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Click to edit Master title styleINSTITUT JANTUNG NEGARA
National Heart Institute
7th August 2010
Anticoagulant Seminar for Healthcare Professionals
Organised by:
WelcomeWelcomeWelcomeWelcome
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National Heart Institute
- Narrow therapeutic index
- Drug interactions
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National Heart Institute
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National Heart Institute
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Fondaparinux
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Ximelagatran
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- Direct thrombin inhibitor
- RELY
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Faculty:
Dr Robaayah Zambahari
Dr Yasmin Ayob
Dr Jameela Sathar
Dr Ng Heng Joo
Dr Emily Tan Lay Koon
Puan Mary Easaw-John
Kong Ming Chai
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Sponsors:
Roche
Sanofi-Aventis
Glaxo
Bohringer
Rigel
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Organising Committee:
Emily Tan Kay Koon
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Vicky Alagandran / Hanis / Safarina
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National Heart Institute
Current Concepts in Anticoagulant Therapy
+ =
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Platelets + Fibrin → Thrombus
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Definition of Anticoagulation
➣➣➣➣ Therapeutic interference ("blood-thinning")
with the clotting mechanism of the blood
to prevent or treat
thrombosis and embolism.
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Platelets + Fibrin → Thrombus
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Antithrombotic Agents: Mechanism of Action
➣➣➣➣ Anticoagulants:
– prevent clot formation and extension
➣➣➣➣ Antiplatelet drugs:
– interfere with platelet activity
➣➣➣➣ Thrombolytic agents:
– dissolve existing thrombi
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➣➣➣➣ Anticoagulants:
– prevent clot formation and extension
➣➣➣➣ Antiplatelet drugs:
– interfere with platelet activity
➣➣➣➣ Thrombolytic agents:
– dissolve existing thrombi
Anticoagulants
Antiplatelets
Thrombolytics/ Fibrinolytics
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National Heart Institute
Antithrombotics (thrombolytics, anticoagulants,and antiplatelet drugs)
Antiplatelet GP IIb/IIIa inhibitors Abciximab, Eptifibatide, Tirofiban
ADP receptor inhibitors
[thienopyridines]
Clopidogrel, Ticlopidine, Prasugrel,
Ticagrelor
Prostaglandin
analogue PGI2
Prostacyclin, Iloprost,
COX inhibitors Aspirin, Triflusal
Thromboxane
inhibitors
Dipyridamole
Phosphodiesterase
inhibitors
Cilostazol, Dipyridamole, Triflusal
Anticoagulants Vit K antagonists
(inhibit II,VII, IX, X)
Warfarin
Factor Xa inhibitors Heparin group LMWH ( Enoxaparin, Dalteparin,
Nadroparin, Reviparin)
Oligosaccharides(Fondaparinux)
Direct Xa
inhibitors
Xabans (Otamixaban, Rivaroxaban)
Direct thrombin
inhibitors
Bivalirudin, Argatroban, Dabigatran
Thrombolytics/
Fibrinolytics
Streptokinase, Urokinase, Alteplase,
Retiplase, Tenecteplase
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Clotting Cascade
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Enhances Antithrombin Activity
Warfarin
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Vitamin KVitamin K
Synthesis of Synthesis of Functional Functional Coagulation Coagulation FactorsFactors
VIIVII
IXIX
XX
IIII
Vitamin K-Dependent Clotting Factors
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WarfarinWarfarin
Synthesis of Synthesis of Non Non Functional Functional Coagulation Coagulation FactorsFactors
AntagonismofVitamin K
Warfarin Mechanism of Action
Vitamin KVitamin K
VIIVII
IXIX
XX
IIII
Warfarin : an anticoagulant by blocking the ability of Vitamin Kto carboxylate the Vitamin K-dependent clotting factors [Factors II, VII, IX, X], reducing their coagulant activity
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Warfarin: Indications
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Atrial Fibrillation
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Mitral Valve Disease
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The
CarboMedics bileaflet valve.
Mechanical heart valves
Starr-Edwards caged-ball valve.
The Omniscience valve
Medtronic-Hall valve.
