Antiplatelet2024_Robert Parker.pdf

Antiplatelet Drugs Christine McCulley, PharmD [email protected] Wayne Parker, PharmD Objectives 1. Explain the molecular mechanism of action of each drug in each drug class.** 2. Describe the antiplatelet actions of these drugs. 3. Describe the routes of administration and elimination processes...

Antiplatelet Drugs Christine McCulley, PharmD [email protected] Wayne Parker, PharmD Objectives 1. Explain the molecular mechanism of action of each drug in each drug class.** 2. Describe the antiplatelet actions of these drugs. 3. Describe the routes of administration and elimination processes of the drugs of each class. 4. Describe the main adverse effects of the drugs of each class. 5. Describe the clinically important drug interactions of the drugs of each class. 6. Describe the main contraindications of the drugs of each class. 7. Describe the use of antiplatelet drugs. Drugs for coagulation disorders Antiplatelet drugs - Aspirin, clopidogrel, ticagrelor, prasugrel, cangrelor, eptifibatide, tirofiban, dipyridamole, cilostazol, vorapaxar Anticoagulants Parenteral Oral Fibrinolytic drugs - Heparin, low molecular weight heparin (enoxaparin, dalteparin), fondaparinux, argatroban, bivalirudin - Warfarin, rivaroxaban, apixaban, edoxaban, dabigatran - Alteplase, tenecteplase, reteplase Drugs for bleeding disorders Coagulation factors; Drugs that - Factor concentrates, Vitamin K, Desmopressin increase synthesis/release of coagulation factors Inhibitors of fibrinolysis - Tranexamic acid, Aminocaproic acid Big Picture Both platelet activation and coagulation cascade regulate blood coagulation Medications are divided into two main groups: antiplatelet (main effect is on platelet activation) and anticoagulant (main effect is on clotting factors) Therapeutic uses of antiplatelet and anticoagulant medications are distinct, but may also overlap General mindset for antiplatelet therapy, think about: (1) secondary prevention of coronary artery disease and stroke, (2) management of acute coronary syndrome Most significant adverse effect associated with antiplatelet and anticoagulants = bleeding Precautions include coagulopathies or any disease that increases risk (hemophilia, thrombocytopenia, hx bleed, leukemia, aplastic anemia, infective endocarditis, etc.) Patient with need for surgery - doses may need to be held Platelet Activation Normal vascular endothelial lining à anticoagulant phenotype (circulating platelets and clotting factors do not adhere to an appreciable extent) Vascular injury à more procoagulant phenotype (platelet adherence and activation) Process of platelet activation is multi-step, involving numerous factors and signaling mechanisms Molecular Mechanisms of Platelet Activation Molecular Mechanisms of Platelet Activation Tissue injury à Proteins such as collagen and von Willebrand factor (VWF) are released from injured vascular endothelium that bind to receptors on the platelet membrane, leading to the synthesis and secretion of molecules to recruit and activate plts Thromboxane A2 (TXA2) and adenosine diphosphate (ADP) are synthesized within platelets and secreted to induce platelet aggregation (the 2 major ADP receptors on plt membrane are P2Y12 and P2Y1 receptors). TXA2 activates thromboxane A2 receptor leading to G protein signaling to activate GPIIb/IIIa receptors to allow for fibrinogen binding. These activation mechanisms (TXA2 and ADP--> G protein signaling) induce a change in the GPIIb/IIIa integrin on the platelet membrane, allowing it to bind fibrinogen, which cross-links adjacent platelets to form a platelet plug Simultaneously, the coagulation cascade is activated, which results in thrombin generation and a fibrin clot, which stabilizes the platelet plug. Thrombin activates platelets via PAR-1 and PAR-4 receptors on platelet surface and stimulates release of ADP and TXA2. Antiplatelet Medication Molecular Targets Inhibition of TXA2 synthesis via irreversible inhibition of COX-1 enzyme (aspirin) Blockade of the P2Y12 receptor (ADP receptor) on the platelet surface (ADP is normal substrate), which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation (clopidogrel, ticagrelor, prasugrel) Blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelet surface, inhibiting fibrinogen binding, thereby reducing platelet aggregation (eptifibatide, tirofiban) Antagonist of the protease-activated receptor-1 (PAR-1) (thrombin is normal substrate) expressed on platelets, which inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation (vorapaxar) Inhibit the enzyme (phosphodiesterase) responsible for breakdown of cAMP in platelet, increasing cAMP which