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Drugs influencing coagulation
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Drugs influencing coagulation .pptx
- 1. Drugs influencing coagulation AHMED FOUAD Cardiology resident
- 2. Classes of Drugs • Prevent coagulation • Dissolve clots • Prevent bleeding and hemorrhage - Hemostatic • Overcome clotting deficiencies (replacement therapies)
- 3. Classes of Drugs • Prevent coagulation • Dissolve clots • Prevent bleeding and hemorrhage - Hemostatic • Overcome clotting deficiencies (replacement therapies)
- 4. Haemostasis Arrest of blood loss from damaged blood vessels
- 5. Blood Clotting • Vascular Phase • Platelet Phase • Coagulation Phase • Fibrinolytic Phase
- 6. Vascular Phase Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor
- 7. Coagulation Phase Two major pathways Intrinsic pathway Extrinsic pathway Both converge at a common point 13 soluble factors are involved in clotting Normally inactive and sequentially activated
- 8. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Intrinsic Pathway Extrinsic Pathway
- 9. Intrinsic Pathway Activated partial thromboplastin test (aPTT) Extrinsic Pathway Prothrombin test (PT/INR)
- 10. Vitamin K Synthesis of Functional Coagulation Factors VII IX X II Vitamin K-Dependent Clotting Factors
- 12. Thrombosis Pathological formation of haemostatic plug within the vasculature in the absence of bleeding
- 13. Arterial • White • Platelet and WBC • With atheroscerosis • Causes ischemia Venous • Red • White head and red tail • Embolus
- 14. Drugs effect ; • fibrin formation • Platelet function • Fibrinolysis Drugs influencing coagulation Anticoagulants • Antiplatelet drugs • Thrombolytic drugs
- 15. Drugs influencing coagulation • Anticoagulants • Antiplatelet drugs • Thrombolytic drugs
- 16. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K
- 17. Anticoagulants • Antithrombin activators – Heparin / LMWH – Synthetic pentasaccharide analogues • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K
- 18. Heparin
- 19. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin
- 20. Heparin • Given s.c. or i.v. • Binds to plasma proteins, endothelial cells & macrophages • Elimination – Depolymerisation in endothelial cells & macrophages (rapid, saturable) – Renal (slow, non-saturable) and RES
- 21. Heparin: variable anticoagulant effect • Variable protein binding • Clearance varies with chain length • Therefore, anticoagulant response monitored by activated partial thromboplastin time (APTT) • Target 1.5 – 2.5 times control
- 23. Heparin: clinical uses • Venous thrombosis ± embolism • Acute coronary syndromes • Arterial thrombosis • Extracorporeal devices (e.g. haemodialysis)
- 24. Initial Parenteral Anticoagulant Therapy in Patients With Definite NSTE-ACS Recommendations COR LOE In patients with NSTE-ACS, anticoagulation, in addition to antiplatelet therapy, is recommended for all patients irrespective of initial treatment strategy. Treatment options include: • Enoxaparin: 1 mg/kg subcutaneous (SC) every 12 hours (reduce dose to 1 mg/kg SC once daily in patients with creatinine clearance [CrCl] <30 mL/min), continued for the duration of hospitalization or until PCI is performed. An initial intravenous loading dose is 30 mg. I A
- 25. Initial Parenteral Anticoagulant Therapy in Patients With Definite NSTE-ACS (cont’d) Recommendations COR LOE (cont’d) • Bivalirudin: 0.10 mg/kg loading dose followed by 0.25 mg/kg per hour (only in patients managed with an early invasive strategy), continued until diagnostic angiography or PCI, with only provisional use of GP IIb/IIIa inhibitor, provided the patient is also treated with DAPT. • Fondaparinux: 2.5 mg SC daily, continued for the duration of hospitalization or until PCI is performed. I B B
