Review: Recurrent stroke: where do we stand with the secondary prevention of noncardioembolic ischaemic strokes?

Abstract

Strokes recur in 6—20% of the patients, most commonly within the first year; after a TIA or minor stroke; most recurrences will occur within the first 90 days. Our ability to identify patients at high risk is poor and most recurrent strokes cannot be explained by traditional risk factors. In 30—45% of the cases the second stroke will be of a different subtype. Moreover, patients are faced with other risks, like cardiac events and cognitive decline. With the population aging, the need for timely and effective secondary prevention strategies is more pressing than ever. This paper summarizes recent advances in pharmacological secondary prevention after a non-cardioembolic ischaemic stroke, and highlights critical questions still in need of answers.

Keywords

Recurrent stroke noncardioembolic stroke secondary prevention antiplatelets statins antihypertensive medication lipid-lowering medication

References

Algra, A. and van Ginj, J. (1996). Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry 60: 197-199.

Alter, M. , Friday, G. , Lai, S.M. , O'Connell, J. and Sobel, E. (1994). Hypertension and risk of stroke recurrence. Stroke 25: 1605-1610.

Alter, M. , Sobel, E. , McCoy, R.L. , Francis, M.E. , Davanipour, Z. , Shofer, F. et al. (1987). Stroke in the Lehigh Valley: risk factors for recurrent stroke. Neurology 37: 503-507.

Amarenco, P. and Steg, P.G. (2007). The paradox of cholesterol and stroke. Lancet 370: 1803-804.

Amarenco, P. , Bogousslavsky, J. , Callahan, A., III , Goldstein, L.B. , Hennerici, M. , Rudolph, A.E. et al. (2006). High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 355: 549-559.

Amarenco, P. , Labreuche, J. , Lavallee, P. and Touboul, P.J. (2004). Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 35: 2902-2909.

Amarenco, P. and Donnan, G.A. (2004). Should the MATCH results be extrapolated to all stroke patients and affect ongoing trials evaluating clopidogrel plus aspirin ? Stroke 35: 2606-2608.

Antithrombotic Trialists' Collaboration. ( 2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. BMJ 324: 71-86.

Ariesen, M.J. , Algra, A. and Kappelle, L.J. (2006). Antiplatelet drugs in the secondary prevention after stroke: differential efficacy in large versus small vessel disease? A subgroup analysis from ESPS-2. Stroke 37: 134-138.

10.

Babikian, V.L. , Wijman, C.A. , Hyde, C. , Cantelmo, N.L. , Winter, M.R. , Baker, E. et al. (1997). Cerebral microembolism and early recurrent cerebral or retinal ischemic events. Stroke 28: 1314-1318.

11.

Baigent, C. , Keech, A. , Kearney, P.M. , Blackwell, L. , Buck, G. , Pollicino, C. et al. (2005). Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366: 1267-1278.

12.

Baird, A.E. (2006). Blood biologic markers of stroke: improved management, reduced cost? Curr Atheroscler Rep. 8: 267-275.

13.

Bhatt, D.L. , Chew, D.P. , Hirsch, A.T. , Ringleb, P.A. , Hacke, W. and Topol, E.J. (2001). Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 103: 363-368.

14.

Bhatt, D.L. , Fox, K.A. , Hacke, W. , Berger, P.B. , Black, H.R. , Boden, W.E. et al. (2006). Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 354: 1706-1717.

15.

Bhatt, D.L. , Marso, S.P. , Hirsch, A.T. , Ringleb, P.A. , Hacke, W. and Topol, E.J. (2002). Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol. 90: 625-628.

16.

Bowman, L. , Armitage, J. , Bulbulia, R. , Parish, S. and Collins, R. (2007). Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J 154: 815-823.

17.

Brown, D.L. , Lisabeth, L.D. , Roychoudhury, C. , Ye,Y. and Morgenstern, L.B. (2005). Recurrent stroke risk is higher than cardiac event risk after initial stroke/transient ischemic attack . Stroke 36: 1285-1287.

18.

Burn, J. , Dennis, M. , Bamford, J. , Sandercock, P. , Wade, D. and Warlow, C. (1994). Long-term risk of recurrent stroke after a first-ever stroke, The Oxfordshire Community Stroke Project. Stroke 25: 333-337.

19.

CAPRIE Steering Committee. (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348: 1329-1339.

20.

Chimowitz, M.I. , Lynn, M.J. , Howlett-Smith, H. , Stern, B.J. , Hertzberg, V.S. , Frankel, M.R. et al. (2005). Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 352: 1305-1316.

