Intravenous Thrombolysis and Risk Factors for Ischemic Stroke

  • Shakti Shrestha Shree Medical and Technical College
  • Ramesh Sharma Poudel Chitwan Medical College Teaching Hospital
  • Lekh Jung Thapa National Institute of Neurological and Allied Sciences
  • Dipendra Khatiwada College of Medical Sciences Teaching Hospital


Thrombolysis is one of the proven potential treatments for the management of acute ischemic stroke. Intravenous recombinant tissue-plasminogen activator (rt-PA) is the only medically approved biological thrombolysing agent for the treatment of acute ischemic stroke within 4.5h of stroke (2.2% symptomatic intracerebral haemorrhage, 12.7% mortality and 58.0% functional independence), but following the guideline and criteria provided by National Institute of Neurological Disorder and Stroke (NINDS) and SITS (Safe Implementation of Thrombolysis in Stroke) studies. Nepal needs to evidently introduce intravenous rt-PA in its clinical setting for treatment of acute ischemic stroke, which has been approved for more than a decade ago in developed countries. Several modifiable and non-modifiable risk factors can affect the outcomes of the treatment with intravenous rt-PA. Early modification of factors predicting the risk outcomes can be a beneficial tool to justify the thrombolytic treatment. This review aims to discuss the major studies on thrombolysis using rt-PA and main factors that can affect the outcomes of treatment in ischemic stroke.



