–76. Epub 2015/03/03.
Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317–29. Epub 2008/09/26.
Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282(21):2019–26. Epub 1999/12/11.
Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7(4):299–309. Epub 2008/02/26.
Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thrombolytic therapy in acute ischemic stroke study investigators. Stroke. 2000;31(4):811–6. Epub 2001/02/07.
Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245–51. Epub 1998/10/27.
Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099–107. Epub 2012/03/23.
The RANTTAS Investigators. A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). Stroke. 1996;27(9):1453–8. Epub 1996/09/01.
Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology. 2001;57(8):1428–34. Epub 2001/10/24.
Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke. 2005;36(4):880–90. Epub 2005/02/26.
Adams Jr HP, Effron MB, Torner J, Davalos A, Frayne J, Teal P, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke. 2008;39(1):87–99. Epub 2007/11/23.
Bogousslavsky J, Victor SJ, Salinas EO, Pallay A, Donnan GA, Fieschi C, et al. Fiblast (trafermin) in acute stroke: results of the European-Australian phase II/III safety and efficacy trial. Cerebrovasc Dis. 2002;14(3–4):239–51. Epub 2002/10/31.
Camerlingo M, Salvi P, Belloni G, Gamba T, Cesana BM, Mamoli A. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions. Stroke. 2005;36(11):2415–20. Epub 2005/10/15.
Clark W, Ertag W, Orecchio E, Raps E. Cervene in acute ischemic stroke: results of a double-blind, placebo-controlled, dose-comparison study. J Stroke Cerebrovasc Dis. 1999;8(4):224–30. Epub 2007/09/27.
Clark WM, Coull BM, Karukin M, Hendin B, Kelley R, Rosing H, et al. Randomized trial of Cervene, a kappa receptor-selective opioid antagonist, in acute ischemic stroke. J Stroke Cerebrovasc Dis. 1996;6(1):35–40. Epub 1996/09/01.
Clark WM, Raps EC, Tong DC, Kelly RE. Cervene (Nalmefene) in acute ischemic stroke: final results of a phase III efficacy study. The Cervene Stroke Study Investigators. Stroke. 2000;31(6):1234–9. Epub 2000/06/03.
Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, et al. Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke. 2000;31(2):347–54. Epub 2000/02/05.
del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29(1):4–11. Epub 1998/01/28.
Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40(12):e647–56. Epub 2009/10/17.
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282(21):2003–11. Epub 1999/12/11.
Ginsberg MD, Palesch YY, Martin RH, Hill MD, Moy CS, Waldman BD, et al. The Albumin in Acute Stroke (ALIAS) Multicenter Clinical Trial Safety Analysis of Part 1 and Rationale and Design of Part 2. Stroke. 2011;42(1):119–27.
Grotta J. Lubeluzole treatment of acute ischemic stroke. The US and Canadian Lubeluzole Ischemic Stroke Study Group. Stroke. 1997;28(12):2338–46. Epub 1997/12/31.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017–25. Epub 1995/10/04.
Levy DE, del Zoppo GJ, Demaerschalk BM, Demchuk AM, Diener H-C, Howard G, et al. Ancrod in acute ischemic stroke results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program. Stroke. 2009;40(12):3796–803.
Ogawa A, Mori E, Minematsu K, Taki W, Takahashi A, Nemoto S, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke. 2007;38(10):2633–9. Epub 2007/08/19.
Rosso C, Corvol JC, Pires C, Crozier S, Attal Y, Jacqueminet S, et al. Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial. Stroke. 2012;43(9):2343–9. Epub 2012/06/16.
Rudolf J. Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized, placebo-controlled phase II safety study. Cerebrovasc Dis. 2002;14(1):33–41. Epub 2002/07/05.
Sacco RL, DeRosa JT, Haley Jr EC, Levin B, Ordronneau P, Phillips SJ, et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA. 2001;285(13):1719–28. Epub 2001/04/13.
Teal P, Davis S, Hacke W, Kaste M, Lyden PD, Fierus M, et al. A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke modified randomized exposure controlled trial (mRECT). Stroke. 2009;40(11):3518–25.
Torgano G, Zecca B, Monzani V, Maestroni A, Rossi P, Cazzaniga M, et al. Effect of intravenous Tirofiban and aspirin in reducing short-term and long-term neurologic deficit in patients with ischemic stroke: a double-blind randomized trial. Cerebrovasc Dis. 2010;29(3):275–81.
Piggot TD. Missing data in meta-analysis: strategies and approaches. Advances in Meta-analysis. New York: Springer; 2012. p. 80–1.
Mandava P, Dalmeida W, Anderson JA, Thiagarajan P, Fabian RH, Weir RU, et al. A pilot trial of Low-dose intravenous Abciximab and unfractionated heparin for acute ischemic stroke: translating GP IIb/IIIa receptor inhibition to clinical practice. Transl Stroke Res. 2010;1(3):170–7. Epub 2010/09/01.
Mandava P, Martini SR, Munoz M, Dalmeida W, Sarma AK, Anderson JA, et al. Hyperglycemia worsens outcome after rt-PA primarily in the large-vessel occlusive stroke subtype. Transl Stroke Res. 2014;5(4):519–25. Epub 2014/04/05.
Mandava P, Shah SD, Sarma AK, Dalmeida D, Kent TA. A pooled analysis indicates the promise and pitfalls of improving upon intravenous rt-PA for ischemic stroke. International Stroke Conference; 2014. San Diego: American Heart Association; 2014.
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Computing resources of the Computational and Integrative Biomedical Research Center at Baylor College of Medicine were utilized for this study (P.M.).
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Drs. Mandava P and Kent TA are copyright holders of pPREDICTS. Drs. Shah SD and Sarma AK have no conflicts of interest.
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This article does not contain any studies with human participants or animals performed by any of the authors.
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Mandava, P., Shah, S.D., Sarma, A.K. et al. An Outcome Model for Intravenous rt-PA in Acute Ischemic Stroke. Transl. Stroke Res. 6, 451–457 (2015). https://doi.org/10.1007/s12975-015-0427-5
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DOI: https://doi.org/10.1007/s12975-015-0427-5