2. Speakers
• Dr Phil Moore
GP and Kingston CCG Deputy Chair (clinical)
and Joint Associate Medical Director
• Dr Raj Patel
Consultant Haematologist
Kings Thrombosis Exemplar Centre
• Helen Williams
Consultant Pharmacist for CV Disease
South London Cardiac and Stroke Network
2
3. Aims for the evening……
• 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
5. 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
6. 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
7. Coagulation Disorders
Thrombophillias Antiphospholipid syndrome
• Generic term describing • Autoimmune,
increased tendency to hypercoagulable state
thrombosis caused by antibodies
– Factor V Leiden 5% of UK against cell membrane
population – 20-40% of VTED
– Antithrombin & protein C and S phospholipids
deficiency -2-10% of VTED • Provoked blood clots in
– Prothrombin G20210A - 1% of UK arteries and veins
population – 10% of VTED
– Hyperhomocysteinaemia - arterial
& venous thrombi
8. VTE: the burden of disease
• Acute VTE = DVT / PE
• In-hospital mortality 6-15%
after PE
• Risk of recurrence
• Post-thrombotic syndrome
• Pulmonary hypertension
9. Current DVT treatment
• 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
9additional bleeding risk
10. Warfarin
Most commonly
used anticoagulant
worldwide
Highly effective
oral anticoagulant
But it has its
limitations….
11.
12. Target INR ranges
Indication Target INR
DVT / 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
13. AF and stroke risk
% of strokes
• AF is the leading cause of attributable to AF
embolic stroke 25
• Risk increases with age 20
• Without preventive
15
treatment, approximately 1
%
in 20 patients (5%) with AF 10
will have a stroke each year
5
• AF related strokes are
associated with higher 0
50-59 60-69 70-79 80-89
mortality and more disability
Age (years)
Kannel WB et al. Am J Cardiol 1998; 82 (8A): 2N–9N.
14. 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
15. CHADS2
CHADS2 is a points-based system for predicting risk of
stroke in AF based on key risk factors1
Congestive heart failure 1 point
Hypertension 1 point
Age >75 years 1 point
Diabetes mellitus 1 point
Stroke or TIA 2 points
The greater the number of points, the greater the risk and need for
anti-thrombotic therapy
Number 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
16. *The adjusted stroke rate
was derived from
multivariate analysis
assuming no aspirin
usage.
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.
17. 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
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.
18. Balancing stroke risk vs. harm
Are all bleeds equal?
•Hb drop of ≥ 2g/dl
•Transfusion of ≥ 2 U
All bleeding events •Symptomatic bleeding
in critical organ
Major bleeding •Fatal haemorrhage
•Intracranial haemorrhage
Life
threatening
•Hb drop of ≥ 5g/dl
bleeding •Transfusion of ≥ 4 U
•Inotropic agent support
•Surgery
19. Exercising Caution
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 NSAIDS
5. Consider a PPI
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
19
fibrillation, Circulation, 115, 2689-2696.
20. AF and QOF 2012
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
20
23. Warfarin for non-rheumatic AF
Warfarin better Placebo better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
RRR 64%*, ARR 2.7%
All trials (95% CI: 49–74%)
100 50 0 –50 –100
RRR (%)† Aspirin
RRR 19% 0.7% ARR
Random effects model; Error bars = 95% CI; *p>0.2 for homogeneity;
Hart RG et al. Ann Intern Med 2007;146:857–67. †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
24. 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
24
25. The GRASP-AF tool
FREE
What 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
27. 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
28. Patient 2
66 year old British woman, newly registered
patient
AF (2009) on warfarin
Hypertension
38. Patient 4
• 76 year old women with AF and prior stroke
• With hypertension, heart failure (LVSD)
39. • 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!
40. • Unfortunately she is bed bound and district nurses
are struggling to bleed her…
• What other options do we have?
–
–
–
Point of care
NOACs
Aspirin instead of warfarin
Point of care INR testing
–
– testing
No antithrombotic therapy
Low molecular weight heparin
• NB. This patient has a mechanical mitral valve!
41. 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?
42. Older AF patients less likely to get warfarin
Younger
Older
Gallagher AM et al. J Thromb & Haem 2008;6:1500-1506
43. 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
45. • “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”
46. Birmingham
Atrial Fibrillation
• 2001–2004; 260 GPs in England Treatment of the Aged
and Wales
• 973 pts 75 years (81.5 ± 4.2)
100 24 (1.8%)
• 72% CHADS2 2
Event free survival
• 40% on warfarin, 42% on 75 Aspirin (A)
Warfarin (W) 48 (3.8%)
aspirin
• Warfarin (target INR 2–3) or 50
RR = 0.48 Stroke:
aspirin (75 mg per day) (0.28–0.80) 0.8% vs. 1.8%
• 25 RR = 0.30
10 endpoint - fatal or disabling p = 0.0027 (0.13-0.63)
stroke (ischaemic or haemo- p = 0.0004
0
rrhagic), other intracranial 0 1 2 3 4 5 6
haemorrhage, or clinically Years after randomisation
significant arterial embolism
Intra-cranial haemorrhage on W vs. A:
0.5% vs. 0.4% (RR 1.15, 0.29 – 4.77, n.s.)
