Anticoagulation Using new anticoagulants in AF, VTE and PE...1 . Recently bedridden for 3 days or more, or major surgery within the last 12 weeks requiring general or local anaesthetics

Anticoagulation Using new anticoagulants in AF, VTE

and PE

Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

Dr Matthew Fay GP Principal The Willows Medical Practice:-Queensbury

GPwSI and Co-Founder Westcliffe Cardiology Service Clinical Partner The Westcliffe Medical Group

Declaration of interests

• The practice has received funding from: Abbott, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Dawn, INRStar, Medtronic, Oberoi Consulting, Pfizer, Roche, Sanofi-Aventis, Servier.

• An advisor to: AF Association, Anticoagulation Europe, Arrhythmia Alliance, Heart Valve Voice, National Stroke Association, Syncope Trust

• A trustee of Thrombosis UK

Learning Points

• Thrombosis • DVT • AF • NOACs • Food for thought

Thrombosis

Haemostasis

Successful haemostasis depends on • vessel wall • coagulation system • fibrinolytic system


Blood Vessels

• constrict to limit blood loss • arteries, veins, capillaries • mechanism not fully understood


9

PLATELETS

On contact with fibrin or collagen platelets release granules which promote aggregation of adjacent platelets to form a mass which covers, for example, an endothelial defect.

Contact with Fibrin or Collagen

Release Granules

Aggregate to form a mass E.g. Covering Endothelial

Defect


10

PLATELETS

Platelet aggregation in this way is a normal phenomenon, and occurs continuously in the body to repair minor endothelial injury.

In excess, a mass is formed in a vessel: THROMBOSIS

Contact with Fibrin or Collagen

Release Granules

Aggregate to form a mass E.g. Covering Endothelial

Defect


Coagulation System



Coagulation

• Cascade • Series of inactive components converted to

active components Coagulation

Cascade

Fibrinogen Fibrin

Soluble Solid


Coagulation

• 1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin

• Tight regulation therefore required • Balance of procoagulant and anticoagulant

forces


Control of Coagulation

• Thrombin destroys factors V and VIII • Thrombin inhibitors

– anti-thrombin III* – alpha 1 anti-trypsin – alpha 2 macroglobulin – protein C and S* * inherited deficiency may predispose to thrombosis


Fibrinolysis

• Breakdown of fibrin • Plasminogen Plasmin Plasminogen activators • Fibrinolytic therapy widely used

– streptokinase – tPA


Endothelium

• Anti-thrombotic – plasminogen activators – prostacyclin – nitric oxide – thrombomodulin


What is a Thrombosis


What is a Thrombosis?

• Solid mass of blood constituents

• Formed within the vascular system

• In life


Thrombosis is different to Clot!

• Clotting means coagulation which can occur within or outside the vascular system in life or post mortem.


Why does thrombosis occur?

• Abnormalities of the vessel wall

– atheroma – direct injury – inflammation


Why does thrombosis occur?

• Abnormalities of blood flow – stagnation – turbulence

• Abnormalities of blood components – smokers – post-partum – post-op



24

PREDISPOSING FACTORS FOR THROMBOSIS

Factors which promote thrombosis can be found in the blood vessel wall, or be concerned with the flow of blood or its constituents.

This group of three factors is known as Virchow’s triad.

WALL

FLOW BLOOD CONSTITUENTS

Virchow’s Triad


25

TYPES OF THROMBI

Thrombi can occlude a vessel which may result in necrosis of the part served (infarction).

Mural thrombus can release fragments (emboli) which can travel in the bloodstream to block distal vessels.

Thrombus on heart valves due to infection can also embolise.

Occlusive

Mural

Vegetation

Infarction

Embolism

Embolism


26

OUTCOMES OF THROMBOSIS

Lysis Fibrosis

Recanalisation Embolism


Thrombosis-DVT

Deep Vein Thrombosis • DVT is the formation of a thrombus in a

deep vein. • Usually in the legs; partially or completely

obstructs blood flow. • Annual incidence is about 1 in 1000

people. • The most serious complication is

pulmonary embolism. • Only about a third of people with a clinical

suspicion of DVT have the condition.

Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

Risk factors for DVT • Risk factors include:

– Previous venous thromboembolism. – Cancer (known or undiagnosed). – Increasing age. – Being overweight or obese. – Male sex. – Heart failure. – Acquired or familial thrombophilia. – Chronic low-grade injury to the vascular wall (for

example vasculitis, hypoxia from venous stasis, or chemotherapy).


