Term
Antiplatelets
Learning Objectives
(3) |
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Definition
•Know the major classes of drugs that inhibit platelet function and their mechanisms of action
•Know the role of each class of antiplatelet drug in the acute treatment of acute coronary syndromes and transient ischemic attacks
•Know which agents are useful for prevention and risk reduction of patients with coronary and peripheral artery disease
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Term
Role of Platelets in Hemostasis
(7) |
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Definition
- Hemostasis is the spontaneous arrest of bleeding from a damaged blood vessel
- Platelets play a key role in hemostasis and thromboembolic disease
- Platelets normally function by:
- Adhering to damaged endothelium
- Releasing a variety of mediators that activate other platelets and non-platelets
- Aggregating to each other
- Platelets can can also aggregate de novo in the blood causing circulating clots that can infarct small blood vessels
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Term
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Definition
- The initial step in thrombogenesis (the formation of a thrombus or clot) is damage to the endothelial cells lining the blood vessel which results in vasospasm and exposure of thrombogenic substances such as collagen and von Willebrand factor (vWF)
- Platelets in the blood adhere to the exposed collagen and proteins such as vWF and become activated
- Activation causes degranulation (release of ADP, and serotonin (5-HT)), and synthesis of thromboxane A2 (TXA2), which activates other platelets and leads to aggregation and the formation of a white thrombus
- Other endogenous substances, such as thrombin and norepinephrine, can also activate platelets
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Term
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Definition
- Following formation of a platelet aggregate or white thrombus, fibrin formation can occur leading to the formation of a red thrombus with enmeshed red cells
- In arteries, high blood flow prevents red thrombus formation until platelet aggregation has caused significant occlusion and flow reduction (stasis); such thrombi are platelet-rich and lead to local occlusive ischemia
- In veins, where blood flow is low, platelet aggregation occurring on the vessel wall or de novo can lead to rapid formation of a red thrombus with long fibrin tails; such tails are platelet-poor, are easily detached and can travel as emboli to distant sites such as the lungs
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Term
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Definition
- The most important platelet inhibitory drugs work through three basic mechanisms:
- Inhibition of platelet prostaglandin (thromboxane) synthesis
- Inhibition of ADP-induced aggregation
- Blockade of GP IIb/IIIa receptors on platelets that mediate platelet aggregation
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Term
Sites of Action of Antiplatelet Drugs
Drugs
(11) |
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Definition
- Cox-1
- GPllb/llla (fibrinogen)
- Abciximab
- eptifibatide
- tirofiban
- P2Y1/P2Y12
- Ticlopidine
- Clopidogrel
- Prasugrel
- Ticagrelor
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Term
Aspirin (Acetylsalicylic acid, ASA)
(8) |
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Definition
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Term
P2Y12 Inhibitors:
Clopidorel, Prasugrel, Ticlopidine, Ticagrelor
(7) |
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Definition
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•Clopidogrel (Plavix), prasugrel (Effient), and ticlopidine (Ticlid) are thioenopyridines that inhibit ADP activation of platelet function by irreversibly blocking ADP binding to platelet ADP receptors (P2Y12 receptors)
•Ticagrelor (Brilinta) is a reversible P2Y12 allosteric antagonist of ADP
•These agents are more effective than aspirin and are used when greater antiplatelet effects are needed to:
–prevent vascular events in patients with transient ischemic attacks and completed strokes
–reduce risk in patients with recent myocardial infarction, acute coronary syndrome, and peripheral artery disease
–reduce the risk of clots in patients undergoing angioplasty (PCI) and after stent placement
•Additive or synergistic effects are obtained when used in combination with aspirin
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Term
Antiplatelet
Clopidogrel (Plavix)
(5) |
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Definition
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•Clopidogrel is a prodrug that requires CYP2C19 for bioactivation
–A significant number of patients (20-30%) have CYP2C19 polymorphisms (CYP2C19*2 and CYP2C19*3) that reduce bioactivation of clopidogrel
–Patients with these polymorphisms do not respond well to clopidogrel therapy and are at increased risk of thrombotic events
–An FDA 2010 "boxed warning" indicates genetic testing for CYP2C19 polymorphisms might be useful to identify poor metabolizers
–Patients taking omeprazole (which competes for CYP2C19) have reduced anti-platelet effects of clopidogrel
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Term
Antiplatelet
Prasugrel (Effient)
