Diener Hans-Christoph, Patrick Wong

Published: European Neurological Review - Volume 3 Issue 2
US Neurology - Volume 4 Issue 2

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The Importance of Treating Stroke
Ischaemic stroke is the leading global cause of disability in the developed world, and the third leading cause of mortality. It is estimated that 8–12% of individuals die within the first 30 days of their initial stroke,¹ and patients who survive the initial attack face an increased risk of subsequent vascular events and stroke, as approximately one-quarter of all strokes occurring each year are recurrent.² Within the first year of survival following the initial attack, 21.5% of patients will experience a recurrent stroke or transient ischaemic attack (TIA).²

The severity of disability resulting from stroke depends on the size and location of the lesion, and patients can be affected physically, neurologically and emotionally. The consequences of stroke are socioeconomic: 75% of stroke survivors are afflicted with disabilities that affect their employability.³ Furthermore, there are significant costs to the stroke patient and his/her family in terms of inpatient care, rehabilitation, care-giving and any necessary follow-up care for lasting disabilities; therefore, in light of this disease burden, prevention of initial and recurrent stroke is a major priority for healthcare providers.

Recent guidelines for primary and secondary stroke prevention suggest focusing on the reduction or control of cardiovascular risk factors such as hypertension, hyperlipidaemia, tobacco usage, diabetes and obesity.^4,5 Antiplatelet therapy is common as well, with aspirin (acetylsalicylic acid) being the most widely used due to its cost-efficiency and agreeable adverseeffect profile. However, primary prevention of stroke is generally less effective than secondary prevention, as indicated by the number of patients needed to treat in order to prevent one stroke per year.⁶

Current Options in Secondary Stroke Prevention
Antiplatelet therapy is one of the leading strategies in preventing recurrent vascular events in patients with a history of stroke or TIA. Current clinical practice guidelines by the American Heart Association (AHA), the American Stroke Association (ASA), the American College of Chest Physicians (ACCP), the American Academy of Neurology (AAN), the European Stroke Organisation (ESO) and the European Society of Cardiology (ESC) recognise the benefits of secondary stroke prevention associated with aspirin, other antiplatelet agents such as clopidogrel and combinations of antiplatelet drugs such as aspirin and extended-release dipyridamole in initial therapy.^5,7–10 The most recent recommendations from the XVII ESO released at the European Stroke Consortium in Nice, France in May 2008 advocate the use of antithrombotic therapy, where patients not requiring anticoagulation should receive antiplatelet therapy, with the combination of aspirin and dipyridamole, or clopidogrel alone where possible. Alternately, aspirin alone or trifusal alone may be used;⁹ however, trifusal is available in only a few countries.

The past two decades have seen great developments in antithrombotic agents for secondary stroke prevention. The administration of aspirin in stroke patients has long since been known to have beneficial effects in reducing the risk of recurrent stroke compared with placebo:¹¹ recurrent vascular events can be reduced by about 13%, while the risk of recurrent stroke can be reduced by up to 23% with aspirin.¹² This protective effect was found to be independent of dosage, to the extent that a low dose can provide the same level of efficacy while offering a more favourable tolerability profile; however, the lack of an impressive risk reduction has spurred on a search for stronger antithrombotic agents.

Keywords:
Stroke Prevention Atrial Fibrillation, Secondary Prevention Ischemic Stroke, Statins Stroke Prevention, TIA Stroke Prevention, Aspirin Stroke Prevention, ASA Stroke Prevention, Secondary stroke Prevention Guidelines, Primary Secondary Prevention Stroke, transient Ischemic Attack Stroke, Ischemic Hemorrhagic Stroke, Ischemic Embolic Stroke, Ischemic Stroke TIA, Lacunar Ischemic Stroke, Secondary Prevention Ischemic Stroke, Hypertension Ischemic Stroke

References:

1. Rosamond WD, Folsom AR, Chambless LE, et al., Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort, Stroke, 1999; 4:736–43.
2. American Heart Association. Heart Disease and Stroke Statistics: 2008 Update. Available at: www.circ.ahajournals.org/cgi/reprint/ CIRCULATIONAHA.107.187998v1
3. Coffey CE, Cummings JL, Starkstein S, et al., Stroke—The American Psychiatric Press Textbook of Geriatric Neuropsychiatry, Second Edition, Washington DC: American Psychiatric Press, 2000; 601–17.
4. Goldstein LB, Adams R, Alberts MJ, et al., Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline, Stroke, 2006;37 (6):1583–1633.
5. Sacco RL, Adams R, Albers G, et al., Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke, Co-sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline, Stroke, 2006;37:577–617.
6. The European Stroke Organisation (ESO) Executive Committee and the ESO Writing Committee, Guidelines for management of ischaemic stroke and transient ischaemic attack 2008, Cerebrovasc Dis, 2008;25(5):457–507.
7. Straus SE, Majumdar SR, McAlister FA, New evidence for stroke prevention: scientific review, JAMA, 2002;288(11):1388–95.
8. Albers GW, Amarenco P, Easton JD, et al., Antithrombotic and thrombolytic therapy for ischemic stroke. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy, Chest, 2004;126(Suppl.):483S–512S.
9. Guyatt G, Schunëmann H, Cook D, et al., Grades of recommendation for antithrombotic agents, Chest, 2001;119 (Suppl 1):3S-7S.
10. Patrono C, Bachmann F, Baigent C, et al., Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology, Eur Heart J, 2004;25(2):166–81.
11. Algra A, van Gijn J, Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin, J Neurol Neurosurg Psychiatry, 1999;65:255.
12. Antithrombotics Trialists’ Collaboration, Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients, BMJ, 2002;324:71–86.
13. The Stroke Prevention In Reversible Ischemia Trial (SPIRIT) Study Group, A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The stroke prevention in reversible ischemia trial (SPIRIT) study group, Ann Neurol, 1997;42(6):857–65.
14. Mohr JP, Thompson JLP, Lazar RM, et al., A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke, N Engl J Med, 2001;345:1444–51.
15. The ESPRIT Study Group, Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial, Lancet Neurol, 2007;6(2):115–24.
16. CAPRIE Steering Committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE), Lancet, 1996;348:1329–39.
17. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators, Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation, N Engl J Med, 2001;345:494–502.
18. Steinhubl SR, Berger PB, Mann JT III, et al., Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial, JAMA, 2002;288: 2411–20.
19. Diener H-C, Bogousslavsky J, Brass LM, et al., Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebocontrolled trial, Lancet, 2004;364:331–7.
20. Bhatt DL, Fox KA, Hacke W, et al., Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events, N Engl J Med, 2006;354:1706–17.
21. Bhatt DL, Flather MD, Hacke W, et al., Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial, J Am Coll Cardiol, 2007;49: 1982–8.
22. Diener HC, Cunha L, Forbes C, et al., European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke, J Neurol Sci, 1996;143:1–13.
23. Guiraud-Chaumeil B, Rascol A, David J, et al., Prévention des récidives des accidents vasculaires cérébraux ischémiques par les anti-agrégants plaquettaires Résultats d’un essai thérapeutique controlé de 3 ans, Rev Neurol (Paris), 1982;138:367–85.
24. Bousser MG, Eschwege E, Haguenau M, et al., ‘AICLA’ controlled trial of aspirin and dipyridamole in the secondary prevention of atherothrombotic cerebral ischemia, Stroke, 1983;14:5–14.
25. American-Canadian Co-operative Study Group, Persantin aspirin trial in cerebral ischemia. Part II: Endpoint results, Stroke, 1985; 16:406–15.
26. Kaye J, A trial to evaluate the relative roles of dipyridamole and aspirin in the prevention of deep vein thrombosis in stroke patients, Bracknell, Berkshire: Boehringer Ingelheim, 1990.
