Managing anticoagulation in atrial fibrillation Dr Katy Rice June 2011

Atrial fibrillation Commonest chronic arrhythmia Increasing prevalence - ageing population -improved survival from CHD Morbidity/mortality from stroke, heart failure Stroke risk reduced by warfarin

Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

Burden of disease AF Prevalence per 1000 population in Scotland (Murphy NF et al 2007) Overall8.7 <45 years years30.5 >85 years70.7

Prevalence of AF in the Renfrew- Paisley study Cohort of men and women aged 45–64 years (n = 15,406) Reproduced with permission of the BMJ Publishing Group from Stewart S et al, Heart 2001: 86:516-21

Extrapolating to Sutton and Merton population PCT population392,300 Registered AF patients (QOF ) 3,959 AF anticoagulated (40%)1,584 Potential AF needing anticoagulation (60%) 2,375 Estimated new AF patients/year 340

Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

Recognition of those at risk of stroke Patients with AF have x 5 risk of stroke AF and no risk factors 1% per year AF and previous stroke/TIA 12% per year Stroke in AF has poorer outcome

Annual stroke rates in AF according to CHADS 2 score Score Risk%

Determine stroke/thromboembolic risk High risk: Previous ischaemic stroke/TIA or thromboembolic event Age >75 with hypertension, diabetes or vascular disease Clinical evidence of valve disease, heart failure, or impaired left ventricular function on echocardiography Moderate risk: Age >65 with no high risk factors Age <75 with hypertension, diabetes or vascular disease Low risk: Age <65 with no moderate or high risk factors Patients with AF

Determine stroke/thromboembolic risk High risk Moderate risk Low risk Consider anticoagulation or aspirin Aspirin 75 to 300 mg/day if no contraindications Contraindications to warfarin? Warfarin, target INR = 2.5 (range 2.0 to 3.0) Reassess risk stratification whenever individual risk factors are reviewed NO YES Patients with AF

New risk scoring systems CHA(2)DS(2)-Vasc (Cong heart failure, Hypertension, Age≥75,Diabetes, Stroke, Vascular disease, Age 65-74, Sex category) HAS-BLED - (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly)

Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

Warfarin and AF Oral anticoagulation reduces stroke risk in AF by 2/3………..but only if time in therapeutic range (INR 2-3) is greater than 65% Oral anticoagulation leads to 2 extra intracranial bleeds per annum per 1000 patients

Benefits versus risks Stroke risk Valvular AF CHADS2 Bleeding risk >75 years Uncontrolled hypertension History of bleeding or intracranial haemorrhage Anaemia Polypharmacy History of poor anticoagulation control Anti-platelet drugs

Warfarin (relative) contraindications Advanced age Multiple comorbidities Cognitive impairment Visual impairment History of falls Alcohol Previous bleed on warfarin Recent history of GI bleeding Uncontrolled hypertension Recent major surgery Pregnancy Inherited coagulation defect Thrombocytopenia

Warfarin preassessment FBC - anaemia (?bleeding) - platelets <100 x 10 9 /l INR or APTT ratio >1.4 needs investigation (liver disease, lupus inhibitor, factor deficiency) Liver function tests

Warfarin determinants of dose Genetic e.g. VKORC1, CYP2C9 genes Age Comorbidities (heart, liver disease, poor nutrition) Medication

Warfarin induction protocols Slow AF No heparin needed Less likely to ‘overshoot’ Less frequent monitoring Fast Acute DVT or PE Need heparin until INR therapeutic Often results in high INRs Frequent tests

AF Induction Protocol Start 3mg daily and check INR after one week If INR <1.4 increase to 5 mg daily and repeat INR in 3 days If INR increase to 4mg daily and repeat in one week If INR continue 3mg daily and repeat INR in one week If INR >2.5 consider dose reduction or omitting dose

Cardioversion for persistent AF NICE guidance : INR 2.5 (range 2-3) for 3 weeks prior and 4 weeks after At Epsom & St Helier we aim for target to reduce likelihood of cancellation due to low INR Monitor weekly Cardiologists insist on venous samples (but probably no need if using Coaguchek) For urgent cardioversion give therapeutic LMWH before and warfarin for 4 weeks after

Aspirin for AF Alternative to warfarin if contraindications or intolerance or patient preference Less effective than warfarin Reduces stroke risk by 22% compared with placebo (warfarin 68%)

Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

Anticoagulant service provision General practice Secondary care Self monitoring -and various combinations of the above!

