All About… AnticoagulationCroydon Hilton28th November 2012

2

Speakers• Dr Phil Moore

GP and Kingston CCG Deputy Chair (clinical)and Joint Associate Medical Director

• Dr Raj PatelConsultant HaematologistKings Thrombosis Exemplar Centre

• Helen Williams Consultant Pharmacist for CV DiseaseSouth London Cardiac and Stroke Network

• Discuss the indications for anticoagulation• Consider the benefits and risks of

anticoagulation – focusing on anticoagulation for specific patients

and conditions– Consider difficult clinical decisions– discuss strategies to minimise bleeding risk and

what to do if bleeding does occur• Introduce the novel oral anticoagulants and

the current South London guidelines

Aims for the evening……

Indications for Anticoagulation

• Atrial Fibrillation (AF)

• DVT/PE treatment and prevention (VTE)

• Cardiomyopathy

• Mechanical Valve Replacement

• Thrombophilias

• Antiphospholipid Syndrome (APLS)

Cardiomyopathy

• Cardiomyopathy is a disease of the heart muscle• Muscle becomes enlarged, thick or rigid• Heart becomes weak and is less able to pump and

maintain a normal electric rhythm• 25-30% of patients with cardiomyopathy also

have AF• Stroke risk mainly associated with

cardiomyopathy in the presence of AF• Anticoagulation can also be considered in the

absence of AF

Mechanical Valve Replacement

• Risk = systemic embolisation• Most cases are cerebrovascular events• Risk is higher than tissue valve hence target

INR range is also higher• Risk higher in patients

– with a hx of embolisation – with co-existing AF

Coagulation Disorders

Thrombophillias

• Generic term describing increased tendency to thrombosis– Factor V Leiden 5% of UK

population – 20-40% of VTED– Antithrombin & protein C and S

deficiency -2-10% of VTED– Prothrombin G20210A - 1% of UK

population – 10% of VTED– Hyperhomocysteinaemia - arterial

& venous thrombi

Antiphospholipid syndrome

• Autoimmune, hypercoagulable state caused by antibodies against cell membrane phospholipids

• Provoked blood clots in arteries and veins

VTE: the burden of disease

• Acute VTE = DVT / PE

• In-hospital mortality 6-15%

after PE

• Risk of recurrence

• Post-thrombotic syndrome

• Pulmonary hypertension

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• LMWH / Fondaparinux / UFH – Continue for at least 5 days or until INR>2 for at

least 24hrs (whichever longer)– LMWH for 6 months in active cancer, reassess

risk/benefit at 6 months• Warfarin for 3 months in provoked proximal

DVT• Warfarin beyond 3 months in unprovoked

proximal DVT if recurrence risk high and no additional bleeding risk

Current DVT treatment

Warfarin

Most commonly used anticoagulant worldwide

Highly effective oral anticoagulant

But it has its limitations….

Target INR ranges

Indication Target INRDVT / PE (VTE) 2-3

Atrial Fibrillation 2-3

Cardiomyopathy 2-3

Antiphospholipid syndrome (APLS) 3-4

Recurrence of VTE whilst on anticoag 3-4

Mechanical heart valves 3-4

British Committee for Standards in Haematology. Br J Haemat 1998; 101: 374-387

• AF is the leading cause of embolic stroke

• Risk increases with age• Without preventive

treatment, approximately 1 in 20 patients (5%) with AF will have a stroke each year

• AF related strokes are associated with higher mortality and more disability

0

5

10

15

20

25

50-59 60-69 70-79 80-89

% of strokes attributable to AF

Kannel WB et al. Am J Cardiol 1998; 82 (8A): 2N–9N.

AF and stroke risk

Age (years)

%

How does AF lead to stroke?

Blood pools in the atria

Blood clot forms

Whole or part of the blood clot breaks off

Blood clot travels to the brain and closes a cerebral artery

causing a stroke

CHADS2

CHADS2 is a points-based system for predicting risk of stroke in AF based on key risk factors1

Congestive heart failure 1 pointHypertension 1 pointAge >75 years 1 pointDiabetes mellitus 1 point Stroke or TIA 2 points

The greater the number of points, the greater the risk and need for anti-thrombotic therapyNumber of points Recommendation

0 Antiplatelet therapy or nothing

1 Anti-coagulant therapy (or antiplatelet)

2 Oral anticoagulant therapy, such as warfarin

1. Gage BF, et al. JAMA 2001; 285: 2864–70; 2. NICE Clinical Guideline 36. Available at: www.nice.org.uk/CG036

CHADS2 score and Risk of Stroke

Adapted from Gage BF, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation JAMA.2001;285:2864-2870.

