NOAC but NICE Conference 16th July 2013

Stroke Prevention in Atrial Fibrillation. NICE, NOACS and the future Dr John Duffy Stroke Consultant LTC Clinical Director

Warfarin LMW Heparin converting to warfarin Dabigitran converting to Warfarin Dabigitran Apixiban converting to Warfarin Apixiban Rivaroxaban converting to Warfarin Rivaroxaban

Background AF most common sustained cardiac arrhythmia 1-2% general population Prevalence increases with age (5-15% of 80 year olds) Thromboembolic risk of AF is not homogeneous, ranging from an annual risk of 1% patients aged 65 yrs with no risk factors, to > 12% per year in patients with previous hx thromboembolism. AF related ischaemic strokes are associated with increased morbidity and mortality (stroke 1996) with risk of death doubled and the cost of care increased 1.5 fold

AF is an increasingly important cause of stroke with increasing age… Fitzmaurice & Murray: Oral Anticoagulation Management & Stroke Prevention. Hayward Medical Communications, 2002

National Recommendations AF is an independent predictor of stroke annual risk 5-6 x higher than patients with SR Prevalence set to double in the next 50 years Benefits of thromboprophylaxis in patients with AF are well established in multpile RCT

National Recommendations National Clinical Guideline for stroke RCP 2008 NICE stroke guidelines 2008 European Society Cardiology guideline for AF 2010 AF National clinical guideline for management in primary and secondary care (NICE 2006 update due 2011)

NICE Guidance re NOACS Apixaban for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation. NICE technology appraisal guidance 275 (2013). Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation. NICE technology appraisal guidance 256 (2012). Dabigatran etexilate for the prevention of stroke and systemic embolism in people with atrial fibrillation with one or more risk factor for stroke or systemic embolism. NICE technology appraisal guidance 249 (2012).

Anticoagulation and AF 6 large RCT’s published between 1989-92 evaluated warfarin for the primary and secondary prevention of thrombo-embolism in patients with non-valvular AF Meta-analysis shows a 64% RRR with warfarin, corresponding to an absolute annual risk reduction in all strokes of 2.7%. Similar benefit for both primary and secondary prevention and for both disabling and non-disabling strokes. Treating 1000 patients with AF for 1 year with warfarin rather than aspirin would prevent 23 ischaemic strokes while causing 9 additional major bleeds

Antiplatelet therapy and AF Near-complete platelet inhibition is achieved with aspirin 75 mg thus if using antiplatelets in AF use doses in the lower end of the range (75mg) Magnitude of stroke reduction from aspirin (19%) is broadly similar to that seen when aspirin is given to vascular disease subjects

Alternative Regimes (lancet 2006) AF Clopidogrel Trial (ACTIVE W) anticoagulation was superior to the combination of clopidogrel-aspirin (RR reduction 40%) Major vascular events were reduced in patients receiving aspirin–clopidogrel, compared with aspirin monotherapy RR 0.89 primarily due to a 28% relative reduction in the rate of stroke Major bleeding was significantly increased in the aspirin-clopidogrel arm (2.0% per yr) and was similar to that with warfarin therapy (RR 1.57) Aspirin plus clopidogrel therapy could be considered an interim measure where warfarin therapy is unsuitable, but not as an alternative to warfarin in patients at high bleeding risk.

NOACS Trials Powered to show non-inferiority to warfarin for the primary end point of stroke or systemic embolus All 3 studies showed non-inferiority however in ROCKET study (Rivaroxaban) the mean time in therapeutic range for warfarin was noted to be lower than expected (55%)

Dabigatran versus Warfarin in Patients with Atrial Fibrillation: RELY study Direct thrombin inhibitor which does not require monitoring half life 12-14hrs. Dagibatran 110mg or 150mg bd vs warfarin 18,113 patients with AF + 1or more risk factors Mean age 71; CHADS 2.1 Excluded if creatinine clearance <30 Follow up 2yrs Primary outcome: stroke + systemic embolism NEJM 2009;361:1139-1151

P 0.05 P 0.003 P <0.001 P <0.001

ROCKET-AF Study Rivoroxaban vs warfarin in 14264 patients moderate-high risk AF patients (mean CHADS score 3.5) Rivoroxaban 20mg od or 15mg od if GFR 30 – 49ml/min Primary outcome: warfarin 2.4%/yr vs 2.1% (p ns) Major bleeding: warfarin 3.4%/yr vs 3.6%/yr (p ns) Intracranial bleeding: warfarin 0.7%/yr vs 0.5%/yr (p 0.02) GI bleeding: warfarin 2.2%/yr vs 3.1%/yr (p <0.001) Overall mortality: warfarin 4.9%/yr vs 4.5%/yr (p ns) Side effects similar in both groups; discontinuation rate slightly higher for Rivaroxaban NEJM DOI: 10.1056/NEJMe1107516

