2Stroke Prevention in Atrial Fibrillation. NICE, NOACS and the future Dr John DuffyStroke ConsultantLTC Clinical Director
3WarfarinLMW Heparin converting to warfarinDabigitran converting to WarfarinDabigitranApixiban converting to WarfarinApixibanRivaroxaban converting to WarfarinRivaroxaban
4BackgroundAF most common sustained cardiac arrhythmia 1-2% general populationPrevalence 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
5AF is an increasingly important cause of stroke with increasing age… Fitzmaurice & Murray: Oral Anticoagulation Management & Stroke Prevention. Hayward Medical Communications, 2002
6National Recommendations AF is an independent predictor of stroke annual risk 5-6 x higher than patients with SRPrevalence set to double in the next 50 yearsBenefits of thromboprophylaxis in patients with AF are well established in multpile RCT
7National Recommendations National Clinical Guideline for stroke RCP 2008NICE stroke guidelines 2008European Society Cardiology guideline for AF 2010AF National clinical guideline for management in primary and secondary care (NICE 2006 update due 2011)
8NICE Guidance re NOACSApixaban 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).
9Anticoagulation and AF 6 large RCT’s published between evaluated warfarin for the primary and secondary prevention of thrombo-embolism in patients with non-valvular AFMeta-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
10Antiplatelet 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
11Alternative 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 strokeMajor 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.
12NOACS TrialsPowered to show non-inferiority to warfarin for the primary end point of stroke or systemic embolusAll 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%)
13Dabigatran 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 warfarin18,113 patients with AF + 1or more risk factorsMean age 71; CHADS 2.1Excluded if creatinine clearance <30Follow up 2yrsPrimary outcome: stroke + systemic embolismNEJM 2009;361:
15ROCKET-AF StudyRivoroxaban vs warfarin in patients moderate-high risk AF patients (mean CHADS score 3.5)Rivoroxaban 20mg od or 15mg od if GFR 30 – 49ml/minPrimary 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 RivaroxabanNEJM DOI: /NEJMe
16ARISTOTLE StudyApixaban 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 lessMean age 70, CHADS 2.1Primary 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 warfarinNo increase in GI bleeding or MINEJM 2011;365:
21CHA2DS2VASc score and stroke rate Risk factors for stroke and thrombo-embolism in non-valvular AFMajor risk factorsClinically relevant non major risk factorsPrevious stroke, TIA or systemic embolism, age > 75 yrsHeart failure or moderate to severe LV systolic dysfunction (e.g. LV EF < 40%)Hypertension, DM, Female sex,Age 65–74 yrs,Vascular diseaseRisk factor-based approach expressed as a point based scoring system, with the acronym CHA2DS2-VASc(maximum score is 9)CCF/LVV dysfunction (<40%)1HypertensionAge >/=75 (MAJOR)2DMStroke/TIA/thromboembolism (MAJOR)Vascular diseaseAge 65-74Female sex
22Recommendations CHA2DS2-VASc score Rx 2 or more OAC 1 OAC or aspirin but prefer OACEither aspirin or no Rx prefer no treatment
23Assessing the Risk Anticoagulation Prior to initiation of anticoagulation assess the risk as well as the potential benefit to the patient of anticoagulation therapyRates 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.
24A score >/=3 equals high risk Clinical CharacteristicsScoreHHypertension >1601AAbnormal liver (cirrhosis or biochemical evidence hepatic dysfunction) and renal function (creatinine >200 or transplantation/dialysis)1 or 2SStrokeBBleeding (previous bleeding history/predisposition to bleeding)LLabile INR (< 60% time in therapeutic range 2-3)EElderly (> 65 years)DDrugs (concominant use of NSAIDA/aspirin) or alcohol abuse (1 point for each)A score >/=3 equals high riskMax 9
25HAS-BLEDHigh risk patients need to be assessed on their individual merits and close monitoring of INR needs to be considered if anticoagulation is administered
26Overwhelming evidence to support anticoagulation in AF patients Why is the use of anticoagulation low in this high risk population?
27Reasons commonly given for not prescribing anticoagulation Advanced AgeHigh falls riskDementiaPoor INR controlPAF v Sustained and Atrial FlutterFrailityHistory previous significant haemorrhage/ risk factors for bleeding
28AgeDoes the benefit of anticoagulation outweigh the increased risk of bleeding in an elderly populationN=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 embolism24 primary events warfarin v 44 aspirinAbsolute risk reduction 2%Yearly risk extra-cranial bleed 1.4% warfarin v 1.6% aspirin(Lancet )
29Age 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)
30FallsStudies evaluating anticoagulation risk in the elderly at high risk of falls indicate only 50% of eligible patients received warfarinFalls frequently cited as reason for no warfarin3 studies specifically assessing risk-benefit analyses all found benefit of warfarin outweighs risk in falling patients with AFEducation shown to reduce risk bleeding in elderly and should be a vital part of the management(Ann Pharmacother 2008)
31Dementia Minimal research conducted in patients with AF and dementia Dementia does not feature in the bleeding risk assessment toolsMost clinicians will anticoagulate community based patients with mild/moderate dementia if medication supervision availableIn more advanced dementia antiplatelet therapy normal used
32PAF v SustainedSubgroup 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)
33Atrial FlutterRisk 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.
34ConclusionsAll patients with Sustained AF/PAF/Atrial Flutter should be considered for anticoagulationRisk 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
35ConclusionsWhen considering risk review the history of falls (+ injury sustained) and the presence of any cognitive difficultiesEnsure patients are well educated about warfarin therapy before initiation of treatment
36Which Agent? In patients with stable control on Warfarin (therapeutic range >70%) continue warfarintherapyConsider NOACS ifnot stable on warfarin therapyfrequent traveller with difficulty accessing clinicsdifficult venepunctureRequire urgent anticoagulation (high risk TIA)
37Ideal 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