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Prasugrel vs ticagrelor in acute coronary syndromes Giuseppe Biondi-Zoccai, MD Sapienza University of Rome, Italy [email protected]
Prasugrel vs ticagrelor in acute coronary
syndromesGiuseppe Biondi-Zoccai, MD
Sapienza University of Rome, [email protected]
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<- Aspirin
<-
<-
PAR inhibitors
<-
P2Y12inhibitors
<-Anticoagulants
IIb/IIIainhibitors
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 RxCV
dea
th, M
I, or
stro
ke
Mehta et al, Lancet 2010
Clopidogrel 600 mg loading, then 150 mg/day for 6 days followed by 75 mg/day
Clopidogrel 300 mg loading , then 75 mg/day
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
And even more so in IDDM
Wiviott et al, Circulation 2008
Less clear-cut benefit in medically managed ACS patients
Wiviott et al, Circulation 2008
CV d
eath
, MI,
or st
roke
HR=0.91 (0.79-1.05), p=0.21
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
Wallentin et al, New Engl J Med 2009
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)
0.84 (0.77–0.92)
0.88 (0.81–0.95)
0.84 (0.75–0.95) 0.79 (0.69–0.91)1.17 (0.91–1.52)
<0.001
<0.001
0.005 0.001 0.22
Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001
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?
Wallentin et al, New Engl J Med 2009
Holter monitoring at first weekTicagrelor(n=1,451)
Clopidogrel(n=1,415) p value
Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, %
5.82.0
3.61.2
0.010.10
Holter monitoring at 30 daysTicagrelor(n= 985)
Clopidogrel(n=1,006) p value
Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, %
2.10.8
1.70.6
0.520.60
Bradycardia-related event, %Ticagrelor(n=9,235)
Clopidogrel(n=9,186) p value
Pacemaker Insertion Syncope Bradycardia Heart block
0.91.14.40.7
0.90.84.00.7
0.870.080.211.00
What about dyspnea and cancer?
Wallentin et al, New Engl J Med 2009
All patientsTicagrelor(n=9,235)
Clopidogrel(n=9,186)
P value
Dyspnoea, % Any With discontinuation of study treatment
13.80.9
7.80.1
<0.001<0.001
Neoplasms arising during treatment, % Any Malignant Benign
1.4 1.2 0.2
1.7 1.3 0.4
0.170.690.02
What about creatinine and uric acid?
Wallentin et al, New Engl J Med 2009
All patientsTicagrelor(n=9,235)
Clopidogrel(n=9,186)
P value*
% increase in creatinine from baseline At 1 month At 12 months Follow-up visit
10 2211 2210 22
8 219 22
10 22
<0.001<0.001
0.59
% increase in uric acid from baseline At 1 month At 12 months Follow-up visit
14 4615 527 43
7 447 31 8 48
<0.001<0.001
0.56
Benefits are highly consistent but…
Cannon et al, Lancet 2010
Learning goals
• Scope of the problem• Prasugrel• Ticagrelor• Reconciling the evidence
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
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)
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
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