18/12/2012 1

Clotting, Anticoagulation, and Novel Anticoagulants for AF and VTE

Dr Tim Moorby

Consultant Haematologist

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Introduction

A new age?

Where have we been?

Where are we now?

Where are we going?

But first some basic understanding

Revising the Theory, Tests of coagulation

How the different anticoagulants work

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Revising the Theory

An over view of the Coagulation Cascade

Tests of Clotting and What they mean

Warfarin

Anti-Thrombin Enhancers

Direct Thrombin Inhibitors

Factor X inhibitors

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Basics

Normal blood doesn’t clot by a complex interaction of prothrombotic and antithrombotic molecules from plasma, endothelium, platelets

Arterial and Venous blood clots are different sorts of clot

Most clots can be understood by Virchow’s triad – flow, blood properties, endothelial properties

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Coagulation Cascade

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Problems with The Coagulation Cascade

Measures coagulation under completely artificial conditions

Tests clotting away from endothelium, platelets, with artificial initiation

However completely holistic tests of clotting don’t allow us to drill down into what the problems may be

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Prothrombin Time

Measures the Extrinsic pathway

Almost completely reliant on Factor VII levels

Usually used to monitor Warfarin, DIC , liver function in paracetamol overdose

Vitamin K dependent clotting factors II, VII, IX, X

Usually translated into INR = International Normalised Ratio

Might be altered by Factor X inhibitors eg Rivaroxaban, Apixaban

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Activated Partial Thromboplastin Time

Measures the Intrinsic Pathway

Mostly used to monitor Intravenous Unfractionated Heparin

Low Molecular Weight Heparins do not alter the APTT at all

Prolonged by Haemophilia A and B, von Willebrands, lupus anticoagulant, liver disease, DIC

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Thrombin Time

Measures Final Common pathway

Prolonged by heparin ( not LMWH unless in excess) or low fibrinogen levels

Prolonged by Factor II inhibitors eg Dabigatran, DIC

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So What does a GP use to assess Clotting?

Most sensitive measure of clotting problems is a Clinical History

Nosebleeds, menorrhagia

Bleeding after tooth extraction

Bleeding after surgery

A coagulation screen is of limited use as many clotting problems don’t show eg platelet function defects, collagen problems

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Warfarin

Discovered in 1950’s

Blocks Vitamin K dependent clotting factor synthesis

Vitamin K is a fat soluble vitamin

But found in green leafy veg

Induces artificial deficiency of Clotting Factors II, VII, IX, X, Protein C & S

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Problems with Warfarin

Annual death rate from warfarin = 1/400

Life threatening bleeding risk = 1/100

Total annual bleeding rate = 4/100

Affected by many drugs

Affected by diet

Affected by liver function

Affected by intrinisic metabolism

An individuals sensitivity to warfarin varies with person, place and time

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Advantages of Warfarin

Cheap !

Easy to check compliance, under- or over-anticoagulation with INR

Tolerant of missing the odd dose

Well known – we all take care with warfarin

Well established infrastructure for safe monitoring

Easy to reverse with Vitamin K po or iv, or in an emergency , clotting factor concentrates

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Anti-Thrombin Enhancers

Act by enhancing the effectivenessof the natural anticoagulant anti thrombin

Unfractionated Heparin ( IV or SC)

Low Molecular Weight Heparin ( LMWH)

Eg Enoxaparin, Tinzaparin, Dalteparin

Fondaparinux

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Enhancing Anti-Thrombin

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Problems with Heparins

Polysaccharides so digested in gut

Have to be given IV or SC

Porcine derived

UFH has very variable metabolism

LMWH / Fondaparinux accumulate in renal failure

LMWH / Fondaparinux are difficult to reverse

Expensive in GP use

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Advantages of Heparins

Anticoagulation is independent of diet and liver function

UFH is extremely reversible with Protamine

LMWH / Fondaparinux have very predictable anticoagulation efficacy

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Direct Thrombin Inhibitors

Derived from leech anticoagulant Hirudin

Inhibit Thrombin = Factor II

Ximelagtran almost came to market in 2007 – but for problems with liver toxicity

Dabigatran now licensed

Orthopaedic DVT / PE prevention

Stroke prevention in AF

Renally excreted

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Using Dabigatran

Orthopaedic prophylaxis = 220mg od

150mg od if moderate renal failure eGFR 30-50ml/min or age over 75

Stroke prophylaxis in AF = 150mg bd

110mg bd if age over 80, or moderate renal failure of if taking Verapamil

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Advantages of Dabigatran

No need to monitor

Can use Thrombin Time to assess if a problem

Predictable effect

Very low rates of intracranial bleeding in AF trials

Possible small mortality benefit in patients with poor INR control ( TTR <67%)

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Disadvantages of Dabigatran

Contraindicated for severe renal failure CrCL<30 ml/mon

Interactions with verapamil, ketoconazole, amiodarone, rifampicin, carbamazepine, phenytoin

Wears off if a dose is missed Dyspepsia – higher discontinuation rates than

warfarin Probably higher risk of GI bleeds than warfarin at

150mg bd dose in AF studies Difficult to reverse if bleeding – maybe dialysis

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Direct Factor X Inhibitors

Rivaroxaban Licensed for

Orthopaedic DVT prevention

Stroke prophylaxis in AF

Acute treatment of DVT and PE

Apixaban Licensed for Orthopaedic DVT prevention

Edoxaban Licensed in Japan !