*The adjusted stroke rate was derived from multivariate analysis assuming no aspirin usage. 

Pisters, R., Lane, D.A., Nieuwlaat, R., De Vos, C.B. et al. (2010), A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey, Chest, 138(5), pp.1093-1100.

HAS-BLED score

Clinical Characteristics Points

H Hypertension 1

A Abnormal liver or renal function 1 or 2

S Stroke 1

B Bleeding 1

L Labile INR 1

E Elderly (age > 65) 1

D Drugs or alcohol 1 or 2

Maximum risk score 9

Balancing stroke risk vs. harmAre all bleeds equal?

• Hb drop of ≥ 2g/dl• Transfusion of ≥ 2 U • Symptomatic bleeding

in critical organ

• Fatal haemorrhage• Intracranial

haemorrhage• Hb drop of ≥ 5g/dl• Transfusion of ≥ 4 U• Inotropic agent support• Surgery

Major bleeding

Life threateningbleeding

All bleeding events

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1. Address uncontrolled hypertension

2. Review benefit/risk of concomitant aspirin:– Hypertensives, diabetics, CHD and no acute ischemic event

or intervention in the last year Stop aspirin when INR in therapeutic range

3. Risk of bleeding is greatest in first 90 days of OAC therapy

• Caution : drug interactions and new drugs

• Close or more frequent monitoring

4. Review concomitant use of NSAIDS5. Consider a PPI

Exercising Caution

Hylek, E.M., Evans-Molina, C, Shea, C. et al. (2007), Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation, Circulation, 115, 2689-2696.

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The percentage of patients with AF and CHADS2 score = 1 on anticoagulant or antiplatelet therapy

For patients with AF and CHADS2 score > 1; the percentage of patients who are receiving anticoagulants

AF and QOF 2012

For my patient……

87 year old man with

hypertension

For my patient……

87 year old man with

hypertension

ANTICOAGULATE!

Random effects model; Error bars = 95% CI; *p>0.2 for homogeneity;†Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)

Warfarin for non-rheumatic AF

Hart RG et al. Ann Intern Med 2007;146:857–67.

Warfarin better Placebo better

RRR (%)†

100 –10050 0 –50

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trialsRRR 64%*, ARR

2.7%(95% CI: 49–74%)

Aspirin RRR 19% 0.7% ARR

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Warfarin is underused - Why?

Patient factors• Refusal, perceived inconvenience• Responsibility associated with

INR monitoring• Inadequate knowledge

Physician factors • Over-estimation of potential

bleeding and falls risk• Safety factors/monitoring

The GRASP-AF toolWhat is it?

• Series of searches of a GPs clinical system• It identifies patients with a history of AF• It looks for relevant medical history• And medication – warfarin, aspirin, Novel Oral Anticoagulants (NOACs)• It calculates CHADS2 and CHA2DS2-VASc score• Flags up contraindications to oral anticoaglants/other reasons for not taking

• Gives a practice over view – Dashboard• Provides various patient lists depending on your chosen search• Gives a simple alert for those at high risk and not on warfarin or a NOAC

Uses free / commonly used software

It helps to improves the management of AF in primary care

FREE

The GRASP-AF audit tooldashboard view - CHADS2

GRASP data- warfarin prescribing 

First upload (%)

Latest upload (%)

South West London Cardiac and Stroke Network 57.29 57.35

North of England Cardiovascular Network 57.98 61.34

Cardiac and Stroke Networks in Cumbria and Lancashire 40.09 42.39

Greater Manchester and Cheshire Cardiac Network 56.55 56.1

South Central Vascular Networks 50.81 54.2

Kent Cardiovascular Network 54.51 55.77

Surrey Heart and Stroke Network 48.13 46.5

Avon, Gloucestershire, Wiltshire & Somerset Cardiac and Stroke Network 53.87 56.59

Dorset Cardiac and Stroke Network 46.58 50

Peninsula Cardiac Managed Clinical Network 53.31 56.26

Black Country Cardiovascular Network 47.06 50

Herefordshire and Worcestershire Cardiac and Stroke Network 54.96 53.47

Shropshire & Staffordshire Heart and Stroke Network 52.01 53.37

North & East Yorkshire and Northern Lincolnshire Cardiac and Stroke Network 58.88 58.88

West Yorkshire Cardiovascular Network 50.53 51.62

National Value 52.74 54.74

Patient 2

66 year old British woman, newly registered patient AF (2009) on warfarin

Hypertension

CHA2DS2VASc

CHA2DS2-VAScscore

Patients (n = 7329)

Adjusted stroke

rate (%/year)

0 1 0

1 422 1.3

2 1230 2.2

3 1730 3.2

4 1718 4.0

5 1159 6.7

6 679 9.8

7 294 9.6

8 82 6.7

9 14 15.2

From ESC AF Guidelines: http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-afib-FT.pdf

Refining Risk Assessment

Refining Risk Assessment

ANTICOAGULATE!