Anticoagulant service provision

Anticoagulation service at St Helier Estimated AF patients on books new AF patients per month Pressure to reduce ‘new:follow-up ratios’ Need to work with GPs to transfer patients to primary care

Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

The new anticoagulants Oral Wide therapeutic index Predictable pharmacokinetics and dynamics negating need for monitoring Rapid onset of action Antidote Minimal non-anticoagulant side-effects Minimal interactions with other drugs and food

The new oral anticoagulant drugs Dabigatran (Pradaxa - Boehringer-Ingelheim) Rivaroxaban (Xarelto - Bayer) - both licensed in UK for thromboprophylaxis post knee and hip replacement. Dabigatran licence for AF expected late June Apixaban (Pfizer)- awaiting FDA approval

Dabigatran Dabigatran etexilate, a pro-drug, is rapidly converted to dabigatran 80% excreted by kidney Half-life of hours Phase 2 data identified 110 mg BID and 150 mg BID as viable doses

RE-LY: A Non-inferiority Trial Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries R Warfarin adjusted (INR ) N=6000 Dabigatran Etexilate 110 mg BID N=6000 Dabigatran Etexilate 150 mg BID N=6000 Blinded Event Adjudication. Open Blinded

Trial Execution Performed December 2005-March 2009 Median Follow up 2.0 years Follow up 99.9% complete Mean time in therapeutic range = 64% (patients on warfarin)

Ischaemic/Unspecified Stroke D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR = % CI = P = 0.35 RR = % CI = P = 0.03 Years of Follow-up Cumulative Hazard Rates Dabigatran110 Dabigatran150 Warfarin

Hemorrhagic Stroke D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR = % CI = P <0.001 RR = % CI = P <0.001 Years of Follow-up Cumulative Hazard Rates Dabigatran110 Dabigatran150 Warfarin

Bleeding D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrateAnnualrateRR 95% CI pRR p Total14.6%16.4%18.2% < Major2.7 %3.1 %3.4 % Life- Threatenin g major 1.2 %1.5 %1.8 % < Gastro- intestinal Major 1.1 %1.5 %1.0 % <0.001

MI, Death and Net clinical Benefit D 110mgD 150mg warfari n D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrate Annual AnnualrateRR 95% CI pRR p MI0.7% 0.5 % Death3.8 %3.6 %4.1 % Net Clinical Benefit 7.1 %6.9 %7.6 % Net Clinical Benefit includes vascular events, death and major bleed

Dabigatran 150 mg vs. 110 mg Dabigatran 110mg Dabigatran 150mg D 150mg vs. D 110 mg Numberrate/yrNumberrate/yr Relative Risk 95% CI p Stroke and systemic embolism 1.5%1.1 % Hemorrhagic stroke 0.1% Major Hemorrhage2.7 %3.1 % Net Clinical Benefit7.1 %6.9 % *Net Clinical Benefit includes vascular events, death and major bleed

Permanent Discontinuation Years of Follow-up Stopping Rates Dabigatran110 Dabigatran150 Warfarin

Adverse events occurring in >5% of any group Dabigatran 110 mg% Dabigatra n 150 mg% Warfarin% Dyspepsia * Dyspnea Dizziness Peripheral edema Fatigue Cough Chest pain Arthralgia Back pain Nasopharyngitis Diarrhea Atrial fibrillation Urinary tract infection Upper respiratory tract infection Common Adverse Events *Occurred more commonly on dabigatran p<0.001

RE-LY Study Conclusions Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses reduced intra-cerebral, life-threatening and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding

Conclusions Both Dabigatran doses offer advantages over warfarin Dabigatran 150 is more effective and dabigatran 110 has a better safety profile Taken twice daily No reversal agent

Dabigatran - financial impact £2.50/day £912.50/year Warfarin cost £383/year(NICE)? Annual cost pressure for S London £ million Planned introduction needed

S & M implementation scenarios ScenarioCost (£) All patients switch from warfarin (minus warfarin costs) 839k New patients only at 60% rate186k Out of range on warfarin only (,65% TTR) 479k Currently untreated only (assuming 50% identified) 593k Warfarin contraindicated only (11%) k

Key issues Can a budget be identified from June 2011? Can subgroups be specified pending NICE HTA? How can clinicians be encouraged to comply with guidance? Can money be released from anticoag services for 2012/13? How should public pressure be dealt with if no money for widespread use?

Recommendations from S London Cardiac and Stroke Network Warfarin to remain agent of choice in short term Dabigatran in patients with contraindications to warfarin Establish S London working group to ensure consistent approach and develop prescribing guidance Develop communication plan and patient information strategy