Prasugrel vs ticagrelor in acute coronary

syndromes

Giuseppe Biondi-Zoccai, MD

Sapienza University of Rome, Italygiuseppe.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<- 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

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