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Using Rivaroxaban

Orthopaedic prophylaxis = 10mg od

Stroke prophylaxis in AF = 20mg od

( Renal failure with eGFR 30-49 ml/min= 15mg daily)

DVT treatment = 15mg bd for 3 weeks then 20mg od until 3 months

No monitoring required

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Advantages of Rivaroxaban

OD dosing

No need to monitor

Less intracranial bleeding in AF trial than warfarin

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Disadvantages of Rivaroxaban

No easily available test if you want to assess anticoagulation – ?anti-Xa level

Wears off if dose is missed

Interactions with azole antifungals, ritonavir

Contraindicated in CrCl <15ml/min

Possibly small increase in GI bleed risk than warfarin in AF studies

Difficult to reverse if bleeding – but clotting factor concentrates may work

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How does this Impact on General Practice ?

Where we are now?

Where might we go?

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Atrial Fibrillation

Underdiagnosed

Undertreated

Catastrophic consequences with Stroke

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Assessing AF Stroke Risk

CHADS2 score

Congestive Heart Failure

Hypertension over 140/90

Age >75yrs

Diabetes

Stroke / TIA / Thromboembolism = 2

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Using CHADS2

ESC recommendations

Score = 0 = Aspirin or no anticoagulant

Score = 1 = Aspirin or OAC

Score > 2 = OAC

CHADS-VASc adds scores for Vascular Disease, extra score for age 75+ and female gender

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HAS-BLED Score to assess bleeding risk of anticoagulants

Hypertension >160 (1)

Abnormal renal (1) or liver (1) function

Stroke in past (1)

Bleeding history (1)

Labile INR – TTR <60% (1)

Elderly >65yrs (1)

Drugs – NSAIDs or antiplatelets ( 1) or Alcohol > 8 units /week (1)

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Using HAS-BLED

Score 3 = 3.74% annual bleeding risk

This is about the annual bleeding risk of warfarin, dabigatran, or rivaroxaban in their recent AF studies.

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Current Practice for AF

Identify AF

Anticoagulate Slow warfarin loading regime 3mg tablets

for 1 week

Target INR 2.5

Consider if suitable for cardioversion

If not suitable for cardioversion then rate control with b-blockers or diltiazem

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Future Possibilities for AF

Identify AF

Anticoagulate

Warfarin, Dabigatran, Rivaroxaban

Consider for Cardioversion

Rate Control

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Future Possibilities for ACS/ Unstable Angina

All major new anticoagulants ( dabigatran, rivaroxaban, apixaban) have been trialled for IHD in acute coronary syndrome

Mostly used on top of dual antiplatelet therapy

All caused excess bleeding above standard therapy

The big question is can these trials be translated to a general avoidance of aspirin with these anticoagulants

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Current Practice for DVT/PE

Suspect DVT or PE

Anticoagulate with LMWH

Confirm DVT / PE

Anticoagulate with warfarin

for 3/12, 6/12, 12/12, lifelong

Identify and eliminate risk factors

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Future Possibilities for DVT / PE ?

Suspect DVT / PE

Start Rivaroxaban

Confirm DVT / PE

Continue Rivaroxaban for 3/12

Identify and eliminate risk factors

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Will we Ever Get Rid of Warfarin?

Probably not…

Heart valves

Renal failure

Patients needing monitoring

Perhaps high bleeding risk patients needing anticoagulation

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Travel Thromboprophylaxis

Poor evidence base

Generally considered that Aspirin is useless for this indication

Low absolute risk

Undoubtedly some high risk patients

Currently I advise GP’s prescribe 4 x Enoxaparin 40mg sc od

1 practice, 1 outbound, 1 return, 1 spare

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?Future of Travel Thromboprophylaxis

Possibility of using oral anticoagulants

x 2 doses (1 outbound, 1 return)

Appropriate doses are anybody’s guess!

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How Can it all go Wrong?

Finance New OAC about £2 per day

Current Hospital clinic approx £17 per INR and dose, with average follow up of 4 weekly (£247 pa) and TTR 68%

Bleeding Overall bleeding risks appear similar at 3.7% per

year

Compliance Without constant INR monitoring will this decline?

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Management of Bleeding

LMWH / Rivaroxaban Wear off by renal excretion Partial reversal with protamine

Warfarin Vitamin K for mild bleeding Clotting factors for major bleeding

Dabigatran Wear off by renal excretion Renal dialysis Novoseven ( approx £6000 per dose)

Rivaroxaban Wear off by GI and renal excretion Clotting facors Novoseven