INR > 3.0: 14% of the time Extra-cranial haemorrhage:
1.4% vs. 1.6% (RR 0.87, 043 – 1.73, n.s.)
Mant J et al. Lancet 2007; 370: 493–503.
47. OAC should not be denied to patients
with CHADS score 1 or more without
seeking expert advice
48. Adverse Effects
Bleeding 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
49. 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
50. Bleeding and referral?
1. Where is the source of the bleeding?
2. Intermittent or continuous?
•Continuous bleeding •Minor bruising
•Haematemesis •Intermittent epistaxis
•Haemoptysis
•Intermittent gum bleeding
•Severe headache/dizziness
•Transient haematuria
•Malaena
•Heavy menstrual bleeding
•Continuous bleeding from cut/graze
CLINICAL
•Continuous haematuria
JUDGEMENT
A&E
Reassure and consider
early INR
51. Also, be aware of
key drug interactions
Drug Effect Management
Amiodarone Warfarin 30-50%
Antifungals Avoid, monitor INR
Broad-spectrum Avoid, monitor for signs of
antibiotics bleeding
Aspirin/NSAIDs Avoid, monitor INR
Metronidazole Avoid, monitor INR. Will need
dose if long-term
Phenytoin / Monitor INR
52. Herbal Interactions
Increased Effect Decreased Effect
Dong quai Alfalfa
Fenugreek Coenzyme Q10
Feverfew Ginseng
Garlic Parsley
Ginger St John’s Wort
Gingko biloba
Fish oils
Red yeast rice
54. 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
55. 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 Warfarin
Skipped dose - Don’t double up Counselling
End of course (if appropriate)
Dose - 1mg brown 3mg blue 5mg pink
56. What about these patients…….
• 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
57. An Ideal Anticoagulant
Properties Benefit
Oral, once daily dosing Ease of administration
No need for overlapping parenteral
Rapid onset of action
anticoagulant
Minimal food or drug interactions Simplified dosing
Predictable anticoagulant effect No coagulation monitoring
Extra renal clearance Safe in patients with renal disease
Simplifies management in case of
Rapid offset in action
bleeding or intervention
Antidote For emergencies
60. Apixaban versus Aspirin
Stroke or Systemic Embolism Major Bleeding
• 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)
60
Granger C et al NEJM 2011
62. Novel oral anticoagulants
SLCSN 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
63. 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
64. 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. So, what should I do for….?
• 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
65
66. So, what should I do for…
• 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
66
67. Major bleeding rates
• 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)
67
68. Bleeding and referral?
1. Where is the source of the bleeding?
2. Intermittent or continuous?
•Continuous bleeding •Minor bruising
•Haematemesis •Intermittent epistaxis
•Haemoptysis
•Intermittent gum bleeding
•Severe headache/dizziness
•Transient haematuria
•Malaena
•Heavy menstrual bleeding
•Continuous bleeding from cut/graze
CLINICAL
•Continuous haematuria
JUDGEMENT
A&E
Reassure and consider
referral
69. Adherence
• 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
69
70. 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
71.
72.
73. What about difficult to manage
patients in VTE?
• 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
74.
75. EINSTEIN DVT: primary efficacy outcome
4.0
Cumulative event rate (%)
Enoxaparin/VKA (n=1,718)
3.0
Rivaroxaban (n=1,731)
2.0
HR=0.68; p<0.001
1.0
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
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/
1,718 1,616 1,581 1,553 1,368 1,358 1,186 380 362 337 325 297 264
VKA
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
76. 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
76
77. Back to our patients with VTE
• 27 year old African male with DVT
– warfarin requirement 35mg
– difficult to maintain INR between 2-3
• Rivaroxaban 20mg daily
78. 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
79. In Summary: Oral Anticoagulation
Indication Oral anticoagulant
Warfarin Dabigatran Rivaroxaban
INR range
VTE prophylaxis following 2-3 220mg od 10mg od
hip/knee replacement surgery 10-35 days 2-5 weeks
Prevention of thromboembolic 2-3 150mg bd 20mg od
events in non valvular AF (110mg bd in (15mg od in selected
Long term selected patients) patients)
Treatment of DVT 2-3 No license at 15mg bd for 3 weeks
3-6 months present then 20mg od
(15mg od)
Prosthetic valves 2- 4 No license at No license at present
Long term (depending on present
locations)
