Mills-Peninsula Cardiovascular Symposium, September 2015 - Kimberly Chapin, Pharm.D.

1. Antiplatelet Therapy:
What’s New, Older
Agents and How
They Work
Kimberly Chapin, Pharm.D.

2. Course Outline
• Review hemostatic mechanisms
• Review mechanisms of action of each class of
antiplatelet agent
• Compare and contrast pharmacology of
antiplatelet agents
• Identify unique places in therapy for each
antiplatelet agent

3. Hemostasis
• Normal physiological
response that prevents
significant blood loss after
vascular injury
• Clot formation involves
multiple system responses:
– Vasoconstriction
– Platelet plug formation
– Coagulation
• Once the vessel heals,
primary fibrinolysis is
triggered and clot formation
processes are inhibited
Image source: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/hypercoagulable-states/

4. Hemostasis: A Balancing Act
Prohemorrhagic
Natural Anticoagulants
(Protein C, Protein S, AT)
Fibrinolytic proteins
•Illness (i.e. Infection, Malignancy,
CV Disease)
•Medications
•Inherited and acquired
bleeding disorders
•Immune Reactions
•Trauma
•Patient factors (i.e. Obesity,
immobility, pregnancy)
•Toxins
Platelets
Coagulation Factors
Fibrinolytic Inhibitors
Prothrombotic

5. Medications That Affect Hemostasis
• Antithrombotics prevent or interfere with the formation and
growth of blood clots.
•Antiplatelet agents—decrease platelet activation and
aggregation release of granule contents, and platelet-
mediated vascular constriction.
»Examples: Aspirin, thienopyridines, glycoprotein IIb/IIIa
Inhibitors, P2Y12 platelet receptor inhibitors, Protease-Activated
Receptor-1 (PAR-1) Antagonist
•Anticoagulants—interfere with clotting factors
»Examples: heparin, low molecular weight heparins (LMWH),
warfarin, factor Xa inhibitors, direct thrombin inhibitors
• Antifibrinolytics inhibit clot dissolution
»Example: Aminocaproic Acid, tranexamic acid
• Thrombolytics dissolve existing clots
»Example: Alteplase (tPA)

6. Platelet Activation and Aggregation
Front. Pharmacol., 24 October 2011 | http://dx.doi.org/10.3389/fphar.2011.00061

7. Aspirin
• Aspirin
– Possible use of salycilates (willow bark) as early as 3000 BC
– Developed into a pharmaceutical agent throughout the 1800s
– OTC ASA available by the early 1900s and widely available
• Common Indications:
– Broad number of indications due to antithrombotic,
analgesic, antipyretic, and anti-inflammatory effects
• Primary and secondary prevention of cardiovascular disease
• Part of acute treatment for ischemic stroke/TIA, and Acute
Coronary Syndrome
• Analgesia
• Anti-inflammatory

8. Aspirin—Mechanism of Action
• Acetylates COX-1 and COX-
2, blocking the conversion
of arachidonic acid to
prostaglandins and
thromboxane A2 (Tx A2)
– Blocks Platelet aggregation
– Irreversible, lasts life of
platelet (7-10 days)
• Low doses inhibit COX-1
• Higher doses inhibit COX-2,
which also leads to
analgesia and reduction in
inflammation

9. Aspirin
• Bioavailability: 50% to 75%
• Cmax: 30-60 min (IR)
• Half life:
– Parent drug: 15-20 min; Salycylates: 3 to 10 hours
– Normal hemostasis returns in ~4-7 days
• Optimal dose is >75mg or ≤325mg
• Bleeding :
– GI bleeds are most common
– Several meta-analyses show ~1-2X increase risk of major bleeding over
placebo
• Aspirin resistance
– Leads to treatment failures, higher rates of death, MI, stroke
– Incidence between 5-40% at doses of 325mg daily
• Aspirin sensitivity/allergy

10. P2Y12 Receptor Antagonists
• Common Indications:
– Secondary prevention of
cardiovascular disease
– Acute Coronary Syndrome
• Percutaneous coronary
intervention (PCI)
• Medical management
– Prevention of stent
thrombosis
– ASA substitute for patients
with ASA sensitivity
Thienopyridine Route Approval
Ticlopidine (Ticlid®) Oral 1991
Clopidogrel (Plavix®) Oral 1997
Prasugrel (Effient®) Oral 2009
Non-thienopyridine Route Approval
Ticagrelor (Brilinta®) PO 2011
Cangrelor (Kengreal®) IV 2015

11. P2Y12 Receptor Antagonists
• The P2Y12 receptor
antagonists block the
binding of adenosine
diphosphate (ADP) to the
platelet receptor P2Y12,
inhibiting activation of the
(GP) IIb/IIIa complex
– Binding to the receptors
– Changing conformation of
the receptor
• Blocks platelet activation
and aggregation

