Antiplatelet Therapy: What’s New, Older

Agents and How They Work

Kimberly Chapin, Pharm.D.

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

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/

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

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)

Platelet Activation and Aggregation

Front. Pharmacol., 24 October 2011 | http://dx.doi.org/10.3389/fphar.2011.00061

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

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

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

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

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

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

• 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

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.

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

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

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

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.

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

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.

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

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

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.

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

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

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

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.