Transcript Suitable for consideration of dabigatran?

CONSENSUS MEETING TO SUPPORT
THE SAFE AND EFFECTIVE USE OF
DABIGATRAN IN NHS SCOTLAND
WELCOME
Denise Coia, Chair, Healthcare Improvement Scotland
INTRODUCTION AND CONTEXT
Dr Brian Robson, Medical Director, Healthcare Improvement Scotland
ATTENDEES
• All 14 territorial NHS boards represented
• Good balance from the clinical community
including 15 GPs, 20 consultant physicians, 20
pharmacists
• 10 patient representatives
• senior management and planning
CONTEXT
• Supporting implementation of the recent SMC guidance
on dabigatran.
• alignment with the quality ambition “ensuring the most
appropriate treatments, interventions, support and
services will be provided at the right time to everyone
who will benefit, and wasteful or harmful variation will be
eradicated.”
PURPOSE OF TODAY
• Agree a majority consensus on the safe effective use of dabigatran.
– This process will act as a platform for other new agents
(rivaroxaban/ apixaban) in late stage clinical development for the
prevention of stroke in atrial fibrillation, if SMC approved.
• To build upon work already undertaken
– Development of the draft consensus statement
– Pre-meeting survey
PROGRAMME
9.00am – 9.30am
Registration & tea/coffee
9.30am
Welcome
Denise Coia, Chair, Healthcare Improvement Scotland
9.30 am – 9.40am
Introduction and context
Dr Brian Robson, Medical Director, Healthcare Improvement Scotland
9.40 am – 9.55 am
Atrial fibrillation - the clinical context
Dr David Murdoch, Consultant Physician and Cardiologist, NHS Greater Glasgow & Clyde
9.55 am – 10.00 am
Scottish Medicines Consortium
Angela Timoney, Chair, SMC
10.00am – 10.15am
Dabigatran - Scottish Medicines Consortium outcome
Alison Campbell, Lead SMC Assessor for Dabigatran
10.15am- 10.25am
Laboratory implications and reversal of bleeding
Dr Julia Anderson, Consultant Haematologist, NHS Lothian
10.25am – 10.40am
Draft consensus statement for the prevention of stroke and systemic embolism in
adult patients with non-valvular atrial fibrillation
Dr David Northridge, Consultant Cardiologist, NHS Lothian
PROGRAMME CONT.
10.40am – 12 noon
World Cafe
Facilitated small-group discussion of key issues, including tea/coffee.
Jane Murkin, Associate Director of Improvement, Healthcare Improvement Scotland
June Watters, NHSScotland Hub Quality Improvement Advisor, Healthcare Improvement
Scotland
12 noon -12.20pm
Feedback and final voting
Jane Murkin, Associate Director of Improvement, Healthcare Improvement Scotland
12.20pm – 12.30pm
Next steps and meeting close
Laura McIver, Chief Pharmacist, Healthcare Improvement Scotland
Jane Murkin, Associate Director of Improvement, Healthcare Improvement Scotland
ATRIAL FIBRILLATION
the clinical context
David Murdoch, NHS GGC Heart MCN
1 in 5 strokes
attributed to AF
AF increases
stroke risk (x5)
more likely to
be fatal (x2)
more disabling
(care costs x1.5)
more likely to
recur.
65% risk
reduction with
warfarin
20% risk
reduction with
aspirin
CHADS2 and CHA2DS2 -VASC
Score
CHA2DS2-VASc
Risk
Score
CHF
1
CHF or LVEF <
40%
1
Hypertension
1
Hypertension
1
Age > 75
2
Diabetes
1
Stroke/TIA/
2
CHADS2 Risk
Age > 75
Diabetes
Stroke or TIA
1
1
Thromboembolism
Vascular Disease
1
Age 65 - 74
1
Female
1
2
CHADS2 and CHA2DS2-VASC: stroke risk
CHADS2
score
0
Adjusted
stroke rate
%/year
CHA2DS2VASc
Adjusted
stroke
score
rate
(%/year)
0
0
1
1.3
2
2.2
3
3.2
4
4.0
5
6.7
6
9.8
7
9.6
8
6.7
9
15.2
1.9
1
2.8
2
4.0
3
5.9
4
8.5
5
12.5
6
18.2
Time in therapeutic range : GGC experience
AF cases on
warfarin >90 days
Total no. = 7465
(% Time in range)
Number of patients
%
<20%
16
0.2%
20-29%
47
0.6%
30-39%
150
2.0%
40-49%
365
5.0%
50-59%
787
10.5%
>60%
6069
81.2%
Unknown
31
0.4%
NHS QIS Cinical Standards Audit 2010:
AF PREVALENCE IN SCOTLAND
NHS QIS Clinical Standards April 2010 - Heart Disease
Total number of records in AF audit
19,470
Denominator upon which the chart is based
19,470
Population
with AF
Submitted
Practices
Population
Numerator
Denominator
1,512
112,292
1.3%
483
29,581
1.6%
Fife
1,357
96,989
1.4%
Forth Valley
2,064
142,264
1.5%
Greater Glasgow & Clyde
9,625
673,305
1.4%
790
60,598
1.4%
Lanarkshire
1,700
129,339
1.3%
Lothian
1,354
98,918
1.3%
Orkney
69
4,189
1.4%
Shetland
138
9,849
1.6%
Tayside
237
12,617
1.4%
Western Isles
141
6,893
1.9%
19,470
1,376,834
1.4%
NHS Board Residence (HB)
Ayrshire & Arran
Dumfries & Galloway
Highland
SCOTLAND
Percentage (%)
NHS QIS Primary Care Atrial Fibrillation Audit 2010 :