12. P2Y12 Receptor Antagonists
Clopidogrel Prasugrel Ticagrelor Cangrelor
Prodrug Yes Yes No No
Route Oral Oral Oral Intravenous
Binding Irreversible Irreversible Reversible Reversible
Onset of
Action
Loading dose:
<2hours
Maintenance: Day
2 of tx
Loading dose:
<0.5 hours
Loading dose:
<0.5 hours
Within 2
minutes of
infusion
Duration of
Action
After d/c, Gradual
decline over 5-10
days
After d/c,
Gradual decline
over 5-10 days
After d/c,
Gradual
decline over 2-
5 days
Return of
platelet
function within
1 hour after d/c
of infusion
Dosing
Frequency
Daily Daily BID Continuous
infusion
Dual ASA
therapy
75-100 mg/day 81 mg/day, up
to 325 mg/day
81 mg/day, up
to 100mg/day
N/A

13. • Bleeding Events
– Newer, more potent agents associated with increased bleeding risks
compared to clopidogrel
– Prasugrel 10 mg daily contraindicated if patient is ≥75 years or weight
<60 kg.
– Hx of stroke or TIA:
• Clopidogrel preferred
• Ticagrelor not contraindicated, but experience is limited
• Prasugrel contraindicated
• Clopidogrel Resistance and Treatment Failures
• Genetic polymorphisms (CYP2C19 and ABCB1), drug interactions,
disease states, compliance, obesity and diabetes,
hyporesponsiveness to clopidogrel
P2Y12 Receptor Antagonists

14. Cangrelor (Kangreal®)
• New IV P2Y12 agent with rapid onset and offset
• Approved as an adjunct to PCI for reducing the risk
of periprocedural myocardial infarction (MI), repeat
coronary revascularization, and stent thrombosis in
patients who have not previously been treated with
an oral P2Y12 inhibitor and who are not being given
a GP IIb/IIIa inhibitor.
• Compared to clopidgrel or placebo
– Slightly higher bleeding, hypersensitivity reactions,
worsening renal function, and dyspnea in cangrelor
patients.

15. Glycoprotein IIb/IIIa Inhibitors
• Indications:
– Acute Coronary Syndrome
• Percutaneous coronary intervention (PCI)
• Medical Management
Agents Route Type of medication Approval
Abciximab (ReoPro®) IV Humanized chimeric fragment of the
mouse antibody 7E3
1998
Tirofiban
(Aggrastat®)
IV Small molecule 1998
Eptifibatide
(Integrilin®)
IV Small molecule 1998

16. Glycoprotein IIb/IIIa Inhibitors
• The platelet integrin receptor GPIIb/IIIa mediates interactions
between platelets and several ligands, primarily fibrinogen, leading
to platelet aggregation
• GPIIb/IIIa antibodies and receptor antagonists inhibit this binding by
antagonizing or binding to the receptor.
Abciximab (ReoPro®)
Noncompetitive
irreversible inhibitor of
intact GPIIb/IIIa receptor
Tirofiban (Aggrastat®)
Eptifabatide (Integrilin)
Competitive and
reversible antagonists that
act specifically on the αIIb-
subunit of GPIIb/IIIa

17. Glycoprotein IIb/IIIa Inhibitors
Tirofiban Eptifibatide Abciximab
Onset 10 min 5 min 30 min
Half Life 2 hours
Normal hemostasis:
4-8 hours
2.5 hours
Normal hemostasis:
4-8 hours
30 min
Normal hemostasis:
72 hours
Clearance Renal
(Dose adjust for
moderate-severe
renal dysfunction)
Renal
(Dose adjust for
moderate-severe renal
dysfunction; CI for HD)
Metabolized via
proteolytic cleavage
Bleeding Major: 1.4%
Minor: 10.5%
Major: 1.3-10.8%
Minor: 3-13.1%
Major: 0.8-3.8%
Minor: 3.2-7.6%
Contra-
indications
History of
thrombocytopenia
Uncontrolled HTN; hx of
stroke (within 30 days),
dialysis paitents
Hypersensitivity to
murine proteins, 6
week hx of major
bleeding, hx of CVA
within 2 years, use in a
patient taking an OAC

18. Glycoprotein IIb/IIIa Inhibitors
• Common adverse events
– Bleeding: GI and arterial access sites most common sites
– Thrombocytopenia
• Within minutes to hours
• Abciximab > tirofiban, eptifibatide
• Cross-reactivity may exist between agents
– Abciximab associated with infusion-related reactions,
headache, hypotension, chest pain, nausea/vomiting
– Abciximab re-exposure associated with higher risk of
hypersensitivity reaction
• Monitoring: Platelets, Hgb/Hct, SCr, PT/aPTT prior to treatment,
then within 6 hours following load, then daily, then once prior to
discharge. ACT during PCI.