21.

Costa, J. , Ferro, J.M. , Matias-Guiu, J. , varez- Sabin, J. and Torres, F. (2005). Triflusal for preventing serious vascular events in people at high risk, Cochrane Database Syst Rev 3:CD004296.

22.

Coull, A.J. and Rothwell, P.M. (2004). Underestimation of the early risk of recurrent stroke: evidence of the need for a standard definition. Stroke 35: 1925-1929.

23.

Dahlof, B. , Devereux, R.B. , Kjeldsen, S.E. , Julius, S. , Beevers, G. , de, F.U. et al. (2002). Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359: 995-1003.

24.

de Lemos, J.A. , Blazing, M.A. , Wiviott, S.D. , Lewis, E.F. , Fox, K.A. , White, H.D. et al. (2004). Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 292: 1307-1316.

25.

Dhamoon, M.S. , Sciacca, R.R. , Rundek, T. , Sacco, R.L. and Elkind, M.S. (2006). Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology 66: 641-646.

26.

Diener, H.C. , Bogousslavsky, J. , Brass, L.M. , Cimminiello, C. , Csiba, L. , Kaste, M. et al. (2004). Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 364: 331-337.

27.

Diener, H.C. , Cunha, L. , Forbes, C. , Sivenius, J. , Smets, P. and Lowenthal, A. (1996). European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 143: 1-13.

28.

Diener, H.C. , Sacco, R. and Yusuf, S. (2007). 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). Cerebrovasc Dis 23: 368-380.

29.

Douglas, Jr, J.S. , Holmes, Jr, D.R. , Kereiakes, D.J. , Grines, C.L. , Block, E. , Ghazzal, Z.M. et al. (2005). Coronary stent restenosis in patients treated with cilostazol. Circulation 112: 2826-2832.

30.

Dzau, V.J. (2001). Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 37: 1047-1052.

31.

Elkind, M.S. (2007). Anticoagulation for secondary stroke prevention: another nail in the coffin? Lancet Neurol. 6: 97-99.

32.

ESPS Group. (1990) European Stroke Prevention Study. Stroke 21: 1122-1130.

33.

Gent, M. , Blakely, J.A. , Easton, J.D. , Ellis, D.J. , Hachinski, V.C. , Harbison, J.W. et al. (1989). The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1: 1215-1220.

34.

Gorelick, P.B. , Richardson, D. , Kelly, M. , Ruland, S. , Hung, E. , Harris, Y. et al. (2003). Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 289: 2947-2957.

35.

Gonzalez-Correa, J.A. and De L. a Cruz, J.P. (2006). Triflusal: an antiplatelet drug with a neuroprotective effect? Cardiovasc Drug Rev 24: 11-24.

36.

Hackam, D.G. and Spence, J.D. (2007). Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study . Stroke 38: 1881-1885.

37.

Haring, H.P. (2002). Cognitive impairment after stroke. Curr Opin Neurol. 15: 79-84.

38.

Hass, W.K. , Easton, J.D. , Adams Jr, H.P. , Pryse-Phillips, W. , Molony, B.A. anderson, S. et al. (1989). A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients, Ticlopidine Aspirin Stroke Study Group. N Engl J Med. 321: 501-507.

39.

Hillen, T. , Coshall, C. , Tilling, K. , Rudd, A.G. , McGovern, R. and Wolfe, C.D. (2003). Cause of stroke recurrence is multifactorial: patterns, risk factors and outcomes of stroke recurrence in the South London Stroke Register. Stroke 34: 1457-1463.

40.

Howard, G. , McClure, L.A. , Krakauer, J.W. and Coffey, C.S. (2007). Stroke and the statistics of the aspirin/clopidogrel secondary prevention trials. Curr Opin Neurol. 20: 71-77.

41.

International Stroke Trial Collaborative Group. ( 1997). The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 349: 1569-1581.

42.

Irie, K. , Yamaguchi, T. , Minematsu, K. and Omae, T. (1993). The J-curve phenomenon in stroke recurrence. Stroke 24: 1844-1849.

43.

Jones, L. , Griffin, S. , Palmer, S. , Main, C. , Orton, V. , Sculpher, M. et al. (2004). Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation . Health Technol Assess. 8: iii-96.

44.

Josan, K. and McAlister, F.A. (2007). Cholesterol lowering for secondary prevention: what statin dose should we use? Vasc.Health Risk Manag. 3: 615-627.