Temporary risk factors • Risk factors that temporarily raise the

likelihood of DVT: – Immobility, significant trauma, or direct trauma

to a vein. – Hormone treatment (for example oestrogen-

containing contraception or hormone replacement therapy).

– Pregnancy and the postpartum period. – Dehydration.


Differential Diagnosis?

• Physical trauma: – Calf muscle tear or strain. – Haematoma (collection of blood) in the

muscle. – Sprain or rupture of the Achilles tendon. – Fracture.


Differential Diagnosis? • Cardiovascular disorders:

– Superficial thrombophlebitis. – Post-thrombotic syndrome. – Venous obstruction or insufficiency, or external

compression of major veins (for example by a fetus during pregnancy, or cancer).

– Arteriovenous fistula and congenital vascular abnormalities.

– Acute limb ischaemia. – Vasculitis. – Heart failure.


• Other conditions including: – Ruptured Baker's cyst. – Cellulitis (commonly mistaken as DVT). – Dependent (stasis) oedema. – Lymphatic obstruction. – Septic arthritis. – Cirrhosis. – Nephrotic syndrome. – Compartment syndrome.


Differential Diagnosis?

When to suspect a DVT • Suspect a DVT if the person has:

– Signs or symptoms of a DVT: • Pain and swelling in one leg, although both legs

may be affected. • Tenderness, changes to skin colour and

temperature, and vein distension. – A risk factor for DVT

• previous VTE • Immobility

• To exclude an alternative cause:

– Carry out a physical examination. – Review the person's general medical history.


Managing a suspected DVT

• Refer immediately if pregnant or given birth within the past 6 weeks. – Requires same-day assessment and management as it is not possible to

accurately assess the risk of DVT in primary care.

• For everyone else, use the two-level DVT Wells score to assess likelihood of DVT and inform further management.


Using the two-level DVT Wells score


Criteria Score

Active cancer (treatment ongoing, within the last 6 months, or palliative). 1

Paralysis, paresis, or recent plaster immobilization of the legs 1

Recently bedridden for 3 days or more, or major surgery within the last 12 weeks requiring general or local anaesthetics

1

Localized tenderness along the distribution of the deep venous system (such as the back of the calf)

1

Entire leg is swollen. 1

Calf swelling by more than 3 cm compared with the asymptomatic leg (measured 10 cm below the tibial tuberosity).

1

Pitting oedema (greater than on the asymptomatic leg) 1

Collateral superficial veins (non-varicose). 1

Previously documented DVT 1

If an alternative cause is considered more likely than DVT. -2

Two-level DVT Wells score

• Validated, simple scoring system that takes into account previous DVT.

oDVT is likely if the score is two points or more. oDVT is unlikely if the score is one point or

less.


Other methods of assessment • Do not use:

– Individual symptoms and signs on their own. • On their own they are poor predictors of the

presence or absence of DVT. – A positive Homans' sign (pain in the calf or

popliteal region on passive, abrupt, forceful dorsiflexion of the ankle with the knee in a flexed position):

• Is insensitive and nonspecific. • Can be painful, and there is a theoretical possibility

of dislodging a thrombus.


If DVT likely (>2 points) • Refer for a proximal leg vein ultrasound scan to

be carried out within 4 hours. • If a proximal leg vein ultrasound scan cannot be

carried out within 4 hours of being requested: – Take a blood sample for D-dimer testing. – Give an interim 24-hour dose of a anticoagulant

• Ensure a proximal leg vein ultrasound scan is carried out within 24 hours of being requested.


Which anticoagulant? • Offer a choice of low molecular weight

heparin (LMWH) – Licensed LMWHs for DVT treatment include

dalteparin, enoxaparin, and tinzaparin. • Offer a choice of Xa Inhibitor

– Apixaban and Rivaroxaban – Fondaparinux is a synthetic pentasaccharide that

inhibits activated factor X but is parentral • Choice of anticoagulant depends on:

– Comorbidities – Contraindications – Cost

• Local policy may also influence choice.


If DVT unlikely (< 1point) • Offer D-dimer testing. • If negative D-dimer test - consider an alternative

diagnosis to explain symptoms. • If positive D-dimer test - refer for a proximal leg

vein ultrasound scan to be carried out within 4 hours.

• If a proximal leg vein ultrasound scan cannot be carried out within 4 hours of being requested: – Give an interim 24-hour dose anticoagulant

• Ensure a proximal leg vein ultrasound scan is carried out within 24 hours of being requested.


