J Clin Neurol.  2015 Jan;11(1):57-65. 10.3988/jcn.2015.11.1.57.

Low-Molecular-Weight Heparin or Dual Antiplatelet Therapy Is More Effective Than Aspirin Alone in Preventing Early Neurological Deterioration and Improving the 6-Month Outcome in Ischemic Stroke Patients

• Yi X
• Chi W
• Wang C
• Zhang B
• Lin J

• KMID: 2179573
• DOI: http://doi.org/10.3988/jcn.2015.11.1.57

Abstract

BACKGROUND AND PURPOSE
Dual antiplatelet therapy (DAT) with clopidogrel and aspirin has been shown to confer greater protection against early neurological deterioration (END) and early recurrent ischemic stroke (ERIS) than aspirin alone in patients who have experienced an acute ischemic stroke. However, few studies have compared the effects of anticoagulation therapy with low-molecular-weight heparin (LMWH), DAT, and aspirin.
METHODS
Patients with acute ischemic stroke (n=1,467) were randomized to therapy groups receiving aspirin (200 mg daily for 14 days, followed by 100 mg daily for 6 months), DAT (200 mg of aspirin and 75 mg of clopidogrel daily for 14 days, then 100 mg of aspirin daily for 6 months), or LMWH (4,000 antifactor Xa IU of enoxaparin in 0.4 mL subcutaneously twice daily for 14 days, followed by 100 mg of aspirin daily for 6 months). The effects of these treatment strategies on the incidence of END, ERIS, and deep-vein thrombosis (DVT) were observed for 10-14 days after treatment, and their impacts on a good outcome were evaluated at 6 months.
RESULTS
The DAT and LMWH were associated with a more significant reduction of END and ERIS within 14 days compared with aspirin-alone therapy. In addition, LMWH was associated with a significantly lower incidence of DVT within 14 days. At 6 months, DAT or LMWH improved the outcome among patients aged >70 years and those with symptomatic stenosis in the posterior circulation or basilar artery compared with aspirin.
CONCLUSIONS
LMWH or DAT may be more effective than aspirin alone for reducing the incidence of END and ERIS within 14 days, and is associated with improved outcomes in elderly patients and those with stenosis in the posterior circulation or basilar artery at 6 months poststroke.

Keyword

acute ischemic stroke; low-molecular-weight heparin; dual antiplatelet therapy; outcomes; early neurological deterioration

MeSH Terms

Aged
Aspirin*
Basilar Artery
Constriction, Pathologic
Enoxaparin
Heparin, Low-Molecular-Weight*
Humans
Incidence
Stroke*
Venous Thrombosis
Aspirin
Enoxaparin
Heparin, Low-Molecular-Weight

Figure

• 

  Fig. 1 General profile of the study. DAT: dual antiplatelet therapy, LMWH: low-molecular-weight heparin.

Reference

1. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997; 349:1641–1649.

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

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

4. Schwammenthal Y, Tsabari R, Shenkman B, Schwartz R, Matetzky S, Lubetsky A, et al. Aspirin responsiveness in acute brain ischaemia: association with stroke severity and clinical outcome. Cerebrovasc Dis. 2008; 25:355–361.

5. Yi X, Zhou Q, Lin J, Chi L. Aspirin resistance in Chinese stroke patients increased the rate of recurrent stroke and other vascular events. Int J Stroke. 2013; 8:535–539.

6. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107:2908–2913.

7. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008; 359:1238–1251.

8. Herbert JM, Dol F, Bernat A, Falotico R, Lalé A, Savi P. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost. 1998; 80:512–518.

9. Makkar RR, Eigler NL, Kaul S, Frimerman A, Nakamura M, Shah PK, et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J. 1998; 19:1538–1546.

10. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345:494–502.

11. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288:2411–2420.

12. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354:1706–1717.

13. SPS3 Investigators. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012; 367:817–825.

14. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, 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, placebo-controlled trial. Lancet. 2004; 364:331–337.

15. Wong KS, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010; 9:489–497.

16. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005; 111:2233–2240.

17. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007; 6:961–969.

18. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013; 369:11–19.

19. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995; 333:1588–1593.

20. Wang QS, Chen C, Chen XY, Han JH, Soo Y, Leung TW, et al. Low-molecular-weight heparin versus aspirin for acute ischemic stroke with large artery occlusive disease: subgroup analyses from the Fraxiparin in Stroke Study for the treatment of ischemic stroke (FISS-tris) study. Stroke. 2012; 43:346–349.