45.

Kam, P.C. , Kaur, N. and Thong, C.L. (2005). Direct thrombin inhibitors: pharmacology and clinical relevance. Anaesthesia 60: 565-574.

46.

Kaplan, R.C. , Tirschwell, D.L. , Longstreth Jr, W.T. , Manolio, T.A. , Heckbert, S.R. , Lefkowitz, D. et al. (2005). Vascular events, mortality and preventive therapy following ischemic stroke in the elderly. Neurology 65: 835-842.

47.

Kennedy, J. , Hill, M.D. , Ryckborst, K.J. , Eliasziw, M. , Demchuk, A.M. and Buchan, A.M. (2007). Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol 6: 961-969.

48.

Kjeldsen, S.E. , Julius, S. , Hedner, T. and Hansson, L. (2001). Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials . Blood Press 10: 190-192.

49.

LaRosa, J.C. , Grundy, S.M. , Waters, D.D. , Shear, C. , Barter, P. , Fruchart, J.C. et al. (2005). Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 352: 1425-1435.

50.

Lavallee, P.C. , Meseguer, E. , Abboud, H. , Cabrejo, L. , Olivot, J.M. , Simon, O. et al. (2007). A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): feasibility and effects. Lancet Neurol. 6:953-960.

51.

Law, M.R. , Wald, N.J. and Rudnicka, A.R. (2003). Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease and stroke: systematic review and meta-analysis . BMJ 326: 1423-1430.

52.

Lawes, C.M. , Bennett, D.A. , Feigin, V.L. and Rodgers, A. (2004). Blood pressure and stroke: an overview of published reviews. Stroke 35: 776-785.

53.

Lawes, C.M. , Rodgers, A. , Bennett, D.A. , Parag, V. , Suh, I. , Ueshima, H. et al. (2003). Blood pressure and cardiovascular disease in the Asia Pacific region. J Hyperens. 21: 707-716.

54.

Lewington, S. , Clarke, R. , Qizilbash, N. , Peto, R. and Collins, R. (2002). Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360: 1903-1913.

55.

Lindgren, A. , Husted, S. , Staaf, G. and Ziegler, B. (2004). Dipyridamole and headache-a pilot study of initial dose titration. J Neurol Sci. 223: 179-184.

56.

Lithell, H. , Hansson, L. , Skoog, I. , Elmfeldt, D. , Hofman, A. , Olofsson, B. et al. (2003). The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 21: 875-886.

57.

Lovett, J.K. , Coull, A.J. and Rothwell, P.M. (2004). Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 62: 569-573.

58.

Magyar, M.T. , Szikszai, Z. , Balla, J. , Valikovics, A. , Kappelmayer, J. , Imre, S. et al. (2003). Early-onset carotid atherosclerosis is associated with increased intima-media thickness and elevated serum levels of inflammatory markers. Stroke 34: 58-63.

59.

Marissal, J.P. and Selke, B. (2004). Economic assessment of the secondary prevention of ischaemic stroke with dipyridamole plus aspirin (Aggrenox/ Asasantin) in France. Pharmacoeconomics. 22: 661-670.

60.

Matias-Guiu, J. , Ferro, J.M. , varez- Sabin, J. , Torres, F. , Jimenez, M.D. , Lago, A. et al. (2003). Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke 34: 840-848.

61.

Matsumoto, M. (2005). Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study, Atheroscler Suppl 6: 33-40.

62.

Mazighi, M. , Lavallee, P.C. , Labreuche, J. and Amarenco, P. (2007). Statin therapy and stroke prevention: what was known, what is new and what is next? Curr. Opin. Lipidol. 18: 622-625.

63.

Meadows, T.A. and Bhatt, D.L. (2007). Clinical aspects of platelet inhibitors and thrombus formation. Circ. Res. 100: 1261-1275.

64.

Mohr, J.P. , Thompson, J.L. , Lazar, R.M. , Levin, B. , Sacco, R.L. , Furie, K.L. et al. (2001). A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med . 345: 1444-1451.

65.

Moroney, J.T. , Bagiella, E. , Paik, M.C. , Sacco, R.L. and Desmond, D.W. (1998). Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke 29: 2118-2124.

66.

Moroney, J.T. , Bagiella, E. , Tatemichi, T.K. , Paik, M.C. , Stern, Y. and Desmond, D.W. (1997). Dementia after stroke increases the risk of long-term stroke recurrence. Neurology 48: 1317-1325.

