Management of atrial fibrillation and secondary prevention of stroke/TIA March 2007  IMPACT. Dept. Medicines Management, Keele University, Keele, Staffordshire ST5 5BG

Prevalence of AF 1,2 Prevalence roughly doubles with each advancing decade from age of 50 O.5% at age years to almost 9% at age years Hospital admissions - AF present in 3-6% of acute medical admissions

Risk factors 1,2 Increasing age Male gender IHD Diabetes Hypertension Thyrotoxicosis Valve disease Lifestyle factors - alcohol, excessive caffeine

Identification and diagnosis 2,3 Patients presenting with –breathlessness –palpitations –syncope or dizziness –chest discomfort –stroke or TIA Perform manual pulse palpation to assess for irregular pulse

Identification and diagnosis 2,3 Consider targeted or opportunistic screening of symptomatic patients or those with risk factors Perform ECG in all patients, whether symptomatic or not, with irregular pulse

Classification of AF 1,3 Paroxysmal - duration less than 7 days, terminates spontaneously Persistent - duration greater than 7 days, would last indefinitely unless cardioverted Permanent - duration greater than 7 days and sinus rhythm not possible All patients with AF will have increased stroke risk

Prognosis 1,2 Sixfold increased risk of stroke Twofold increased risk of death Heart failure Cardiac ischaemia Quality of life - reduced exercise tolerance and impairment in cognitive function

 IMPACT. Dept. Medicines Management, Keele University, Keele, Staffordshire ST5 5BG Treatment strategies for AF 3

Rate control 3

Warfarin versus aspirin in AF 4 Adjusted dose warfarin reduces relative risk of stroke by 60% ARR = 8% a year for secondary prevention (NNT = 13 for one year) ARR = 3% a year for primary prevention (NNT = 33 for one year) Target INR of 2.5 (range 2 - 3)

Warfarin versus aspirin in AF 4 Aspirin reduces relative risk of stroke by 20% ARR = 2.5% a year for secondary prevention (NNT = 40 for one year) ARR = 1.5% a year for primary prevention (NNT = 66 for one year)

Risks of long-term anticoagulation 2 Increased risk of bleeding associated with INRs > 3 Increased risk of stroke associated with INRs < 2 Annual rate of major haemorrhage (intracranial haemorrhage, transfusion of at least 2 units of blood or event requiring hospital admission) was 1% control vs. 1.3% warfarin-treated patients Low-dose aspirin also increases risk of major haemorrhage

Antithrombotic therapy 5 Warfarin is more effective than aspirin in reducing CV events Modest increase in risk of bleeding with warfarin Trade-off between potential harms and benefits of warfarin Need to determine baseline risk to identify AF patients most likely to benefit

 IMPACT. Dept. Medicines Management, Keele University, Keele, Staffordshire ST5 5BG Stroke risk stratification 3

Stroke – the facts 6 130,000 people/year in England and Wales have a first stroke 60,000 deaths each year due to stroke Third most common cause of death in England and Wales Largest single cause of disability in England and Wales

Risk factors 7 Raised BP Age AF Heart failure Previous TIA IHD Lack of physical activity Diabetes Smoking

Secondary prevention of stroke/TIA 8,9 Key interventions Lifestyle changes –Stopping smoking –Regular exercise –Reducing salt intake –Avoiding excess alcohol –Healthy diet and achieving a satisfactory weight Good BP control – ideal BP target is < 130/80 mmHg Antiplatelets Statins

Drug treatment of BP 9 Step 1 thiazide (bendroflumethazide 2.5mg) or ACEI (enalapril, lisinopril or ramipril) If BP not controlled and compliance good Step 2 Combine thiazide + ACEI Step 3 Combine thiazide + ACEI +dihydropyridine CCB (amlodipine, felodipine or nifedipine)

Drug treatment of BP 9 If BP still not controlled and good compliance Consider additional antihypertensives –cardioselective b-blocker (atenolol, bisoprolol) –alpha blocker (standard doxazosin tablets) Consider referral to specialist Ideal BP target is < 130/80 mmHg

PROGRESS trial 10,11 6,105 patients with previous stroke or TIA Perindopril with/without indapamide vs. placebo Primary outcome – total stroke (fatal or non-fatal stroke) Follow-up 3.9 years

PROGRESS trial - results 10,11 Single therapy Perindopril 4mg od alone showed no significant reduction in stroke risk vs. placebo Reduced BP by 5/3 mmHg Combination therapy Perindopril + indapamide reduced BP by 12/5 mmHg 8.5% had stroke with combination vs. 14.4% placebo NNT = 17 (over 3.9 years)

PROGRESS trial - conclusion 10,11 Confirms benefit of BP reduction in stable patients with history of cerebrovascular disease Only combination therapy (ACEI + thiazide) was effective Trial did not include a subgroup randomised to thiazide alone

