New p2y12 blockers is the best anti platelet agent for patients undergoing PCI

Dual Antiplatelet Therapy is a Cornerstone of ACS Treatment • Dual antiplatelet therapy with ASA and P2Y12 inhibition has been shown to be effective for secondary prevention in ACS pati

Dr Tan Huay Cheem

MBBS, M Med(Int Med), FRCP(UK), FAMS, FACC, FSCAI Director, National University Heart Centre, Singapore (NUHCS) Associate Professor of Medicine, Yong Loo Lin School of Medicine

National University of Singapore President, Asia Pacific Society of Interventional Cardioloogy

New P2Y12 Blockers is the Best Anti-platelet agent

for Patients Undergoing PCI

14 th Vietnam National Congress of Cardiology

Da Nang City Vietnam 2014

Great Debates on Antiplatelet and Anticoagualant Therapies

Debate At Medical Meetings

Humorous discussion for

the entertainment

of the audience with

little or no significant

scientific content

Do Not Be Misled!!

Do Not Turn blind eye to Current Evidence!

Proper Interpretation of Trial Evidence

Milestones in ACS Management Anti-thrombin Rx

Dual Antiplatelet Therapy is a Cornerstone of ACS Treatment

• Dual antiplatelet therapy with ASA and P2Y12 inhibition has been shown

to be effective for secondary prevention in ACS patients

• Clopidogrel has been core of post-ACS treatment

CURE Investigators N Engl J Med 2001; 345: 494-502

COMMIT Investigators Lancet 2005; 366: 1607-21

Current Dual Antiplatelet Regimen

Why Not Clopidogrel?

Variability in Clopidogrel Response

Change in ADP-Induced platelet

aggregation 75 mg chronic dosing

Time from loading dose to cath (h)

Maximal aggregation 5µmol/L ADP (%) following 600 mg loading dose

Metabolism of P2Y12 Inhibitors

Albert Schömig et al NEJM 2009

Clopidogrel Resistance Among Asians:

Prevalence of CYP2C19 Polymorphisms in 300 Asian Subjects

• Loss-of-function – 1 or more *2/*3 Alleles

• Gain-of-function – 1 or more *17 alleles

CYP2C19*2 and *3 loss-of-function polymorphisms and low prevalence of the CYP2C19*17

with a lower prevalence of loss-of-function polymorphisms but a higher prevalence of the

*17 gain-of-function polymorphism

Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542

Clopidogrel Pharmacogenetic Differences

Among 3 Major Asian Ethnicities

CYP2C19 Poor Metabolisers CYP2C19 *2 or *3

CYP2C19 Normal Metabolisers CYP2C19 WT or combination *2/*3 and *17 CYP2C19 Rapid Metaboliser CYP2C19 *17

Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542

CYP2C19 and Clopidogrel Response

RM= rapid metaboliser NM= normal metaboliser PM= poor metaboliser

CYP2C19 only accounts for 17% of variability in

on-clopidogrel platelet reactivity

Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542

10 min Post-PCI

Angiolillo DJ et al Thromb Res 2005; 115: 101-8

New P2Y12 Receptor Antiplatelet Agents

• Prasugrel

• Ticagrelor

Prasugrel vs Clopidogrel: More Effective Platelet P2Y12 Inhibition

Time Post-dose (Day/Hour)

• More rapid

• More potent

• More consistent platelet

inhibition

• Less frequent “resistance”

• More efficient generation of

its active metabolite

IPA in Healthy Subjects

1 Wiviott SD et al Am Heart J 2006; 152-627

2 Payne CD et al Am J Cardiol 2006; 98: S8

TRITON TIMI 38 Main Trial Design

1o endpoint: CV death, MI, stroke

2o endpoint: Stent thrombosis

Safety endpoints: TIMI major bleeds, life-threatening bleeds

Duration of therapy: 6–15 months

TRITON TIMI 38: Balance of Efficacy and Safety

Wiviott SD et al N Engl J Med 2007; 357: 2001 15

TRITON TIMI 38 Bleeding Events (n=13 457)

Wiviott SD et al N Engl J Med 2007; 357: 2001 15

Ticagrelor

• New chemical class of P2Y12 inhibitors

- Cyclo-pentyl-triazole-pyrimidine (CPTP): not a thienopyridine or ATP analogue

- Inhibits adenosine reuptake

• Direct-acting

- Not a prodrug; does not require metabolic activation

- Onset (within 2 hours); peak plasma levels within 2-3 hours

- Greater and more consistent inhibition of platelet aggregation vs clopidogrel

• Reversibly bound

- Degree of inhibition reflects plasma concentration

- Offset of effect (36-48 hours)