is an anti-aggregant (dipyridamole, cilostazol) Clopidogrel, ticagrelor, prasugrel Cilostazol, dipyridamole vorapaxar eptifibatide, tirofiban Antiplatelet Drug Classes Cyclooxygenase Inhibitors Phosphodiesterase Inhibitors GPIIb/IIIa Inhibitors P2Y12 Receptor (ADP Receptor) Inhibitors PAR-1 Receptor Inhibitor Thienopyridines: Clopidogrel Prasugrel Aspirin (acetylsalicylic acid) Dipyridamole Cilostazol Eptifibatide (IV) Tirofiban (IV) Cyclo-pentyl-triazolopyrimidine: Ticagrelor ATP analogue: Cangrelor (IV) Vorapaxar Aspirin MOA: irreversible inhibition of COX-1 and COX-2 enzymes, but antiplatelet action specifically due to irreversible inhibition of COX-1 which inhibits synthesis of TXA2 Antiplatelet effect lasts until new platelets can be generated, duration 24-36 hours Adverse effects: GI, tinnitis, risk of hypersensitivity reaction (especially in those with asthma, rhinitis, nasal polyps), bleeding (GI mostly, but also rarely ICH) Indication: Acute coronary syndrome- in emergency department: chew 162-325 mg immediately (even if patient takes a daily low dose aspirin) Usually in combination with P2Y12 inhibitor initially and up to 12 months Secondary prevention of atherosclerotic CVD, which includes CAD, stroke/TIA, and PAD Primary prevention of CVD? Off label: VTE prophylaxis for total hip or total knee arthroplasty (in patients at lower-risk for clot) Clinical Pearl: space out daily aspirin from other non selective NSAIDs (take ibuprofen 8h before or 30 min after) PO or PR Antiplatelet dose ranges from 81 mg – 325 mg (lower than analgesic/ant-inflammatory dose) Clopidogrel (Plavix)- P2Y12 (ADP) Receptor Inhibitor, irreversible Clopidogrel Prasugrel Ticagrelor Indications: Acute coronary syndrome (ACS) – as part of dual antiplatelet regimen with aspirin Continued post-ACS to reduce the risk of recurrent ACS or stent thrombosis To reduce the rate of MI and stroke in patients with a history of recent MI, recent stroke/TIA, or established peripheral atherosclerotic disease (frequently used for secondary prevention of ischemic stroke/TIA) Prodrug, requires conversion to active metabolite for therapeutic effect Via CYP450, with CYP2C19 thought to be the primary enzyme responsible Variable response could be due to genetic polymorphisms in CYP2C19 (Boxed Warning, higher prevalence in Eastern Asians) or a drug interaction PPIs – specifically omeprazole, inhibit CYP enzyme to dec. conversion to active metab Smoker’s paradox? Smoking induces CYP enzymes to inc. conversion to active metab Notable, rare adverse effect: TTP, hypersensitivity (cross reactivity with prasugrel) Dosed once daily Prasugrel (Effient)- P2Y12 (ADP) Receptor Inhibitor, irreversible Indication: reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI Contraindicated in patients history of TIA or CVA, active bleeding, or likely to undergo urgent CABG; generally not recommended for >= 75 year olds Higher risk of bleeding (Boxed Warning) Notable, rare adverse effect: TTP, hypersensitivity Like clopidogrel, also a prodrug, but different CYP enzymes responsible for conversion to active metabolite (genetic variations not clinically relevant) Dosed once daily Ticagrelor (Brilinta) - P2Y12 (ADP) Receptor Inhibitor, reversible Indications: To reduce the risk of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. Ticagrelor also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS. To reduce the risk of first MI or stroke in patients with coronary artery disease at high risk for such events. Binds to an area distinct from the ADP binding site; reversible binding allows ticagrelor to redistribute to new platelets as they are formed PLATO trial: the composite primary end point (first event of death from vascular causes, MI, or stroke) occurred significantly less often in patients receiving ticagrelor vs. clopidogrel, no difference in bleeding risk Boxed warning for bleeding risk, do not use if active bleeding or urgent CABG Specifically noted in the package insert that concomitant aspirin dose must be 98% Onset / Time to max 2h / 3-7d effect 30 min/ 2h 30 min/ 2 h 2 min / 2 min Platelet function return to baseline 5 days 5 days 5-9 days 1h Contraindications (other than hx hypersensitivity to the drug) Active bleeding Active bleeding History of intracranial hemorrhage Active bleeding Prior TIA or stroke Active bleeding Thrombotic Thrombocytopenia Purpura Drug-induced TTP is a thrombotic microangiopathy caused by small vessel platelet thrombi à leads to thrombocytopenia from platelet consumption in microthrombi à leads to hemolytic anemia as RBCs fragmented by turbulent circulation as they pass across thrombi Most common drug causes: certain