(5) |
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Definition
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•Newer thienopyridine with a more rapid onset of action than clopidogrel or ticlopidine, and greater and more predictable inhibition of platelet aggregation (IPA)
•It is a prodrug, but generation of its active metabolite is more efficient than clopidogrel
–Nearly complete activation of prasugrel compared with ~15% absorption/bioactivation of clopidogrel
–Compared to clopidogrel, prasugrel showed a significant reduction in CV death, MI, and stroke in patients with ACS scheduled for angioplasty; incidence of stent thrombosis also reduced
- Small, but significantly increased risk of major bleeding
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Term
Antiplatelet
Ticagrelor (Brilinta)
(5) |
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Definition
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•Ticagrelor (Brilinta) is a reversible P2Y12 allosteric antagonist of ADP
–Approved by the FDA in 2011
•Does not require activation
•More rapid pharmacokinetics than the thienopyridines
•Recent clinical trials (PLATO) indicate it may be superior to clopidogrel
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Term
Adverse Effects of P2Y12 Inhibitors
(11) |
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Definition
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•All are associated with increased bleeding risk
•Adverse effects of ticlopidine include:
–Nausea, dyspepsia, and diarrhea in 20% of patients
–Leukopenia in 1% of patients (can be life-threatening)
–Thrombotic thrombocytopenic purpurea (TTP)
•Clopidogrel has fewer adverse effects than ticlopidine
–Rarely associated with neutropenia
–TTP rarely occurs with this agent
•Because of fewer adverse effects and better dosing regimen, clopidogrel is preferred over ticlopidine
•Due to more consistent and effective platelet inhibition, prasugrel is superior to clopidogrel
•Recent trials indicate ticagrelor is superior to clopidogrel
–
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Term
Platelet GP IIb/IIIa Inhibitors
(6) |
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Definition
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•The platelet glycoprotein IIb/IIIa (aIIbb3) complex functions as a receptor for fibrinogen, vitronectin, fibronectin, and von Willebrand factor (vWF)
•Activation of the GP IIb/IIIareceptor is the final common pathway for platelet aggregation
•GP IIb/IIIa inhibitors are used to treat patients with acute coronary syndromes (these agents are all given parenterally)
–Abciximab (ReoPro) is a humanized monoclonal antibody that binds the IIb/IIIa complex
–Eptifibatide (Integrilin) is a cyclic peptide analog containing a KGD (LysGlyAsp) sequence, the portion of fibrinogen that binds the IIb/IIIa receptor
–Tirofiban (Aggrastat) is a non-peptide RGD-mimetic; the RGD (ArgGlyAsp) sequence is found in fibrinogen, vWF and other integrin receptor ligands
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Term
Uses of Antiplatelet Drugs
(4)
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Definition
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•Arterial Thrombosis: Activation of platelets is considered to be a primary event in the thrombotic complications of TIAs, strokes, unstable angina/ acute coronary syndrome (ACS), and MIs
–Aspirin and thioenpyridines are used to prevent ischemia in patients with TIAs and strokes, unstable angina/ACS and acute MIs, and with ACS undergoing angioplasty and stent palcement
–GP IIb/IIIa inhibitors are often used in combination with other antiplatelet drugs in treating ACS and acute MI
•Venous Thrombosis: Activation of platelets does not play a major role in venous thrombosis so antiplatelet drugs are not considered to be very effective for prevention of venous thrombi
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Term
Key Concepts: Antiplatelet Drugs
(5) |
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Definition
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•Antiplatelet drugs are used to prevent platelet activation and aggregation in arterial blood vessels
•There is a hierarchy of antiplatelet drug efficacy:
–Aspirin < thienopyridines < GPIIb/IIIa inhibitors
•Combination therapy with drugs from different classes can be additive or synergistic
•Bleeding is the greatest risk with these drugs; therapeutic benefit should outweigh risk of bleeding
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Term
Recent AHA Guidelines:
Antiplatelet Drugs |
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Definition
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•The remaining slides give some current recommendations for antiplatelet drugs use for prevention and acute treatment cardiovascular disease states
•The main therapeutic challenge is balancing the risks of bleeding with the benefits of preventing cardiac and brain damage due to infarction and ischemic stroke
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Term
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease:
(3)
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Definition
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•Aspirin 75–162 mg daily is recommended in all patients with coronary artery disease unless contraindicated.
