Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: a randomized, prospective, placebo-controlled clinical trial

Tzu-Hsien Tsai, Cheng-Hsien Lu, Christopher Glenn Wallace, Wen-Neng Chang, Shu-Feng Chen, Chi-Ren Huang, Nai-Wen Tsai, Min-Yu Lan, Pei-Hsun Sung, Chu-Feng Liu, Hon-Kan Yip, Tzu-Hsien Tsai, Cheng-Hsien Lu, Christopher Glenn Wallace, Wen-Neng Chang, Shu-Feng Chen, Chi-Ren Huang, Nai-Wen Tsai, Min-Yu Lan, Pei-Hsun Sung, Chu-Feng Liu, Hon-Kan Yip

Abstract

Introduction: Mortality and disability following ischemic stroke (IS) remains unacceptably high with respect to the conventional therapies. This study tested the effect of erythropoietin (EPO) on long-term neurological outcome in patients after acute IS. This study aimed to evaluate the safety and efficacy of two consecutive doses of EPO (5,000 IU/dose, subcutaneously administered at 48 hours and 72 hours after acute IS) on improving the 90-day combined endpoint of recurrent stroke or death that has been previously reported. A secondary objective was to evaluate the long-term (that is, five years) outcome of patients who received EPO.

Methods: This was a prospective, randomized, placebo-controlled trial that was conducted between October 2008 and March 2010 in a tertiary referral center. IS stroke patients who were eligible for EPO therapy were enrolled into the study.

Results: The results showed that long-term recurrent stroke and mortality did not differ between group 1 (placebo-control; n = 71) and group 2 (EPO-treated; n = 71). Long-term Barthel index of <35 (defining a severe neurological deficit) was lower in group 2 than group 1 (P = 0.007). Multiple-stepwise logistic-regression analysis showed that EPO therapy was significantly and independently predictive of freedom from a Barthel index of <35 (P = 0.029). Long-term major adverse neurological event (MANE; defined as: death, recurrent stroke, or long-term Barthel index < 35) was lower in group 2 than group 1 (P = 0.04). Log-Rank test showed that MANE-free rate was higher in group 2 than group 1 (P = 0.031). Multiple-stepwise Cox-regression analysis showed that EPO therapy and higher Barthel Index at day 90 were independently predictive of freedom from long-term MANE (all P <0.04).

Conclusion: EPO therapy significantly improved long-term neurological outcomes in patients after IS.

Trial registration: ISRCTN71371114 . Registered 10 October 2008.

Figures

Figure 1
Figure 1
Correlation between long-term Barthel Index <35 and clinical outcome. Receiver operating characteristics (ROC) curve analysis revealed long-term Barthel Index <35 was the most powerful predictor of long-term major adverse neurological event with a sensitivity of 93.8% and a specificity of 72.7%, P <0.001. AUC, area under the curve.
Figure 2
Figure 2
Determining the long-term major adverse neurological event-free rate. Kaplan–Meier survival plot. Five-year cumulative (log-rank test) freedom from major adverse neurological event (MANE) was significantly higher in group 2 than in group 1 patients, P = 0.031.