67.

Moroney, J.T. and Desmond, D.W. (1997). Predictors in stroke outcome. Neurology 48: 1475-1476.

68.

Muller, T.H. (2001). Inhibition of thrombus formation by low-dose acetylsalicylic acid, dipyridamole and their combination in a model of platelet-vessel wall interaction. Neurology 57: S8-S11.

69.

Norrving, B. (2003). Long-term prognosis after lacunar infarction. Lancet Neurol. 2: 238-245.

70.

PATS Collaborating Group. (1995). Post-stroke antihypertensive treatment study, A preliminary result. Chin Med J (Engl) 108: 710-717.

71.

Pedersen, T.R. , Faergeman, O. , Kastelein, J.J. , Olsson, A.G. , Tikkanen, M.J. , Holme, I. et al. (2005). High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 294: 2437-2445.

72.

Pergola, P.E. , White, C.L. , Graves, J.W. , Coffey, C.S. , Tonarelli, S.B. , Hart, R.G. et al. (2007). Reliability and validity of blood pressure measurement in the Secondary Prevention of Small Subcortical Strokes study . Blood Press Monit. 12: 1-8.

73.

Petty, G.W. , Brown Jr, R.D. , Whisnant, J.P. , Sicks, J.D. , O' Fallon, W.M. and Wiebers, D.O. (2000). Ischemic stroke subtypes: a population-based study of functional outcome, survival and recurrence. Stroke 31: 1062-1068.

74.

Petty, G.W. , Brown Jr, R.D. , Whisnant, J.P. , Sicks, J.D. , O'Fallon, W.M. and Wiebers, D.O. (1998). Survival and recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 1975 through 1989. Neurology 50: 208-216.

75.

PROGRESS Collaborative Group. (2001). Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 358: 1033-1041.

76.

Purroy, F. , Montaner, J. , Molina, C.A. , Delgado, P. , Ribo, M. and varez-Sabin, J. (2007). Patterns and predictors of early risk of recurrence after transient ischemic attack with respect to etiologic subtypes. Stroke 38: 3225-3229.

77.

Rashid, P. , Leonardi-Bee, J. and Bath, P. (2003). Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 34: 2741-2748.

78.

Ringleb, P.A. , Bhatt, D.L. , Hirsch, A.T. , Topol, E.J. and Hacke, W. (2004). Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events. Stroke 35: 528-532.

79.

Robinson, J.G. , Smith, B. , Maheshwari, N. and Schrott, H. (2005). Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 46: 1855-1862.

80.

Rodgers, A. , MacMahon, S. , Gamble, G. , Slattery, J. , Sandercock, P. and Warlow, C. (1996). Blood pressure and risk of stroke in patients with cerebrovascular disease, The United Kingdom Transient Ischaemic Attack Collaborative Group. BMJ 313: 147.

81.

Roth, G.J. and Majerus, P.W. (1975). The mechanism of the effect of aspirin on human platelets, I. Acetylation of a particulate fraction protein. J Clin Invest 56: 624-632.

82.

Rothwell, P.M. , Giles, M.F. , Chandratheva, A. , Marquardt, L. , Geraghty, O. , Redgrave, J.N. et al. (2007). Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet 370: 1432-1442.

83.

Sacco, R.L. , Adams, R. , Albers, G. , Alberts, M.J. , Benavente, O. , Furie, K. et al. (2006a). 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 37: 577-617.

84.

Sacco, R.L. , Prabhakaran, S. , Thompson, J.L. , Murphy, A. , Sciacca, R.R. , Levin, B. et al. (2006b). Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovasc Dis. 22: 4-12.

85.

Sacco, R.L. , Shi, T. , Zamanillo, M.C. and Kargman, D.E. (1994). Predictors of mortality and recurrence after hospitalized cerebral infarction in an urban community: the Northern Manhattan Stroke Study . Neurology 44: 626-634.

86.

Sacco, R.L. , Wolf, P.A. , Kannel, W.B. and McNamara, P.M. (1982). Survival and recurrence following stroke, The Framingham study. Stroke 13: 290-295.

87.

Samsa, G.P. , Bian, J. , Lipscomb, J. and Matchar, D.B. (1999). Epidemiology of recurrent cerebral infarction: a medicare claims-based comparison of first and recurrent strokes on 2-year survival and cost. Stroke 30: 338-349.

88.

Schmieder, R.E. (2005). Mechanisms for the clinical benefits of angiotensin II receptor blockers. Am J Hypertens. 18: 720-730.