19. Cyclic AMP Inhibitors
Common Indications:
• Prevention of stroke
(Aggrenox®)
• Intermittent claudication
(Cilostazol)
• Evaluation of coronary
artery disease
(Dipyridmadole)
Agent Route
Dipyridamole
(Persantine®)
PO, IV
Dipyridamole +
Aspirin (Aggrenox®)
PO
Cilostazol (Pletal®) PO

20. Cyclic AMP Inhibitors
• Mechanism of Action:
– Both dipyridamole and cilostasol:
• Inhibit the phosphodiesterase enzymes that break down cAMP,
thereby increasing cAMP levels that block the platelet response to
ADP and prevent platelet activation
– Dipyridamole:
• Blocks thromboxane synthase and the thromboxane receptor
preventing thromboxane A2 formation, which inhibits platelet
aggregation.
• Increases plasma adenosine levels and potentiates nitric oxide
signaling through cyclic GMP, which inhibits platelet aggregation.

21. Cyclic AMP Inhibitors
• Dipyridamole/Aspirin (Aggrenox)
– Extended release form of dipyridamole with low dose of
aspirin (25mg)
– Mainly used for secondary prevention of stroke
– Common side effect is headache
• Dipyridamole (IV, immediate release oral)
– IV formulation dilates coronary arteries for stress testing
– Immediate release PO form rarely used
• Cilostazol (Pletal)
– Mostly used for Peripheral Artery Disease and claudication
– May be alternative agent to ASA or Clopidogrel if allergies or
intolerances exist and dual antiplatelet therapy is necessary

22. Thrombin Receptor (PAR-1) Antagonists
Indication:
• Reduction of thrombotic
cardiovascular
events(cardiovascular
death, myocardial infarction
[MI], stroke, urgent
coronary revascularization)
in patients with a history of
MI or with peripheral
arterial disease.
Agent Route Approval
Vorapaxar
(Zontivity®)
Oral May 2014
Atopaxar Oral Not FDA
approved

23. Thrombin Receptor (PAR-1) Antagonists
• Platelet activation by
thrombin is mediated via two
Protease-Activated Receptors
(PARs):
– (PAR-1) is the major human
platelet receptor, exhibiting 10–
100-times higher affinity for
thrombin when compared with
the PAR-4
• Voraxapar and atopaxar
selectively and competitively
antagonize the PAR-1 receptor.

24. Vorapaxar (Zontivity®)
Bioavailability 100%. Oral administration only.
Time to peak 1 to 2 hours
Metabolism Hepatic via CYP3A4 and CYP2J2
Excretion Primarily through feces (58%); urine (25%)
Half-life
elimination
Effective half-life: 3 to 4 days
terminal elimination half-life (vorapaxar and active metabolite):
approximately 8 days (range, 5 to 13 days)
Onset ≥80% inhibition of thrombin receptor-activating peptide (TRAP)-
induced platelet aggregation within 1 week
Duration Dose and concentration dependent; inhibition of TRAP-induced
platelet aggregation at a level of 50% can be expected 4 weeks after
discontinuation.
Bleeding
Concerns
Any: 26%; Major: 13%; Use is contraindicated in patients with history
of stroke, TIA, or ICH; or active pathological bleeding.
Special
Considerations
There is no experience with use of vorapaxar as monotherapy or with
other antiplatelet agents other than aspirin and clopidogrel

25. Potential Future Agents/Targets
• Antibodies targeting Von Willebrand factor (vWf)
• GPIba receptor antibodies
• Monoclonal antibodies that inhibit collagen–GPVI
interactions
• Thromboxane & Prostaglandin Endoperoxide Receptor
Antagonists

26. Conclusion
• Several mechanisms may be targeted to inhibit
platelet activation and aggragation.
• Several agents have an established place in treating
acute cardiovasular events as well as primary and
secondary prevention of cardiovascular events.
• Clinical data, pharmacology, bleed risk, and patient
specific factors must all be considered for safe use
of anti-platelet agents

27. Refrences
• Zontivity (vorapaxar). Prescribing information. Merck & Co, Inc; April 2015.
• Abciximab (Reopro). Prescribing information. Eli Lilly and Company. December 2013.
• Eftifibatide (Integrilin). Prescribing information. Merck Sharp & Dohme Corp.. April
2014.
• Aggrenox Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc.
December 2013.
• Clopidogrel Prescribing information. Bristol-Myers Squibb/Sanofi Pharmaceuticals
Partnership. July 2015.
• Brilinta Prescribing Information. AstraZeneca. September 2015.
• Effient .Prescribing information. Eli Lilly and Company July 2015.
• Kengreal. Prescribing information. The Medicines Company. June 2015.
• McQuaid KR, et al. Systematic review and meta-analysis of adverse events of low-
dose aspirin and clopidogrel in randomized controlled trials. Am J Med.
2006;119(8):624
• LexiComp Database. Accessed September 2015.
• Facts and Comparisons Database. Accessed September 2015.