- 26. Initial Parenteral Anticoagulant Therapy in Patients With Definite NSTE-ACS (cont’d) Recommendations COR LOE (cont’d) • If PCI is performed while the patient is on fondaparinux, an additional anticoagulant with anti-IIa activity (either UFH or bivalirudin) should be administered because of the risk of catheter thrombosis. • UFH IV: initial loading dose of 60 IU/kg (maximum 4,000 IU) with initial infusion of 12 IU/kg per hour (maximum 1,000 IU/h) adjusted per activated partial thromboplastin time to maintain therapeutic anticoagulation according to the specific hospital protocol, continued for 48 hours or until PCI is performed. I B B In patients with NSTE-ACS (i.e., without ST elevation, true posterior MI, or left bundle-branch block not known to be old), intravenous fibrinolytic therapy should not be used. III: Harm A
- 27. Heparin: adverse effects • Bleeding • Heparin-induced thrombocytopenia (HIT) – Immune-mediated • Osteoporosis
- 29. Type I ◦ Rapid onset: 2-5 d ◦ Characterized by mild decrease in platelet count without thrombosis or immune response Type II ◦ Considerably more severe ◦ Occurs after more than 5 d administration (avg 9 d) ◦ Immune mediated ◦ Antibody binding between heparin-platelet complex ◦ Causes platelet activation, complement activation, white clot ◦ High morbidity Incidence thrombosis 20% Mortality after thrombosis 40%
- 32. LMWHs • Dalteparin • Enoxaparin • Tinzaparin
- 38. Synthetic pentasaccharide analogues Bioavailability(s.c.) elimination half life (h) LMWH 80-90% renal 4 Fondaparinux 100% renal 17 Idraparinux 100% renal 80
- 39. Acts by antithrombin III inhibition of Xa. Administered SQ or IV q day. Rapidly and completely absorbed; peak steady state 3 hr; 94% bound to ATIII. Eliminated unchanged in urine in 72 hr with normal renal function. DC before surgery 2 days, longer with renal disease
- 41. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K
- 42. Direct thrombin inhibitors • Recombinant hirudins • Bivalirudin • Ximelagatran / Melagatran • Dabigatran
- 43. Recombinant hirudins • Given i.v. , s.c. • Elimination renal • Half life 1-2 h
- 44. Bivalirudin • Given i.v. • Elimination renal & hepatic • Half life 25 min
- 45. Ximelagatran • Promising oral direct thrombin inhibitor • Converted to the active form melagatran in vivo • No dosing problems • No monitoring needed. • Recent atrial fibrillation study showed it to possibly be superior to warfarin.
- 46. Dabigatran • Given orally • Elimination renal • Half life 12 h • Substrate for P-glycoprotein in kidney, GIT
- 47. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K
- 48. Apixaban • Direct Factor Xa inhibitor • Oral bioavailability 60% • Half life 12 h • Elimination hepatic > renal
- 49. Rivaroxaban • Direct Factor Xa inhibitor • Oral bioavailability 80% • Half life 7-11 h • Elimination renal > hepatic
- 50. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K
- 51. Warfarin Reduces the post-translational carboxylation of glutamate residues of factors II, VII, IX, X
- 52. Warfarin Synthesis of Non Functional Coagulation Factors Antagonism of Vitamin K Warfarin Mechanism of Action Vitamin K VII IX X II
- 53. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Intrinsic Pathway Extrinsic Pathway Vit. K dependent Factors Affected by Oral Anticoagulants
- 54. Warfarin • Anticoagulant effect seen after 2-3 days • Monitored by international normalized ratio (INR) • Well absorbed form GIT • Highly protein bound • Metabolised by CYP-450
- 62. Drug interaction- with Warfarin Drugs that Increase Warfarin Activity Decrease binding to Albumin Inhibit hepatic metaboli; Decrease synthesis of Clotting Factors NSAID, Cimetidine, antifungals Antibiotics (oral) Category Mechanism Representative Drugs
- 63. Drug interaction with Warfarin cont: Drugs that promote bleeding Inhibition of platelets NSAID, Aspirin Inhibition of clotting heparin Factors Drugs that decrease Warfarin activity Induction of metabolizing Barbiturates Enzymes Griseofulvin Promote clotting factor Vitamin K Synthesis Reduced absorption cholestyramine colestipol
- 64. Warfarin: adverse effects • Bleeding • Rashes • Alopecia • Teratogenicity
- 65. Available Direct Acting Oral Anticoagulants (DOACs) • Dabigatran • Rivaroxaban • Apixaban • Edoxaban
- 67. DOAC Mechanism of Action Inhibits Factor Xa Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor Dabigatran
- 68. DOAC Indications and Dosing NVAF DVT PE Rivaroxaban Apixaban 20 mg once daily with evening meal 5mg twice daily Rivaroxaban Apixaban 15 mg twice daily x 21 days 10 mg twice daily x 7 days 20 mg once daily with evening meal 5 mg twice daily
