“ Anticoagulation and the Heart ” M. Samir Arnaout M.D Associate Professor of Medicine C Cardiology Division di l Di i i American University of Beirut-Medical Center
ADP ADP Thrombin Thrombin TXA 2 TXA PAF PAF PLATELET PLATELET ASPIRIN ASPIRIN Vasopressin Vasopressin Epi Epi ASPIRIN ASPIRIN HEPARINS HEPARINS ASPIRIN ASPIRIN ASPIRIN ASPIRIN CLOPIDOGREL CLOPIDOGREL ASPIRIN ASPIRIN ASPIRIN ASPIRIN ASPIRIN ASPIRIN 5HT HT ASPIRIN ASPIRIN Collagen Collagen GP IIb/IIIa GP IIb/IIIa GP IIb/IIIa GP IIb/IIIa Thi k Thickness of line Thickness of line Thi k f li f li indicates strength indicates strength Fibrinogen Fibrinogen of activator of activator GP IIb/IIIa GP IIb/IIIa PLATELET PLATELET
Oral Anticoagulant Oral Anticoagulant Oral Anticoagulant Oral Anticoagulant
Clotting Cascade Clotting Cascade Clotting Cascade Clotting Cascade
Vitamin K Vitamin K-Dependent Vitamin K Vitamin K Dependent Dependent Dependent Clotting Factors Clotting Factors Vitamin K Vitamin K VII VII VII VII Synthesis of Synthesis of IX IX Functional Functional Coagulation Coagulation Coagulation Coagulation X X Factors Factors II II
Warfarin Mechanism of Warfarin Mechanism of Warfarin Mechanism of Warfarin Mechanism of Action Action Vitamin K Vitamin K Antagonism g VII VII VII VII of Synthesis of Synthesis of IX IX Vitamin K Non Non Functional Functional Functional Functional X X Coagulation Coagulation II II Factors Factors Warfarin Warfarin
Warfarin: I ndications Warfarin: I ndications Warfarin: I ndications Warfarin: I ndications � Prophylaxis and/or treatment of: Prophylaxis and/or treatment of: – Venous thrombosis and its extension V Venous thrombosis and its extension V th th b b i i d it d it t t i i – Pulmonary embolism Pulmonary embolism – Thromboembolic complications associated with AF and Th Thromboembolic complications associated with AF and Th b b b li b li li li ti ti i t d i t d ith AF ith AF d d cardiac valve replacement cardiac valve replacement � Post MI, to reduce the risk of death, recurrent MI, P Post MI, to reduce the risk of death, recurrent MI, P t MI t t MI t d d th th i k i k f d f d th th t MI t MI and thromboembolic events such as stroke or and thromboembolic events such as stroke or systemic embolization systemic embolization t t i i b li b li ti ti � Prevention and treatment of cardiac embolism Prevention and treatment of cardiac embolism The Fifth American College of Chest Physicians Consensus Conference
Antithrombotic Agents: Antithrombotic Agents: Antithrombotic Agents: Antithrombotic Agents: Mechanism of Action Mechanism of Action � Anticoagulants: prevent clot formation Anticoagulants: prevent clot formation and extension and extension � Antiplatelet drugs: interfere with � Antiplatelet drugs: interfere with Antiplatelet drugs: interfere with Antiplatelet drugs: interfere with platelet activity platelet activity � Thrombolytic agents: dissolve existing Th Th Thrombolytic agents: dissolve existing b l b l i i di di l l i i i i thrombi thrombi
Prothrombin Time (PT) Prothrombin Time (PT) ( ( ) ) � Historically, a most reliable and “relied Historically, a most reliable and “relied upon” clinical test upon” clinical test However: However: – Proliferation of thromboplastin reagents with Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has vitamin K i i i i K K d dependent clotting factors has d d d l l i i f f h h occurred occurred – Concept of correct “intensity” of anticoagulant Concept of correct “intensity” of anticoagulant Concept of correct “intensity” of anticoagulant Concept of correct “intensity” of anticoagulant therapy has changed significantly (low intensity) therapy has changed significantly (low intensity) – Problem addressed by use of INR (International Problem addressed by use of INR (International Problem addressed by use of INR (International Problem addressed by use of INR (International Normalized Ratio) Normalized Ratio)
I NR: I nternational I NR: I nternational Normalized Ratio Normalized Ratio li li d d i i � A mathematical “correction” (of the PT ratio) for A mathematical “correction” (of the PT ratio) for differences in the sensitivity of thromboplastin differences in the sensitivity of thromboplastin differences in the sensitivity of thromboplastin differences in the sensitivity of thromboplastin reagents reagents � Relies upon “reference” thromboplastins with Relies upon reference thromboplastins with Relies upon “reference” thromboplastins with Relies upon reference thromboplastins with known sensitivity to antithrombotic effects of oral known sensitivity to antithrombotic effects of oral anticoagulants anticoagulants � INR is the PT ratio one would have obtained if the INR i INR is the PT ratio one would have obtained if the INR i th th PT PT ti ti ld h ld h bt i bt i d if th d if th “reference” thromboplastin had been used “reference” thromboplastin had been used � Allows for comparison of results between labs and � Allows for comparison of results between labs and Allows for comparison of results between labs and Allows for comparison of results between labs and standardizes reporting of the prothrombin time standardizes reporting of the prothrombin time J Clin Path J Clin Path 1985 1985; ; 38 38: :133 133- -134 134; WHO Tech Rep Ser. # ; WHO Tech Rep Ser. #687 983 687 983. .
