1. NOAC but NICE
Conference
16th July 2013

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

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

4. 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

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

6. 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

7. 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)

8. 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).

9. Anticoagulation and AF
6 large RCT’s published between 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

10. 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

11. 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.

12. 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%)

13. 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:

14. P 0.05
P 0.003
P <0.001
P <0.001

15. ROCKET-AF Study
Rivoroxaban vs warfarin in 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: /NEJMe

16. 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:

17. 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:
Copyright © American Heart Association 17

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

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

20. 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

21. 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

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

23. 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.

24. 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

25. 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

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

27. 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

28. 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 )

29. 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)

30. 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)

31. 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

32. 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)

33. 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.

34. 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

35. 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

36. 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)

37. 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

38. NOAC but NICE
Conference
16th July 2013