Anticoagulant therapies: how do they work?

Mary Byrne, St James’s Hospital

Outline of presentation

Anticoagulants Warfarin Heparin Dabigatran

Laboratory monitoring

Warfarin

Most widely used anticoagulant in world

1% of UK population (8% of >80yrs)

40,000 people on Warfarin in Ireland

Clinical indications Treatment of venous thrombosis (VTE),

pulmonary embolism (PE) and their extension.

Prophylaxis and treatment of thromboembolic complications associated with rheumatic heart disease, atrial fibrillation (AF) and/or prosthetic heart valve replacement.

Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolisation after myocardial infarction.

Aim of Warfarin therapy

Maintain a level of anticoagulation Minimise the risk of thrombosis Minimise the risk of haemorrhagic

complication Dependant on the length of time

and extent that a persons INR stays outside the therapeutic range

History of Warfarin discovery

History of Warfarin discovery 1920s: prairies of North America

and Canada Cattle dying of internal bleeding

with no precipitating cause Query dietary problem “Sweet clover disease” Farmers recommended not to feed

cattle the mouldy sweet clover hay

History of Warfarin discovery

Karl Link experimented with “uncoagulated” blood from affected cattle

Team isolated compound 3,3’-methylene-bis[4-hyfroxycoumarin]

Oxidised in mouldy hay to form dicoumarol.

History of Warfarin discovery

Research work funded by the: Wisconsin Alumni Research

Foundation Patented in 1941

Variation of dicoumarol (warfarin) patented as rat poison in 1948

Transition to clinical application (Coumadin)

The need for anticoagulation

Why do thromboses occur? How are they treated? How are they prevented?

Thrombosis and haemostasis

Virchow’s Triad for thrombosis

What is haemostasis? Balance between four major components

Vascular endothelium Platelets Coagulation pathway

Procoagulant Anticoagulant

Fibrinolysis

Coagulation pathway

Procoagulant proteins Anticoagulant proteins

Balance between activation and control of coagulation

Coagulation pathway

Coagulation pathway

Mechanism of action of Warfarin

Interferes with the biochemistry of vitamin K dependant coagulation factors in the liver

Vitamin K dependant coagulation factors Factor II VII IX X Protein C and Protein S

Involved in coagulation and anticoagulation pathways in haemostasis

Coagulation pathway

Warfarin

Vitamin K cycle and warfarin

Active coagulation factors

Warfarin

Warfarin therapy

Inter-individual differences Narrow therapeutic range Bleeding risk Outside anticoagulation range

Higher mortality Increased risk of stroke Increased rate of hospitalisation

Warfarin

Environmental factors Vitamin K intake Illness Concurrent medication Genetic variation (VKORC1 and CYP2C9)

Warfarin interactions

Pharmacokinetic interactions Drugs which interfere with clearance Antibiotics which affect intestinal flora

Pharmacodynamic interactions Drugs which have anti-platelet effect

(aspirin and NSAIDS) Drugs associated with falls in the

elderly

Drug interactions

Reduce anticoagulant effect Reduce absorption (cholestyramine)

Potentiate anticoagulant effect Inhibit clearance (metronidazole, amiodarone)

Inhibit anticoagulant effect Enhance clearance (barbiturates)

Warfarin and bleeding Major bleeding events 7.2/100 patient years Fatal bleeding events 1.3/100 patient years

Bleeding May be lower in specialised anticoagulation

clinics More likely within the first 90 days Can occur when INR is raised or within the

therapeutic range

Wadelius M and Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges.The pharacogenetics Journal (2007) 7, 99-111

Warfarin and bleeding

Reversal of warfarin

Discontinue warfarin Vitamin K Prothrombin complex concentrates

Monitoring Warfarin therapy

Laboratory testing Point of care testing Self testing

Test = INR (International Normalised Ratio)

INR PT (Prothrombin Time)

INR calculated from the Prothrombin Time (PT)

Reported as time (sec), INR Sensitive to factor II V VII X fibrinogen Normal range variations PT:

Measures the plasma clotting time in the presence of a highly sensitive activating reagent

INR

Surrogate measure of the effectiveness of Warfarin therapy

Different reagent and analytical systems are widely used

INR

ISI: International Sensitivity Index Compares local reagent with

international reference preparation

Coagulation pathway

PT

Delivery of Warfarin monitoring

In-patient Out-patient

Warfarin clinic (SJH: 1500 active patients)

Primary Care Team Warfarin clinic

Delivery of Warfarin monitoring

Point of care / self testing Coagucheck XS Plus Hemosense INRatio Protime 3 (ITC)