I NR E I NR E I NR Equation I NR Equation ti ti ISI ISI ISI ISI Patient’s PT in Seconds Patient’s PT in Seconds Patient’s PT in Seconds Patient’s PT in Seconds ( ( ( ) ) ) INR = INR = Mean Normal PT in Seconds Mean Normal PT in Seconds INR = International Normalized Ratio INR = International Normalized Ratio ISI = International Sensitivity Index
Warfarin: Dosing I nformation Warfarin: Dosing I nformation Warfarin: Dosing I nformation Warfarin: Dosing I nformation � Individualize dose according to patient Individualize dose according to patient response(as indicated by INR) response(as indicated by INR) response(as indicated by INR) response(as indicated by INR) � Use of large loading dose not Use of large loading dose not recommended* recommended* recommended* recommended* – May increase hemorrhagic complications May increase hemorrhagic complications – Does not offer more rapid protection Does not offer more rapid protection � Low initiation doses are recommended for Low initiation doses are recommended for elderly/frail/liver elderly/frail/liver- -diseased/malnourished diseased/malnourished pat e ts pat e ts patients patients *Harrison L, et al. Ann Intern Med Harrison L, et al. Ann Intern Med 1997 1997; ;126 126: :133 133- -136 136.
Loading Dose then Loading Dose then Loading Dose then Loading Dose then Maintenance Dose Maintenance Dose Daily Dose
Maintenance Dose Only Maintenance Dose Only Maintenance Dose Only Maintenance Dose Only Daily Dose
Loading Dose then Loading Dose then Loading Dose then Loading Dose then Maintenance Maintenance Maintenance Maintenance Maintenance Dose Maintenance Dose Dose Only Dose Only Daily Dose Daily Dose
Conversion from Heparin Conversion from Heparin Conversion from Heparin Conversion from Heparin to Warfarin to Warfarin � May begin concomitantly with heparin May begin concomitantly with heparin th th therapy therapy � Heparin should be continued for a minimum Heparin should be continued for a minimum of four days of four days – Time to peak antithrombotic effect of warfarin is Time to peak antithrombotic effect of warfarin is delayed delayed 96 96 hours (despite INR) hours (despite INR) � When INR reaches desired therapeutic When INR reaches desired therapeutic range, discontinue heparin (after a range, discontinue heparin (after a minimum of four days) minimum of four days)
Relative Contraindications Relative Contraindications Relative Contraindications Relative Contraindications to Warfarin Therapy to Warfarin Therapy � Pregnancy Pregnancy � Situations where the risk of Situations where the risk of hemorrhage is greater than the hemorrhage is greater than the hemorrhage is greater than the hemorrhage is greater than the potential clinical benefits of therapy potential clinical benefits of therapy – Uncontrolled alcohol/drug abuse U Uncontrolled alcohol/drug abuse U t t ll d ll d l l h l/d h l/d b b – Unsupervised dementia/psychosis Unsupervised dementia/psychosis
Signs of Warfarin Signs of Warfarin Signs of Warfarin Signs of Warfarin Overdosage Overdosage � Any unusual bleeding: Any unusual bleeding: – Blood in stools or urine Blood in stools or urine – Excessive menstrual bleeding Excessive menstrual bleeding Excessive menstrual bleeding Excessive menstrual bleeding – Bruising Bruising – Excessive nose bleeds/bleeding gums E E Excessive nose bleeds/bleeding gums i i bl bl d /bl d /bl di di – Persistent oozing from superficial injuries Persistent oozing from superficial injuries – Bleeding from tumor, ulcer, or other Bleeding from tumor, ulcer, or other lesion lesion
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