Secondary Prevention of Stroke

Summary

Stroke is a common disorder and a leading cause of disability and death. Ischaemia is a more common cause than haemorrhage and radiological imaging is required to accurately differentiate these. Some specific risk factors for stroke are non-modifiable – these include age, gender, racial and hereditary factors. Certain risk factors for ischaemic stroke can be identified and modification of these can be used for secondary prevention – examples include hypertension, heart diseases, atrial fibrillation, diabetes mellitus, dyslipidaemia, smoking, excessive alcohol consumption and carotid stenosis. Carotid endarterectomy is valuable in selected patients. In ischaemic stroke and transient ischaemic attack antithrombotic therapy is an option used in secondary prevention. In atrial fibrillation, warfarin should be used where possible in secondary prevention. When warfarin is contraindicated aspirin should be used. In other patients, an antiplatelet regime is appropriate – aspirin is commonly used and is the least expensive regime. Other antiplatelet agents such as dipyridamole, ticlopidine and clopidogrel may have a place. Younger patients with ischaemic stroke may have a thrombophilia state and should be appropriately investigated.

Key words

Cerebrovascular disorders - cerebral ischaemia - risk factors - atrial fibrillation - anticoagulants - aspirin - platelet aggregation inhibitors - dipyridamole - ticlopidine - clopidogrel - hypertension

• References

• 1 Terent A. Stroke morbidity. In: Whisnant J. editor. Stroke: populations, cohorts, and clinical trials. Oxford; Boston: Butterworth-Heineman; 1993
• 2 Wolf PA, D'Agostino RB, O'Neal MA. Secular trends in stroke incidence and mortality: The Framingham Study. Stroke 1992; 23: 1551-5.
• 3 Dyken ML, Wolf PA, Barnett HJM, Bergan JJ, Hass WK, Kannel WB, Kuller L, Kurtzke JF, Sundt TM. Risk factors in stroke: a statement for physicians by the Subcommittee on Risk Factors and Stroke Council. Stroke 1984; 15: 1105-11.
• 4 Broderick JP, Phillips SJ, Whisnant JP, O'Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline in stroke. Stroke 1989; 20: 577-82.
• 5 Gillum RF. Strokes in blacks. Stroke 1988; 19: 1-6.
• 6 Wade DT. Stroke (acute cerebrovascular disease). In: Stevens A, Raftery J. (eds) Health Care Needs Assessment: The epidemiologically based needs assessment reviews, Vol 1. Oxford: Radcliffe Medical Press; 1994
• 7 Dunbabin D. Cost effective intervention in stroke. Pharmaco Economics 1992; 2: 468-99.
• 8 Department of. Health. Health of the Nation. London: HMSO; 1992
• 9 Dennis M, Burn JP, Sandercock PAG, Bamford JM, Wade DT, Warlow CP. Long term survival after first-ever stroke.: the Oxfordshire Community Stroke Project. Stroke 1993; 24: 796-800.
• 10 Langton-Hewer R. Rehabilitation after stroke. Q J Med 1990; 76: 659-74.
• 11 Malmgren R, Bamford J, Warlow C, Sandercock P, Slattery J. Projecting the number of patients with first ever strokes and patients newly handicapped by stroke in England and Wales. BMJ 1989; 298: 656-60.
• 12 The AD Hoc Committee on the classification and outline of cerebrovascular disease. II. Stroke 1975; 6: 566-616.
• 13 Gorelick PB, Sacco R L, Smith D B, Alberts M, Mustone-Alexander L, Rader D, Ross J L, Raps E, Ozer M N, Brass L M, Malone M E, Goldberg S, Booss J, Hanley D F, Toole J F, Greengold N L, Rhew D C. Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. J Amer Med Assoc 1999; 281: 1112-20.
• 14 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333: 1581-7.
• 15 Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. 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: 1245-51.
• 16 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - I: prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106.
• 17 Grotta J. Cerebrovascular disease in young patients. Thromb Haemost 1997; 78: 13-23.
• 18 Brown MM, Bevan DJ. Is inherited thrombophilia a risk factor for arterial stroke?. Neurol Neurosurg Psychiatry. 1998 65. 617.