Percentage of submitted practices population diagnosed with AF
1.3%
A y r s hi r e & A r r an
1.6%
D umf r i es & Gal l ow ay
1.4%
Fi f e
1.5%
For t h V al l ey
Gr eat er Gl as gow & C l y de
1.4%
H i ghl and
1.4%
Lanar k s hi r e
1.3%
Lot hi an
1.3%
1.4%
Or k ney
1.6%
Shet l and
1.4%
T ay s i de
1.9%
Wes t er n I s l es
0. 0%
0. 2%
0. 4%
0. 6%
0. 8%
1. 0%
1. 2%
1. 4%
%
N H S B oar d R es i denc e (H B )
Sc ot l and
1. 6%
1. 8%
2. 0%
NHS QIS Primary Care Atrial Fibrillation Audit 2010:
Percentage of AF Patients with High CHADS2 Score
Ayrshire & Arran
Dumf ries & Gallow ay
59.4%
56.6%
Fif e
54.4%
Forth Valley
53.9%
Greater Glasgow & Clyde
Highland
51.1%
57.5%
Lanarkshire
52.0%
Lothian
53.4%
60.6%
Orkney
Shetland
53.8%
72.8%
Tayside
63.9%
Western Isles
0.0%
20.0%
60.0%
40.0%
80.0%
%
NHS Board Residence (HB)
Scotland
100.0%
NHS QIS Primary Care Atrial Fibrillation Audit 2010:
Percentage of AF Patients with High CHADS2 Score being prescribed warfarin only
45.6%
Ayrshire & Arran
51.7%
Dumf ries & Gallow ay
32.9%
Fif e
38.2%
Forth Valley
42.9%
Greater Glasgow & Clyde
46.0%
Highland
Lanarkshire
36.3%
30.2%
Lothian
67.5%
Orkney
Shetland
12.7%
52.5%
Tayside
50.6%
Western Isles
0.0%
10.0
%
20.0
%
30.0
%
40.0
%
50.0
%
%
60.0
%
NHS Board Residence (HB)
70.0
%
80.0
%
Scotland
90.0
%
100.0
%
NHS QIS Primary Care Atrial Fibrillation Audit 2010:
Percentage of AF Patients with Medium CHADS2 Score being prescribed warfarin only
Ayrshire & Arran
38.2%
Dumf ries & Gallow ay
37.9%
Fif e
33.1%
Forth Valley
30.0%
Greater Glasgow & Clyde
34.8%
Highland
39.5%
35.8%
Lanarkshire
29.5%
Lothian
35.3%
Orkney
Shetland
7.9%
45.9%
Tayside
Western Isles
0.0%
25.8%
10.0%
20.0%
30.0%
40.0%
50.0%
%
NHS Board Residence (HB)
Scotland
60.0%
NHS QIS Primary Care Atrial Fibrillation Audit 2010:
Percentage of AF Patients with Low CHADS2 Score being prescribed warfarin only
Ayrshire & Arran
34.7%
Dumf ries & Gallow ay
40.8%
Fif e
22.2%
Forth Valley
31.0%
Greater Glasgow & Clyde
23.5%
Highland
30.4%
24.3%
Lanarkshire
16.9%
Lothian
Orkney
Shetland
11.1%
8.7%
59.1%
Tayside
Western Isles
11.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
%
NHS Board Residence (HB)
Scotland
80.0%
AF- the clinical context summary
• Commonest arrhythmia, especially in the elderly
• Formal stroke risk assessment not routinely performed
• Warfarin underused in patients at high risk of stroke
• TTR > 60% can be achieved in the majority of patients
SCOTTISH MEDICINES CONSORTIUM
Angela Timoney, Chair, SMC
SMC Remit
Provide advice to NHS Boards and ADTCs on comparative and costeffectiveness of:
• New Medicines
• New Formulations of Medicines
• Major new indications for Medicines
– 80 products (approx) per annum
• Provide advice as close to product launch as possible (within 3-6
months)
– “shape practice, not change practice!”
SMC Remit
Assess only licensed medicines (QSE)
Assess clinical effectiveness
Assess comparative cost-effectiveness
NOT assessing safety (duty of Regulator: EMA/MHRA)
but consider relative safety
From data provided by the licence holder
SMC Advice: Accepted, Accepted with restrictions, Not recommended
Post-SMC: NHS Board ADTCs
Review at
SMC
Accepted/
Accepted restricted
Not
recommended
Use in NHS Scotland
only under exceptional
circumstances (IPTR)
Non-formulary
drug
Review at ADTC
Me-too
(no added
value)
Important
new
development
Formulary drug
DABIGATRAN
SMC ASSESSMENT & OUTCOME
Alison Campbell, NDC
Overview
• Direct thrombin inhibitor
• Already licensed for thromboprophylaxis in
elective hip/knee replacement surgery
• Regulatory authority
– CHMP positive opinion mid-April for stroke prevention
in patients with atrial fibrillation
– Licence granted early August 2011
Comparative efficacy: RELY Study (1)
• Over 18,000 patients
• Non-valvular AF and > one additional risk factor for stroke
• Randomised to:
– Dabigatran - two doses tested (blinded): 110mg and 150mg bd
– Warfarin (open label), adjusted to achieve INR of 2-3
• Well matched populations
• Primary outcome: composite of stroke or systemic embolism
• Non-inferiority study
– superiority to be tested if non-inferiority confirmed
Comparative efficacy: RELY Study (2)
• 150mg dabigatran superior to warfarin in terms of clinical
efficacy
• 110mg dose of dabigatran is non-inferior to warfarin
• Reduction in stroke – all types and severity
• Absolute risk of events is low
• Net clinical benefit –includes strokes/emboli, MI, death
from any cause and also major bleeds.