Thrombosis-AF

Personalised package of care and information

Diagnosis of AF

Stroke prevention

Rate control strategies

Ablation strategies

Nice AF Guideline DRAFT: January 2014

Symptomatic Asymptomatic

Symptomatic

Rhythm Control Strategy

On-going annual assessment NICE AF Guideline June 2014

Stroke Risk

Stroke risk in AF: CHADS2

CHADS2 risk criteria Score

Cardiac failure 1

Hypertension 1

Age >75 yrs 1

Diabetes mellitus 1

Stroke or TIA (previous history) 2

Stroke risk in AF: CHA2DS2VASc CHA2DS2VASc risk criteria Score

Cardiac failure 1

Hypertension 1

Age >75 yrs 2

Diabetes mellitus 1

Stroke or TIA (previous history) 2

Vascular disease (IHD, PAD) 1

Age >75 yrs 1

Sex Category 1

AF PIE: PAST

Fuster V. Circulation 2012; epubl April 18

AF PIE: FUTURE

AVERROES

Apixaban (%)

Aspirin (%)

Assessment that INR could be maintained in therapeutic range

17 17 X

Assessment that INR could not or was unlikely to be measured at requested intervals

43 43 X

Uncertainty about patients ability to adhere to instructions regarding VKA Therapy 16 15 X

CHADS2 score of 1 and VKA therapy not recommended by physician 21 22 X

Patients refusal to take VKA 38 37

Multiple reasons for unsuitability of VKA therapy 51 52 X

Cum

ulat

ive

Risk

0.

0 0.

01

0.03

0.

05

0 3 6 9 12 18 21

ASA 81-324 mg/d

Apixaban 2.5-5 mg bd

No. at Risk ASA Apix

2791 2720 2541 2124 1541 626 329 2809 2761 2567 2127 1523 617 353

Months

RR= 0.46 95%CI= 0.33-0.64 p<0.001

AVERROES: Stroke or SEE 5600 patients, 36 countries, 522 centres

Cum

ulat

ive

Risk

0.

0 0.

005

0.01

0 0.

015

0.02

0

0 3 6 9 12 18 21

ASA

Apixaban

No. at Risk ASA Apix

2791 2744 2572 2152 1570 642 340 2809 2763 2567 2123 1521 622 357

Months

RR= 1.14 95%CI= 0.74-1.75 P= 0.56

AVERROES - Major Bleeding

N Engl J Med. 2011;364:806-817

Bleeding Risk

HAS-BLED risk criteria Points awarded

Hypertension (i.e. Uncontrolled BP) 1

Abnormal renal and liver function (1 point each) 1 or 2

Stroke 1

Bleeding 1

Labile INRs 1

Elderly (e.g. age >65 years, frail condition) 1

Drugs or alcohol (1 point each) 1 or 2

Maximum 9 points

Bleeding risk in AF: HAS-BLED

NICE AF Guideline June 2014

Antiplatelet Use for Stroke Prevention in AF

Aspirin vs Placebo in Stroke Prevention in AF

Favors Placebo/ Control

Antiplatelet therapy reduces incidence of stroke by about 22%

Hart R, et al. Ann Intern Med. 2007;146:857-867.

All Trials

100% 50% 0% -50% -100%

AFASAK-1 SPAF I EAFT ESPS-II LASAF, daily

UK-TIA, 300 mg daily

Favors Antiplatelet

LASAF, alternate day

UK-TIA, 1200 mg daily JAST Aspirin Trials SAFT ESPS II, Dipyridamole ESPS II, Combination

Vitamin K Oral Anticoagulant Use for Stroke Prevention in AF

Warfarin vs Placebo in Stroke Prevention in AF

100% 50% 0% -50% -100%

AFASAK-1

SPAF BAATAF

CAFA

SPINAF

EAFT

ALL Trials

Favors Warfarin Favors Placebo/ Control

Hart R, et al. Ann Intern Med. 2007;146:857-867.

Warfarin reduces incidence of stroke by about 64%

Time in therapeutic range (TTR) matters

0 500 1000 1500 2000

Survival to stroke (days)

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

surv

ival

71–100%

Warfarin group

61–70% 51–60% 41–50% 31–40% <30% Non warfarin

Morgan CL et al. Thrombosis Research 2009;124:37–41.

- 58 -

Non Vitamin K Oral Anticoagulant Use for

Stroke Prevention in AF

The perfect anticoagulant • Effective • Oral • Fast onset of action • Short half life • Predictable pharmacokinetics • No drug/food interactions • Fully reversible • Do the NOACs fulfill these criteria?

