1. Prasugrel vs ticagrelor in acute coronary syndromes
Giuseppe Biondi-Zoccai, MD
Sapienza University of Rome, Italy

2. Learning goals Scope of the problem Prasugrel Ticagrelor
Reconciling the evidence

3. Learning goals Scope of the problem Prasugrel Ticagrelor
Reconciling the evidence

4. The platelet: our common foe
Anticoagulants
PAR inhibitors
<-
<-
<- Aspirin
P2Y12
inhibitors
<-
<-
IIb/IIIa
inhibitors
Jackson et al, Nat Rev Drug Discov 2003

5. Aspirin Oral drug Irreversibly inactivates cyclooxygenase
Inhibits production of thromboxane A2 (TXA)
Limits TXA-mediated platelet activation and aggregation
Does not impact on other activation pathways and has highly variable response

6. Clopidogrel
Oral drug
Irreversibly inactivates the P2Y12 platelet receptor for ADP
Limits P2Y12-mediated platelet activation and aggregation
Does not impact on other activation pathways and has highly variable response

7. State-of-the-art aspirin plus clopidogrel Rx
Clopidogrel 600 mg loading, then 150 mg/day for 6 days followed by 75 mg/day
Clopidogrel 300 mg loading , then 75 mg/day
CV death, MI, or stroke
Mehta et al, Lancet 2010

8. Treatment alternatives
Tan et al, Cardiovasc Ther 2012

9. Learning goals Scope of the problem Prasugrel Ticagrelor
Reconciling the evidence

10. Prasugrel
Oral drug
Irreversibly inactivates the P2Y12 platelet receptor for ADP (more potently and predictably than clopidogrel)
Limits P2Y12-mediated platelet activation and aggregation
Does not impact on other activation pathways
60 mg loading, 10 mg maintenance (5 mg if >75 years or <60 kg)
Aspirin dose is irrelevant

11. Clopidogrel, prasugrel and ticagrelor
Tan et al, Cardiovasc Ther 2012

12. Prasugrel has an established and favorable risk-benefit profile
Wiviott et al, New Engl J Med 2008

13. Risk stratification is of course key
Montalescot et al, Lancet 2009

14. Dose adjustment is possible
Erlinge et al, J Am Coll Cardiol 2012

15. Loading with both clopidogrel and prasugrel is not prohibitive
Loh et al, Am J Cardiol 2013

16. Particularly risk-beneficial in diabetics
Wiviott et al, Circulation 2008

17. Wiviott et al, Circulation 2008
And even more so in IDDM
Wiviott et al, Circulation 2008

18. Less clear-cut benefit in medically managed ACS patients
CV death, MI, or stroke
HR=0.91 ( ), p=0.21
Wiviott et al, Circulation 2008

19. Last but not least
Are you afraid of increased neoplastic risk after assuming prasugrel?
Do you know how long does it take to develop cancer after you are exposed to a nuclear bomb (e.g. Hiroshima)?
Any purported association between prasugrel and cancer risk in TRITON-TIMI 38 patently lacks biologic plausibility

20. Learning goals Scope of the problem Prasugrel Ticagrelor
Reconciling the evidence

21. Ticagrelor
Oral drug
Reversibly antagonizes the P2Y12 platelet receptor for ADP
Thus limits P2Y12-mediated platelet activation and aggregation
Does not impact on other activation pathways
180 mg load, 90 mg x 2/day maintenance
Must be associated with mg/day aspirin

22. Clopidogrel, prasugrel and ticagrelor
Tan et al, Cardiovasc Ther 2012

23. Steadily increasing benefit in all ACS
Wallentin et al, New Engl J Med 2009

24. Remarkable safety profile vs clopidogrel
Wallentin et al, New Engl J Med 2009

25. Benefits across the board
All patients*
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
HR for (95% CI)
p value
Primary objective, n (%)
CV death + MI + stroke
864 (9.8)
1,014 (11.7)
0.84 (0.77–0.92)
<0.001
Secondary objectives, n (%)
Total death + MI + stroke
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
CV death
Stroke
901 (10.2)
1,290 (14.6)
504 (5.8)
353 (4.0)
125 (1.5)
1,065 (12.3)
1,456 (16.7)
593 (6.9)
442 (5.1)
106 (1.3)
0.88 (0.81–0.95)
0.84 (0.75–0.95)
0.79 (0.69–0.91)
1.17 (0.91–1.52)
0.005
0.001
0.22
Total death
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
Wallentin et al, New Engl J Med 2009