– Significant difference for 150mg
Comparative Safety
• Balance between stroke prevention and bleeding
• Annual rate of major bleeding
– dabigatran 110mg statistically significantly lower than warfarin
– numerically but not statistically significantly lower for 150mg
• Increased risk of GI bleeding over warfarin
– statistically significant for 150mg
– Numerically higher for 110mg
• Relationship between age and bleeding
• Other GI symptoms – dyspepsia (formulation effect?)
• No apparent effect on LFTs
– longer term data required
• Half-life increases with reducing renal function
Clinical Effectiveness
• Comparison with warfarin:
– 150mg superior for stroke prevention: similar for bleeding risk
– 110mg similar for stroke prevention: superior for bleeding risk
• AF related strokes more likely to be disabling and higher
risk of mortality
• INR in target range 64% of time (UK centres, 72%)
– “observed benefits of dabigatran compared to warfarin diminish
with improving INR control”
– No therapeutic monitoring for dabigatran
• Higher risk of MI
• Lack of reversibility: no specific antidote
• Consideration of aspirin or no treatment as comparator
Health economics: principles
•
Compare the costs and benefits of two or more alternative courses of action
– Is the “premium price” of the new medicine justified by its additional benefits?
•
Costs (net)
– cost of treatment minus future treatment avoided (ie negative cost)
•
Quality-adjusted life years, QALYs
– Primary outcomes from clinical trials not enough
– What does the benefit means for the patient?
– Weighting (utility) to time periods to reflect how good/bad QoL during this time
– Single measure to combine changes in length and quality of life (QoL)
– Make decisions in a consistent way
– Not the only criterion
•
Threshold for decisions
– No simple cost per QALY cut-off (incremental cost-effectiveness ratio, ICER)
– ICER of <£20k is generally acceptable - if economic case robust
Comparative Health Economics (1)
• Cost-utility analysis vs relevant comparators
– Warfarin, Aspirin, No treatment
• Recommended posology (sequence)
– 150mg bd and switch to 110mg bd at age ~80years (some discretion)
• Events (stroke, bleeds) are rare but can be catastrophic
– Costs/disutility from a stroke/ICH sustained over a long time
• INR monitoring costs were important influence
– over-estimated in the base-case
• Base case ICER ~ £7k.
– Lower against aspirin <£6k and <£2k vs no treatment
Comparative Health Economics (2)
For 10,000 patients treated instead of warfarin.
Expected lifetime differences:
•
186 fewer ischaemic strokes
•
563 fewer intracranial haemorrhages
•
397 more extracranial haemorrhages
•
241 more myocardial infarctions
•
Nineteen patients have to be commenced on dabigatran sequence
rather than warfarin to avoid one additional death or major disabling
event
data taken from Scottish Medicines Consortium dabigatran detailed advice document, available here:
http://www.scottishmedicines.org.uk/SMC_Advice/Advice/672_11_dabigatran_Pradaxa/dabigatran_Pradaxa
Comparative Health Economics (3)
•
INR monitoring savings appeared to be overestimated.
– More plausible range tested increased ICER from £7k to >£13k
– Tested all the way to zero
•
Time in therapeutic range (TTR) for warfarin.
– Reviewed according to quartiles of the treatment centres TTR
– Best INR control, hazard ratio for net clinical benefit favoured warfarin
– Trial TTR similar to clinical practice: wide inter-patient / inter-service variability
•
Use of 110mg
– Cost-effectiveness poorer: clinical efficacy benefit “lost”
– ICER could exceed the usual threshold with combination of factors
– Relatively low ICER vs aspirin or no treatment (stroke reduction benefit)
•
Non-significant differences in the model
– Some risks working in opposite directions
•
Overall case demonstrated (range of cost-effectiveness)
Budget impact
• Medicine cost is £917 (cf to <£25)
• Manufacturer proposes offset costs
– INR monitoring avoided: not immediately cash releasing
– Longer term events avoided
• Dependent on implementation strategy ………………..
• Other agents on the horizon
LABORATORY IMPLICATIONS AND
REVERSAL OF DABIGATRAN
Dr Julia Anderson, Consultant Haematologist, Royal Infirmary of Edinburgh
New Anticoagulants
ORAL
PARENTERAL
TF/VIIa
TTP889
TFPI (tifacogin)
X
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
TAK 442
Betrixaban
IX
VIIIa
Va
Xa
APC (drotrecogin alfa)
sTM (ART-123)
IXa
AT
II
Dabigatran
Fibrinogen
Fondaparinux
Idraparinux
Idrabiotaparinux
DX-9065a
Otamixaban
IIa
Fibrin
Adapted from Weitz & Bates, J Thromb Haemost 2007
DABIGATRAN: PK AND PD STUDIES
PK Study: healthy male volunteers
• Peak concentration 2-3 hours
after ingestion
• Half-life 12-17 hours
• 80% renal excretion
• Drug interactions: quinine,
amiodarone, verapamil,
rifampicin
• No “routine” monitoring is
required
Stangier J, Rathgen K, Stahle H et al. B J Clin Pharmacol 2007 64 3 292-303
Stangier J, Stahle H, Rathgen H et al. Clinical Pharmacokinetics 2008 47 1 47-59
Curvilinear relationship
Linear relationship
Too sensitive
Linear relationship
Precise
Sensitive
Linear relationship
Low sensitivity
Not suitable
Plots of global assays vs Dabigatran concentration (ng/ mL)
(Stangier J, Rathgen H , Stahle H et al. BJClin Pharm 2007 64(3) 292-303)
MEASURING DRUG EFFECT
1.