Patient 344 year old woman, diagnosed with PAF (2011)

PMH: Depression (2008), Reflux oesophagitis (2003), Aspirin intolerance (2003)

CHADS-Vasc

So, what should I do here?

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CHADS-Vasc Validation (BMJ 2011)

CHADS-Vasc

So, what should I do here?

No need to anticoagulate now!

CHADS Vasc at aged 65yrs!

CHADS Vasc at aged 65yrs!

But…….anticoagulate now!

Patient 4• 76 year old women with AF and prior stroke• With hypertension, heart failure (LVSD)

• Unfortunately she is bed bound and district nurses are struggling to bleed her…

• What other options do we have?– NOACs– Aspirin instead of warfarin– Point of care INR testing– No antithrombotic therapy– Low molecular weight heparin

• NB. This patient has a mechanical mitral valve!

• Unfortunately she is bed bound and district nurses are struggling to bleed her…

• What other options do we have?– NOACs– Aspirin instead of warfarin– Point of care INR testing– No antithrombotic therapy– Low molecular weight heparin

• NB. This patient has a mechanical mitral valve!

Point of care testing

Challenging Issues

• What about a 93 year old frail old lady with AF? How old is too old?

• What about the 56 year old with a history of GI bleed?

• Is aspirin treating the doctor or the patient?

Older AF patients less likely to get warfarin

Gallagher AM et al. J Thromb & Haem 2008;6:1500-1506

Younger

Older

Falls – what is the risk?

• Markov decision analytic model was used to determine the preferred treatment strategy in patients > 65 yrs/old

• Patients need to fall >295 times per year for risk to outweigh benefit

• Mean number of falls / year of elderly people who fall: 1.8

Man-Son-Hing et al Arch Intern Med. 1999;159:677-685

Date of download: 11/20/2012Copyright © 2012 American Medical Association.

All rights reserved.

From: Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding

Arch Intern Med. 2012;172(19):1484-1491. doi:10.1001/archinternmed.2012.4261

Figure. Time-to-outcome analysis according to resuming warfarin therapy status. A, Thrombosis (P = .002, log-rank test); B, recurrent gastrointestinal tract bleeding (GIB) (P = .10, log-rank test); C, death (P < .001, log-rank test); and D, death including only patients who died at least 7 days after the index GIB (P < .001, log-rank test).

Figure Legend:

• “The decision to not resume warfarin therapy in the 90 days following a GIB event is associated with increased risk for thrombosis and death”

• “For many patients who have experienced warfarin-associated GIB, the benefits of resuming anticoagulant therapy will outweigh the risks”

Birmingham

Atrial Fibrillation

Treatment of the Aged• 2001–2004; 260 GPs in England and Wales

• 973 pts 75 years (81.5 ± 4.2)

• 72% CHADS2 2• 40% on warfarin, 42% on

aspirin• Warfarin (target INR 2–3) or

aspirin (75 mg per day)• 10 endpoint - fatal or disabling

stroke (ischaemic or haemo-rrhagic), other intracranial haemorrhage, or clinically significant arterial embolism

BAFTA:

RR = 0.48 (0.28–0.80) p = 0.0027

0 1 2 3 4 5 6

Aspirin (A)Warfarin (W)

Years after randomisation

Eve

nt

free

su

rviv

al

100

75

50

25

0

Mant J et al. Lancet 2007; 370: 493–503.

24 (1.8%)

48 (3.8%)

Intra-cranial haemorrhage on W vs. A:0.5% vs. 0.4% (RR 1.15, 0.29 – 4.77, n.s.)

Extra-cranial haemorrhage:1.4% vs. 1.6% (RR 0.87, 043 – 1.73, n.s.)

INR > 3.0: 14% of the time

Stroke: 0.8% vs. 1.8%RR = 0.30(0.13-0.63)p = 0.0004

OAC should not be denied to patients with CHADS score 1 or more without

seeking expert advice

Adverse EffectsBleeding is common… we are talking about

anticoagulants….. Even if INR in range:

GI/GU bleeds: INR often in range Soft tissue bleed: INR often supra-therapeutic

Risk factors: • age >65• Age >75 with AF (ICH)• Higher target INR range• Hx GI bleed, • Hx stroke, renal insufficiency

Signs and Symptoms of Bleeding

• Epistaxis, gum bleeding, bleeding from cuts or scrapes or heavier than usual menstrual period

• Severe worsening bruising not due to injury• Red or dark urine• Red or black bowel motions• Coughing blood• Dark or blood stained vomit• Severe headache or dizziness

Bleeding and referral?