References

    1. Granziera C, Daducci A, Meskaldji DE, Roche A, Maeder P, Michel P, et al. A new early and automated MRI-based predictor of motor improvement after stroke. Neurology. 2012;79:39–46. doi: 10.1212/WNL.0b013e31825f25e7.
    1. Siemonsen S, Lobel U, Sedlacik J, Forkert ND, Mouridsen K, Ostergaard L, et al. Elevated T2-values in MRI of stroke patients shortly after symptom onset do not predict irreversible tissue infarction. Brain. 2012;135:1981–1989. doi: 10.1093/brain/aws079.
    1. Pan Y, Wang A, Liu G, Zhao X, Meng X, Zhao K, et al. Cost-effectiveness of clopidogrel–aspirin versus aspirin alone for acute transient ischemic attack and minor stroke. J Am Heart Assoc. 2014;3:e000912. doi: 10.1161/JAHA.114.000912.
    1. Wang Y, Zhao X, Liu L, Wang D, Wang C, Li H, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. doi: 10.1056/NEJMoa1215340.
    1. Guerini F, Frisoni GB, Morghen S, Speciale S, Bellelli G, Trabucchi M. Clinical instability as a predictor of negative outcomes among elderly patients admitted to a rehabilitation ward. J Am Med Dir Assoc. 2010;11:443–448. doi: 10.1016/j.jamda.2009.10.005.
    1. Prosser J, MacGregor L, Lees KR, Diener HC, Hacke W, Davis S. Predictors of early cardiac morbidity and mortality after ischemic stroke. Stroke. 2007;38:2295–2302. doi: 10.1161/STROKEAHA.106.471813.
    1. Patel AB, Kostis JB, Wilson AC, Shea ML, Pressel SL, Davis BR. Long-term fatal outcomes in subjects with stroke or transient ischemic attack: fourteen-year follow-up of the systolic hypertension in the elderly program. Stroke. 2008;39:1084–1089. doi: 10.1161/STROKEAHA.107.500777.
    1. Roth DL, Dhamoon MS. Racial disparities in long-term stroke outcomes: evidence from nationwide epidemiologic studies. Neurology. 2014;83:384–385. doi: 10.1212/WNL.0000000000000654.
    1. Rohan V, Baxa J, Tupy R, Cerna L, Sevcik P, Friesl M, et al. Length of occlusion predicts recanalization and outcome after intravenous thrombolysis in middle cerebral artery stroke. Stroke. 2014;45:2010–2017. doi: 10.1161/STROKEAHA.114.005731.
    1. Stecksen A, Asplund K, Appelros P, Glader EL, Norrving B, Eriksson M. Thrombolytic therapy rates and stroke severity: an analysis of data from the Swedish stroke register (Riks-Stroke) 2007–2010. Stroke. 2012;43:536–538. doi: 10.1161/STROKEAHA.111.630590.
    1. Yeo LL, Paliwal P, Teoh HL, Seet RC, Chan BP, Liang S, et al. Timing of recanalization after intravenous thrombolysis and functional outcomes after acute ischemic stroke. JAMA Neurol. 2013;70:353–358. doi: 10.1001/2013.jamaneurol.547.
    1. Shimamatsu K, Inamasu H. A safe and easy introduction of darbepoetin-alpha in patients receiving maintenance hemodialysis and epoetin monotherapy: A “half-and-half” combination therapy. Curr Ther Res Clin Exp. 2013;74:5–8. doi: 10.1016/j.curtheres.2012.12.001.
    1. Takasawa K, Tomosugi N, Takaeda C, Maeda T, Ueda N. Regulation of Hepcidin-25 by short- and long-acting rhEPO may be dependent on ferritin and predict the response to rhEPO in hemodialysis patients. Nephron Extra. 2014;4:55–63. doi: 10.1159/000362212.
    1. Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A. 2003;100:4802–4806. doi: 10.1073/pnas.0630444100.
    1. Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol. 2006;48:176–184. doi: 10.1016/j.jacc.2006.04.008.
    1. Nakamura R, Takahashi A, Yamada T, Miyai N, Irie H, Kinoshita N, et al. Erythropoietin in patients with acute coronary syndrome and its cardioprotective action after percutaneous coronary intervention. Circ J. 2009;73:1920–1926. doi: 10.1253/circj.CJ-09-0219.
    1. Lin JS, Chen YS, Chiang HS, Ma MC. Hypoxic preconditioning protects rat hearts against ischaemia–reperfusion injury: role of erythropoietin on progenitor cell mobilization. J Physiol. 2008;586:5757–5769. doi: 10.1113/jphysiol.2008.160887.
    1. Lipsic E, van der Meer P, Henning RH, Suurmeijer AJ, Boddeus KM, van Veldhuisen DJ, et al. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol. 2004;44:473–479. doi: 10.1097/01.fjc.0000140209.04675.c3.
    1. van der Meer P, Voors AA, Lipsic E, van Gilst WH, van Veldhuisen DJ. Erythropoietin in cardiovascular diseases. Eur Heart J. 2004;25:285–291. doi: 10.1016/j.ehj.2003.11.017.