• 19 Makris M, Rosendaal FR, Preston FE. Familial thrombophilia: genetic risk factors and management. J Intern Med Suppl 1997; 740: 9-15.
• 20 Levine SR, Brey RL. Neurological aspects of antiphospholipid antibody syndrome. Lupus 1996; 5: 347-53.
• 21 Goldberg SN, Conti-Kelly AM, Greco TP. A family study of anticardiolipin antibodies and associated clinical conditions. Am J Med 1995; 99: 473-9.
• 22 Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke 1991; 22: 312-8.
• 23 Sacco RL. Ischemic stroke. In: Gorelick PB, Alter MA. eds. Handbook of neuroepidemiology. New York: Marcel Dekker; 1994: 77-119
• 24 Wolf PA, Cobb JL, D'Agostino RB. Epidemiology of stroke. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM. eds. Stroke: pathophysiology, diagnosis, and management. 2nd ed. New York: Churchill Livingstone; 1992: 3-27.
• 25 Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH. Familial aggregation of stroke: the Framingham Study. Stroke 1993; 24: 1366-71.
• 26 Kittner SJ, White LR, Losonczy KG, Wolf PA, Hebel R. Black-white differences in stroke incidence in a national sample. The contribution of hypertension and diabetes mellitus. JAMA 1990; 264: 1267-70.
• 27 Pullicino P, Greenberg S, Trevisan M. Genetic stroke risk factors. Curr Opin Neurol 1997; 10: 58-63.
• 28 European Carotid Surgery Trialists' Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (706–99%) or with mild (0–29%) carotid stenosis. Lancet 1991; 337: 1235-43.
• 29 North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-53.
• 30 Rothwell PM, Warlow CP. Making sense of the measurement of carotid stenosis. Cerebrovasc Dis 1996; 6: 54-8.
• 31 Rothwell PM, Slattery J, Warlow CP. Clinical and angiographic predictors of stroke and death from carotid endarterectomy: systematic review. BMJ 1997; 315: 1571-7.
• 32 Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998; 12 339: 1415-25.
• 33 Scottish Intercollegiate Guidelines Network (SIGN). Management of patients with stroke. II; Management of carotid stenosis and carotid endarterectomy. Edinburgh: SIGN; 1997 (SIGN publication no. 14.)
• 34 Hankey GJ, Slattery JM, Warlow CP. Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events?. J Neurol Neurosurg Psychiatry 1992; 55: 640-52.
• 35 Hankey GJ, Slattery JM, Warlow CP. Can the long term outcome of individual patients with transient ischaemic attacks be predicted accurately?. J Neurol Neurosurg Psychiatry 1993; 56: 752-9.
• 36 Kappelle LJ, Eliasziw M, Fox AJ, Sharpe BL, Barnett HJ. Importance of intracranial atherosclerotic disease in patients with symptomatic stenosis of the internal carotid artery. The North American Symptomatic Carotid Endarterectomy Trail. Stroke 1999; 30: 282-6.
• 37 Crawley F, Brown MM, Clifton AG. Angioplasty and stenting in the carotid and vertebral arteries. Postgrad Med J 1998; 74: 7-10.
• 38 MacWalter RS. Treatment for carotid atherosclerosis – Who should have it and who should not?. Scott Med J 1999; 44: 39-40.
• 39 Lowe GD, Jaap AJ, Forbes CD. Relationship of atrial fibrillation and high haematocrit to mortality in acute stroke. Lancet 1983; 1: 784-6.
• 40 Sandercock P, Bamford J, Dennis M, Burn J, Slattery J, Jones L, Boonya-karnkul S, Warlow C. Atrial fibrillation and stroke: prevalence in different types of stroke and influence on early and long term prognosis. BMJ 1992; 305: 1460-5.
• 41 Anonymous Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-57. [published erratum appears in Arch Intern 1994; 154: 2254]
• 42 Laupacis A, Albers G, Dalen J, Dunn M, Feinberg W, Jacobson A. Antithrombotic therapy in atrial fibrillation. Chest 1995; 108 (4 Suppl) 352-9S.