Poor compliance
2.
An anticoagulated patient presents with an acute bleed
- is over-anticoagulation responsible for the bleed?
3.
An anticoagulated patient presents with suspected recurrent
thrombosis:
- is the anticoagulant intensity appropriate?
- does an alternative drug need to be given?
4.
Transition from one anticoagulant to another
ECARIN CLOT TIME (ECT)
•
•
•
•
•
Not universally available in laboratories
Not standardised
Ecarin available from commercial sources
Whole blood and plasma ECT methods
Cost £12 - £15 per kit
Nowak G. Pathophysiol Haemost Thromb 2004; 33:173-183;
Koster A, Potzsch B, Madlener K Ch 19
Greinacher A Ch 14 Lepirudin for the Treatment of Heparin-induced
thrombocytopenia
OTHER LAB ISSUES:
• Increase in “reflex testing” – cost in technician time and
cost of reagents
• Need to consider new ways to request coag assays to identify
patients taking dabigatran
• Costs of replacing fibrinogen assays with new reagents
unaffected by dabigatran
• Estimated cost in NHS Lothian: £16,000 per annum
REVERSAL OF DABIGATRAN
• Little clinical experience of management of major
bleeding or drug overdose
• Many recommendations are based on speculation
NO SPECIFIC ANTIDOTE
– Use of rec fVIIa, APCC and PCCs can be considered,
– but this is largely speculation/ based on non-clinical data
– off-licence use; safety issues (thrombosis)
– Fresh frozen plasma does not reverse dabigatran
– use to prevent dilutional coagulopathy
– Desmopressin acetate (DDAVP): no data
– Dabigatran etexilate well-adsorbed to activated charcoal
– give within one hour of inadvertent swallowing
– Susceptible to haemodialysis; 60% removal within 2-8 hours
ESTIMATED PATIENT NUMBERS
• Lothian NHS Trust : use of Octaplex 2008-9 to reverse
major haemorrhage in patients on warfarin in Lothian
• 316 product releases
(thanks to SNBTS, Mike McGinnis)
GUIDELINES FOR MANAGEMENT OF
BLEEDING WITH DABIGATRAN - FOR
POSSIBLE INCLUSION INTO LOCAL
MANAGEMENT PROTOCOLS
http://www.pharmac.govt.nz/2011/06/13/Dabigatran%20b
leeding%20management.pdf
OTHER POLICIES NEED TO BE IN PLACE
• Policies required for:
– Reversal to or from parenteral anticoagulants
– Reversal to or from warfarin
– For discontinuation before elective surgery
– Hidden cost in terms of staff education and time
SUMMARY
•
Dabigatran affects global assays of haemostasis, but no single test can
“measure” anticoagulant effect
•
Assays may be required in given clinical situations
» which labs should be equipped to do ECTs and other tests?
•
Could cause increase in reflex testing in labs (increased cost)
» improved systems to order coagulation tests required
•
Cost involved in changes to fibrinogen assays
•
No antidote: Boards need to develop reversal policies
• Safety of off-licence use of products
• Cost of rFVIIa and APCCs
»
rFVIIa costs £3676.40 for 8mg dose ?rpt dose required
»
FEIBA costs £0.74 per unit, so average treatment:£2960 ?rpt dose required
• ?Need for a National Reversal Policy
DRAFT CONSENSUS STATEMENT FOR
THE PREVENTION OF STROKE AND
SYSTEMIC EMBOLISM IN ADULT
PATIENTS WITH NON-VALVULAR
ATRIAL FIBRILLATION
Dr David Northridge, Consultant Cardiologist, NHS Lothian
No conflicts to declare
Dabigatran press coverage
“Pradaxa will greatly improve patients’ quality of life by allowing
them to eat what they want without fear of triggering a stroke or
haemorrhage. It also removes the need for blood tests associated
with warfarin, which is used as rat poison.”
http://www.dailymail.co.uk/health/article-2031179/No-rat-poison-New-stroke-drug-better-warfarin.html
“…top officials set to meet this month to discuss its introduction”
http://news.scotsman.com/news/New-drug-to-save-75000.6830779.jp
DRAFT CONSENSUS STATEMENT
Prevention of stroke and systemic embolism
in adult patients with non-valvular atrial fibrillation
On balance of risks and benefits, warfarin remains the anticoagulant of choice for moderate or
high risk AF patients (CHA2DS2-VASC ≥ 2) with good INR control (Time in Treatment Range (TTR) ≥ 60%)
START
Make efforts to improve
compliance. If noncompliance1 is still a
concern, assess risk and
consider stopping
therapy.
No
Is the patient
complying with their
warfarin regimen?
(≥3 months therapy)
Yes
Has the
patient been prescribed
warfarin?
No
After review
of the individual and their
stroke risk (CHA2DS2-VASC ≥ 2) and
bleeding risk factors, can the patient be
(re)considered for
warfarin?
Yes
No
Continue on warfarin.
Yes
Prescribe warfarin.
No
Does the patient have
an allergy to, or intolerable side
effects from, warfarin?
Yes
Does the patient have
good INR control?
e.g. range (TTR) ≥ 60%
CHA2DS2-VASC
Yes
No
1Non-compliance
Non-compliance alone is not an
indication for initiating therapy with
dabigatran as many of the causes
of non-compliance with warfarin
may also result in non-compliance
with dabigatran e.g. alcoholism.
chaotic lifestyle, wilful noncompliance.
2Contraindications
Many contraindications to warfarin
therapy will also apply to
dabigatran e.g. high bleeding
risks, severe renal impairment,
coagulation disorders, and liver
failure. In such cases the use of
dabigatran will not be appropriate.