St. Jude bileaflet valve
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Deep Vein Thrombosis
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Pulmonary Embolism
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Warfarin: Indications
➣➣➣➣ Prophylaxis and/or treatment of:
– Venous thrombosis and its extension
– Pulmonary embolism
– Thromboembolic complications associated with AF and cardiac valve replacement
➣➣➣➣ LV thrombus Post MI, to reduce the risk of death,
recurrent MI, and thromboembolic events such as
stroke or systemic embolization
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Warfarin: Major Adverse Effect—Hemorrhage
➣➣➣➣ Factors that may influence bleeding risk:
– Intensity of anticoagulation
– Concomitant clinical disorders
– Concomitant use of other medications
– Quality of management
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Special Considerations in the Elderly: Bleeding
➣➣➣➣ Increased age associated with increased
sensitivity at usual doses
➣➣➣➣ Comorbidity
➣➣➣➣ Increased drug interactions
➣➣➣➣? Increased bleeding risk independent of the
above
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Prothrombin Time (PT)
➣➣➣➣ Historically, a most reliable and “relied upon” clinical test
However:
– Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent
clotting factors has occurred
– Concept of correct “intensity” of anticoagulant therapy has
changed significantly (low intensity)
– Problem addressed by use of INR (International Normalized Ratio)
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J Clin Path 1985; 38:133J Clin Path 1985; 38:133--134; WHO Tech Rep Ser. #687 983.134; WHO Tech Rep Ser. #687 983.
INR: International Normalized Ratio
➣➣➣➣ A mathematical “correction” (of the PT ratio) for
differences in the sensitivity of thromboplastin reagents
➣➣➣➣ Relies upon “reference” thromboplastins with known
sensitivity to antithrombotic effects of oral anticoagulants
➣➣➣➣ INR is the PT ratio one would have obtained if the
“reference” thromboplastin had been used
➣➣➣➣ Allows for comparison of results between labs and
standardizes reporting of the prothrombin time
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(( ))PatientPatient’’s PT in Secondss PT in Seconds
Mean Normal PT in SecondsMean Normal PT in SecondsINR =INR =
ISIISI
INR = International Normalized RatioISI = International Sensitivity Index
INR Equation
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Adapted from: Poller L. Thromb Haemost vol 60, 1988.Adapted from: Poller L. Thromb Haemost vol 60, 1988.
Relationship Between PT Ratio and INR
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*Harrison L, et al. Ann Intern Med 1997;126:133*Harrison L, et al. Ann Intern Med 1997;126:133--136.136.
Warfarin: Dosing Information
➣➣➣➣ Individualize dose according to patient response
(as indicated by INR)
➣➣➣➣ Use of large loading dose not recommended*
– May increase hemorrhagic complications
– Does not offer more rapid protection
➣➣➣➣ Low initiation doses are recommended for
elderly/frail/liver-diseased/malnourished patients
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CoaguChek
Simple, fast and convenient wayof direct monitoring of their INR results.