• 43 (Stroke Prevention in Atrial Fibrillation Investigators). Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-8.
• 44 Anonymous Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993; 342: 1255-62.
• 45 Anonymous The efficacy of aspirin in patients with atrial fibrillation. Analysis of pooled data from 3 randomized trials. The Atrial Fibrillation Investigators. Archives of Internal Medicine 1997; 157: 1237-40.
• 46 Royal College of Physicians of Edinburgh. Consensus Conference on Atrial Fibrillation in Hospital and General Practice. 3&4 September 1998. Scott Med J 1998; 43: 166-7.
• 47 Halperin JL, Petersen P. Thrombosis in the cardiac chambers: ventricular dysfunction and atrial fibrillation. In Cardiovascular Thromboepidemiology and Thromboneurology. 2 Ed. Eds Verstrate M, Fuster V, Topol EJ. Philadelphia: Lippincott-Raven; 1998
• 48 Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 (5 Suppl) 579-89S.
• 49 Green CJ, Hadorn DC, Bassett K, Kazanjian A. Anticoagulation in chronic nonvalvular atrial fibrillation: a critical appraisal and meta-analysis. Can J Cardiol 1997; 13: 811-5.
• 50 (Stroke Prevention in Atrial Fibrillation Investigators). Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687-91.
• 51 Scottish Intercollegiate Guidelines Network (SIGN). Antithrombotic therapy. Edinburgh: SIGN; 1999. (SIGN publication no. 36.)
• 52 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-8.
• 53 Levine HJ, Pauker SG, Eckman MH. Antithrombotic therapy in valvular heart disease. Chest 1995; 108 (4 Suppl) 360-70S.
• 54 Stein PD, Alpert JS, Dalen JE, Horstkotte D, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114 (5 Suppl) 602-10S.
• 55 Gohlke-Barwolf C, Acar J, Burckhardt D, Oakley C, Butchart E, Krayen-buhl P, Hall R, Bodnar E, Krzeminska-Pakula M, Delahaye JP. et al. Guidelines for prevention of thromboembolic events in valvular heart disease. Ad Hoc Committee of the Working Group on Valvular Heart Disease, European Society of Cardiology. J Heart Valve Dis 1993; 2: 398-410.
• 56 Jonas S. Anticoagulant therapy in cerebrovascular disease: a review and meta-analysis. Stroke 1988; 19: 1043-8.
• 57 PROGRESS Management Committee. Blood pressure lowering for the secondary prevention of stroke: rationale and design for PROGRESS. J Hypertens 1996; 14 (suppl 2) S41-S46.
• 58 Anonymous Post-stroke antihypertensive treatment study. A preliminary result. PATS Collaborating Group. Chin Med J 1995; 108: 710-7.
• 59 Amery A, Birkenhager W, Brixko P. et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; i: 1349-54.
• 60 Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester P. Morbidity and mortality in the Swedish Trial in Old Patients with hypertension (STOP-Hypertension). Lancet 1991; 338: 1281-5.
• 61 MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. British Medical Journal 1992; 304: 405-12.
• 62 Staessen JA, Fagard R, Thijs L. et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350: 757-64.
• 63 SHEP Cooperative, Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255-64.
• 64 Collins R, Peto R, MacMahon S. et al. Blood pressure, stroke, and coronary heart disease – Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335: 827-38.
• 65 MacMahon S, Peto R, Cutler J. et al. Blood pressure, stroke, and coronary heart disease – Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74.
• 66 Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755-62.
• 67 Davis TM, Millns H, Stratton IM, Holman RR, Turner RC. Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 29. Arch Intern Med 1999; 159: 1097-103.
• 68 Qizilbash N, Duffy SW, Warlos C, Mann J. Lipids are risk factors for ischemic stroke overview and review. Cerebrovasc Dis 1992; 2: 127-36.
• 69 Summary of the National Cholesterol Education Program (NCEP) Adult Treatment Panel II Report. JAMA 1993; 269: 3015-23.
• 70 Fine-Edelstein JS, Wolf PA, O'Leary DH. et al. Precursors of extracranial carotid atherosclerosis in the Framingham Study. Neurology 1994; 44: 1046-50.