Published 2009 162 patients recruited Crossover study Self selected group On long tem anticoagulant

Other anticoagulants

Indirect Xa inhibitors (Heparin) Direct thrombin inhibitors

(Dabigitran, Argatroban) Direct Xa inhibitors

Different modes of action on coagulation cascade

Other anticoagulants

Indirect Xa inhibitors (Heparin) Direct thrombin inhibitors

(Dabigatran, Argatroban)

Different modes of action on coagulation cascade

Indirect Xa inhibitors

Enhance action of antithrombin Heparin

unfractionated UFH low molecular weight LMWH

Heparin Discovered in 1916 Utilised when there is need for rapid

anticoagulant effect Prevention of VTE and treatment of DVT and PE Early treatment of unstable angina and MI Cardiac surgery, bypass, vascular surgery, and

coronary angioplasty Selected patients with disseminated

intravascular coagulation

Heparin and Low-Molecular-Weight Heparin, Mechanisms of Action, Pharmacokinetics,Dosing, Monitoring, Efficacy, and SafetyHirsh J et al CHEST 2001; 119:64S–94S

Low Molecular Weight Heparin

Prevention of VTE and treatment of DVT and PE

Early treatment of unstable angina and MI

Heparin: mechanism of action

Mechanism is mediated through antithrombin in the coagulation cascade

Inhibits platelet function

Coagulation pathway

Heparin

Antithrombin1000X

Unfractionated heparin Continuous IV route

Low molecular weight heparin SC route

enoxaparin (Clexane) tinzaparin (Innohep)

Heparin and bleeding The risk of heparin-associated bleeding

increases with Dose Concomitant thrombolytic therapy or

other drugs Recent surgery Trauma Invasive procedures Concomitant haemostatic defects

Heparin and bleeding Reversal of heparin

Stop treatment (Half life = 90 minutes) Protamine Sulphate

Limitations of heparin

Osteopoenia Heparin Induced

Thrombocytopoenia

Monitoring heparin therapy

Relationship between heparin dose, efficacy and safety

Need for laboratory monitoring APTT (Unfractionated heparin)

Anti Xa assay (Low molecular weight heparin)

APTT

Activated Partial Thromboplastin Time APTT ratio calculated from the APTT Sensitive to factor VIII IX XI XII Normal range variations APTT:

Measures the clotting time of plasma after the activation of the coagulation cascade with Silica.

Coagulation pathway

Heparin

Antithrombin1000X

APTT

Direct Thrombin Inhibitors (DTI)

Dabigatran Inhibits thrombin directly, no

cofactor required as in heparin Predictable anticoagulant response Dabigatran etexilate, oral prodrug

that is converted to dabigatran

Dabigatran

Rapid onset of action Lack of interaction with food and

drugs No need for routine monitoring Broad therapeutic window Fixed dose administration Renal excretion

Dabigatran licence (EU)

2008 Prevention of VTE after elective TKR

or THR 2011

Stroke prevention in and systemic embolism in adult patients with nonvalvular atrial fibrillation (AF)

Direct Thrombin Inhibitors (DTI)

Direct Thrombin Inhibitor

Dabigatran trials

REDEEM (post MI) RE-LY (AF) RE-NOVATE (DVT prophylaxis) RE-MODEL RE-MOBILISE

Non-inferiority trial, 18113 patients recruited

AF and risk of stroke Rates of stroke and systemic embolism

Dose of 110mg: same as warfarin Dose of 150mg: lower than warfarin

Rates of major haemorrhage Dose of 110mg: lower than warfarin Dose of 150 mg: same rate as warfarin

Considerations with dabigatran

Non compliance No reversible agent Safety vs efficacy at extremes of

body weight Renal impairment Cost

Dabigatran and bleeding

No reversal agent or antidote currently

Supportive care and control of bleeding

Eliminate by natural excretion through kidney unless renal impairment

Plasma half life: 12 – 17 hrs

Laboratory monitoring Not necessary generally Rarely needed

Suspected overdose Bleeding Need for emergency surgery Impaired renal function Pregnancy Obesity Children

Laboratory monitoring

APTT of limited use Specific test using a snake venom

called Ecarin Not widely available

Dabigatran headlinesBleeding Risk with Dabigatran in the Frail

ElderlyN ENGL J MED 2012; 366:864-866 March 1, 2012

Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication - Safety Review of Post-Market Reports of Serious Bleeding EventsPosted 12/07/2011

Irreversible catastrophic brain haemorrhage after minor injury in a patient on dabigatran

Journal of Neurosurgery,published online March 6, 2012;

Thank you for your attention!