Requires a drop of capillary blood and
one monute →→→→ INR
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* Elderly, frail, liver disease, malnourished: 2 mg/day* Elderly, frail, liver disease, malnourished: 2 mg/day
Warfarin: Dosing & Monitoring
➣➣➣➣ Start low
– Initiate 5 mg daily*
– Educate patient
➣➣➣➣ Stabilize
– Titrate to appropriate INR
– Monitor INR frequently (daily then weekly)
➣➣➣➣ Adjust as necessary
➣➣➣➣ Monitor INR regularly (every 1–4 weeks) and
adjust
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* Effective below 2.5* Effective below 2.5
Relationship Between INR & Efficacy/Safety
➣➣➣➣ Low-intensity treatment:
– Efficacy rapidly diminishes below INR 2.0*
– No efficacy below INR 1.5
➣➣➣➣ High-intensity treatment:
– Safety compromised above INR 4
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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
Warfarin: Current Indications/Intensity
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Current Daily Dose (mg)Current Daily Dose (mg)
2.0 2.0 5.05.0 7.57.5 10.010.0 12.512.5
WarfarinWarfarin
INRINR Dose Adjustment*Dose Adjustment* Adjusted Daily Dose (mg)Adjusted Daily Dose (mg)
1.01.0--2.02.0 Increase x 2 daysIncrease x 2 days 5.05.0 7.57.5 10.010.0 12.512.5 15.015.0
2.02.0--3.03.0 No changeNo change —— —— —— —— ——
3.03.0--6.06.0 Decrease x 2 daysDecrease x 2 days 1.251.25 2.52.5 5.05.0 7.57.5 10.010.0
6.06.0--10.010.0†† Decrease x 2 daysDecrease x 2 days 00 1.251.25 2.52.5 5.05.0 7.57.5
10.010.0--18.018.0§§ Decrease x 2 daysDecrease x 2 days 00 00 00 00 2.52.5
>18.0>18.0§§ Discontinue warfarinDiscontinue warfarin and consider hospitalization/reversaland consider hospitalization/reversalof anticoagulationof anticoagulation
†† Consider oral vitamin K, 2.5Consider oral vitamin K, 2.5––5 mg5 mg
§§ Oral vitamin K, 2.5Oral vitamin K, 2.5––5 mg5 mg
* Allow 2 days after dosage change for clotting factor equilibra* Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or decreastion. Repeat prothrombin time 2 days after increasing or decreasing ing warfarin dosage and use new guide to management (INR = Internatiwarfarin dosage and use new guide to management (INR = International Normalized Ratio). After increase or decrease of dose for onal Normalized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qdqd, alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qd).).
Dosage Adjustment Algorithm
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Drug Interactions with Warfarin: Potentiation
Level of
Evidence Potentiation
Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid[600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen, tetracycline, flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen, iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
I
II
III
IV
†In a small number of volunteer subjects, an inhibitory drug interaction occurred.
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Drug Interactions with Warfarin: Inhibition
Level of
Evidence Inhibition
Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate
Dicloxacillin
Azathioprine, cyclosporine, etretinate, trazodone
I
II
III
IV
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Drug Interactions with Warfarin:
No Effect
Level of
Evidence No Effect
Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine‡
Ibuprofen, ketoconazole
Diltiazem, tobacco, vancomycin
I
II
III
IV
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Effective Patient Education
➣➣➣➣ Teach basic concepts of safe, effective anticoagulation
➣➣➣➣ Discuss importance of regular INR monitoring
➣➣➣➣ Counsel on use of other medications, alcohol
➣➣➣➣ Develop creative strategies for improving compliance
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Reversing action of warfarin
• Plasma
– Rapid but short-lasting
• Vitamin K
– Not rapid, but lasts 1-2 weeks. Do not use if wishing to restart warfarin within next week.
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New Anticoagulation Drugs
• Direct Thrombin Inhibitors
– Dabigatran, hirudin, bivalirudin, and argatroban
• Synthetic pentasaccharide
– Fondaparinux
• Acivated Protein C
• Tissue Factor Pathway Inhibitor (TFPI)
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Why do we need new anticoagulation drugs?
• Heparin-induced thrombocytopenia
• Heparin prophylaxis is imperfect
• Heparin-associated osteoporosis
• Warfarin takes several days for its effect
• Warfarin is not as effective in some situations e.g
antiphospholipid syndrome
• Warfarin interacts with many other drugs
• Warfarin is dangerous if not monitored
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Synthetic Pentasaccharide
• E.g Fonaparinux
• Synthetic, single molecular entity
• Targets Factor Xa
• Does not cause thrombocytopenia
• Shown promise in DVT prevention during
orthopedic procedures.
• Also being examined in ischaemic heart disease
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Dabigatran
• Promising oral direct thrombin inhibitor
• No dosing problems
• No monitoring needed.
• Recent atrial fibrillation study showed it to
possibly be superior to warfarin.
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Enhances Antithrombin Activity
Dabigatran
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Conclusion
Anticoagulant therapy is used extensively.
Current mainstays of treatment are heparin or heparin-
like drugs and oral warfarin.
Both have problems but when monitored closely are
generally safe.
New anticoagulation drugs are arriving and in particular
dabigatran may revolutionise oral anticoagulation
therapy
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Thank youThank youThank youThank you