• 71 Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. Stroke, Statins, and Cholesterol: A Meta-Analysis of Randomized, Placebo-Controlled, Double-Blind Trials With HMG-CoA Reductase Inhibitors. Stroke 1997; 28: 946-50.
• 72 Crouse 3rd JR, Byington RP, Hoen HM, Furberg CD. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med 1997; 157: 1305-10.
• 73 Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, Cuddy TE, Moye LA, Piller LB, Rutherford J, Simpson LM, Braunwald E. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators. Circulation 1999; 99 (2) 216-23.
• 74 Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ 1989; 298: 789-94.
• 75 Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 12 274: 155-60.
• 76 Sacco RL, Elkind M, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, Shea S, Paik MC. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 53-60.
• 77 Gorelick PB, Rodin MB, Langenberg P, Hier DB, Costigan J. Weekly alcohol consumption cigarette smoking and the risk of ischemic stroke: results of a case-control study at three urban medical centers in Chicago, Illinois. Neurology 1989; 39: 339-43.
• 78 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165-76.
• 79 Gustafsson C, Blomback M, Britton M, Hamsten A, Svensson J. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke 1990; 21: 47-51.
• 80 Tohgi H, Kawashima M, Tamura K, Suzuki H. Coagulation-fibrinolysis abnormalities in acute and chronic phases of cerebral thrombosis and embolism. Stroke 1990; 21: 1663-7.
• 81 Warner TD. Relationships between the endothelin and nitric oxide pathways. Clin Exp Pharmacol Physiol 1999; 26: 247-52.
• 82 Patrono C, Coller B, Dalen JE, Fuster V, Gent M, Harker LA, Hirsh J, Roth G. Platelet-active drugs. The relationship among dose, effectiveness, and side effects. Chest 1998; 114: 470S-88S.
• 83 Anonymous The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349: 1569-81.
• 84 Anonymous CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997; 349: 1641-9.
• 85 The SALT, Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 345-9.
• 86 The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-6.
• 87 UK-TIA Study Group. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044-54.
• 88 Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995; 332: 238-48.
• 89 Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry 1996; 60: 197-9.
• 90 Barnett H.J.M, Kaste M, Meldrum H, Eliasziw M. Aspirin dose in stroke prevention. Beautiful hypotheses slain by ugly facts. Stroke 1996; 27: 588-92.
• 91 Komiya T, Kudo M, Urabe T, at al. Compliance with antiplatelet therapy in patients with ischemic cerebrovascular disease. Stroke 1994; 25: 2337-42.
• 92 Helgason CM, Hoff JA, Kondos GT. et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331-6.
• 93 Dippel DW, The results. of CAPRIE, IST and CAST Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events. International Stroke Trial. Chinese Acute Stroke Trial. Thromb Res 1998; 92 (1 Suppl 1) S13-6.
• 94 Bousser MG, Eschwege E, Haguqnau M, Lefaucconnier JM, Thibult N, Touboul D, Touboul PJ. “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Stroke 1983; 14: 5-14.
• 95 American-Canadian Co-operative Study Group. Persantine aspirin trial in cerebral ischemia. Part II: endpoint results Stroke 1985; 16: 406-15.
• 96 Guiraud-Chaumeil B, Rascol A, David J, Boneu V, Clanet M, Biertne R. Prevention des recidives des accidents vasculaires cerebraux ischemiques par les anti-agregants plaquettaires. Resultats d'un essai therapeutique control. Rev Neurol (Paris) 1982; 138: 367-85.
• 97 Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
• 98 Muller TH, Su CAPF, Weisenberger H. et al. Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo. Br J Clin Pharmacol 1990; 30: 179-86.
• 99 Gent M, Blakely JA, Easton JD. et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-20.
• 100 Hass WK, Easton JD, Adams Jr. HP, Pryse-Phillips W, Molony BA, Anderson S, Kamm B A. randomized trial comparing ticlopidine hydro-chloride with aspirin for the prevention of stroke in high-risk patients Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321: 501-7.
• 101 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
• 102 Riddell DR, Owen JS. Nitric oxide and platelet aggregation. Vitam Horm 1999; 57: 25-48.