Antiplatelet Therapies

1. ANTIPLATELET
THERAPY
Alireza Kashani
SET 2 Cardiothoracic Training
Liverpool Hospital

2. Thrombus Formation

3. What is Tissue Factor?
• A cell surface glycoprotein :
• Abundantly expressed in damaged endothelial and exposed
subendothelial cells and also in the atherosclerotic plaques
• Also derived from circulating microparticles (MPs) released during
plaque rupture
• Forms a complex with and activates factor VII
• VII > VIIa
• X > Xa and IX > IXa
• Prothrombin > Thrombin

4. Platelet
Activation
Self-Amplification

7. Aspirin
• Acetyl-Salicylic Acid
• Platelet COX Inhibition by Acetylation
• COX I:
• Cardiovascular Protection
• Toxic Gastric Side Effects
• Reduction in TXA2
• COX II: NOT INHIBITED AS MUCH
• PGE2 : Inflammatory Response
• At low dose permits production of PGI2
• Until the end of life of the platelets
• Vascular Endothelial COX I:
• Reduction in both TXA2 and PGI2
• However this enzyme can be reproduced here

8. Aspirin
• GI Bleeding requiring hospitalization:
• 2/1000 patients treated per year
• Small Increase in haemorrhagic stroke
• Bleeding is dose-dependent
• Doubling as the dose is increased from less than 100 mg to less
than 200 mg
• Blocks platelet aggregation in response to TXA2; however,
this can be overcome by other stimuli, in particular with
thrombin.
• Anti-inflammatory effects through blocking platelet-neutrophil
interactions through higher doses.

9. Aspirin Nonresponsiveness
• Present in16% of those with prior MI and is associated
with 4x increase in:
• DEATH
• RE-INFARCTION
• RE-HOSPITALIZATION
Over 12 Months

10. Aspirin Nonresponsiveness
• Definition:
• High urinary concentration of TXA2 metabolite ≈ 2X risk of MI
• Platelet function tests and presumed clinical unresponsiveness ≈
3X lifetime risk of:
• MI
• Stroke
• Death
• Mechanism:
• GP polymorphism
• Platelet activation by pathways other than COX
• Enhanced inflammatory activity with increased expression of COX-
2

11. Aspirin Nonresponsiveness
• Detection:
• Not a straight forward test
• What to do?
• Add-On Clopidogrel might help
• Those with Aspirin resistance might be resistant to clopidogrel

12. Aspirin
• Primary Prevention:
• Assessing potential risk versus overall benefit (including cancer
prevention) is the key
• Secondary Prevention
• The balance strongly favors the benefits
• All patients with prior CV events
• Prior MI : 25% reduction in re-MI
• Stable Angina > β-blockers + Aspirin 75 mg/d : 34% reduction in MI or
sudden death in comparison with placebo
• UAP: 46% risk reduction
• Coronary Angioplasty: 53%
• Prior Stroke: 22%
• Peripheral Arterial Disease : 23%

13. Aspirin
• Cancer Prevention
• Cardiovascular Indications:
• ACS:
• AMI + Fibrinolytic Therapy / Primary PCI
• UAP + Conservative/Invasive Strategies
• Antiinflammatory:
• It is an important point to factor in the inflammatory response in the
genesis of cardiovascular disease. Hence, the preventative effects
of aspirin is not limited only to platelet inhibition.

14. Aspirin
• Other:
• Post CABG : should be started within 48h. It reduces the total
mortality by 2/3
• Prevention of AF-Related Stroke:
• Warfarin Contraindicated
• CHADS-VASc Score of <2 : CHF, HTN, >75, DM, CVA, TIA, TE,
Vascular Disease
• Arteriovenous Shunts
• Stroke Prevention in intra-cranial arterial stenosis : HIGH DOSE
ASPIRIN (325-1300 mg/day) WAS BETTER THAN WARFARIN
• Urgent Therapy in TIAs and minor strokes:
• Part of the regimen : Aspirin + Clopidogrel + Statin + Anti-HTN ± Anti-
Coagulation

15. Aspirin
• What Dose?
• 75-150 mg/d covers a wide range of conditions
• NSTE ACS : 75-100 mg/d
• 80 mg/d completely blocks platelet aggregation through COX
• 30 mg/d to prevent TIA
• This takes 2 days before it is effective
• AMI : 160 mg to achieve a much faster inhibition
• Side Effects:
• The most serious is GIT Bleeding
• The most common is GI Upset : Dyspepsia, Nausea, and Vomiting
• GI Side Effects: Dose Dependent
• Enteric-Coated:
• Reduced Gastric Side Effects
• Reduced Bio-Availability
• Increased Risk of Cardiovascular Side Effects
• Kidney Injury, decreased uric acid secretion, increased risk of gout:
more commonly seen in elderly even with low-dose aspirin