1. Di Carlo A. Human and economic burden of stroke. Age Ageing. 2009;38(1):4-5.
2. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics-2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25–146.
3. European cardiovascular disease statistics 2008. European Heart Network. Brussels; 2008.
4. Saka O, McGuire A, Wolfe C. Cost of stroke in the United Kingdom. Age Ageing. 2009;38(1):27-32.
5. Kulshreshtha A, Anderson LM, Goyal A, Keenam NL. Stroke in South Asia: A Systematic Review of Epidemiologic Literature from 1980 to 2010. Neuroepidemiology. 2012;38(9):123-9.
6. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375(9727):1695–703.
7. Counsell C, Dennis M, McDowall M, Warlow C. Predicting outcome after acute and subacute stroke: development and validation of new prognostic models. Stroke. 2002; 33(4):1041-7.
8. Reid JM, Gubitz GJ, Dai D, Kydd D, Eskes G, Reidy Y, et al. Predicting functional outcome after stroke by modelling baseline clinical and CT variables. Age Ageing. 2010;39(3):360-6.
9. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet. 2008;371(9624):1612-23.
10. Intercollegiate Stroke Working Party (ISWP). National clinical guidelines for stroke. 2nd ed. Suffolk: The Lavenham Press Ltd;2010.
11. Jivan K, Ranchod K, Modi G. Management of ischemic stroke in the acute setting: review of the current status. Cardiovasc J Afr. 2013;24(3):86-92
12. Rana PV. Early management of acute ischemic stroke: review of literature and proposed guidelines. Kathmandu Univ Med J. 2004;2(1):55-66
13. 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(9558):275-82.
14. Blakeley JO, Llinas RH. Thrombolytic therapy for acute ischemic stroke. J Neurol Sci. 2007;261(1-2),55-62.
15. Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart. 2003;89(11):1358-62.
16. Scottish Intercollegiate Guidelines Network. Management of patients with stroke or TIA: assessment, investigation, immediate management and secondary prevention, a national clinical guideline. Number 108, SIGN: Edinburgh. 2008
17. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005; 36(1):66-73.
18. Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012; 379(9834):2364-72
19. Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos A, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke. 2008;39(12):3316-22.
20. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, et al. Alteplase at 0.6mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke. 2006;37(7):1810-15.
21. IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-63
22. IST-3 collaborative group. Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. Lancet Neurol. 2013;12(8):768-76
23. Shaik MM, Loo KW, Gan SH. Burden of stroke in Nepal. Int J Stroke. 2012:7(6):517-20
24. Bambauer KZ, Johnston SC, Bambauer DE, Zivin JA. Reasons why few patients with acute stroke receive tissue plasminogen activator. Arch Neurol. 2006;63(5):661-4.
25. Bobrow BJ, Demaerschalk BM, Wood JP, Villarin A, Clark L, Jennings A. Views of emergency physicians on thrombolysis for acute ischemic stroke. J Brain Dis. 2009;1: 29-37.
26. Coull A, Lovett JK, Rothwell PM; Oxford Vascular Study. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ. 2004;328(7435):326-8.
27. Ford GA, Sandercock P. Current controversies: thrombolysis for patients with acute ischaemic stroke aged over 80. J R Coll Physicians Edinb. 2010;40(1):49-53.
28. Nakayama H, Jorgensen HS, Raaschou HO, Olsen TS. The influence of age of stroke outcome: the Copenhagen Stroke Study. Stroke. 1994;25(4):808-13.
29. Jørgensen HS, Reith J, Nakayama H, Kammersgaard LP, Raaschou HO, Olsen TS. What determines good recovery in patients with the most severe strokes? The Copenhagen Stroke Study. Stroke. 1999;30(10):2008-12.
30. Brown DL, Johnston KC, Wagner DP, Haley EC Jr. Predicting major neurological improvement with intravenous recombinant tissue plasminogen activator treatment of stroke. Stroke. 2004; 35(1):147-50.
31. Kimura K, Kazui S, Minematsu K, Yamaguchi T; Japan Multicentre Stroke Investigator’s Collaboration. Analysis of 16,922 patients with acute ischemic stroke and transient ischemic attack in Japan. A hospital-based prospective registration study. Cerebrovasc Dis. 2004;18(1):47-56.
32. Kimura K, Iguchi Y, Shibazaki K, Iwanaga T, Yamashita S, Aoki J. IV t-PA therapy in acute stroke patients with atrial fibrillation. J Neurol Sci. 2009;276(1-2):6-8.
33. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke. 2008;39(10):2749-55.
34. Ribo M, Molina C, Montaner J, Rubiera M, Delgado-Mederos R, Arenillas JF, et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke. 2005;36(8):1705-9.
35. Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J. Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad Emerg Med. 2006;13(2): 174-80.
36. Gray CS, Hildreth AJ, Sandercock PA, OConnell JE, Johnston DE, Cartidge NE, et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 2007;6(5):397-406.
37. Batty GD, Kivimaki M, Davey Smith G, Marmot MG, Shipley MJ. Post-challenge blood glucose concentration and stroke mortality rates in non-diabetic men in London: 38-year follow-up of the original Whitehall prospective cohort study. Diabetologia. 2008; 51(7):1123-6.
38. Matz K, Keresztes K, Tatschl C, Nowotny M, Dachenhausen A, Brainin M, Tuomilehto J. Disorders of glucose metabolism in acute stroke patients: an underrecognized problem. Diabetes Care. 2006;29(4):792-7.
39. Ahmed N, Wahlgren N, Brainin M, Castillo J, Ford GA, Kaste M, et al. Relationship of blood pressure, antihypertensive therapy, and outcome in ischaemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). Stroke. 2009;40(7):2442-9.
40. Brott T, Lu M, Kothari R, Fagan SC, Frankel M, Grotta JC, et al. Hypertension and its treatment in the NINDS rt-PA Stroke Trial. Stroke. 1998;29(8):1504-9.
41. Lindsberg PJ, Soinne L, Roine RO, Salonen O, Tatlisumak T, Kallela M, et al. Community-based thrombolytic therapy of acute ischemic stroke in Helsinki. Stroke. 2003;34(6):1443-9.
42. Vauthey C, de Freitas GR, van Melle G, Devuyst G, Bogousslavsky J. Better outcome after stroke with higher serum cholesterol levels. Neurology. 2000;54(10):1944-9.
43. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-59.
44. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med. 1989;320(14):904-10.
45. Paciaroni M, Hennerici M, Agnelli G, Bogousslavsky J. Stations and stroke prevention. Cerebrovasc Dis. 2007;24(2-3):170-82.
46. Jimenez-Conde J, Biffi A, Rahman R, Kanakis A, Butler C, Sonni S, et al. Hyperlipidemia and reduced white matter hyperintensity volume in patients with ischemic stroke. Stroke. 2010;41(3):437-42.
47. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ. 1989;298(6676):789-94.
48. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109-18.
49. Ovbiagele B, Saver JL. The smoking–thrombolysis paradox and acute ischemic stroke. Neurology. 2005;65(2):293-5.
50. De Silva DA, Ebinger M, Davis SM. Gender issues in acute stroke thrombolysis. J Clin Neurosci. 2009;16(4):501-4.
51. Di Legge S, Saposnik G, Nilanont Y, Hachinski V. Neglecting the difference: does right or left matter in stroke outcome after thrombolysis? Stroke. 2006;37(8):2066-9.
52. Savitz SI, Schlaug G, Caplan L, Selim M. Arterial occlusive lesions recanalize more frequently in women than in men after intravenous tissue plasminogen activator administration for acute stroke. Stroke. 2005;36(7):1447-51.
53. Meseguer E, Mazighi M, Labreuche J, Arnaiz C, Cabrejo L, Slaoui T, et al. Outcome of intravenous recombinant tissue plasminogen activator therapy according to gender: a clinical registry study and systematic review. Stroke. 2009;40(6):2104-10.
54. Jovanovic DR, Beslac-Bumbasirevic Lj, Budimkic M, Pekmezovic T, Zivkovic M, Kostic VS;SETIS Investigation Group. Do women benefit more from systemic thrombolysis in acute ischemic stroke? A Serbian experience with thrombolysis in ischemic stroke (SETIS) study. Clinl Neurol Neurosurg. 2009;111(9):729–32.
55. Kent DM, Buchan AM, Hill MD. The gender effect in stroke thrombolysis. Of CASES, controls and treatment-effect modification. Neurology. 2008;71(14):1080–3.
56. Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke. 2005;36(1):62-5.
How to Cite
Shrestha, S., Poudel, R. S., Thapa, L. J., & Khatiwada, D. (2014). Intravenous Thrombolysis and Risk Factors for Ischemic Stroke. Journal of Nepal Medical Association, 52(193), 745-750.
Review Article