Indications and Dosing

Dabigatran Apixaban Edoxaban Rivaroxaban

Prevention of VTE post THR/TKR

110mg bd 2.5mg bd 10mg od

Prevention of CVA in AF

150mg bd (110mg bd)

5mg bd (2.5mg bd)

60mg od 20mg od

Treatment of acute VTE 150mg bd

10mg bd for 7/7

5mg bd 60mg od

15mg bd for 3/52 20mg od

SPC Dabigatran, Rivaroxaban, Apixaban

Renal function

Anticoagulant Creatinine clearance (ml/min) 30-50 30-15 <15

Apixaban 5mg bd 2.5mg bd AVOID Dabigatran 150mg bd (110mg bd) AVOID Edoxaban 60mg 30mg AVOID Rivaroxaban 15mg od 15mg od AVOID

How do NOACs affect the coagulation screen?

Coagulation tests with Anticoagulant Drugs

Test UFH LMWH Warfarin Rivaroxaban Apixaban Dabigatran PT - - ↑↑↑ ↑/- -/↑ -/↑ APTT ↑↑↑ -/↑ ↑ -/↑ -/↑ ↑↑↑ Fibrinogen - - - - - - Thrombin Time

↑↑↑

↑

- - - ↑↑↑

Anti-Xa ↑

↑↑↑ - ↑↑↑

↑↑↑

-

Haemoclot ↑↑ ↑ - - - ↑↑↑

Rivaroxaban and Apixaban: The PT and APTT cannot be used to determine whether anticoagulant drug present

Switching from one anticoagulant to another

Switching from warfarin to NOAC

• Apixaban – Wait till INR < 2.0

• Dabigatran – Wait till INR < 2.0

• Edoxaban – Wait till INR < 2.5

• Rivaroxaban – Wait till INR < 3.0 AF – Wait till INR < 2.5 DVT, PE

ESC Practical Guide on the use of NOAC 2013

What to do if a dose of a NOAC is missed?

• Once daily regimens – Take the forgotten dose up to 12hrs after time

of usual intake • Twice daily regimens

– Take the forgotten dose up till 6hrs after time of usual intake

Bleeding

• Local measures • Stop NOAC temporarily • Tranexamic acid • Coagulation screen • Renal function • Discuss with haematologist if ongoing issue

Elective minor (when warfarin would not be stopped)

Dabigatran Rivaroxaban Apixaban

Minor dental work 12 hours post dose 18-24 hours post dose

>24 hours post dose

Major dental work 24 hours post dose Next dose > 4 hours post procedure

24 hours post dose Next dose > 4 hours post procedure

24-48 hours post dose Next dose > 4 hours post procedure

Upper/lower Endoscopy + simple biopsy Cataract removal Joint injection



24-48 hours post dose Next dose > 4 hours post procedure

NHS GGC Guidance based on SPC Dabigatran, Rivaroxaban, Apixaban

Emergency Surgery and Bleeding

Warfarin

• Vitamin K – IV 6 hours – PO 24 hours

• Prothrombin complex concentrates (PCCs) – Factors II, VII, IX, X – Reversal within 30 minutes

• Can assess INR for effectiveness/safety

NOACs • No specific reversal agent • Well-adsorbed to activated charcoal

– give within two hour of swallowing • Dialysis

– Dabigatran – yes – Rivaroxaban, apixaban – no

• General principles – Check coagulation screen

• Assess effect – Check renal function

• Assess half life • Products

– largely speculation/ based on non-clinical data – off-licence use; safety issues (thrombosis)

Vitamin K - no Immediate Effect on INR • Schematic diagram showing effect of vitamin K on INR • Vitamin K has a slow onset (>24 hours)1

– Vitamin K supports generation of normal, functioning clotting factors in the liver – Effectivity of INR normalization depending on VKA used (different half-lifes; (from

9–11 hours for acenocoumarol, to 90–140 hours for phenprocoumon)1,2

1. Heidbuchel et al, 2013; 2. Scharf et al, 2009

Day 1 Day 2

PD profile (INR) of VKA t½ of VKA ~4–5 days

INR

PD profile (INR) after administration of vitamin K 3

2

Vitamin K injection

4

Emergencies in Anticoagulated Patients

• Schematic diagram showing PK/PD characteristics of VKA and rivaroxaban – Reversal strategies may be required if action of drug is long and needs to be antagonized

in emergency situations

1. Makris et al, 2012; 2. Kubitza et al, 2005; 3. Kubitza et al, 2008

Day 1 Day 2

PD profile (INR) of VKA

PK/PD profile of rivaroxaban

t½ of VKA ~4–5 days

t½ of rivaroxaban 5–9 hours (young) or 11–13 hours (elderly)