chemotherapeutic agents, immunosuppressive agents, drugs of abuse, emicizumab (hemophilia A prophylaxis) Possible link to P2Y12 receptor antagonists - i.e., clopidogrel and especially *ticlopidine which is now *off market GPIIb/IIIa Receptor Inhibitors: eptifibatide and tirofiban, (abciximab) MOA: prevents cross-linking by interfering with ability of fibrinogen to bind GPIIb/IIIa receptor IV bolus, then continuous infusion with monitoring Indications: acute coronary syndrome, patients undergoing primary PCI, as an alternative Not routinely used Need to renally adjust dose (renally excreted) AE: bleeding Contraindications (eptifibatide): active bleeding within last 30 days, history of stroke within 30 days or hx hemorrhagic stroke, severe HTN > 200/110, major surgery in last 6 weeks, HD Dipyridamole MOA: phosphodiesterase inhibitor = less enzymatic breakdown of cAMP = more cAMP à inhibit platelet function and causes vasodilation Also inhibits adenosine deaminase May also stimulate release of prostacyclin (PGI2) Formulated as a capsule in combination with aspirin: aspirin 25mg/extended release dipryamidole 200 mg (brand name: Aggrenox) Indication: secondary prevention of ischemic stroke or TIA Off label: hemodialysis graft patency, symptomatic carotid artery stenosis Adverse effects (dipyramidole): headache (39%), hypotension due to vasodilation GI side effects, tinnitus possible due to aspirin Note low dose of aspirin Not seen often in practice Alone, IV infusion, used as a diagnostic agent for evaluation of coronary artery disease (+ radiotracer after infusion) Cilostazol MOA: phosphodiesterase III inhibitor à increases cAMP à inhibits platelet aggregation and causes vasodilation Also inhibits vascular smooth muscle cell proliferation Indication: intermittent claudication in peripheral artery disease Studies showed improvement in walking distance and quality of life Boxed warning: contraindicated in heart failure of any severity AE: headache**, diarrhea**, dizziness, palpitations High fat meals increase absorption, take between meals Drug interactions w/ CYP inhibitors (grapefruit juice, diltiazem, omeprazole) increase cilostazol level Can be used with aspirin and/or clopidogrel Vorapaxar, PAR-1 receptor antagonist Not routinely used Indication: History of MI or established Peripheral Arterial Disease PK: long t1/2 = about 8 days (and long receptor dissociation time) Inhibition of plt aggregation lasts up to 4 weeks after discontinuation Brand only: Zontivity Boxed warning: Bleeding risk. Do not use in patients with a history of stroke, TIA, or intracranial hemorrhage; or active bleeding. Antiplatelet Use in Acute Coronary Syndrome Acute STEMI – dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor Loading dose of aspirin: chew uncoated 162-325 mg immediately Choice of P2Y12 is based in part on the reperfusion strategy chosen (see chart) DAPT continued usually 12 months depending on bleeding risk and ischemic predictors Antiplatelet Use in Acute Coronary Syndrome Acute NSTEMI/ unstable angina – dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor Loading dose of aspirin: chew uncoated 162-325 mg immediately Choice of, and timing of, P2Y12 inhibitor depends on treatment strategy (invasive vs non-invasive) Non-invasive: preference for ticagrelor over clopidogrel based on PLATO trial, prasugrel may have higher risk of bleeding based on TRILOGY-ACS trial DAPT continued usually 12 months depending on bleeding risk and ischemic predictors Choice of P2Y12 Inhibitor in ACS More potent (ticagrelor or prasugrel) preferred for acute coronary syndrome who require PCI, initially and up to one year For stable patients with CAD undergoing elective PCI, clopidogrel used most often/most studied in clinical trials Dual Antiplatelet Therapy (DAPT) = aspirin + P2Y12 inhibitor DAPT likely decreases the risk of these ischemic events by preventing stent thrombosis, as well as by lowering the risk of adverse events due to plaque rupture at sites remote from the stented location Optimal duration of DAPT after stent placement depends on patientspecific ischemic and bleeding risks Bleeding is the most frequent complication of DAPT. Bleeding risk is higher with clopidogrel + aspirin > aspirin alone or clopidogrel alone. Bleeding risk is higher with more potent P2Y12 receptor blockers (prasugrel and ticagrelor) than with clopidogrel. Secondary prevention of ischemic stroke Monotherapy with either aspirin, clopidogrel, or aspirin/dipyridamole is generally recommended, with choice based on patient factors, contraindications, cost, availability Prasugrel is contraindicated in patients with history of TIA or stroke