For further information refer to
SPC
Draft v0.8 5/9/11
Consider prescribing dabigatran in these patient groups.
TTR <60% despite evidence
that patient complying1
Major bleed due to high
INR
Allergy or intolerable side
effects from warfarin.
Contraindications to
warfarin2
Dosing
• ≤ 75 years, 150mg twice daily
• 75 – 80 years, 150mg twice daily or 110mg twice daily*
• ≥ 80 years, 110mg twice daily
Congestive heart failure
(inc LVD)
1
Hypertension
1
Aged 75 or more
2
Diabetes
1
Stroke/TIA/thromboembolism
2
Vascular disease
(prior MI, PAD or aortic plaque)
1
Aged 65-74
1
Female
1
*following individual assessment at the discretion of the physician when thromboembolic risk is low and the bleeding risk high.
3Monitored
For further prescribing information refer to the SPC.
Individual NHS boards may wish to consider prescribing dabigatran in those patient groups in whom the use of warfarin is logi stically
more challenging e.g. patients with inability to access services, difficult venepuncture, poor understanding of the process 3.
dosage systems
Dabigatran capsules must be
retained within their original
packaging until the point of
consumption and are therefore
unsuitable for re-packaging into
monitored dosage systems.
Do you agree that Warfarin remains anticoagulant of
choice for AF patients with good INR control?
• 72 % of respondents agree
• What about the rest ?
Warfarin is out-dated and wouldn’t get a license to-day.
Continuing its use along with the new anticoagulants
would be the worst of all possible worlds!
• Whatever happens we are stuck with warfarin for the
foreseeable future
• Dabigatran has been approved for use in Scotland by SMC BUT
it is NOT suitable for all patients, only non-valvular AF
• 40% Patients with: Valvular A fib
Prosthetic Heart Valves
DVT
Pulmonary thromboembolism
All need Warfarin
Dabigatran is superior and would be treatment of choice
if not for financial concerns
The savings from discontinuing INR monitoring will
offset the cost of Dabigatran
•
Hard to ignore the cost of Dabigatran
•
£76.40 per month, £917 pa
•
add prescribing/dispensing costs = total over £1000 pa
•
63,000 eligible patients in Scotland
•
Potential financial impact of up to £60m
•
Warfarin drug costs estimated at £15 pa
•
INR monitoring circa £50 pa lab costs, £70 clinic/primary care
•
However, this is not the focus for to-day, the financial impact will be a
matter (headache!) for individual boards
•
Our main concern is that dabigatran may be inferior to warfarin in
many cases
Why not offer Dabigatran to all (all new) patients with
non-valvular AF?
• The benefits of Dabigatran over warfarin reported in the
RELY trial were only seen in centres with poor INR control
in the warfarin treated patients
• In the centres with the best control, warfarin treated
patients fared better
Dabigatran compared with warfarin at different levels of
INR control in AF: an analysis of the RE-LY trial
Risk of stroke and systemic embolism
TTR
<57
57-65
65-72
>72
110mg Dabigatran
1.91
1.67
1.34
1.23
150mg Dabigatran
1.1
1.04
1.04
1.27
Warfarin
1.92
2.06
1.51
1.34
Risk of major bleeding
TTR
<57
57-65
65-72
>72
110mg Dabigatran
2.36
3.18
2.82
2.81
150mg Dabigatran
2.54
3.33
3.80
3.60
Warfarin
3.59
4.13
3.40
3.11
Lars Wallentin et al. Lancet 2010: 376; 975-83
Dabigatran compared with warfarin at different levels of
INR control in AF: an analysis of the RE-LY trial
Mortality
TTR
<57
57-65
65-72
>72
110mg Dabigatran
4.17
3.97
3.19
3.60
150mg Dabigatran
3.85
3.75
3.64
3.30
Warfarin
5.72
4.09
3.70
3.04
Stroke, embolism, MI, death or major bleeding
TTR
<57
57-65
65-72
>72
110mg Dabigatran
7.65
7.84
6.88
6.85
p=0.036
150mg Dabigatran
Warfarin
6.83
10.13
7.09
8.03
7.41
7.13
7.07
6.42
p=0.0006
Lars Wallentin et al. Lancet 2010: 376; 975-83
Do you consider that a patient with TTR >60% has ‘good
INR control’?
• Yes 50%
• No 42%
TTR in patients attending anticoagulant clinics in North of Scotland
TTR
No. Patients
Cumulative %
Av Visits/year
<40%
<50%
<60%
<70%
<80%
<100%
147
290
536
864
1277
1880
8%
15.5%
28.5%
46%
68%
100%
22.9
25.8
21.6
16.4
14.0
9.3
Dr Chris Lush 2011
How to be certain ‘poor INR control’ isn’t due to poor compliance?
The degree to which INR is out with therapeutic range is also
important, eg brief episodes of very high INR
Clinical judgement is required
• Agreed, please discuss
DRAFT CONSENSUS STATEMENT
Prevention of stroke and systemic embolism
in adult patients with non-valvular atrial fibrillation
On balance of risks and benefits, warfarin remains the anticoagulant of choice for moderate or
high risk AF patients (CHA2DS2-VASC ≥ 2) with good INR control (Time in Treatment Range (TTR) ≥ 60%)
START
Make efforts to improve
compliance. If noncompliance1 is still a
concern, assess risk and
consider stopping therapy.
No
Is the patient
complying with their
warfarin regimen?
(≥3 months therapy)
Yes
Has the
patient been prescribed
warfarin?
No
Yes
No
Continue on warfarin.
Does the patient have
an allergy to, or intolerable side
effects from, warfarin?