27. Algra A, Van Gijn J, Algra A, et al.,Secondary prevention after cerebral ischaemia of presumed arterial origin: is aspirin still the touchstone?, J Neurol Neurosurg Psychiatry, 1999;66(5):557–9.
28. The ESPRIT Study Group, Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial, Lancet, 2006;1367: 1665–73.
29. Rodgers A, MacMahon S, Gamble G, et al., Blood pressure and risk of stroke in patients with cerebrovascular disease, The United Kingdom Transient Attack Collaborative Group, BMJ, 1996;313: 147.
30. Blood Pressure Lowering Treatment Trialists’ Collaboration, Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively designed overviews of randomised trials, Lancet, 2003;362:1527–35.
31. PROGRESS Collaborative Group, Randomised trial of a perindopril-based blood-press-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack, Lancet, 2001;358: 1033–41. Errata, Lancet, 2001;358:1556, 2002;359:2120.
32. The Heart Outcomes Prevention Evaluation Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients, N Engl J Med, 2000; 342:145–53. Errata, N Engl J Med, 2000;342:748, 1736.
33. Kaschina E, Unger T, Angiotensin AT1/AT2 receptors: regulation, signalling and function, Blood Press, 2003;12: 70–88.
34. Schmieder RE, Mechanisms for the clinical benefits of angiotensin II receptor blockers, Am J Hypertens, 2005;18: 720–30.
35. Brewster UC, Setaro JF, Perazella MA, The renin-angiotensinaldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states, Am J Med Sci, 2003;326:15–24.
36. Dahlöf B, Devereux RB, Kjeldsen SE, et al., Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet, 2002;359:995–1003.
37. Schrader J, Lüders S, Kulschewski A, et al., Morbidity and Mortality after Stroke, Eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES), Stroke, 2005;36:61218–26.
38. Schrader J, Lüders S, Kulschewski A, et al., The ACCESS Study: evaluation of acute candesartan cilexetil therapy in stroke survivors, Stroke, 2003;34:2699–703.
39. The ONTARGET Investigators, Telmisartan, ramipril, or both in patients at high risk for vascular events, N Engl J Med, 2008;358: 1547–59.
40. Pfeffer MA, McMurray JJV, Velazquez EJ, et al., Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both, N Engl J Med, 2003; 349:1893–1906.
41. Diener HC, Sacco R, Yusuf S for the Steering Committee and PRoFESS Study Group, Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS), Cerebro Dis, 2007;23:368–380.
42. Sacco RL, Diener H-C, Yusuf S, et al., Aspirin and extendedrelease dipyridamole versus clopidogrel for recurrent stroke, N Engl J Med, 2008;359(12):1238–51.
43. Akhtar M, Ordovas K, Martin A, et al., Effect of chronic sustained-release dipyridamole on myocardial blood flow and left ventricular function in patients with ischemic cardiomyopathy, Conges Heart Fail, 2007;13:130–35.
44. Hirsh J, Guyatt G, Albers GW, et al.,The seventh ACCP conference on antithrombotic and thrombolytic therapy: evidence-based guidelines, Chest, 2004;126(Suppl. 1): S172–3.
45. Yusuf S, Phil D, Diener H-C, et al., Telmisartan to prevent recurrent stroke and cardiovascular events, N Engl J Med, 2008;359 (12):1225–37.
46. Jandeleit-Dahm KA, Tikellis C, Reid CM, et al., Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes, J Hypertens, 2005;23:463–73.
47. Ruilope LM, Segura J, Losartan and other angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence, Clin Ther, 2003;25: 3044–64.
48. Silverstein RL, Fenves AZ, Ram CV, ARBs and target organ protection. Exploring benefits beyond their antihypertensive effects, Postgrad Med, 2004;116:31–8.
49. Lenzi GL, Altieri M, Maestrini I, Post-stroke depression, Rev Neurol (Paris), 2008;164(10):837–40.
50. De Keyser J, Uyttenboogaart M, Koch MW, et al., Neuroprotection in acute ischemic stroke, Acta Neurol Belg, 2005;105:144–48.
51. Schabitz WR, Fisher M, Perspectives on neuroprotective stroke therapy, Biochem Soc Trans, 2006;34:1271–6.
52. Hill MD, Stroke: the dashed hopes of neuroprotection, Lancet Neurol, 2007;6:2–3.