ARISTOTLE Study Apixaban 5mg bd vs warfarin in 18,201 patients with AF + 1 or more risk factors (creat. cl <25 excluded) Used 2.5mg bd if 2 of: age 80+, creat 133 or more, weight 60kg or less Mean age 70, CHADS 2.1 Primary outcome: warfarin 1.6%/yr vs 1.27% (p 0.01) Major bleeding: warfarin 3.09%/yr vs 2.13%/yr (p <0.001) Intracranial bleeding: warfarin 0.8%/yr vs 0.33/yr (p <0.001) Overall mortality: warfarin 3.94%/yr vs 3.52%/yr (p 0.05) Overall adverse events similar; discontinuation rate slightly higher for warfarin No increase in GI bleeding or MI NEJM 2011;365: 981-92

Stroke risk reductions from randomized trials of antithrombotic agents in atrial fibrillation. Stroke risk reductions from randomized trials of antithrombotic agents in atrial fibrillation. Relative risk reduction on a scale with 10 strokes for no antithrombotic therapy (placebo) is shown. The 22% relative risk reduction of antiplatelet therapy vs placebo and the 64% relative risk reduction of warfarin vs placebo are from Hart et al (Ann Intern Med. 2007;146:857–867). The 28% relative risk reduction of clopidogrel vs aspirin is from Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-A) (N Engl J Med. 2009;360:2066–2078), the 43% relative risk reduction of warfarin vs clopidogrel (Clop) plus aspirin is from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-W) (Lancet. 2006;367:1903–1912), and the warfarin rate is reset to the 64% relative risk reduction compared with control from the overview (Ann Intern Med. 2007;146:857–867). The 36% relative risk reduction of dabigatran 150 mg (Dabi) vs warfarin is from Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) (N Engl J Med. 2009;361:1139–1151), the 12% relative risk reduction of rivaroxaban (Riva) vs warfarin is from the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) (for stroke or systemic embolism) (N Engl J Med. 2011;365:883–891), and the 21% relative risk reduction of apixaban (Apix) vs warfarin is from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (N Engl J Med. 2011;365:981–992). Granger C B , Armaganijan L V Circulation 2012;125:159-164 Copyright © American Heart Association 17

CONCLUSIONS Anticoagulation should be recommended in every patient with persistent or paroxysmal AF unless clinically contraindicated

When assessing patient with AF for anticoagulation therapy How do we assess potential benefit?

Adjusted Stroke rate (%/yr) CHADS2 (JAMA 2001;285:2864–2870) CHADS2 score Patients (n=1733) Adjusted Stroke rate (%/yr) 120 1.9 1 463 2.8 2 523 4.0 3 337 5.9 4 220 8.5 5 65 12.9 6 18.2

CHA2DS2VASc score and stroke rate Risk factors for stroke and thrombo-embolism in non-valvular AF Major risk factors Clinically relevant non major risk factors Previous stroke, TIA or systemic embolism, age > 75 yrs Heart failure or moderate to severe LV systolic dysfunction (e.g. LV EF < 40%) Hypertension, DM, Female sex, Age 65–74 yrs,Vascular disease Risk factor-based approach expressed as a point based scoring system, with the acronym CHA2DS2-VASc (maximum score is 9) CCF/LVV dysfunction (<40%) 1 Hypertension Age >/=75 (MAJOR) 2 DM Stroke/TIA/thromboembolism (MAJOR) Vascular disease Age 65-74 Female sex

Recommendations CHA2DS2-VASc score Rx 2 or more OAC 1 OAC or aspirin but prefer OAC Either aspirin or no Rx prefer no treatment

Assessing the Risk Anticoagulation Prior to initiation of anticoagulation assess the risk as well as the potential benefit to the patient of anticoagulation therapy Rates of ICH are lower than in the past, typically between 0.1 and 0.6% (ECS 2010) Fear of falls seems exaggerated with estimates that a patient would need to fall 300 times per year for the risk of ICH to outweigh the benefit of OAC in stroke prevention.