After review
of the individual and their
stroke risk (CHA2DS2-VASC ≥ 2) and
bleeding risk factors, can the patient be
(re)considered for
warfarin?
Yes
Prescribe warfarin.
No
Yes
Does the patient have
good INR control?
e.g. range (TTR) ≥ 60%
CHA2DS2-VASC
Yes
No
1Non-compliance
Non-compliance alone is not an
indication for initiating therapy with
dabigatran as many of the causes
of non-compliance with warfarin
may also result in non-compliance
with dabigatran e.g. alcoholism.
chaotic lifestyle, wilful noncompliance.
2Contraindications
Many contraindications to warfarin
therapy will also apply to
dabigatran e.g. high bleeding
risks, severe renal impairment,
coagulation disorders, and liver
failure. In such cases the use of
dabigatran will not be appropriate.
For further information refer to
SPC
Draft v0.8 5/9/11
Consider prescribing dabigatran in these patient groups.
TTR <60% despite evidence
that patient complying1
Major bleed due to high INR
Allergy or intolerable side
effects from warfarin.
Contraindications to warfarin2
Dosing
• ≤ 75 years, 150mg twice daily
• 75 – 80 years, 150mg twice daily or 110mg twice daily*
• ≥ 80 years, 110mg twice daily
Congestive heart failure
(inc LVD)
1
Hypertension
1
Aged 75 or more
2
Diabetes
1
Stroke/TIA/thromboembolism
2
Vascular disease
(prior MI, PAD or aortic plaque)
1
Aged 65-74
1
Female
1
*following individual assessment at the discretion of the physician when thromboembolic risk is low and the bleeding risk high.
3Monitored
For further prescribing information refer to the SPC.
Individual NHS boards may wish to consider prescribing dabigatran in those patient groups in whom the use of warfarin is logi stically
more challenging e.g. patients with inability to access services, difficult venepuncture, poor understanding of the process 3.
dosage systems
Dabigatran capsules must be
retained within their original
packaging until the point of
consumption and are therefore
unsuitable for re-packaging into
monitored dosage systems.
Patients with allergy to or intolerable side effects
from warfarin
• Yes 94%
• But, many of these patients can be successfully
treated with acenocoumarol
Patients with contraindications to warfarin
eg high bleeding risk/safety concerns
• Yes 83%
• Patients who have had a bleed on warfarin, or those at
high risk of bleeding, may not be safer with Dabigatran
Risk of Major Bleeding by Age in the RE-LY trial
Age
<75
>75
110mg Dabigatran
1.89 (RR 0.50-0.77)
4.43 (RR 0.83-1.23)
150mg Dabigatran
2.12 (RR 0.57-0.86)
5.10 (RR 0.98-1.42)
Warfarin
3.04
4.37
John Eikelboom et al. Circulation 2011;123:2363-2372
What can we learn from the introduction of
dabigatran elsewhere?
“Dozens of elderly patients have suffered bleeds – and at least two have
died – after taking an anti-blood clotting drug which was rushed onto the
market by Pharmac in a deal worth more than $100m.”
“The Centre for Adverse Reactions Monitoring (Carm) has received
around 50 reports of people experiencing bleeding since the drug was
introduced two months ago as a replacement for the standard bloodthinning drug warfarin.”
Sunday Star Times, New Zealand
Sunday 11/09/2011
http://www.stuff.co.nz/national/health/5602413/Pharmac-attacked-for-rushing-drug
Other patient groups?
Patients who are unable to comply with INR
monitoring, eg learning difficulties/dementia ?
• Yes, may-be
• But, dabigatran is unstable when removed from its
packaging
• Very difficult to include dabigatran in medication
compliance devices
Other patients groups?
Patients who have difficulty accessing monitoring
services?
• Patients who require domiciliary monitoring
• Patients with needle phobia/difficult veins
(capillary blood/near patient testing)
• Remote and rural
• Work/shift patterns
Let’s wait for SIGN and NICE
What about the other new anticoagulants?
•
NICE appraisal Dec 2011
•
SIGN antithrombotic guideline review next year
Thrombin Inhibitors
Dabigatran (RE-LY)
Ximelagatran (SPORTIF)
Factor Xa Inhibitors
Rivaroxaban (Rocket AF)
Apixaban (Aristotle)
Edoxaban (Engage AF)
Drug Interactions/Contraindications to dabigatran
• Contraindications
• Cautions
•
Severe renal impairment
•
Verapamil - 110 mg dose
•
Gastritis or Oesophagitis
•
•
Allergy to E110
•
Ketoconazole
Itraconazole
Cyclosporine
Tacrolimus
Amiodarone
Dronedarone
Quinidine
Clarithromycin
•
Rifampicin
Carbamazepine
Phenytoin
St Johns Wort
Who will be responsible for switching to Dabigatran ?
How will we get GPs to stick to this ?
• Big issues, please discuss
We need to agree priority groups for implementation in
a standardised fashion nationally
• Agreed!
DRAFT CONSENSUS STATEMENT
Prevention of stroke and systemic embolism
in adult patients with non-valvular atrial fibrillation
On balance of risks and benefits, warfarin remains the anticoagulant of choice for moderate or
high risk AF patients (CHA2DS2-VASC ≥ 2) with good INR control (Time in Treatment Range (TTR) ≥ 60%)
START
Make efforts to improve
compliance. If noncompliance1 is still a
concern, assess risk and
consider stopping
therapy.
No
Is the patient
complying with their
warfarin regimen?
(≥3 months therapy)
Yes
Has the
patient been prescribed
warfarin?
No
After review
of the individual and their
stroke risk (CHA2DS2-VASC ≥ 2) and
bleeding risk factors, can the patient be
(re)considered for
warfarin?
