1. Giuseppe Biondi-Zoccai gbiondizoccai@gmail.com Division of Cardiology, University of Turin, Turin, Italy

2.  Dual antiplatelet therapy with aspirin and clopidogrel is effective and safe in patients with acute coronary syndromes (ACS).  Recent data suggest a superior anti- thrombotic efficacy of both prasugrel and ticagrelor in combination to aspirin instead of clopidogrel.  However, there is yet no direct comparison of prasugrel vs. ticagrelor.

3.  We aimed to perform a systematic review and meta-analysis employing adjusted indirect comparison methods comparing prasugrel vs. ticagrelor plus aspirin in patients with ACS.

4.  We searched PubMed for: ◦ randomized clinical trials ◦ reporting on the comparison of prasugrel vs. clopidogrel or ticagrelor vs. clopidogrel ◦ in patients with ACS ◦ reporting on at least 1-month events  The primary end-point was the rate of major adverse cardiac events (MACE, ie death, myocardial infarction or stroke).

5.  Secondary end-points included components of MACE, Academic Research Consortium definite stent thrombosis, TIMI major bleeding (not related to CABG), and compliance.  Standard and adjusted indirect comparison odds ratios (OR) were computed (with 95% confidence intervals) according to Song et al, BMJ 2003;326:472.

6.  From 289 initial citations, 3 trials were finally retrieved, enrolling 32,893 patients.  Either prasugrel or ticagrelor appeared superior to clopidogrel for 9-month death (OR=0.83 [0.74-0.93], p<0.001), myocardial infarction (OR=0.79 [0.73-0.86], p<0.001), MACE (OR=0.83 [0.77- 0.89], p<0.001), and stent thrombosis (OR=0.55 [0.45-0.68], p<0.001).  No differences in stroke (OR=0.90 [0.73-1.11], p=0.320) were found, despite more bleedings (OR=1.28 [1.09-1.49], and discontinuation (OR=1.08 [1.02-1.15], p=0.01).

7.  Head-to-head comparison of prasugrel vs. ticagrelor showed no significant differences in the risk of death (OR=1.22 [0.96-1.55], p=0.106), myocardial infarction (OR=0.89 [0.75- 1.06], p=0.202), stroke (OR=1.19 [0.77-1.84], p=0.441), MACE (OR=0.99 [0.86-1.13], p=0.862), stent thrombosis (OR=0.71 [0.47- 1.09], p=0.115), or major bleeding (OR=1.06 [0.77-1.45], p=0.738).  Conversely, treatment discontinuation was more frequent with ticagrelor (OR=0.85 [0.72-1.00], p=0.053).

8. Funnel plots comparing prasugrel or ticagrelor vs. clopidogrel for the risk of: death, myocardial infarction or stroke (A); death (B); myocardial infarction (C); stroke (D); definite or probable stent thrombosis (E).

9. Funnel plots comparing prasugrel or ticagrelor vs. clopidogrel for the risk of: major bleeding (A); major non-CABG bleeding (B); major CABG-bleeding (C); any bleeding (D); minor bleeding (E); discontinuation (F)

10. Funnel plots comparing prasugrel vs. ticagrelor for the risk of key clinical events. Odds ratios (OR) 1.0 favor ticagrelor.

11.  New antiplatelet agents such as prasugrel and ticagrelor are both more potent than clopidogrel for patients with ACS.  Head-to-head comparison suggests that they are largely similar in efficacy and safety, even if prasugrel appears more tolerated than ticagrelor.