Net clinical benefit of OAC Net clinical benefit - stroke, systemic embolism, ICH – events prevented per 100 person years Singer 2009

All cause mortality benefit OAC Hart 2007 metanalysis 11 RCT’s: Mean age 69 yrs Mortality reduction of 26% (95% CI 3%-43%) Go et al 2003 (ATRIA cohort) – ‘real world’: 11,526 patients, mean age 71yrs Approx 40% > 75yrs, 10% > 85 yrs Mortality reduction 31% (95% CI 23% - 39%)

Risk – treatment paradox AF – highest prevalence in the elderly Elderly – highest risk of stroke Elderly – most likely to benefit from OAC Elderly – least likely to receive OAC White 1999

Risk – treatment paradox Under-use of OAC in AF: US, Italy, Canada, Germany: 20-40% eligible In relation to age: Canada, Japan: 70% in patients < 75 yrs 30% in patients > 75yrs UK 2013: 55-70% in patients < 75 (1/3 eligible total) 40-55% in patients > 75 (2/3 eligible total) Stafford 1998, Ageno 2001, CQIN 1998, Geisler 2001 Partington 2007, Furosho 2008 Mohammed 2013

Quality of INR control Efficacy of warfarin limited by quality of INR control (time in therapeutic range – TTR): Multiple food and drug interactions Variable pharmacodynamics Narrow therapeutic window (INR 2-3) Need for regular monitoring and dose adjustment

Quality of INR control Connolly 2008

Novel oral anticoagulants Direct thrombin inhibitor: Dabigatran etixilate Factor Xa inhibitors: Rivaroxaban Apixaban Edoxaban Quick onset of action Short half life and offset No monitoring Steady plasma concentration Less food and drug interactions

Efficacy vs safety NOACs Ruff 2013

ESC guidelines 2012 No antithrombotic therapy (or aspirin) Oral anticoagulant (or aspirin) Oral anticoagulant (VKA or NOAC)

Assessment of bleeding risk HASBLED score: Score: 0 = 1% 1 = 1% 2 = 1.8% 3 = 3.74% >4 = > 8% Score 3 or more – caution and careful monitoring with OAC/aspirin NOT CONTRAINDICATION BP >160 systolic Dialysis or Cr > 200 LFT – bil x2, ALT/AST x 3 Labile INR (TTR<60%) NSAIDS, antiplatelets Pisters 2011

How not to use HASBLED Case study: 74 yr old gentleman Right sided acute stroke Known AF RA – on NSAIDS BP ranges 160-170 mmHg systolic CHADSVASC = 4 (4% annual stroke risk) HASBLED = 4 (8.7% annual bleeding risk) Bleeding > stroke risk – therefore not OAC !!!!

Falls Commonly sited reason not to use OAC or stop treatment. Gage 2005: - Retrospective cohort ~ 20,000 patients AF. - Falls associated with 3 x risk ICH: - Warfarin not associated with increased risk of ICH in patients who fall: - Warfarin treatment associated with significantly reduced composite of death, hospitalisation for stroke, MI, ICH (~25%). Donze 2012: - Prospective analysis of > 500 high risk fallers with AF. - No increased risk of ICH with warfarin.

Combination anti-thrombotics Hansen 2010: Follow up study of >82,000 patients hospitalised for AF.

Cognitive impairment Shireman 2004: Flaker 2010: Retrospective analysis of >10,000 elderly US patients with AF. Dementia associated with trend suggesting more bleeding events, but didn’t reach significance – HR 1.56 (95% CI 0.95-2.57) Flaker 2010: Post-hoc ACTIVE-W. 2,500 had MMSE. 7% dementia. MMSE score correlated to TTR. TTR MMSE Engineer ways to optimise compliance

Frailty Poli 2011: Prospective study of > 3,000 elderly AF patients naïve to OAC. Average age 84 yrs (range 80 – 102). TTR 62% Major bleeding rate 1.9% per year. Perera 2009: Prospective evaluation of 220 frail patients. Frailty associated with poor outcome compared to non-frail irrespective of anti-thrombotic used. Frail seem to be at higher risk of stroke than bleeding compared to non-frail.

Patient counselling Explain how AF increases stroke risk Discuss stroke risk (CHADS-VASC) – more than likely lose of independence if this occurs. Explain risk of ICH – LOW – (<1%) Explain risk of extracranial bleeding (aspirin = OAC) Unlikely to lose independence if this occurs Informed patient decision

Warfarin & NOACs PATIENT CHOICE Well controlled INR Labile INR CKD / CrCl < 30 Requires good renal function GI bleed High risk ICH Prosthetic heart valve Difficulty with INR monitoring or dose adjustment Rheumatic heart disease PATIENT CHOICE

Summary AF is extremely common, and will increase with our aging population. Stroke related to AF is often devastating with high human and economic implications. Anticoagulation is superior to aspirin or no anti-thrombotic therapy in terms of overall benefit / mortality in patients with AF. This net clinical benefit increases with age, however observed rates of anticoagulation use are lowest in the elderly. Anticoagulation decisions in the frail can be very difficult.

Summary There are still a large number of strokes we can avoid. The default position for elderly patients (>75 yrs) with AF should be that they are offered OAC unless there is a good reason not to. Bleeding risk tools (e.g. HASBLED) should be use to optimise patient related factors, rather than rule OAC out. NOACs offer an alternative to warfarin that may improve overall use and efficacy of anticoagulation for AF. There are still a large number of strokes we can avoid.

Thanks for listening!