Prasugrel vs ticagrelor in acute coronary syndromes Giuseppe Biondi-Zoccai, MD Sapienza University of Rome, Italy giuseppe.biondizoccai@uniroma1.it

Learning goals Scope of the problem Prasugrel Ticagrelor Reconciling the evidence

Learning goals Scope of the problem Prasugrel Ticagrelor Reconciling the evidence

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

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

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

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

Treatment alternatives Tan et al, Cardiovasc Ther 2012

Learning goals Scope of the problem Prasugrel Ticagrelor Reconciling the evidence

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

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

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

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

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

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

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

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

Less clear-cut benefit in medically managed ACS patients CV death, MI, or stroke HR=0.91 (0.79-1.05), p=0.21 Wiviott et al, Circulation 2008

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

Learning goals Scope of the problem Prasugrel Ticagrelor Reconciling the evidence

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 75-100 mg/day aspirin

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

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

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

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

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

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

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

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

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

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

Learning goals Scope of the problem Prasugrel Ticagrelor Reconciling the evidence

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

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

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

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

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

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)

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

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

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.

Many thanks for your attention For these slides and further ones on similar topics feel free to visit: www.metcardio.org/slides.html For additional details or queries feel free to contact me directly: giuseppe.biondizoccai@uniroma1.it