- 69. DOAC Indications and Dosing NVAF DVT PE Dabigatran Edoxaban 150 mg twice daily 60 mg daily Dabigatran Edoxaban LMWH lead in x 5-10 days LMWH lead in x 5-10 days 150 mg twice daily 60 mg daily
- 70. DOAC Renal Dosing Rivaroxaban NVAF CrCl 15-50 mL/min 15 mg once daily CrCl < 15 mL/min Use warfarin DVT/PE CrCl < 30 mL/min Use warfarin 2.5 mg Apixaban twice daily** NVAF Must meet 2 of the following Age 80 years or older Actual body weight 60 kg or less Serum Creatinine 1.5 mg/dL or greater **No dose reduction in DVT/PE patients. However, patients with SCr > 2.5 or CrCl < 25 mL/min not studied
- 71. DOAC Renal Dosing Dabigatran NVAF CrCl 15-30 mL/min 75mg bid CrCl < 15 mL/min Use warfarin DVT/PE CrCl < 30 mL/min Use warfarin Edoxaban NVAF CrCl >95 mL/min DO NOT USE CrCl 15-50 mL/min 30mg daily CrCl < 15mL/min Use warfarin DVT/PE CrCl 15-50 mL/min 30mg daily CrCl < 15mL/min Use warfarin
- 72. DOAC Hepatic Dosing Child- Pugh Class Rivaroxaban Apixaban A No Adjustment No Adjustment B Use warfarin Use with caution- limited clinical experience C Use warfarin Use warfarin Child- Pugh Score calculator can be found at PresNet Anticoagulation Oral Anticoagulants Rivaroxaban (Xarelto) Child-Pugh Classification Score
- 73. DOAC Hepatic Dosing Child- Pugh Class Dabigatran Edoxaban A No Adjustment No Adjustment B No Adjustment Use Warfarin C Use warfarin Use warfarin Child- Pugh Score calculator can be found at PresNet Anticoagulation Oral Anticoagulants Rivaroxaban (Xarelto) Child-Pugh Classification Score
- 74. Focus on Venous Thromboembolism and Non-valvular Atrial Fibrillation
- 75. DOAC Selection • DVT of leg or PE with active cancer • Pregnant • DVT of leg or PE without active cancer
- 76. Anticoagulant Selection • Valvular atrial fibrillation • Valve replacement • Myocardial infarction requiring dual antiplatelet therapy • Breast feeding
- 77. Anticoagulant Selection Does patient have CrCl < 30, mechanical heart valve, moderate to severe hepatic impairment (Child- Pugh B or C), significant drug-drug interactions6? Will the patient have trouble paying for a DOAC? Yes Yes No No • Valvular atrial fibrillation • Valve replacement • Myocardial infarction requiring dual antiplatelet therapy • Pregnant or breast feeding • Non-valvular atrial fibrillation • Secondary VTE prevention • VTE prophylaxis following knee/hip replacement surgery
- 78. Anticoagulant Selection Does patient have CrCl < 30, mechanical heart valve, moderate to severe hepatic impairment (Child- Pugh B or C), significant drug-drug interactions6? Yes Patient Characteristics Favoring DOAC • Highly like to be adherent with DOAC therapy and follow up plan • Reliable to notify health care provider about changes to health and pertinent medical issues • Confirmed ability to obtain DOAC on a longitudinal basis from a financial, insurance coverage and retail availability standpoint • Unstable diet or malnutrition • Frequent illness or health status changes • Frequent medicine changes or need for medications that interact with warfarin but not with DOAC • Frequent medical procedures with bleeding risk No Patient/ Family Preference
- 79. Blann, A. D et al. BMJ 2003;326:153-156
- 81. Enoxaparin TO/FROM DOAC Stop old medication and start new medication when the next dose is due Abo-Salem J Thromb Thrombolysis (2014)
- 82. DOAC TO DOAC Stop DOAC 1 and start DOAC 2 when the next dose is due Abo-Salem J Thromb Thrombolysis (2014)
- 83. DOAC to Warfarin/Warfarin to DOAC Abo-Salem J Thromb Thrombolysis (2014)
- 84. Warfarin to DOAC • Discontinue warfarin • Begin rivaroxaban when INR below 3.0 • Begin dabigatran or apixaban when INR below 2.0
- 85. DOAC to warfarin • Need overlap therapy until INR equal or above 2.0 1. DOAC • May interfere with INR reading • Must use DOAC trough for INR draw • Make clear to the patient that they MUST go in for an INR draw right before next DOAC dose is due. OR 2. LMWH • Transition like normal LMWH bridge per PMG policy. • Start LMWH when next DOAC dose due.
- 86. Anticoagulant Transitions • Warfarin to DOAC, DOAC to Warfarin ** INR < 3.0 for Rivaroxaban
- 87. Summary of anti thrombotic