A score >/=3 equals high risk Clinical Characteristics Score H Hypertension >160 1 A Abnormal liver (cirrhosis or biochemical evidence hepatic dysfunction) and renal function (creatinine >200 or transplantation/dialysis) 1 or 2 S Stroke B Bleeding (previous bleeding history/predisposition to bleeding) L Labile INR (< 60% time in therapeutic range 2-3) E Elderly (> 65 years) D Drugs (concominant use of NSAIDA/aspirin) or alcohol abuse (1 point for each) A score >/=3 equals high risk Max 9

HAS-BLED High risk patients need to be assessed on their individual merits and close monitoring of INR needs to be considered if anticoagulation is administered

Overwhelming evidence to support anticoagulation in AF patients Why is the use of anticoagulation low in this high risk population?

Reasons commonly given for not prescribing anticoagulation Advanced Age High falls risk Dementia Poor INR control PAF v Sustained and Atrial Flutter Fraility History previous significant haemorrhage/ risk factors for bleeding

Age Does the benefit of anticoagulation outweigh the increased risk of bleeding in an elderly population N=973 patients recruited from primary care registers >/=75yrs (mean age 82) Randomly assigned warfarin or aspirin (75mg) End point fatal/disabling CVA, other ICH, arterial embolism 24 primary events warfarin v 44 aspirin Absolute risk reduction 2% Yearly risk extra-cranial bleed 1.4% warfarin v 1.6% aspirin (Lancet 2007 370. 493-503)

Age Cohort study of patients with AF 1996-2003 (n=13559) Adjusted net clinical benefit was greatest for patients with history of ischaemic stroke (2.48% per yr) and those older 84 years (2.34% per yr) (Ann Int Med 2009) Age commonly associated with not prescribing warfarin despite clear clinical benefit thus implementation of better models for stratifying bleeding risk in frail elderly population are required (Drugs Ageing 2010)

Falls Studies evaluating anticoagulation risk in the elderly at high risk of falls indicate only 50% of eligible patients received warfarin Falls frequently cited as reason for no warfarin 3 studies specifically assessing risk-benefit analyses all found benefit of warfarin outweighs risk in falling patients with AF Education shown to reduce risk bleeding in elderly and should be a vital part of the management (Ann Pharmacother 2008)

Dementia Minimal research conducted in patients with AF and dementia Dementia does not feature in the bleeding risk assessment tools Most clinicians will anticoagulate community based patients with mild/moderate dementia if medication supervision available In more advanced dementia antiplatelet therapy normal used

PAF v Sustained Subgroup analysis of the ACTIVE W trial compared incidence of thromboembolic events and major bleeds in patients with PAF (n=1202) and persistent AF (n=5495). Patients with PAF had similar risk for thromboembolism as patients with sustained AF. Risk significantly lowered with warfarin (J Am Coll Cardiol 2007) Stroke risk in paroxysmal AF is not different from that in persistent or permanent therefore, patients with paroxysmal AF should receive OAC according to their calculated risk score. (ESC 2010)

Atrial Flutter Risk of stroke linked to atrial flutter has been studied retrospectively in a large number of older patients, and was similar to that seen in AF. Prophylaxis in patients with atrial flutter should follow the same guidelines as in AF patients.

Conclusions All patients with Sustained AF/PAF/Atrial Flutter should be considered for anticoagulation Risk stratification should be under-taken using CHADS2, CHA2DS2VASc (for those CHADS2 scores of 0/1) and the risk of bleeding should be assessed using HAS-BLED or equivalent system

Conclusions When considering risk review the history of falls (+ injury sustained) and the presence of any cognitive difficulties Ensure patients are well educated about warfarin therapy before initiation of treatment

Which Agent? In patients with stable control on Warfarin (therapeutic range >70%) continue warfarin therapy Consider NOACS if not stable on warfarin therapy frequent traveller with difficulty accessing clinics difficult venepuncture Require urgent anticoagulation (high risk TIA)

Ideal approach might be to use both drugs Which drug for which patient? Patients aged 75 and over: Apixaban (alternative: Dabigatran 110mg bd) Patients under 75 at lower risk of bleeding: Dabigatran 150mg bd (alternative: Apixaban) Patients under 75 at higher risk of bleeding: Apixaban (alternative: Dabigatran 110mg bd) Patients with significant peptic ulcer disease or ischaemic heart disease: Apixaban (alternative: warfarin) Patients with a history of intracranial bleeding: Dabigatran 110mg bd (alternative: Apixaban) Creatinine clearance 15-29: Apixaban

NOAC but NICE Conference 16th July 2013