All About… Anticoagul ation Croydon Hilton 28 th November 2012
Nov 02, 2014
All About… AnticoagulationCroydon Hilton28th November 2012
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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
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• 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