    1. 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:e647–e656. doi: 10.1161/STROKEAHA.109.564872.
    1. Hasselblatt M, Ehrenreich H, Siren AL. The brain erythropoietin system and its potential for therapeutic exploitation in brain disease. J Neurosurg Anesthesiol. 2006;18:132–138. doi: 10.1097/00008506-200604000-00007.
    1. Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, et al. Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg. 2009;111:171–180. doi: 10.3171/2009.3.JNS081332.
    1. Yip HK, Chang LT, Chang WN, Lu CH, Liou CW, Lan MY, et al. Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke. 2008;39:69–74. doi: 10.1161/STROKEAHA.107.489401.
    1. Yip HK, Tsai TH, Lin HS, Chen SF, Sun CK, Leu S, et al. Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit Care. 2011;15:R40. doi: 10.1186/cc10002.
    1. Bushnell DL, Gupta S, Mlcoch AG, Barnes WE. Prediction of language and neurologic recovery after cerebral infarction with SPECT imaging using N-isopropyl-p-(I 123) iodoamphetamine. Arch Neurol. 1989;46:665–669. doi: 10.1001/archneur.1989.00520420085027.
    1. Muir KW, Weir CJ, Murray GD, Povey C, Lees KR. Comparison of neurological scales and scoring systems for acute stroke prognosis. Stroke. 1996;27:1817–1820. doi: 10.1161/01.STR.27.10.1817.
    1. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Med J. 1965;14:61–65.
    1. Dromerick AW, Edwards DF, Diringer MN. Sensitivity to changes in disability after stroke: a comparison of four scales useful in clinical trials. J Rehabil Res Dev. 2003;40:1–8. doi: 10.1682/JRRD.2003.01.0001.
    1. Harrison JK, McArthur KS, Quinn TJ. Assessment scales in stroke: clinimetric and clinical considerations. Clin Interv Aging. 2013;8:201–211.
    1. Nakao S, Takata S, Uemura H, Kashihara M, Osawa T, Komatsu K, et al. Relationship between Barthel Index scores during the acute phase of rehabilitation and subsequent ADL in stroke patients. J Med Invest. 2010;57:81–88. doi: 10.2152/jmi.57.81.
    1. Quinn TJ, Langhorne P, Stott DJ. Barthel index for stroke trials: development, properties, and application. Stroke. 2011;42:1146–1151. doi: 10.1161/STROKEAHA.110.598540.
    1. Adams HP, Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41. doi: 10.1161/01.STR.24.1.35.
    1. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke. 2000;31:1240–1249. doi: 10.1161/01.STR.31.6.1240.
    1. Hankey GJ. Stroke: how large a public health problem, and how can the neurologist help? Arch Neurol. 1999;56:748–754. doi: 10.1001/archneur.56.6.748.
    1. Bravata DM. Intravenous thrombolysis in acute ischaemic stroke: optimising its use in routine clinical practice. CNS Drugs. 2005;19:295–302. doi: 10.2165/00023210-200519040-00002.
    1. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A. 2000;97:10526–10531. doi: 10.1073/pnas.97.19.10526.
    1. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–282. doi: 10.1016/S0140-6736(07)60149-4.
    1. Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495–505.
    1. Fattore G, Torbica A, Susi A, Giovanni A, Benelli G, Gozzo M, et al. The social and economic burden of stroke survivors in Italy: a prospective, incidence-based, multi-centre cost of illness study. BMC Neurol. 2012;12:137. doi: 10.1186/1471-2377-12-137.
    1. Gall SL, Tran PL, Martin K, Blizzard L, Srikanth V. Sex differences in long-term outcomes after stroke: functional outcomes, handicap, and quality of life. Stroke. 2012;43:1982–1987. doi: 10.1161/STROKEAHA.111.632547.
    1. Sveen U, Bautz-Holter E, Sodring KM, Wyller TB, Laake K. Association between impairments, self-care ability and social activities 1 year after stroke. Disabil Rehabil. 1999;21:372–377. doi: 10.1080/096382899297477.
    1. Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med. 2003;198:971–975. doi: 10.1084/jem.20021067.
    1. Tsai TH, Yeh KH, Sun CK, Yang CH, Chen SM, Hang CL, et al. Estimated glomerular filtration rate as a useful predictor of mortality in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Am J Med Sci. 2013;345:104–111. doi: 10.1097/MAJ.0b013e318258f482.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