16. Aspirin Contraindications
• Absolute:
• Aspirin Intolerance
• Hx of GI Bleeding
• PUD
• Other potential source of GI or GU Bleeding
• Relative:
• Gout
• Dyspepsia
• IDA
• Possibility of increased peri-operative bleeding
• Note:
• Hemophilia in case of strong cardiovascular indications is not an
absolute contraindication.

17. Aspirin Interactions
• Warfarin : Increased risk of bleeding
• NSAIDS:
• COX-1 inhibitors: Interfere with cardioprotective effects of aspirin
• Ibuprofen, Naproxen
• COX-2 inhibitors: less than above
• ACE-Inh: opposing effects on haemodynamics of the kidneys.
• ACE-Inh when chronically used for HF, Post MI Protection, or high-risk
protection even when the aspirin was given they were still beneficial.
Aspirin might reduce but can not eliminate this effect.
• A good policy is to keep the aspirin at a low dose.
• Phenobarbital, phenytoin, and rifampin by inducing the hepatic
metabolizing enzymes reduce the efficacy of the aspirin
• Effects of OHA and Insulin are enhanced by aspirin.
• Combination of Thiazides and Aspirin : Increased risk of Gout

18. ADP-Mediated Antiplatelets
• ADP
• Released during platelet
activation
• Externalized
• Coupled with G Proteins:
• P2Y1
• Platelet shape change
• GPIIb/IIIa activation initiation
• P2Y12
• Perpetuates GPIIb/IIIa
activation
• Stabilizes the platelet
aggregation
• Rapid activation of
intravascular TF

19. ADP-Mediated Antiplatelets
• ADP Antagonism:
• Inhibit platelet shape change
• Inhibit platelet GPIIb/IIIa activation
• Reduce activation of intravascular TF
• Hence:
• Reduce platelet aggregation
• Destabilize the aggregated platelets
• Potentially disaggregate the platelets
• Anticoagulation effects
• Group:
• Ticlopidine
• Clopidogrel
• Prasugrel
• Ticagrelor

21. Ticlopidine
• The first of this group
• Adverse reactions:
• Neutropenia which occurs within the first 3 months and patients that
are started on this should undergo FBC check prior to commencement
and every 2 weeks up to 3 months
• TTP
• Liver Abnormalities
• Indications:
• Prevent repeat stroke or TIA in those intolerant of or resistant to
Aspirin
• Coronary artery stenting in combination with aspirin for up to 30 days
• Due to the above ADRs it is rarely used; however, it is still
available to those:
• Allergic to or intolerant of Clopidogrel
• Living in countries in which Clopidogrel is not readily available

22. Ticlopidine Pharmacokinetics
• Nonlinear
• Markedly decreased clearance on repeated dosing
• To achieve maximum platelet aggregation inhibition : 4-7
days when given with aspirin
• This can be expedited by oral loading
• The plasma half-life during constant dosing 4-5 days
• Metabolism:
• Hepatic Metabolism
• Renal Excretion

23. Clopidogrel
• P2Y12 ADP Receptor Inhibitor
• Prevention of GPIIb/IIIa receptor activation and transformation
• Substantially less myelotoxic than ticlopidine
• Less major GI bleeding than aspirin
• The same as aspirin, the clopidogrel resistance also
occurs

24. Clopidogrel
• Inactive prodrug requires in vivo oxidation by hepatic or
intestinal cytochrome isoenzymes:
• CYP3A4
• 2C19
• Onset of action:
• A single oral dose: within hours, and reaches a steady state in 3-7
days
• Upstream before PCI
• 600 mg : 2 hours
• 300 mg : 24 – 48 hours

25. Clopidogrel
• It is recommended that clopidogrel should be stopped for 5
days before CABG to avoid major bleeding.
• Dose adjustment is not necessary in elderly and those with
renal disease.
• Side effects:
• Neutropenia : 0.02%
• Major bleeding without an increase in intracranial bleeding
• Contraindication:
• Major bleeding
• Interactions:
• PPIs and Statins inhibit hepatic activation of Clopidogrel esp. those
which inhibit P450 Cytochrome like Omeprazole or Atorvastatin
• This is not proven in vivo