Sche

mat

ic d

iagr

am

PD, pharmacodynamic; PK, pharmacokinetic; t½, half-life

Rivaroxaban-Induced Anticoagulation Reversal with PCC

• 20 mg rivaroxaban was administered bid for 2.5 days followed by PCC (Prothrombin Complex Concentrate - Cofact®, 50 U/kg body weight)

• Prolongation of PT was reversed completely by PCC

• ETP was reversed by PCC with an overshoot in effects

• Limitation – PT agent used showed low sensitivity

to rivaroxaban – Prolongation of PT in this study was

approximately 4 seconds at maximum

18 −

16 −

14 −

12 −

10 −

Time

PT in

seco

nds

Placebo

PCC

Eerenberg et al. Circulation 2011;124:1573–1579

Rivaroxaban (2.5 days)

PCC

Specific Reversal Agents for Non-VKA Oral Anticoagulants

Company Compound Reversal for:

Status Factor Xa inhibitor

Factor IIa inhibitor

LMWH/ fondaparinux

Portola Pharma-ceuticals

PRT064445/ (andexanet alfa) Universal No

Yes (antithrombin-

mediated Factor Xa inhibition)

Phase II completed One phase III with

apixaban completed; rivaroxaban and

edoxaban - onngoing

Boehringer Ingelheim

BI 655075 (idarucizumab) No Specific for

dabigatran No Phase I completed;3

phase III started4

Perosphere, Inc.

PER977 (aripazine) Universal Universal Universal Phase I completed5

Dabigatran antidote: idarucizumab

Disclaimer: idarucizumab is not currently licensed for use Date of prep: March 2015 UK/CVS-141014b

Idarucizumab development process

Monoclonal mouse antibody developed with high dabigatran binding affinity Monoclonal antibody was then humanized and directly

expressed as a Fab fragment in mammalian cells

Humanized Fab

Chimeric Fab

Human

Mouse

Mouse antibody

Fab region

Fc region


van Ryn J. Presented at the AHA Congress, Los Angeles, USA. 5 November 2012. Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928

Idarucizumab characteristics

Fully humanized antibody fragment (Fab)

Potently binds dabigatran

No prothrombotic or antithrombotic effects

Short half-life

No endogenous targets

Intravenous administration

van Ryn J. Presented at the AHA Congress, Los Angeles, USA. 5 November 2012. Presentation 9928;

van Ryn J et al. Circulation 2012;126:A9928


Idarucizumab mode of action

Disclaimer: idarucizumab is not currently licensed for use

Idarucizumab rapidly binds to dabigatran in the plasma Idarucizumab alters the

equilibrium – dabigatran dissociates from thrombin

Antidote (idarucizumab)

Thrombin

Dabigatran molecule

Dabigatran inhibiting thrombin

Dabigatran bound to plasma proteins

Unbound dabigatran

Date of prep: March 2015 UK/CVS-141014b

Practical Considerations


Starting a patient on a NOAC

• Check patient is not taking interacting drugs • Counsel patient: it is an anticoagulant

– Head injury, trauma, melaena, significant GI bleed, prolonged epistaxis, large ecchymoses/ haematoma

• Compliance- important to take as advised (od Rivaroxaban, bd Apixaban, bd Dabigatran)

• Baseline FBC, renal and liver function

Summary of use of NOACs • Benefits of novel anticoagulants

– Non inferior/superior to warfarin – More stable anticoagulation (in patients poorly controlled

on warfarin) – Shorter half life – No requirement for anticoagulant monitoring – Fewer drug-drug interactions – No food-drug interactions – Less intracranial bleeding

• But – Limited reversal options – Increased drug costs compared to warfarin – Current lack of familiarity

Fig 2 Cumulative incidences for major adverse cardiovascular event during two year follow-up for patients receiving warfarin versus no oral anticoagulant .

Ying Xian et al. BMJ 2015;351:bmj.h3786

©2015 by British Medical Journal Publishing Group

Fig 3 Major adverse cardiovascular event (MACE) and home time according to warfarin treatment at discharge, overall and in clinically relevant subgroups.

Ying Xian et al. BMJ 2015;351:bmj.h3786

©2015 by British Medical Journal Publishing Group

Learning Points

• Thrombosis • DVT • AF • NOACs • Food for thought

Thank you for your attention

[email protected]

@fatherofhan

Documents

Anticoagulation Using new anticoagulants in AF, VTE and PE...1 . Recently bedridden for 3 days or more, or major surgery within the last 12 weeks requiring general or local anaesthetics