A&EReassure and consider

early INR

1. Where is the source of the bleeding?

2. Intermittent or continuous?

• Continuous bleeding

• Haematemesis

• Haemoptysis

• Severe headache/dizziness

• Malaena

• Heavy menstrual bleeding

• Continuous bleeding from cut/graze

• Continuous haematuria

• Minor bruising

• Intermittent epistaxis

• Intermittent gum bleeding

• Transient haematuria

CLINICAL JUDGEMENT

Also, be aware of key drug interactions

Drug Effect ManagementAmiodarone Warfarin 30-50%

Antifungals Avoid, monitor INR

Broad-spectrum antibiotics

Avoid, monitor for signs of bleeding

Aspirin/NSAIDs Avoid, monitor INR

Metronidazole Avoid, monitor INR. Will need dose if long-term

Phenytoin / Monitor INR

Herbal InteractionsIncreased Effect Decreased EffectDong quai AlfalfaFenugreek Coenzyme Q10Feverfew GinsengGarlic ParsleyGinger St John’s WortGingko bilobaFish oilsRed yeast rice

Food Interactions

Vitamin K-containing food:• Kale• Swiss chard• Spinach (cooked)• Brussel sprouts• Scallion (raw)• Broccoli (cooked)• Cabbage (cooked)• Mayonnaise

Vitamin K content

Alcohol Interactions

• Intermittent binge drinking can result in higher INR– Alcohol acts as a mild anticoagulant

• Chronic alcohol intake can result in lower warfarin concentrations– Metabolic enzyme induction

When to take - Same time each day

Alcohol - May potentiate warfarin – moderation and no binges!

Risk of bleeding – Avoid high risk sports! Advice on managing bleeds

Follow up - Regular clinic attendance

Aspirin - Only if prescribed, and avoid OTC anti-inflammatory drugs

Reason for taking - AF, DVT, PE, other

Interactions - Drugs – inc OTC; Foods

Notify - GP, Dentist, Pharmacist that taking

INR – Target Range

Skipped dose - Don’t double up

End of course (if appropriate)

Dose - 1mg brown 3mg blue 5mg pink

WarfarinCounselling

• A 49 year old male with AF– Hypertension and brittle diabetes– frequent antibiotics for leg ulcers– Resulting in labile INR

• A 63 year old female with AF– hair loss with all VKAs, – severe oesophagitis– wants once daily option

What about these patients…….

An Ideal Anticoagulant

Properties BenefitOral, once daily dosing Ease of administration

Rapid onset of action No need for overlapping parenteral anticoagulant

Minimal food or drug interactions Simplified dosing

Predictable anticoagulant effect No coagulation monitoring

Extra renal clearance Safe in patients with renal disease

Rapid offset in action Simplifies management in case of bleeding or intervention

Antidote For emergencies

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Apixaban versus Aspirin

• AVERROES trial (double-blind, n = 5,599)• Apixaban far more effective (SSE) than aspirin• Apixaban comparable safety (major bleeds) to aspirin• Apixaban better tolerated than aspirin (d/c 17.9% vs 20.5% per year)

Stroke or Systemic Embolism Major Bleeding

Granger C et al NEJM 2011

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Apixaban versus Warfarin (ARISTOTLE)

Stroke or Systemic Embolism

Connolly S et al NEJM 2011

Novel oral anticoagulantsSLCSN Positioning 2012/13 (1)

An alternative to warfarin for SPAF in patients with CHADS2 ≥ 1 who:

• have a warfarin allergy, warfarin specific-contraindication or are unable to tolerate warfarin therapy

• are unable to comply with the specific monitoring requirements of warfarin

• are unable to achieve a satisfactory INR after an adequate trial of warfarin

• have had an ischaemic stroke whilst stable on warfarin therapy

SLCSN Positioning 2012/13 (2)• Warfarin remains the first-line option for most

patients• Initiation by clinicians with ‘expertise in

initiating anticoagulation’• Initiating clinician responsible for at least first

3 months of therapy:– Address side effects– Emphasise importance of adherence

• Transfer to GP when ‘stable’ and in line with approved indications

For more information…..

• Position statement• Prescribing guidance

– dabigatran– rivaroxaban

• Suggested pathway of care• Transfer of care guidance

(TBC)• Patient info leaflet

dabigatran vs warfarin• Frequently asked

questions

65

• A 49 year old male with AF– Hypertension and brittle diabetes– frequent antibiotics for leg ulcers– Resulting in labile INR

• Started dabigatran 150mg bd– Renal function annually– Assess for side effects (dyspepsia)– Reinforce adherence

So, what should I do for….?