26. Clopidogrel
• Genetic Testing:
• The CYP2C19*2 allele:
• Increased rates of ischemic events and stent thrombosis after PCI
• 30% of Western Europeans
• 40% of Asians and Africans
• Indications:
• Reduction of atherosclerotic events (MI, Stroke, Vascular Death) in
patients with recent stroke, recent MI, or with established arterial
disease
• ACS whether or not PCI (with or without stent) or CABG is performed
• Dosage:
• For loading 600 mg is better
• How Long After PCI?
• DES : at least 12 months
• BMS : 1 month

27. Prasugrel
• Newer thienopyridine
• Irreversible and noncompetitively inhibits P2Y12 exactly
the same as Clopidogrel
• A prodrug
Digestion
Hydrolyzed By
Intestinal Cells to
Thiolactone
Single Step
Activation in
the Liver by
either
CYP3A4 or
CYP2B6

28. Prasugrel
• The active metabolite’s elimination half-life: 7 hours (2-15
hours)
• CYP3A Inhibitors:
• Verapamil and Diltiazem
• Do not alter its activity but decrease the maximum concentration by
34-46%
• Its platelet aggregation inhibition is 5-9 times more potent
than that of Clopidogrel
• Initiation of Action : 1 hour

29. Prasugrel
• TRITON-TIMI 38 Trial:
• 2 arms in patients undergoing PCI:
• Prasugrel: 60 mg then 10 mg/d
• Clopidogrel: 300mg then 75 mg/d
• Follow Up for 6-15 months
• Prasugrel
•  Primary endpoint of cardiovascular death, MI, and stroke from 12%
to 9.9% (p<0.001)
•  Stent Thrombosis from 2.4% to 1.1% (p<0.001)
• 46 patients needed to be treated for 5 months to avoid one primary end
point as opposed to 167 patients treated to result in one major bleeding
(not CABG related)

30. Prasugrel
• Indication:
• Patients with ACS who are to be managed with PCI for:
• Unstable Angina
• NSTEMI
• STEMI (either primary or delayed)
• Risks:
• FDA Black Box Warning:
• Serious Bleeding
• Occasionally TTP
• If possible the bleeding should be managed without stopping prasugrel, esp. in the first few
weeks after ACS
• Risk factors based on TRITON 38 data analysis:
• Use of GPIIb/IIIa Inhibitor even for short period of time
• A history of stroke or TIA
• Age 75 years or older
• Female gender
• Body weight < 60 kg
• Femoral Access
• Patients with a history of stroke or TIA or low body weight should not receive
prasugrel.

31. Ticagrelor
• Oral Reversibly Binding
Noncompetitive P2Y12
receptor inhibitor
• Half Life: 12 hours
• The level of inhibition is
determined by plasma
ticagrelor level and to a
lesser extent an active
metabolite
• More rapid and consistent
action than clopidogrel
• Quicker Offset than
Prasugrel
• NO HEPATIC ACTIVATION
IS REQUIRED.

32. Ticagrelor
• Inhibits hepatic CYP3A
• Increase blood levels of drugs such as :
• Amlodipine
• Simvastatin
• Atorvastatin
• Moderate CYP3A inhibitors:
• Diltiazem, Verapamil, and Amlodipine
• Increase levels of Ticagrelor
• Reduce the speed of offset

33. Ticagrelor
• PLATO Trial:
• Patient pool:
• Moderate-high risk NSTE-ACS planned for either conservative or
invasive management
• STEMI planned for primary PCI
• Randomized:
• Clopidogrel: 300 mg Loading / 75 mg D (9333 patients)
• Ticagrelor: 180 mg Loading / 90 mg BD (9291 patients)
• Results:
• Death 4.5% vs. 5.9% P < 0.001
• Primary PCI group death 9.8% vs. 11.7% P < 0.001
• General composite endpoint 9% vs. 10.7% P : 0.0025

34. Ticagrelor
• Adverse Effects:
• Bleeding
• Dyspnea
• Most frequently within the first week of Rx
• Maybe transient or persistent until the Rx is ceased
• It is not linked to deterioration in cardiac or pulmonary function.
• Increased Frequency of Ventricular Pauses
• Asymptomatic Uric Acidaemia
• Mechanism of Vent. Pauses and Dyspnea remains unclear
• Caution:
• Advanced SA nodal dysfunction
• 2nd/3rd-degree AV blocks
• PLATO trial stated that Ticagrelor effects are less when
combined with high-dose aspirin.

