Anticoagulant Seminar for Healthcare Professionals PowerPoint...Click to edit Master title style...

Click to edit Master title styleINSTITUT JANTUNG NEGARA

National Heart Institute

7th August 2010

Anticoagulant Seminar for Healthcare Professionals

Organised by:

WelcomeWelcomeWelcomeWelcome



- Narrow therapeutic index

- Drug interactions



Fondaparinux



Ximelagatran



- Direct thrombin inhibitor

- RELY



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

Thank youThank youThank youThank you



Sponsors:

Roche

Sanofi-Aventis

Glaxo

Bohringer

Rigel




Organising Committee:

Emily Tan Kay Koon


Vicky Alagandran / Hanis / Safarina



Current Concepts in Anticoagulant Therapy

+ =



Platelets + Fibrin → Thrombus



Definition of Anticoagulation

➣➣➣➣ Therapeutic interference ("blood-thinning")

with the clotting mechanism of the blood

to prevent or treat

thrombosis and embolism.



Platelets + Fibrin → Thrombus



Antithrombotic Agents: Mechanism of Action

➣➣➣➣ Anticoagulants:

– prevent clot formation and extension

➣➣➣➣ Antiplatelet drugs:

– interfere with platelet activity

➣➣➣➣ Thrombolytic agents:

– dissolve existing thrombi



➣➣➣➣ Anticoagulants:

– prevent clot formation and extension

➣➣➣➣ Antiplatelet drugs:

– interfere with platelet activity

➣➣➣➣ Thrombolytic agents:

– dissolve existing thrombi

Anticoagulants

Antiplatelets

Thrombolytics/ Fibrinolytics



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



Clotting Cascade



Enhances Antithrombin Activity

Warfarin



Vitamin KVitamin K

Synthesis of Synthesis of Functional Functional Coagulation Coagulation FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K-Dependent Clotting Factors



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



Warfarin: Indications



Atrial Fibrillation



Mitral Valve Disease



The

CarboMedics bileaflet valve.

Mechanical heart valves

Starr-Edwards caged-ball valve.

The Omniscience valve

Medtronic-Hall valve.

St. Jude bileaflet valve



Deep Vein Thrombosis



Pulmonary Embolism



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



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



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



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)



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



(( ))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



Adapted from: Poller L. Thromb Haemost vol 60, 1988.Adapted from: Poller L. Thromb Haemost vol 60, 1988.

Relationship Between PT Ratio and INR



*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



CoaguChek

Simple, fast and convenient wayof direct monitoring of their INR results.

Requires a drop of capillary blood and

one monute →→→→ INR



* 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



* 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



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



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



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.



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



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



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



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.



New Anticoagulation Drugs

• Direct Thrombin Inhibitors

– Dabigatran, hirudin, bivalirudin, and argatroban

• Synthetic pentasaccharide

– Fondaparinux

• Acivated Protein C

• Tissue Factor Pathway Inhibitor (TFPI)



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



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



Dabigatran

• Promising oral direct thrombin inhibitor

• No dosing problems

• No monitoring needed.

• Recent atrial fibrillation study showed it to

possibly be superior to warfarin.



Enhances Antithrombin Activity

Dabigatran



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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