Yes
No
Continue on warfarin.
Yes
Prescribe warfarin.
No
Does the patient have
an allergy to, or intolerable side
effects from, warfarin?
Yes
Does the patient have
good INR control?
e.g. range (TTR) ≥ 60%
CHA2DS2-VASC
Yes
No
1Non-compliance
Non-compliance alone is not an
indication for initiating therapy with
dabigatran as many of the causes
of non-compliance with warfarin
may also result in non-compliance
with dabigatran e.g. alcoholism.
chaotic lifestyle, wilful noncompliance.
2Contraindications
Many contraindications to warfarin
therapy will also apply to
dabigatran e.g. high bleeding
risks, severe renal impairment,
coagulation disorders, and liver
failure. In such cases the use of
dabigatran will not be appropriate.
For further information refer to
SPC
Draft v0.8 5/9/11
Consider prescribing dabigatran in these patient groups.
TTR <60% despite evidence
that patient complying1
Major bleed due to high
INR
Allergy or intolerable side
effects from warfarin.
Contraindications to
warfarin2
Dosing
• ≤ 75 years, 150mg twice daily
• 75 – 80 years, 150mg twice daily or 110mg twice daily*
• ≥ 80 years, 110mg twice daily
Congestive heart failure
(inc LVD)
1
Hypertension
1
Aged 75 or more
2
Diabetes
1
Stroke/TIA/thromboembolism
2
Vascular disease
(prior MI, PAD or aortic plaque)
1
Aged 65-74
1
Female
1
*following individual assessment at the discretion of the physician when thromboembolic risk is low and the bleeding risk high.
3Monitored
For further prescribing information refer to the SPC.
Individual NHS boards may wish to consider prescribing dabigatran in those patient groups in whom the use of warfarin is logi stically
more challenging e.g. patients with inability to access services, difficult venepuncture, poor understanding of the process 3.
dosage systems
Dabigatran capsules must be
retained within their original
packaging until the point of
consumption and are therefore
unsuitable for re-packaging into
monitored dosage systems.
DRAFT CONSENSUS STATEMENT
Prevention of stroke and systemic embolism
in adult patients with non-valvular atrial fibrillation
Potential Advantages of warfarin over dabigatran
•
Patients with good INR control using warfarin may achieve slightly
better health benefits than those using dabigatran i.e. benefits of
dabigatran diminish with improving INR control.
•
It is much easier to manage major bleeding with patients on warfarin.
The anticoagulant effect of warfarin is easier to measure and rapid
reversal can be achieved with Vitamin K and prothrombin complex
concentrates. There is currently no licensed product available to
rapidly reverse dabigatran.
•
•
•
INR monitoring enables assessment of compliance with medication
whereas dabigatran causes little alteration in routine coagulation
tests and is not monitored routinely.
Patients with poor compliance may be at greater risk of
thromboembolic complications with dabigatran as its shorter half life
will potentially result in more time without any degree of anticoagulation.
Rates of major GI bleeding / GI symptoms are greater with
dabigatran, particularly with 150mg twice daily dose in patients ≥ 75
years.
•
The safety profile of dabigatran is still not fully understood and there
is no long-term safety data.
•
There is limited knowledge of use of dabigatran in certain patient
groups e.g. extremes of body weight, renal or hepatic impairment,
women of childbearing potential.
•
Warfarin has been in clinical use for almost 60 years.
Draft v0.8 5/9/11
Potential Advantages of dabigatran over warfarin
•
In the RE-LY clinical trial, high dose dabigatran 150mg twice daily
has been shown to reduce risk of stroke compared with warfarin at
no extra risk of bleeding.
•
In the RE-LY clinical trial, low dose dabigatran 110mg twice daily has
been shown to reduce risk of major haemorrhage compared with
warfarin with the same reduction in risk of stroke.
•
There is no need for anticoagulant monitoring.
•
The dose regimen is uncomplicated – i.e. fixed (less scope for clinical
/ patient error)
•
A more stable level of anticoagulation is achieved.
•
There are fewer potential interactions with other medication, alcohol
and diet. However in patients concomitantly receiving verapamil, the
dose of dabigatran should be reduced to 110mg twice daily.
•
There is a rapid onset of action (2-4 hours after first dose). Use with
caution post surgery.
•
There is a rapid offset of action. Therapeutic effect lost within 24-48
hours post dose.
RE-LY clinical trial
Connolly SJ, Ezekowitz MD, Yusuf et al. Dabigatran versus Warfarin in
patients with atrial fibrillation. N Engl J Med 2009;361(12):1139 1151
WORLD CAFE
Jane Murkin, Associate Director of Improvement, Healthcare Improvement Scotland
June Watters, Quality Improvement Advisor, NHS Scotland Quality Improvement
Hub
SESSION INTRODUCTION
• Background and context
• Session aims
• World Cafe approach
• Questions to explore
• Practicalities
CARE IS NOT SAFE –
INSTITUTE OF MEDICINE REPORT
“Between the care we have
and the care we could have,
lies not a gap, but a chasm”
CROSSING THE QUALITY CHASM
A New Health System for the 21st Century
Committee on Quality of Health Care in America
INSTITUTE OF MEDICINE
NATIONAL ACADEMY PRESS
Washington, D.C.
http://www.nap.edu/openbook.php?isbn=0309072808
ADVERSE EVENTS
IN HOSPITAL
• 3.7% Harvard 1991
• 16.6% Australia 1995
• 10.8% London 2001
50% PREVENTABLE
3 million bed days in UK
£1 billion per annum in UK
• Acute hospitals 9.5% - HAI
(July 2007 HPS)
• Pre work SPSP
• SPSP Data – what are we learning in relation to harm
HOW SAFE ARE CLINICAL SYSTEMS?