26. Non-CABG bleeding also ↑ by ticagrelor
Wallentin et al, New Engl J Med 2009

27. But this is offset by ↓ CABG-related bleeds
Cannon et al, Lancet 2010

28. Are bradyarrhythmias major issues?
Holter monitoring at first week
Ticagrelor
(n=1,451)
Clopidogrel
(n=1,415)
p value
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
5.8
2.0
3.6
1.2
0.01
0.10
Holter monitoring at 30 days
(n= 985)
(n=1,006)
2.1
0.8
1.7
0.6
0.52
0.60
Bradycardia-related event, %
(n=9,235)
(n=9,186)
Pacemaker Insertion
Syncope
Bradycardia
Heart block
0.9
1.1
4.4
0.7
4.0
0.87
0.08
0.21
1.00
Wallentin et al, New Engl J Med 2009

29. What about dyspnea and cancer?
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
P value
Dyspnoea, %
Any
With discontinuation of study treatment
13.8
0.9
7.8
0.1
<0.001
Neoplasms arising during treatment, %
Malignant
Benign
1.4
1.2
0.2
1.7
1.3
0.4
0.17
0.69
0.02
Wallentin et al, New Engl J Med 2009

30. What about creatinine and uric acid?
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
P value*
% increase in creatinine from baseline
At 1 month
At 12 months
Follow-up visit
10  22
11  22
8  21
9  22
<0.001
0.59
% increase in uric acid from baseline
14  46
15  52
7  43
7  44
7  31
8  48
0.56
Wallentin et al, New Engl J Med 2009

31. Benefits are highly consistent but…
Cannon et al, Lancet 2010

32. Learning goals Scope of the problem Prasugrel Ticagrelor
Reconciling the evidence

33. Biondi-Zoccai et al, Int J Cardiol 2011
First and foremost: both prasugrel and ticagrelor are lifesaving vs clopidogrel
Biondi-Zoccai et al, Int J Cardiol 2011

34. Adjusted indirect comparison
Biondi-Zoccai et al, Int J Cardiol 2011

35. Adjusted indirect comparison
Biondi-Zoccai et al, Int J Cardiol 2011

36. Adjusted indirect comparison
Biondi-Zoccai et al, Int J Cardiol 2011

37. Do you trust platelet responsiveness assays?
Alexopoulos et al, J Am Coll Cardiol 2012

38. Biondi-Zoccai et al, BMJ 2008 (but also Gurbel et al, JAMA 2012;
I personally don’t
Biondi-Zoccai et al, BMJ 2008 (but also Gurbel et al, JAMA 2012;
Collet et al, NEJM 2012; Gaglia et al, Cardiovasc Revasc Med 2013; etc)

39. Alexopoulos et al, Circ Cardiovasc Interv 2012
Even if you believe…
Alexopoulos et al, Circ Cardiovasc Interv 2012

40. Reconciling the evidence
Biondi-Zoccai et al, Curr Vasc Pharmacol 2012

41. Take home messages
Both prasugrel and ticagrelor are superior to clopidogrel in acute coronary syndromes.
Prasugrel is best avoided in those at moderately high or high bleeding risk (e.g. prior stroke/TIA) or when coronary intervention is not likely. A 5 mg/day dose should be used in the elderly or for weight <60 kg.
Ticagrelor is best avoided in those at high bleeding risk, and must be associated with low-dose aspirin.
Awaiting the ACCOAST trial, ticagrelor appears more appealing than prasugrel for NSTEACS if antiplatelet Rx is to be instituted in the ER, but equipoise holds for STEMI.

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