Optimal Management in Patients with Oral-Anticoagulant Anticoagulant Boonjong Saejueng, MD Cardiac Unit, Chest Disease Institute, Nonthaburi, Thailand
Outlines ν Overview of mechanism of warfarin ν Monitoring of warfarin therapy with PT and INR and dosing ν Model of warfarin management ν Warfarin pharmocogenomics
Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII IX X II Synthesis of Non Functional Coagulation Factors Warfarin
Clotting Cascade
Vitamin K Mechanism of Action
Warfarin CYP1A1 CYP1A2 CYP3A4 R-warfarin R-warfarin warfarin R-warfarin Vitamin K Reductase S-warfarin S-warfarin S-warfarin S-warfarin CYP2C9 Oxidized Vitamin K Reduced Vitamin K CO 2 O 2 Calumenin Hypofunctional F. II, VII, IX, X Protein C, S, Z γ-glutamyl carboxylase Functional F. II, VII, IX, X Proteins C, S, Z
Warfarin ν Most commonly prescribed anticoagulant drug ν Prophylaxis and Treatment ν Effectiveness and safety depend on maintaining Prothrombin time (INR) υ Upper limit of therapeutics range : Risk of bleeding υ Lower limit of therapeutics range : Risk of thromboembolic event
Warfarin: Current Indications/Intensity Indication INR Range Target Prophylaxis of venous thrombosis (high-risk surgery) 2.0 3.0 2.5 Treatment of venous thrombosis Treatment of PE Prevention of systemic embolism Tissue heart valves AMI (to prevent systemic embolism) Valvular heart disease Atrial fibrillation Mechanical prosthetic valves (high risk) 2.5 3.5 3.0 Certain patients with thrombosis and the antiphospholipid syndrome AMI (to prevent recurrent AMI) Bileaflet mechanical valve in aortic position, NSR 2.0 3.0 2.5
Mechanical Prosthetic Heart Valves Patient Characteristics Recommendation Bileaflet mechanical valve in the aortic position, Goal INR 2.5; range, 2.0 3.0 left atrium of normal size, NSR, normal ejection fraction Tilting disk valve or bileaflet mechanical valve in Goal INR 3.0; range, 2.5 3.5* the mitral position Bileaflet mechanical aortic valve and AF Goal INR 3.0; range, 2.5 3.5* Caged ball or caged disk valves Goal INR 3.0; range, 2.5 3.5; and aspirin therapy (80 100 mg/d) Additional risk factors Goal INR 3.0; range, 2.5 3.5; and aspirin therapy (81 mg/d) Systemic embolism, despite adequate therapy Goal INR 3.0; range, 2.5 3.5; with oral anticoagulants and aspirin therapy (81 mg/d) * Alternative: goal INR 2.5; range, 2.0 3.0; and aspirin therapy (80 100 mg/d)
Risk of Intracranial Hemorrhage in Outpatients Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902 902 Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin p time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted ed in an increase in the risk of bleeding.
Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation INR below 2.0 results in a higher risk of stroke Hylek EM, et al. NEJM 1996;335:540-546. 546.
Outlines ν Overview of mechanism of warfarin ν Monitoring of warfarin therapy with PT and INR and dosing ν Model of warfarin management ν Warfarin pharmocogenomics
Prothrombin Time (PT) ν Historically, a most reliable and relied upon clinical test However: υ Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent K clotting factors has occurred υ Concept of correct intensity of anticoagulant therapy has changed significantly (low intensity) υ Problem addressed by use of INR (International Normalized Ratio)
INR: International Normalized Ratio ν A mathematical correction (of the PT ratio) for differences in the sensitivity of thromboplastin reagents ν Relies upon reference thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants ν INR is the PT ratio one would have obtained if the reference thromboplastin had been used ν Allows for comparison of results between labs and standardizes reporting of the prothrombin time J Clin Path 1985; 38:133-134; 134; WHO Tech Rep Ser. #687 983.