Primary research into the reliability of systems within 7 NHS
organisations and ideas for improvement
( Health Foundation May 2010)
Reliability in healthcare – This is not simply a matter of
putting in place proper guidelines and expecting
practitioners to follow them. It involves identifying in
advance the points at which those mistakes can happen,
the different elements that contribute to those mistakes and
the systems that practitioners should follow in order to
ensure pt safety
MEASUREMENT FOR IMPROVEMENT
Process mapping
FMEA
Future State
Measurement
of
Improvement
Current
State
Up to 50% of process
steps involve a ‘hand-off’,
leading to error, duplication
or delay
Principles for increasing reliability
LEVEL 1 RELIABILITY PERSONAL INTENT,
(80% TO 95 % SUCCESS)
Level 2 Reliability
Reliability Science, System design
and Human Factors
10-2 Performance
(95% to 99.5% success)
•
Feedback of information on
•
Standardise processes
compliance
•
Make the desired action the default
•
“Opt-out” – The desired action = flow
VIGILANCE AND HARD WORK: 10-1
PERFORMANCE
•
Awareness and training
of work
•
Personal check lists
•
Build design aids into the system
•
Common equipment, standard
•
Create redundancies and time lapses
order sheets
A MODEL FOR
LEARNING AND
CHANGE
When you
combine
the 3
questions
with the…
…the Model
for
Improvement.
PDSA cycle,
you get…
The Improvement Guide, API, 2009.
QUALITY STRATEGY
•
Achieving safe, reliable, effective & person centred care
•
The what v the how
•
How do we ensure we achieve this when implementing Dabigatran?
•
What will the implementation approach be?
•
How will improvement approaches and methodologies support us?
•
How do we ensure we do not introduce other risks – unintended
consequences- how will we know?
•
What processes will we test and implement ?
•
What will we measure and how?
•
Who are the people in the process we need to engage and involve in the
implementation ?
•
Co design with patients – how will we involve them in the process?
PROCESS
•
Dedicated time to explore key questions to support safe and effective
introduction and implementation of this new medication
•
Facilitators to support
•
Opportunity to shape and influence the approach and identify emerging
themes, priority areas and identify key next steps
•
Ensure the level of focus is not just on the what and the who but also the
how
•
Opportunity for everyone to explore both questions
•
Generate ideas
•
Parking lot – if any relevant issues identified through discussion use Post it
notes and park to ensure we maximise the opportunity to really consider the
how!
GROUP 1
Which segmented population of patients will you initially
introduce dabigatran for and why?
How will you ensure safe and effective implementation?
GROUP 2
What will you require to support the clinical decision
making process?
How will you ensure safe and effective implementation of
dabigatran?
By : NHS board, Multidisciplinary teams, GPs
GROUP 2
Monitoring of warfarin. What’s good INR control? Should we
use 60% TTR?
What’s your experience?
How to manage bleeding? Would national policy be useful?
SESSION AIMS
• Delegates in the half of the room nearest to the
door to make their way upstairs to the
CARRINGTON SUITE.
• Delegates in the half of the room furthest from
the door to remain here in the FETTES SUITE.
• Videoconferencers to remain dialled in to
FETTES SUITE.
FEEDBACK AND FINAL VOTING
Jane Murkin, Associate Director of Improvement, Healthcare Improvement Scotland
It’s voting time
(the following 8 slides contain the
results of live voting undertaken
on 21 September 2011)
Please select the work area most appropriate to you.
1.
Admin/management
2.
Consultant/Nurse
Specialist/Pharmacist
3.
GP
4.
Other
65%
13%
11%
1
2
3
11%
4
Do you agree that on balance of risks and benefits, warfarin
remains the anticoagulant of choice for moderate or high
risk AF patients with good INR control?
90%
1.
Yes
2.
No
3.
Unable to comment
8%
1
2
2%
3
Do you consider that a patient with a time in
treatment range (TTR)>60% has ‘good INR
control’?
47%
1.
Yes
2.
No
3.
Unable to comment
34%
19%
1
2
3
The next 4 slides will indicate patients that may be
suitable for consideration for dabigatran.
Please indicate for each patient group whether you
agree their suitability or not for dabigatran.
Patient Group: Compliant patients with TTR<60%
Suitable for consideration of dabigatran?
78%
1.
Yes
2.
No
3.
Unable to comment
11%
1
2
11%
3
Patient Group: Patients with major bleed due to high
INR (international normalised ratio)
Suitable for consideration of dabigatran?
1.
Yes
2.
No
3.
Abstain
40%
32%
27%
1
2
3
Patient Group: Patients with allergy to or intolerable
side effects to warfarin?
Suitable for consideration of dabigatran?
1.
Yes
2.
No
3.
Abstain
90%
10%
0%
1
2
3
Patient Group: Patients with contraindications to
warfarin therapy?
Suitable for consideration of dabigatran?
43%
1.
Yes
2.
No
3.
Abstain
33%
23%
1
2
3
NEXT STEPS AND MEETING CLOSE
Jane Murkin, Associate Director of Improvement, Healthcare Improvement Scotland
Laura McIver, Chief Pharmacist, Healthcare Improvement Scotland
NEXT STEPS
• Refresh consensus statement based on today’s
discussion
• Issue finalised consensus statement to NHS boards.
• Follow-up improvement work.
• Addressing the arrival of further new agents
THANK YOU
CONSENSUS MEETING TO SUPPORT
THE SAFE AND EFFECTIVE USE OF
DABIGATRAN IN NHS SCOTLAND