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Antiplatelet Therapy in General Overview. Prof. Lale Tokgözoğlu MD, FACC, FESC Hacettepe University Faculty of Medicine Department of Cardiology. Cause of Death by Gender in Europe:. WHO 2008. Platelets are important in atherothrombosis.

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antiplatelet therapy in general overview

Antiplatelet Therapy in General Overview

Prof. Lale Tokgözoğlu MD, FACC, FESC

Hacettepe University Faculty of Medicine

Department of Cardiology

platelets are important in atherothrombosis
Platelets are important in atherothrombosis
  • After release from bone marrow, circulate for 7-10 days without interaction with vessel wall
  • If exposed to subendothelium, platelets activated
unstable plaques activate platelets

Platelet

Adhesion

Platelet

Activation

Platelet

Aggregation

Thrombotic

Occlusion

Unstable plaques activate platelets

Plaque

Fissure or Rupture

slide5

Adhesion mediated by vWF, agonists like ADP, secreted granules and TXA2 cause aggregation, exposed GPIIbIIIa receptors crosslink with fibrinogen to form platelet aggregates

Adhesion

Aggregation

1

3

Activation

2

Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

slide6

THROMBUS

FIBRIN

THROMBOCYTE

AGGREGATION

THROMBOCYTE

ADHESION

ENDOTHELIUM

MONOCYTE

MACROPHAGE

SMOOTH MUSCLE CELL

platelets also important in stent thrombosis mechanism of ami after stent implantation
Platelets also important in stent thrombosis:Mechanism of AMI after stent implantation

Relative frequency

12%

Atherothrombosis at newlocation (after 27 months)

Restenosis (after 19 months)

48%

Stent thrombosis (after 9 months)

40%

Alexopoulos D. Am Heart J 2010; 159: 439-445

different mechanisms of antiplatelet drugs
Different mechanisms of antiplatelet drugs:
  • COX-1 inhibitorsASA, Omega 3
  • Phosphodiesterase inhibitorsDipyrdamole, Cilostazol
  • ADP-P2Y12 interaction blokersTiclopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor
  • GP IIb/IIIa blokers
  • Thrombin receptor antagonists
slide10

Blocking different pathways for additional clinical benefit:

Clopidogrel

Prasugrel

Cangrelor

Epinephrine Collagen

ADP

Heparin, hirudin

AA

Aspirin

TxA2

GPIIb/IIIa

PLATELET

GP IIb/IIIa antagonists

Aggregation

slide11
ASA
  • Inactivates COX irreversibly blocking TXA2 formation (potent mediator of aggregation and vasoconstriction)
  • Effective 15-30 minutes after oral administration
  • Large dose over 10 gr eicosapentaenoic acid also blocks TXA2
phosphodiesterase inhibitors
Phosphodiesterase Inhibitors
  • Dipyridamole stimulates PGI2 synthesis, blocks uptake of adenosine
  • Clinical trials failed to show efficacy alone, enhances warfarin and ASA
  • MR form useful for stroke prevention
  • Cilostazol may be useful in claudicatio and has vasodilatory and antiplatelet effects
thienopyridines
Thienopyridines
  • Bind to P2Y12 receptor inhibiting interaction with ADP that would result in activation and aggregation
  • Prodrugs requiring transformation to active metabolites
ticlopidine dramatically changed interventional cardiology by making stent implantation safe
Ticlopidine dramatically changed interventional cardiology by making stent implantation safe

Schomig, NEJM 1996

antiplatelet resistance
Antiplatelet Resistance:
  • Genetic polymorphism in platelet proteins (CYP2C19 reduced function alleles have 30 % decrease in active clopidogrel)
  • Drug interaction (NSAID , drugs metabolized with Cytochrome P450 )
  • Environmental factors(Smoking, DM, HTN, HLP, ACS)

VARIABILITY IN RESPONSE NOT ALWAYS RESISTANCE:

Insufficent dosing, differences in assays and cutoffs, no gold standart

is aspirin resistance clinically significant
Is Aspirin Resistance Clinically Significant?
  • 326 stable CAD
  • 5.2 % Aspirin resistance
  • In HOPE study, @ 5 year follow up MI, stroke, death rate 1.8 % increased in the group with 11- deoxythromboxane B2 level !