89.

Schrader, J. , Luders, S. , Kulschewski, A. , Hammersen, F. , Plate, K. , Berger, J. et al. (2005). Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 36: 1218-1226.

90.

Schror, K. (2002). The pharmacology of cilostazol. Diabetes Obes Metab 4: S14-S19.

91.

Sivenius, J. , Tuomilehto, J. , Immonen-Raiha, P. , Kaarisalo, M. , Sarti, C. , Torppa, J. et al. (2004). Continuous 15-year decrease in incidence and mortality of stroke in Finland: the FINSTROKE study. Stroke 35: 420-425.

92.

Steinhubl, S.R. , Berger, P.B. , Mann, J.T., III , Fry, E.T. , DeLago, A. , Wilmer, C. et al. (2002). Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288: 2411-2420.

93.

Storey, R.F. , Sanderson, H.M. , White, A.E. , May, J.A. , Cameron, K.E. and Heptinstall, S. (2000). The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity . Br J Haematol. 110: 925-934.

94.

Talelli, P. , Ellul, J. , Terzis, G. , Lekka, N.P. , Gioldasis, G. , Chrysanthopoulou, A. et al. (2004). Common carotid artery intima media thickness and post-stroke cognitive impairment. J Neurol Sci. 223: 129-134.

95.

Talelli, P. , Terzis, G. , Katsoulas, G. , Chrisanthopoulou, A. and Ellul, J. (2007). Recurrent stroke: The role of common carotid artery intima-media thickness. J Clin Neurosci. 14: 1067-1072.

96.

Teo, K. , Yusuf, S. , Sleight, P. Anderson, C. , Mookadam, F. , Ramos, B. et al. (2004). Rationale, design and baseline characteristics of 2 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 148: 52-61.

97.

The ESPRIT Study Group. (2006). Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 367: 1665-1673.

98.

The ESPRIT Study Group. (2007). Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial. Lancet Neurol 6: 115-124.

99.

The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. (1997). A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 42: 857-865.

100.

Thom, T. , Haase, N. , Rosamond, W. , Howard, V.J. , Rumsfeld, J. , Manolio, T. et al. (2006). Heart disease and stroke statistics-2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113: e85-151.

101.

Touboul, P.J. , Hennerici, M.G. , Meairs, S. , Adams, H. , Amarenco, P. , Bornstein, N. et al. (2007). Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004 and Brussels, Belgium, 2006. Cerebrovasc Dis. 23: 75-80.

102.

Toyoda, K. , Okada, Y. and Kobayashi, S. (2007). Early recurrence of ischemic stroke in Japanese patients: the Japan standard stroke registry study. Cerebrovasc Dis. 24: 289-295.

103.

Tsivgoulis, G. , Vemmos, K. , Papamichael, C. , Spengos, K. , Manios, E. , Stamatelopoulos, K. et al. (2006). Common carotid artery intima-media thickness and the risk of stroke recurrence. Stroke 37: 1913-1916.

104.

van Wijk., I. , Kappelle, L.J. , van Gijn, J. , Koudstaal, P.J. , Franke, C.L. , Vermeulen, M. et al. (2005). Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study . Lancet 365: 2098-2104.

105.

Vaughan, C.J. (2003). Prevention of stroke and dementia with statins: Effects beyond lipid lowering. Am J Cardiol. 91: 23B-29B.

106.

Vergouwen, M.D. , de Haan, R.J. , Vermeulen, M. and Roos,Y.B. (2008). Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 39: 497-502.

107.

Wing, L.M. , Reid, C.M. , Ryan, P. , Beilin, L.J. , Brown, M.A. , Jennings, G.L. et al. (2003). A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 348: 583-592.

108.

Wu, L. , Iwai, M. , Nakagami, H. , Li, Z. , Chen, R. , Suzuki, J. et al. (2001). Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury . Circulation 104: 2716-2721.

109.

Yusuf, S. , Sleight, P. , Pogue, J. , Bosch, J. , Davies, R. and Dagenais, G. (2000). Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients, The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 342: 145-153.

110.

Yusuf, S. , Zhao, F. , Mehta, S.R. , Chrolavicius, S. , Tognoni, G. and Fox, K.K. (2001). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 345: 494-502.

111.

Zhang, H. , Thijs, L. and Staessen, J.A. (2006). Blood pressure lowering for primary and secondary prevention of stroke. Hypertension 48: 187-195.