INR Equation INR = ( Patient s s PT in Seconds ) Mean Normal PT in Seconds ISI INR = International Normalized Ratio ISI = International Sensitivity Index
How Different Thromboplastins Influence the PT Ratio and INR Blood from a single patient Thromboplastin Reagent Patient s PT (Seconds) Mean Normal (Seconds) PTR ISI INR A 16 12 1.3 B 18 12 1.5 C 21 13 1.6 D 24 11 2.2 E 38 14.5 2.6
How Different Thromboplastins Influence the PT Ratio and INR Blood from a single patient Thromboplastin reagent Patient s PT (Seconds) Mean Normal (Seconds) PTR ISI INR A 16 12 1.3 3.2 2.6 B 18 12 1.5 2.4 2.6 C 21 13 1.6 2.0 2.6 D 24 11 2.2 1.2 2.6 E 38 14.5 2.6 1.0 2.6
Relationship Between PT Ratio and INR Adapted from: Poller L. Thromb Haemost vol 60, 1988.
Potential Problems with the INR Limitations ν Unreliable during induction ν Loss of accuracy with high ISI thromboplastins ν Incorrect ISI assignment by manufacturer ν Incorrect calculation of INR due to failure to use proper mean normal plasma value to derive PT ratio Solutions ν Use thromboplastin reagents with low ISI values (less than 1.5) ν Use thromboplastin reagents with low ISI values ν Use thromboplastin reagents with low ISI values and use plasma calibrants with certified INR values ν Use mean normal PT derived from normal plasma samples for every new batch of thromboplastin reagent
Warfarin: Dosing Information ν Individualize dose according to patient response (as indicated by INR) ν Use of large loading dose not recommended* υ May increase hemorrhagic complications υ Does not offer more rapid protection ν Low initiation doses are recommended for elderly/frail/liver- diseased/malnourished patients *Harrison L, et al. Ann Intern Med 1997;126:133-136. 136.
Loading Dose then Maintenance Dose Daily Dose
Maintenance Dose Only Daily Dose
Loading Dose then Maintenance Dose Daily Dose Maintenance Dose Only Daily Dose
Warfarin Dosing Schedule Mon Tue Wed Thu Fri Sat Sun Total Weekly Dose 5 5 5 5 5 5 5 35 mg 2.5 5 5 2.5 5 5 5 30 mg 2.5 5 2.5 5 2.5 5 5 27.5 mg
Outlines ν Overview of mechanism of warfarin ν Monitoring of warfarin therapy with PT and INR and dosing ν Model of warfarin management ν Warfarin pharmocogenomics
Why Anticoagulation Clinic (AC) ν Warfarin is one of the most commonly prescribed medications with narrow Rx index: efficacy vs. complications ν Successful anticoagulant management requires: - careful monitoring of the INR - ongoing patients education - good communication between patients and healthcare providers
Outlines ν Overview of mechanism of warfarin ν Monitoring of warfarin therapy with PT and INR and dosing ν Model of warfarin management ν Warfarin pharmocogenomics
Pharmacogenetics and Pharmacogenomics ν Pharmacogenetics: the effect of genetic variation on drug response, including disposition, safety and tolerability, and efficacy. ν Pharmacogemomics: the application of genome science (genomics) to the study of human variability in drug response.
Genotype frequencies of CYP2C9 polymorphisms CYP2C9 Genotype Activity Population frequency African White Asian Japanese Northern Thai Subject s Subjects Subjects Subjects Subjects *1/*1 Normal 87 65 97 97 95 *1/*2 Minor reduction 9 20 0 0 0 *2/*2 Moderately reduced 0 1 0 0 0 *1/*3 Moderately reduced 4 12 4 3 5 *2/*3 Moderately reduced 0 1 0 0 0 *3/*3 Very low 0 0 0 0 0 J. Kirchheiner, Cli. Pharm. 2005 H.Takahashi, Pharmacogenetics, 2003
Genotype frequencies of VKORC1 polymorphisms Ethnic Groups n A (%) B (%) European 199 38 59 Caucasian 120 38 52 African 96 13 49 East Asian 120 89 10 Chinese 147 87 10 Malay 85 66 30 Indian 43 45 48 Northern Thai 242 81 19 A. Wu, Future med, 2007