Circulation 2002, 105: 1650

JACC 2003:41; 961

asa resist a nce vs clopidogrel resist a nce vs dual resist a nce

No resistance

ASA resistance

CLOPI resistance

Dual resistance

ASA resistance vs. clopidogrel resistance vs. dual resistance

The prevalence of drug resistance: ASA 16%, CLOPI 15%, dual 9%

The risk is 7x higher with dual resistence and 4.5x higher with multivessel PCI

40

37%

35

30

26%

25

Percentage

20

15

10

5

0

Periprocedur.MI

Ischaemic events within

30 days

Eshtehardi P, Am Heart J 2010; 159: 891-898

slide21

Definition of Resistance Varies with Method Used: ASA Resistance Measured by PFA-100 and Aggregometry

Stable AP n= 325 patients

Partial response

Routine assessment of platelet aggregation not recommended (II-B)

23.8 %

RESISTANT

5.5 %

9.5 %

90.5 %

Aspirin Resistant

70.7 %

Aspirin Sensitive

Aggregometry

Response to ADP and AA

PFA-100

Gum P. Am J Cardiol 2001;88:230-235

600 mg c lopidogrel loading is faster and more effective
600 mg clopidogrel loading is faster and more effective !

0

*P=0.01

** P=0.02

‡ P=0.0008

20

40

Aggregation inhibition (%)

**

*

60

*

Clopidogrel, 300 mg

Clopidogrel, 600 mg

**

80

0

2

4

6

Hours

Zidar F, et al. J Am Coll Cardiol. 2004;43(5, suppl A);Abstract 1100-1159.

armyda ii
ARMYDA-II

Circulation 2005;111:2099

doubling loading and maintenance dose of c lopidogrel in acs patients undergoing pci
Doubling loading and maintenance dose of clopidogrel in ACS patients undergoing PCI

CV death, MI or stroke

Clopidogrel standard

15% RRR

0.04

Clopidogrel double

0.03

Cumulative hazard

0.02

HR 0.85

95% CI: 0.74-0.99

p=0.036

0.01

0.00

0

3

6

9

12

15

18

21

24

27

30

Days

slide25
Clopidogrel to Prasugrel Crossover Study: Less variability with prasugrel since it produces higher concentrations of active metabolite

Healthy volunteers Crossover study

IPA (20 µM ADP) 24 hours

Platelet aggregation inhbition (%)

N=66

Clopidogrel effective

Clopidogrel resistant

Clopidogrel reply

Prasugrel reply

Brandt et al. J Am Coll Cardiol 2005;45(3 Suppl 1):87A – abstract 868-5

triton timi 38 13608 patients with acs
TRITON-TIMI 38: 13608 patients with ACS

R

Prasugrel

60 mg LD/ 10 mg MD

ASA

UA/NSTEMI (TIMI Risk Score ≥ 3)

12.0 month planned median

& Planned PCI

Double-blind treatment 6 - 15 months planned follow-up

14.5 month actual median

STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days)

ASA

Clopidogrel

300 mg LD/ 75 mg MD

Day 3

Day 30

Day 90

Day 450

Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke

=

Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR

=

Key safety end point: non-CABG related TIMI Major Bleeding

Wiviott SD et al. New Engl J Med 2007;357:2001-2015; Wiviott SD et al. Am Heart J 2006;152:627-635

slide27

TRITON TIMI-38:

Balance of efficacy and safety in patients < 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804)

16

CV death, NF MI, or NF stroke

14

Clopidogrel 11.0%

12

HR 0.74

(95% CI: 0.66-0.84)

p<0.001, NNT 37

10

Endpoint (%)