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• A 63 year old female with AF– hair loss with all VKAs, – severe oesophagitis– wants once daily option

• Started rivaroxaban 20mg daily– Renal function annually– Assess for side effects (headache, syncope)– Reinforce adherence

So, what should I do for…

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• RE-LY: 3.36% warfarin versus 3.11% dabigatran 150mg bd / 2.71%

dabigatran 110mg bd– Fewer life threatening bleeds with dabigatran (both doses)– Reduction in intra-cranial haemorrhage (both doses)– More GI bleeds (1.02% warfarin, 1.51% dabigatran 150mg

bd / 1.12% dabigatran 110mg bd)

• ROCKET-AF: 3.4% warfarin versus 3.6% rivaroxaban– Reduced intra-cranial haemorrhage and fatal bleeds with

rivaroxaban– Increased transfusions with rivaroxaban– More GI bleeds (2.2% warfarin versus 3.2% rivaroxaban)

Major bleeding rates

Bleeding and referral?

A&EReassure and consider

referral

1. Where is the source of the bleeding?

2. Intermittent or continuous?

• Continuous bleeding

• Haematemesis

• Haemoptysis

• Severe headache/dizziness

• Malaena

• Heavy menstrual bleeding

• Continuous bleeding from cut/graze

• Continuous haematuria

• Minor bruising

• Intermittent epistaxis

• Intermittent gum bleeding

• Transient haematuria

CLINICAL JUDGEMENT

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• No way to know if the patient is complying• Not suitable as an alternative to warfarin if

compliance is an issue• Need to reinforce adherence at every

opportunity– Initiation– First prescription (NMS)– Subsequent clinical reviews– At each repeat prescription and supply

Adherence

Counselling• Reduces the chance of unwanted blood clots forming

which helps prevent strokes• Take regularly - any time is ok

– Forgotten doses • W – if before midnight• D – if within 6 hrs of next dose (miss)• R – take immediately, do not double within the same day

• Like all medicines – unwanted side effects– If unusual bleeding, such as dark or bloody stools, urine or

unexplained bruising tell your doctors– NSAIDs can’t be taken with anticoagulants– Specifics Dabigatran- indigestion; rivaroxaban- dizziness,

headache

• 27 year old African with DVT– warfarin requirement 35mg– difficult to maintain INR 2-3

• 84 year old man PE 10 years ago– Was prescribed warfarin– Had a subdural and told never to have warfarin

again– Creatinine clearance 46mls/min

What about difficult to manage patients in VTE?

Number of subjects at risk

Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400 369 363 345 309 266

Enoxaparin/VKA

1,718 1,616 1,581 1,553 1,368 1,358 1,186 380 362 337 325 297 264

EINSTEIN DVT: primary efficacy outcome C

um

ula

tive

eve

nt

rate

(%

)

0 30 60 90 120 150 180 210 240 270 300 330 360

Rivaroxaban (n=1,731)

Enoxaparin/VKA (n=1,718)

Time to event (days)

HR=0.68; p<0.001

0

1.0

2.0

3.0

4.0

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510

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Issues in VTE management

• Which patients?– Patients on long-term LMWH / patients in whom warfarin is

unsuitable (as per AF guidance) – All patients?

• Who should prescribe?– Acute vs primary care– Dose adjustment at 3 weeks– Duration – appropriate cessation at ??? months

• Monitoring renal function• Adherence

• 27 year old African male with DVT– warfarin requirement 35mg– difficult to maintain INR between 2-3

• Rivaroxaban 20mg daily

Back to our patients with VTE

• 84 year old man PE 10 years ago– Was prescribed warfarin– Had a subdural and told never to have warfarin

again– Creatinine clearance 46mls/min

• Cautiously; rivaroxaban 15mg daily

Back to our patients with VTE

In Summary: Oral AnticoagulationIndication Oral anticoagulant

WarfarinINR range

Dabigatran Rivaroxaban

VTE prophylaxis following hip/knee replacement surgery

2-3 220mg od10-35 days

10mg od2-5 weeks

Prevention of thromboembolic events in non valvular AFLong term

2-3 150mg bd(110mg bd in

selected patients)

20mg od(15mg od in selected

patients)

Treatment of DVT 3-6 months

2-3 No license at present

15mg bd for 3 weeks then 20mg od

(15mg od)Prosthetic valvesLong term

2- 4(depending on

locations)

No license at present

No license at present