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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