8

Prasugrel 8.3%

6

TIMI major bleeding

4

HR 1.24

(95% CI: 0.91-1.69)

p=0.17, NNH 222

Prasugrel 1.9%

2

Clopidogrel 1.5%

0

0

30

90

180

270

360

450

Days

Wiviott SD et al. Circulation 2010;122:394-403

slide29
In Clopidogrel group ,30 % of subjects had reduced function allele for CYP, these had 3X more stent thrombosis
genetic and platelet fx tests are complementary
Genetic and Platelet Fx Tests are Complementary

Genome

Transcriptome

Environment

Genetics

Proteome

Phenotype

Platelet function testing

variable response to clopidogrel
Variable Response to Clopidogrel

Test:

Increase dose

Alternative treatment:

Genetic, platelet function

+ Personalise

- Complex

+ Easy

- Efficacy, safety ?

+ Efficacy

- Cost ? Bleeding ?

slide32

Patients undergoing PCI with high platelet activity randomised to 75 mg C or 600 loading plus 150 mg C: GRAVITAS Study

Primary end point

Bleeding results

Percentage of patients with persistently high platelet reactivity at 30 days

AHA 2010

cangrelor
Cangrelor
  • Potent inhibitor of ADP induced aggregation
  • ATP analogue that inhibits P2Y12 by 100 %
  • No renal/hepatic metabolism to be activated
  • İv,rapid action, platelets back to normal in 60 minutes
  • Has additive effects to clopidogrel
  • Two short term trials discontinued for less than expected efficacy
ticagrelor
Ticagrelor
  • Stable, high affinity inhibitor of ADP induced aggregation
  • Oral agent acting directly on P2Y12 receptor without transformation
  • Rapid and greater action
  • Reversibility
  • 180 mg loading ,90 mg bid
  • Higher doses cause dyspnea and ventricular pause
plato study
PLATO Study
  • . Lancet. 2002;359:189-198

NEJM 2009; 361:1045

slide36

Glycoprotein IIb/IIIa Inhibitors Block

the Common Final Pathway to Platelet Aggregation regardless of the stimulus for activation

glycoprotein iib iiia inhibitors
Glycoprotein IIb/IIIa Inhibitors
  • Monoclonal Ab against IIb/IIIa: Abciximab
  • Peptide antagonist: Eptifibatid
  • Nonpeptide antagonist: Tirofiban
gp iib iiia inhibit ors in acs 30 day death mi n 31 402

High risk

  • Diabetic
  • - ASA use on admission
GP IIb/IIIa Inhibitors in ACS:30 day death / MI (N=31,402)

Study

Placebo

Gp IIb/IIIa

Odds Ratio

95% CI

PRISM 7.1% 5.8%*0.80 0.60-1.06

PRISM-PLUS 12.0% (*) 8.7% 0.70 0.50-0.98(† ) 13.6%*1.17 0.80-1.70

PARAGON-A 11.7% (l) 10.3% 0.87 0.58-1.29(h) 12.3% 1.06 0.72-1.55

PURSUIT 15.7% (l) 13.4% 0.83 0.70-0.99(h) 14.2% 0.89 0.79-1.00

PARAGON-B 11.4% 10.6% 0.92 0.77-1.09

GUSTO-IV 8.0% (24h) 8.2% 1.02 0.83-1.24(48h) 9.1% 1.15 0.94-1.39

Overall 11.8% 10.8%t 0.91 0.85-0.98

0

1.0

2.0

Gp IIb/IIIa iyi

Placebo iyi

P=.015

Boersma E, et al. Lancet. 2002;359:189-198.

prism plus t hrombus size

50

40

30

20

10

0

PRISM-PLUS: Thrombus size

Odds Ratio: 0.77

P=0.022

Probable

Probable

Small

Cumulative

(%)

Small

Medium

24.1%

Medium

17.1%

Big

Big

Occlusion

Occlusion

Tirofiban + Heparin

(n=608)

Heparin

(n=622)

Circulation. 1999;100:1609-1615.

acuity timing gp iib iiia at the time of pci vs upstream in everyone
ACUITY, timing GP IIb/IIIa at the time of PCI vs. upstream in everyone

Deferred PCI

Routine Upstream

GP IIb/IIIa

GP IIb/IIIa

(N=4,605)

(N=4,602)