- Functional recovery of all circulating platelets

Onset/Offset: Inhibition of Platelet Aggregation

Ticagrelor IPA at day 3 (72hrs) post dosing was similar

to clopidogrel IPA at day 5 (120hrs) post dosing

Gurbel PA et al Circulation 2009; 120: 2577-2585

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

Clopidogrel

If pre-treated, no additional loading dose;

if naive, standard 300 mg loading dose,

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)

Clopidogrel-treated or -naive;

randomised within 24 hours of index event

(N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;

CV = cardiovascular; TIA = transient ischaemic attack

PLATO Study Design

Wallentin L et al N Engl J Med 2009; 361:1045-1057

PLATO: Planned Invasive vs Medically Managed Patients

Other (n = 53)

Unknown (n = 7) STEMI (n = 233)

James SK et al BMJ 2011; 342: 3527

Unstable angina

(n = 676)

Unstable angina (n = 873)

PLATO: Time to First Primary Efficacy Event (Composite of CV Death, MI or Stroke)

*Excludes patients with any primary event during the first 30 days

PLATO: Primary Efficacy Endpoint Over Time

(Composite of CV Death, MI or Stroke)

Wallentin L et al N Engl J Med 2009; 361:1045-1057

PLATO: Hierarchical Testing of Major Efficacy Endpoints

(n=9333)

Clopidogrel (n=9291)

HR for ticagrelor (95%

CI)

Primary endpoint, n (%/year)

Secondary endpoints, n (%/yr)

CV death + MI + stroke + severe

recurrent ischemia + recurrent ischemia

+ TIA + arterial thrombus

1290 (14.6) 1456 (16.7) 0.88 (0.81-0.95) <0.001

Wallentin L et al N Engl J Med 2009; 361:1045-1057

PLATO Invasive Primary endpoint: CV Death, MI or Stroke

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Cannon CP et al Lancet 2010; 375: 283-293

Myocardial infarction Cardiovascular death

PLATO Incidence of Stent Thrombosis:

Patients with Planned Invasive Treatment

*Intent for invasive or medical management declared prior to randomization

Patients with intent for invasive

treatment*

Ticagrelor (n=6732)

Clopidogrel (n=6676)

HR for ticagrelor (95% CI) P value

Wallentin L et al N Engl J Med 2009; 361:1045-1057

PLATO: Major Bleeding Complications

Platelet Response to Clopidogrel Is Attenuated in Diabetic Patients

Undergoing Coronary Stent Implantation

32

ADP aggregation after a 600-mg clopidogrel loading dose

Geisler T et al Diabetes Care 2007; 30: 372 - 374

Increased Risk of Ischaemic Events in Diabetic Patients

Increased risk for diabetics

1.0

Adapted from James S et al Eur Heart J 2010; 31: 3006–3016

Days after randomisation

HR (95% CI) = 0.88(0.76–1.03)

No Diabetes

Ticagrelor (n=6999) Clopidogrel (n=6952)

Primary endpoint benefits with ticagrelor consistent with the overall PLATO trial

No interaction between diabetes status and treatment observed (p=0.49)

p for interaction = 0.49

Adapted from James S et al Eur Heart J 2010; 31: 3006–3016

What Does Guidelines Say?

What Should I Do?

Optimal Window (‘Sweet Spot’) of Platelet Inhibition

for PCI or CABG

Montalescot G et al J Am Coll Cardiol 2010; 56: 2003-2005

ESC 2014 Guidelines on Myocardial Revascularisation:

ACC/ AHA 2014 Guidelines on NSTE-ACS

Amsterdam et al J Am Coll Cardiol 2014

Conclusions

• Treatment needs to be individualised to ischemic risk, bleeding

complications, compliance and cost

• The clinical availability of potent inhibitors of P2Y12 platelet receptors has changed the acute coronary syndrome (ACS) treatment paradigm

• Recent NSTE-ACS guidelines of the (ESC) have recommended

ticagrelor and prasugrel in preference to clopidogrel for ACS patients

at moderate to high risk of ischemic events based on large randomised clinical trials demonstrating superior efficacy of these more potent agents versus clopidogrel

• Mortality was reduced with ticagrelor in PLATO trial which provide a unique advantage not seen with any other oral antiplatelet agents