21. Qureshi AI, Ziai WC, Yahia AM, Mohammad Y, Sen S, Agarwal P, et al. Stroke-free survival and its determinants in patients with symptomatic vertebrobasilar stenosis: a multicenter study. Neurosurgery. 2003; 52:1033–1039. discussion 1039-1040.

22. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA. 1998; 279:1265–1272.

23. Adams HP Jr, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999; 53:122–125.

24. Bath PM, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet. 2001; 358:702–710.

25. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke. 1995; 26:14–20.

26. Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke. 2009; 40:e443–e450.

27. Nolte CH, Albach FN, Heuschmann PU, Brunecker P, Villringer K, Endres M, et al. Silent new DWI lesions within the first week after stroke. Cerebrovasc Dis. 2012; 33:248–254.

28. Yi X, Lin J, Wang C, Zhang B, Chi W. Low-molecular-weight heparin is more effective than aspirin in preventing early neurologic deterioration and improving six-month outcome. J Stroke Cerebrovasc Dis. 2014; 23:1537–1544.

29. Yi X, Lin J, Wang C, Zhang B, Chi W. A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. J Stroke Cerebrovasc Dis. 2014; 23:1975–1981.

30. Han SW, Kim SH, Lee JY, Chu CK, Yang JH, Shin HY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol. 2007; 57:96–102.

31. Wong KS, Lam WW, Liang E, Huang YN, Chan YL, Kay R. Variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis. Stroke. 1996; 27:1084–1087.

32. Wong KS, Li H, Chan YL, Ahuja A, Lam WW, Wong A, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke. 2000; 31:2641–2647.

33. Guidelines writing group. Chinese acute ischemic stroke management guideline. Chin J Neurol. 2010; 43:1–8.

34. Wang Q, Chen C, Chen XY, Han JH, Soo Y, Leung TW, et al. Low-molecular-weight heparin and early neurologic deterioration in acute stroke caused by large artery occlusive disease. Arch Neurol. 2012; 69:1454–1460.

35. Awadh M, MacDougall N, Santosh C, Teasdale E, Baird T, Muir KW. Early recurrent ischemic stroke complicating intravenous thrombolysis for stroke: incidence and association with atrial fibrillation. Stroke. 2010; 41:1990–1995.

36. Yi X, Lin J, Han Z, Zhou X, Wang X, Lin J. The incidence of venous thromboembolism following stroke and its risk factors in eastern China. J Thromb Thrombolysis. 2012; 34:269–275.

37. Wang Y, Johnston SC. CHANCE Investigators. Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event. Am Heart J. 2010; 160:380–386.e1.

38. Wong KS, Chen C, Ng PW, Tsoi TH, Li HL, Fong WC, et al. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study. Lancet Neurol. 2007; 6:407–413.

39. Park KY, Chung CS, Lee KH, Kim GM, Kim YB, Oh K. Prevalence and risk factors of intracranial atherosclerosis in an asymptomatic Korean population. J Clin Neurol. 2006; 2:29–33.

40. Turan TN, Makki AA, Tsappidi S, Cotsonis G, Lynn MJ, Cloft HJ, et al. Risk factors associated with severity and location of intracranial arterial stenosis. Stroke. 2010; 41:1636–1640.

41. Lavallée PC, Labreuche J, Faille D, Huisse MG, Nicaise-Roland P, Dehoux M, et al. Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease. Cerebrovasc Dis. 2013; 36:131–138.

42. Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology. 2000; 55:490–497.

43. Kasner SE, Lynn MJ, Chimowitz MI, Frankel MR, Howlett-Smith H, Hertzberg VS, et al. Warfarin vs aspirin for symptomatic intracranial stenosis: subgroup analyses from WASID. Neurology. 2006; 67:1275–1278.

44. Bogousslavsky J, Regli F, Maeder P, Meuli R, Nader J. The etiology of posterior circulation infarcts: a prospective study using magnetic resonance imaging and magnetic resonance angiography. Neurology. 1993; 43:1528–1533.

45. Kim JS, Nah HW, Park SM, Kim SK, Cho KH, Lee J, et al. Risk factors and stroke mechanisms in atherosclerotic stroke: intracranial compared with extracranial and anterior compared with posterior circulation disease. Stroke. 2012; 43:3313–3318.