Overall exposure

98.3%

55.7%

6.2

Rand. to angio/interv (h)

6.2

Rand. to GP IIb/IIIa (h)

0.6

4.6

Net clinical benefit

11.7

11.7

Ischaemic EP

7.1

7.9

Bleeding EP

6.1

4.9

Stone GW et al. JAMA 2007;297:591-602

target benefit of triple antiplatelet therapy
TARGET: Benefit of triple antiplatelet therapy

6 months death/MI

Clopidogrel and tirofiban

18

16

14

12

10

8

6

4

2

0

Clopidogrel and abciximab

No clopidogrel only tirofiban

15.5%

No clopidogrel only abciximab

10.9%

Patients

(%)

8.4%

7.2%

0 30 60 90 120 150 180

Days

Chan A, et al. J Am Coll Cardiol. 2003;42:1188-1195.

relation between age dosing and bleeding
Relation between age, dosing and bleeding

Age

Excess dose %

Major bleeding %

Eur Heart J Suppl 2007, 9 (Suppl A) A23-A31.

antithrombotic treatment options in myocardial revascularisation stemi
Antithrombotic treatment options in myocardial revascularisation: STEMI

a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs

Eur Heart J 2010. On line

antithrombotic treatment options in myocardial revascularisation nste acs
Antithrombotic treatment options in myocardial revascularisation: NSTE-ACS

a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs

Eur Heart J 2010. On line

antiplatelets for ischemic stroke or preventing systemic embolism
Antiplatelets for ischemic stroke or preventing systemic embolism

Warfarin vs placebo

Warfarin vs low dose Warfarin

Warfarin vs ASA

Warfarin vs ASA + clopidogrel

0

0.3

0.6

0.9

1.2

1.5

1.8

2.0

Warfarin better

Other better

Camm, ESC 2009

what is the ideal antiplatelet drug
What is the ideal antiplatelet drug?

Effective platelet inhibition without bleeding

Uniformly effective in all patients (no resistance)

Simple dosage

No side effects

No drug interactions

Reasonable price

FOR NOW:

Beware of drug interactions and bleeding

Keep ASA dose low in combination

Calculate GPI dose meticulously

new horizons in antiplatelet therapy
New Horizons in Antiplatelet Therapy:

TRA thrombin receptor antagonists

Antagonists to A1 domain on vWF: ARC1779

Collagen induced platelet aggregation blockers : CTRP-1

triton timi 38 therapeutic considerations for subgroups
TRITON-TIMI 38: Therapeutic considerations for subgroups

Age ≥75 years or weight <60 kg:

Prasugrel 10 mg equivalent to clopidogrel

(Prasugrel 5 mg under investigation)

Majority of patients:

Significant benefit

with prasugrel 10 mg

(MD)

16%

Prior stroke/TIA:

Prasugrel is contraindicated

4%

80%

prague 8 with 600 mg load patients undergoing elective pci
PRAGUE-8 (with 600 mg load): Patients undergoing elective PCI

20

Pre-treatment

No Pre-treatment

Clop 600 mg

Clop 600 mg

(n=155)

(n=143)

p=NS

15

11.9

p=0.006

Percentage patients

10

8.4

7.1

p=NS

5

2.8

1.3

0.7

0

D/MI/CVA/UTVR

Troponin >3XULN

Major + Minor

Bleeding

Widimsky P et al. Eur Heart J 2008;29:1495-1503

isar choice
ISAR-CHOICE

Circulation 2005;112:2946

slide53

30th DAY DEATH / MI WITH GPI

16.7

18

Placebo

GP IIb-IIIa Inhibitor

14.1

14

11.6

10.9

10.2

10.1

% Parients

9

10

5.9

4.8

6

3.9

3.6

1.8

2

0

EPIC

CAPTURE

EPILOG

EPISTENT

PRISM-PLUS

PURSUIT

variable clopidogrel response
Variable Clopidogrel Response

At 5 Days

UA Patients* (n = 32)

Nonresponders

22%

Responders

47%

Low responders

32%

*Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily.

Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2):166-171.