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#109 Anti-platelets after stroke: Are two better than one?


CLINICAL QUESTION
In non-cardioembolic ischemic stroke, should we treat with two anti-platelet agents (like adding dipyridamole or clopidogrel to ASA) or just one?

BOTTOM LINE
Evidence supports using single agent (ASA or clopidogrel) after stroke or transient ischemic attack. Some evidence favours combined dipyridamole and ASA (DP-ASA, Aggrenox®) but new results question this benefit.   


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EVIDENCE
Over ten meta-analyses examine dual vs. single anti-platelet in secondary stroke prevention.1-10  
  • Interpretation challenged by: inconsistent results, different endpoints, and different inclusion criteria. 
  • DP-ASA vs. ASA: 
    • Stroke: statistically significant relative risk reduction ~20% with combination.1,8 
      • Number Needed to Treat (NNT) 100 over 3.5 years.11 
    • No difference in major bleeds.1,5 
    • Discontinuation due to headache more common with DP-ASA.  
      • Number Needed to Harm (NNH) 16 over two years.12 
    • New Randomized Controlled Trial (RCT) showed increased stroke with DP-ASA, hazard ratio 1.52 (95% confidence interval: 1.01-2.29).13 
  • Clopidogrel + ASA vs. clopidogrel (one RCT):14 
    • Similar efficacy for stroke prevention. 
    • Major bleeds doubled with combination (NNH 76). 
  • Clopidogrel + ASA vs. ASA: 
    • Similar efficacy1,2 except:   
      • Recent Chinese RCT: possible reduced stroke5 (NNT 29 over 90 days) when clopidogrel added for 21 days in acute stroke.15 
    • Similar bleeding1,4-6 except:  
      • One RCT: Possible increased major bleeding (NNH 100) and death (NNH 142) over 3.4 years with combination.16 
  • Clopidogrel vs. DP-ASA (one RCT):17 
    • Similar efficacy, less major bleeding with clopidogrel (NNH 200 over 2.5 years). 
Context: 
  • ASA alone is effective, with statistically significant relative risk reduction in:1,18 
    • Stroke ~20%; estimated NNT 79 over 6-12 months. 
    • Major vascular events ~25%. 
  • Clopidogrel alone has similar efficacy to ASA alone in stroke.19 
  • Guidelines recommend either ASA, DP-ASA, or clopidogrel.20 
    • This reflects present evidence (and its inconsistency). 
  • Costs per 90 days: ASA $5, clopidogrel $71, DP-ASA $94. 
March 17, 2014

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Author(s):

  • Adrienne J Lindblad BSP ACPR PharmD
  • G. Michael Allan MD CCFP

1. Malloy RJ, Kanaan AO, Silva MA, et al. Clin Ther. 2013; 35(10):1490-1500.e7.

2. Thijs V, Lemmens R, Fieuws S. Eur Heart J. 2008; 29(9):1086-92.

3. Lee M, Saver JL, Hong KS, et al. Ann Intern Med. 2013; 159(7):463-70.

4. Huang Y, Li M, Li JY, et al. PLoS One. 2013; 8(6):e65754.

5. Wong KS, Wang Y, Leng X, et al. Circulation. 2013; 128(15):1656-66.

6. Geeganage CM, Diener HC, Algra A, et al. Stroke. 2012; 43(4):1058-66.

7. De Schryver EL, Algra A, van Gijn J. Cochrane Database Syst Rev. 2007; (3):CD001820.

8. Verro P, Gorelick PB, Nguyen D. Stroke. 2008; 39(4):1358-63.

9. Sudlow CL, Mason G, Maurice JB, et al. Cochrane Database Syst Rev. 2009; (4):CD001246.

10. O'Donnell MJ, Hankey GJ, Eikelboom JW. Stroke. 2008 May; 39(5):1638-46.

11. ESPRIT Study Group. Lancet. 2006; 367:1665-73.

12. Diener HC, Cunha L, Forbes C, et al. J Neurol Sci. 1996; 143:1-13.

13. Uchiyama S, Ikeda Y, Urano Y, et al. Cerebrovasc Dis. 2011; 31:601-13.

14. Diener HC, Bogousslavsky J, Brass LM, et al. Lancet. 2004; 364:331-7.

15. Wang Y, Wang Y, Zhao X, et al. New Engl J Med. 2013; 369:11-9.

16. SPS3 Investigators, Benavente OR, Hart RG, et al. New Engl J Med. 2012; 367:817-25.

17. Sacco RL, Diener Hc, Yusuf S, et al. New Engl J Med. 2008; 359;1238-51.

18. Sandercock PA, Counsell C, Gubitz GJ, et al. Cochrane Database Syst Rev. 2008; (3):CD000029.

19. CAPRIE Steering Committee. Lancet. 1996; 398:1329-39.

20. Coutts S, Kelloway L, on behalf of the Prevention of Stroke Writing Group. Chapter 2: Prevention of Stroke. In Lindsay MP, Gubitz G, Bayley M, and Phillips S (Editors) on behalf of the Canadian Stroke Best Practices and Standards Working Group. Canadian Best Practice Recommendations for Stroke Care: 2012; Ottawa, Ontario Canada: Canadian Stroke Network.

Authors do not have any conflicts of interest to declare.