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#105 The new anti-platelet ticagrelor: Is it better than the old “new” clopidogrel?


CLINICAL QUESTION
How does the newer anti-platelet drug ticagrelor (Brillinta®) compare to clopidogrel for post-acute coronary syndrome (ACS)?

BOTTOM LINE
After ACS, ticagrelor reduces combined cardiovascular death, stroke, and myocardial infarction (MI) about 2% more than clopidogrel. Ticagrelor increases a few adverse events, particularly 6% more dyspnea, and effectiveness remains uncertain in North America.  


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EVIDENCE
PLATO, multinational Randomized Controlled Trial (RCT) of 18,624 patients hospitalized for ACS +/- ST elevation, comparing ticagrelor vs. clopidogrel (both with usual care including ASA) for 12 months maximum,1,2 found statistically significant reduction in: 
  • Primary endpoint (composite of cardiovascular death, MI, or stroke), Number Needed to Treat (NNT) 53. 
  • Other outcomes better: 
    • Recurrent MI: NNT 91. 
    • Death from vascular causes: NNT 91. 
    • Death from any cause: NNT 71. 
    • No significant difference in stroke. 
  • Adverse reactions: 
    • No significant difference in any bleeding except: 
      • Bleeding worse when coronary artery bypass patients excluded, Number Needed to Harm (NNH) 143. 
      • Worse fatal intracranial hemorrhage, NNH 926. 
    • Any dyspnea, NNH 17; Requiring discontinuation, NNH 125. 
    • Non-fatal arrhythmias (ventricular pauses) were significantly increased with ticagrelor as well.3 
  • Subgroup analysis of 1,800 patients in PLATO from North America showed much less favourable results: mortality was actually lower in clopidogrel group at 12 months.2,3 
  Context: 
  • Ticagrelor has several theoretical benefits over clopidogrel: it is a reversible platelet inhibitor, hepatic metabolism not required for activation (less intra-individual variability in response), and faster onset/offset of action.3,4 
  • Benefits of ticagrelor seem maintained in higher risk groups like those with renal insufficiency5 and diabetes.6 
    • Ticagrelor proposed as an alternative in clopidogrel non-responders.7 
  • Unanswered concerns: 
    • No clear explanation why ticagrelor worse in North America.8 
    • Dyspnea unexplained3 but is not associated with structural cardiac damage or pulmonary function test abnormalities.9,10 
  • Ticagrelor is significantly more expensive than clopidogrel ($310/90 days vs. $100/90 days)11 and requires twice-daily dosing. 
  • Given the cost, increased harms, and uncertainty around effectiveness in North America, clinicians should: 
    • Consider clopidogrel a reasonable alternative in intolerant patients started on ticagrelor in hospital. 
January 20, 2014

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Author(s):

  • G. Michael Allan MD CCFP
  • Marco Mannarino MD CCFP
  • Ricky D. Turgeon BSc(Pharm) ACPR PharmD

1. Wallentin L, Becker RC, Budaj A, et al. N Engl J Med. 2009; 361:1045–57.

2. Bates ER. ACP J Club. 2009; 151(6):JC6-4.

3. Steiner JB, Wu Z, Ren J. ClinExpPharmacol Physiol. 2013 Jul; 40(7):398–403.

4. Gurbel PA, Bliden KP, Butler K, et al. Circulation. 2009; 120:2577–85.

5. James S, Budaj A, Aylwad P, et al. Circulation. 2010; 122:1056–67.

6. Saucedo JF. Prim Care Diabetes. 2012; 6:167–77.

7. Gurbel PA, Bliden KP, Butler K, et al. Circulation. 2010; 121:1188–99.

8. Gaglia, MA Jr, Waksman R. Circulation. 2011;123:451–6.

9. Storey RF, Bliden KP, Shankar BP, et al. J Am CollCardiol. 2010; 56:185–93.

10. Butler K, Maya J, Teng R. Curr Med Res Opin. 2013; 29(5):569–77.

11. Kolber MR, Lee J, Nickonchuk T. Price Comparison. Accessed online at: http://www.acfp.ca/Portals/0/docs/ACFPPricing2013FINAL_Feb27.pdf

Authors do not have any conflicts of interest to declare.