53. Blake AD, Dipyridamole is neuroprotective for cultured rat embryonic cortical neurons, Biochem Biophys Res Commun, 2004; 314(2):501–4.
54. Farinelli SE, Green LA, Friedman WJ, Neuroprotective actions of dipyridamole on cultured CNS neurons, J Neurosci, 1998;18(14): 5112–23.
55. Zheng Z, Schwab S, Grau A, et al., Neuroprotection by early and delayed treatment of acute stroke with high dose aspirin, Brain Res, 2007;1186:275–80.
56. Gomes I, Aspirin: a neuroprotective agent at high doses?, Natl Med J India, 1998;11(1):14–17.
57. Krikov M, Thone-Reineke C, Müller S, et al., Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BNDF/TrkB system in rats, J Hypertens, 2008;26(3):544–52.
58. Fagan SC, Kozak A, Hill WD, et al., Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection, J Hypertens, 2006;24:535–9.
59. Faure S, Oudart N, Javellaud J, et al., Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil, J Hypertens, 2006;24:2255–61.
60. Engelhorn T, Doerfler A, Heusch G, et al., Reduction of cerebral infarct size by the AT1-receptor candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination, An experimental study in rats, Neurosci Lett, 2006;406:92–6.
61. Groth W, Blume A, Gohlke P, et al., Chronic pre-treatment with candesartan improves recovery from focal cerebral ischaemia in rats, J Hypertens, 2003;21:2175–82.
62. Thone-Reineke C, Zimmermann M, Neumann C, et al., Are angiotensin receptor blockers neuroprotective?, Curr Hypertens Rep, 2004;6:257–66.
63. Lee JH, Lack of antiapoptotic effects of an antiplatelet drug, aspirin and clopidogrel, and antioxidant, MCI-186, against focal ischemic brain damage in rats, Neurol Res, 2005;27: 483–92.
64. Paciaroni M, Agnelli G, Caso V, et al., Prior use of antithrombotic agents and neurological functional outcome at discharge in patients with ischemic stroke, J Thromb Haemost, 2006;4: 1957–61.
65. Sivenius J, Cunha L, Diener HC, et al., Antiplatelet treatment does not reduce the severity of subsequent stroke. European Stroke Prevention Study 2 Working Group, Neurology, 1999;53(4):825–9.
66. Aldandashi S, Noor R, Wang CX, et al., Combination treatment with dipyridamole, aspirin, and tPA in an embolic model of stroke in rats, Exp Neurol, 2007;205:563–8.
67. Feigin V, Ratnasabapathy Y, Anderson C, Does blood pressure lowering treatment prevents dementia or cognitive decline in patients with cardiovascular and cerebrovascular disease?, J Neurol Sci, 2005;229–230:151–5.
68. The PROGRESS Collaborative Group, Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease, Arch Intern Med, 2003;163: 1069–75.
69. Forette F, Seux M, Staessen J, et al., Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial, Lancet, 1998;352:1347–51.
70. Lithell H, Hansson L, Skoog I, et al., for the SCOPE Study Group, The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomised double-blind intervention trial, J Hypertens, 2003;21:875–86.
71. Diener H-C, Sacco RL, Yusuf S, et al., Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study, Lancet Neurol, 2008; 7(10):875–84.
72. Rankin J, Cerebral vascular accidents in patients over the age of 60, II: prognosis, Scot Med J, 1957;2:200–15.
73. Mahoney FI, Barthel DW, Functional evaluation: The Barthel Index, Md State Med J, 1965;14:61–5.
74. Folstein M, Folstein S, McHugh PR, Mini-mental state: a practical method for grading the cognitive state of patients for the clinician, J Psychiatr Res, 1975;12:189–98.
75. Guo S, Kim WJ, Lok J, et al., Neuroprotection via matrixtrophic coupling between cerebral endothelial cells and neurons, Proc Natl Acad Sci U S A, 2008;105:7582–7.
76. The ACTIVE Steering Committee, Rationale and design of ACTIVE: the atrial fibrillation clopidgrel trial with irbesartan for prevention of vascular events, Am Heart J, 2006;151:1187–93.
77. Teo K, Yusuf S, Sleight P, et al., Rationale, design and baseline characteristics of two large, simple randomized trials evaluating telmisartan, ramipril and their combination in high-risk patients: the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials, Am Heart J, 2004;148:52–61.