Antiplatelets – NICE 12 Aspirin+dipyridamole m/r combination for ischaemic stroke or TIA for 2 years - then revert to low dose aspirin long-term Reserve clopidogrel for patients intolerant of low dose aspirin and who have experienced an occlusive vascular event or have symptomatic peripheral arterial disease Genuine aspirin intolerance defined as hypersensitivity reactions or severe dyspepsia, should be differentiated from mild dyspeptic symptoms Patients who previously did not tolerate high dose aspirin may tolerate low dose

ESPRIT study 13 RCT in 2,739 patients with TIA or non-disabling stroke in last 6 months Assigned to aspirin (mean dose 75mg daily) with or without dipyridamole 200mg bd Primary outcome – composite of death from all vascular causes, non-fatal stroke, non- fatal MI or major bleeding complications Mean follow-up 3.5 years

ESPRIT study - results 13 Primary outcome events significantly reduced in combination group (12.7% versus 15.7%) ARR = 3% NNT = 33 (over 3.5 years) No significant difference in incidence of major or minor bleeding Suggests a possible benefit of continuing combination treatment beyond 2 years

Statins - HPS 9,14 Heart Protection Study – subgroup analysis of patients with cerebrovascular disease 18.7% on simvastatin 40mg had a major vascular event vs. 23.6% placebo ARR = 4.9% NNT = 20 (for 5 years) Consider simvastatin 40mg if total C > 3.5 mmol/l

Statins - SPARCL 15,16 RCT in 4,731 patients with recent history of stroke or TIA Compared atorvastatin 80mg daily vs. placebo Primary outcome was fatal or non-fatal stroke Median follow-up 5 years Drug company sponsored trial

Statins - SPARCL 15,16 SPARCL study - results Primary outcome reduced with high dose statin 5 year ARR 2.2% NNT = 46 (CI ) for 5 years Increased risk of haemorrhagic stroke and increased liver enzyme levels with atorvastatin 80mg No difference in overall mortality

References 1.Iqbal B et al. Recent developments in atrial fibrillation. BMJ 2005; 330: National Collaborating Centre for Chronic Conditions. Atrial fibrillation: national clinical guideline for management in primary care and secondary care. London: Royal College of Physicians, NICE Clinical Guideline 36. The management of atrial fibrillation, June Lip G et al. ABC of antithrombotic theray: Antithrombotic therapy for atrial fibrillation. BMJ 2002; 325: Walraven C et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation. JAMA 2002; 288: Markus HS. Medicine 2004; 32: Williams B et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ March 2004; 328: Intercollegiate Stroke Working Party, RCP. National Clinical Guidelines for stroke – 2 nd edition concise guide PROGRESS Collaborative Group. Lancet 2001; 358: National Prescribing Centre. MeReC Extra – secondary prevention of stroke: what does the PROGRESS trial add? December NICE Technology Appraisal 90, May Clopidogrel and modified- release dipyridamole in the prevention of occlusive vascular events. 13.National Prescribing Centre. Merec Rapid Review – ESPRIT supports current NICE guidance, June 2006 (1): Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin 40mg in 20,536 high-risk individuals: a randomised placebo-controlled trial. The Lancet 2002;360: NeLM In-Focus Review. High dose atorvarstatin after stroke or transient ischaemic attack (SPARCL trial), August National Prescribing Centre. MeReC Extra - Statins after stroke - the SPARCL study. November National Prescribing Centre. MeReC Extra; June 2002 : Issue 5.

Atrial fibrillation 17 QOF indicators Practice can produce a register of patients with AF % of patients with AF diagnosed after 1 April 2006 with ECG or specialist confirmed diagnosis % of patients with AF currently treated with anti- coagulation drug therapy or anti-platelet therapy

Stroke and TIA 17 QOF indicators Practice can produce a register of patients with stroke or TIA % of new patients with a stroke who have been referred for further investigation % of patients with TIA or stroke who have a BP record in the notes in preceding 15 months in whom the last BP reading (measured in previous 15 months) is 150/90 mmHg or less % of patients with TIA or stroke who have had a record of total cholesterol in the last 15 months % of patients with TIA or stroke whose last measured cholesterol (measured in previous 15 months) is 5 mmol/l or less % of patients with a stroke shown to be non- haemorrhagic, or a history of TIA, who have a record that an anti-platelet agent or anti- coagulant is being taken (unless a C/I or side- effects are recorded) % of patients with stroke or TIA who have had influenza immunisation in the preceding 1 September to 31 March

ACE inhibitors - HOPE study 18 Analysis of stroke data Ramipril reduced incidence of stroke compared to placebo Absolute risk reduction ARR = 1.5% (ramipril 3.4% vs. placebo 4.9%) NNT = 67 (for 4.5 years) Unclear if benefits due to ACEI or antihypertensive action?