35. Cangrelor
• Rapid-acting, reversible, potent, competitive inhibitor of
the P2Y12 receptor
• Intravenous
• Onset of action (85% inhibition of AD-induced platelet
aggregation) 20 minutes
• CHAMPION Trial: Cangrelor use in NSTE ACS patients
undergoing PCI was associated with significant reduction
in early ischaemic events when compared with
clopidogrel.
• When Cangrelor is added to Clopidogrel: further reduction
in platelet reactivity but did not alter cardiac surgery-related
bleeding

36. Vorapaxar
• A potent, competitive PAR-1
antagonist
• In a large outcome trials (12944
patients)
• Failed to improve the primary end
point of a composite major
cardiovascular events
• Reduced the secondary endpoint
of cardiovascular death, MI, or
stroke (p = 0.02)
• Significant increase in major
bleeding including ICH (p <
0.0001)
• Trial was terminated.
• In another large trial with 26499
the same endpoints met but
indicated those without a history
of stroke have a lesser risk of
ICH.

37. Atopaxar
• The same group of medication
• No outcome trials are available
• Current Phase 2 trial on patients with NSTE ACS has
failed to show any benefits.

38. Dipyridamole & Sulfinpyrazone
• Dipyridamole:
• Site of action is the same as
prostacyclin.
• It helps to reduce recurrent
stroke when given with
aspirin*
• Sulfinpyrazone:
• Site of action is similar to
aspirin and it inhibits the COX
pathway.
• Requires multiple daily doses
and is more expensive
• It is a uricosuric agent and is
indicated in chronic or
intermittent gouty arthritis.

39. Dual Antiplatelet Therapy
• Substantial data shows that adding clopidogrel to aspirin is beneficial
in the setting of acute vascular injury, whether procedure-induced as
in stenting, or spontaneous as in ACS, including AMI.
• CHARISMA Trial: high-risk subgroups benefited from dual antiplatelet
therapy.
• ACS Recommends:
• STEMI, NSTEMI patients with intended PCI:
• 300-600 mg Loading of Clopidogrel
• 75 mg/d for 1 year
• OASIS-7 Trial:
• 17263 patients randomized to two arms of standard and double-dose loading:
• 600 mg day 1, 150 mg on days 2-7, and 75 mg/d:
• Reduced cardiovascular events and stent thrombosis at 30 days when compared with
standard dosing
• Efficacy and safety did not differ between high-dose and low-dose aspirin
• CURE Trial (12562 patients)
• Clopidogrel + Aspirin : reduced the composite of combined death, MI, and
stroke at 9 months by 20% (p < 0.001)
• Clopidogrel increased major bleeding (3.7% vs. 2.7% P = 0.003)

40. 2011 ACC/AHA Guidelines
• Preoperative:
• CLASS I:
• Aspirin (100 mg to 325 mg daily) should be administered to CABG patients
preoperatively (Level of Evidence: B)
• In patients referred for elective CABG, clopidogrel and ticagrelor should be
discontinued for at least 5 days before surgery (Level of Evidence: B) and
prasugrel for at least 7 days (Level of Evidence: C) to limit blood
transfusions.
• In patients referred for urgent CABG, clopidogrel and ticagrelor should be
discontinued for at least 24 hours to reduce major bleeding complications.
(Level of Evidence: B)
• In patients referred for CABG, short-acting intravenous GPIIb/IIIa inhibitors
(eptifibatide or tirofiban) should be discontinued for at least 2 to 4 hours
before surgery and abciximab for at least 12 hours beforehand to limit blood
loss and transfusions. (Level of Evidence: B)
• CLASS IIb:
• In patients referred for urgent CABG, it may be reasonable to perform
surgery less than 5 days after clopidogrel or ticagrelor has been
discontinued and less than 7 days after prasugrel has been discontinued.
(Level of Evidence: C)

41. 2011 ACC/AHA Guidelines
• Postoperative:
• CLASS I:
• If aspirin (100 mg to 325 mg daily) was not initiated preoperatively, it
should be initiated within 6 hours postoperatively and then continued
indefinitely to reduce the occurrence of SVG closure and adverse
cardiovascular events. (Level of Evidence: A)
• CLASS IIa:
• For patients undergoing CABG, clopidogrel 75 mg daily is a reasonable
alternative in patients who are intolerant of or allergic to aspirin. (Level
of Evidence: C)