•Clopidogrel 75 mg daily is recommended as an alternative for patients who are intolerant of or allergic to aspirin.
•Combination therapy with both aspirin 75 to 162 mg daily and clopidogrel 75 mg daily may be considered in patients with stable coronary artery disease
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Term
2011 Update (CONTD):
ACS & PCI w/stents
(5) |
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Definition
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•A P2Y12 receptor antagonist in combination with aspirin is indicated in patients after ACS or PCI with stent placement.
•For patients receiving a stent during PCI for ACS, thienopyridine therapy should be given for at least 12 months.
•If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy after stent implantation, earlier discontinuation (eg, <12 months) is reasonable.
–Note: The risk for serious CV events with early discontinuation of thienopyridines is greater for patients with drug-eluting stents than those with bare-metal stents.
•After PCI, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses.
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Term
2011 Update (Cont):
Bypass Grafts
(2) |
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Definition
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•For patients undergoing coronary artery bypass grafting, aspirin should be started within 6 hours after surgery to reduce saphenous vein graft closure. Dosing regimens ranging from 100 to 325 mg daily for 1 year appear to be efficacious.
•For patients undergoing coronary artery bypass grafting, clopidogrel (75 mg daily) is a reasonable alternative in patients who are intolerant of or allergic to aspirin.
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Term
Antiplatelet
2011 Update (Cont):
Peripheral Artery Disease
(2) |
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Definition
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•For patients with symptomatic atherosclerotic peripheral artery disease of the lower extremity, antiplatelet therapy with aspirin (75–325 mg daily) or clopidogrel (75 mg daily) should be started and continued.
•The benefits of aspirin in patients with asymptomatic peripheral artery disease of the lower extremities are not well established.
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Term
Antiplatelet
AHA 2011 Update (Cont):
Anticoagulants
(3) |
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Definition
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•Antiplatelet therapy is recommended in preference to anticoagulant therapy with warfarin or other vitamin K antagonists to treat patients with atherosclerosis.
•If there is a compelling indication for anticoagulant therapy, such as atrial fibrillation, prosthetic heart valve, left ventricular thrombus, or concomitant venous thromboembolic disease, warfarin should be administered (to achieve appropriate INR) in addition to the low-dose aspirin (75–81 mg daily).
•Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with increased risk of bleeding and should be monitored closely |
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Term
Antiplatelet
2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction
(4)
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Definition
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• Aspirin (162 and 325 mg) should be given to the patient with suspected STEMI as early as possible and should be continued indefinitely (75 to 162 mg/d), regardless of the strategy for reperfusion and regardless of whether additional antiplatelet agents are administered. True aspirin allergy is the only exception to this recommendation.
•Clopidogrel combined with aspirin is recommended for STEMI patients who undergo coronary stent implantation. In patients in whom aspirin is contraindicated because of aspirin sensitivity, clopidogrel is probably useful as a substitute for aspirin to reduce the risk of occlusion.
•Clopidogrel is not recommended for treatment before cardiac catheterization or for patients who may have CABG surgery in 5-7 days.
• It is reasonable to start treatment with abciximab as early as possible in patients undergoing primary PCI (with or without stenting). Tirofiban or eptifibatide may be useful as antiplatelet therapy to support primary PCI for STEMI.
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