ARISTOTLE TRIAL Dr R Nyabadza GPST1 Ward 32

Structure AF, stroke and CHA 2 -DS 2 VASC Anticoagulant choices ARISTOTLE trial Cost NICE guidance and the future

AF and Stroke 1-2% of general population Prevalence to double in next 50 years Increases stroke risk 5-fold 20% of strokes due to AF Rhythm control not superior to rate control Anticoagulation is key CHA 2 -DS 2 VASC Score recommended in new ESC guidelines (2010)

CHA 2 -DS 2 VASC Score ConditionPoints CCCF or LV systolic dysfunction1 HBP >140/90mmHg (or treated)1 A2A2 Age ≥75 years2 DDiabetes mellitus1 S2S2 Previous stroke/TIA2 VVascular disease (PVD, MI)1 AAge years1 ScSex category (Female)1

Annual stroke risk CHA 2 -DS 2 VASC ScoreStroke risk %

New ESC Recommendations ScoreRiskAnticoagulant 0LowNone or Aspirin (none preferable) 1ModerateNew OAC or Warfarin ≥2Moderate to HighNew OAC or Warfarin (INR 2-3)

Recent studies RE-LY Dabigatran 110mg bd: non-inferior to warfarin for stroke and systemic embolism, lower bleeding risk Dabigatran 150mg bd: lower stroke and systemic embolism, similar haemorrhage risk as warfarin, though  rate of GI bleed

Recent studies contd. AVERROES Compared apixaban with aspirin in patients intolerant of or unsuitable for VKA Stopped early due to clear evidence of reduction of stroke and systemic embolism in apixaban 5mg bd group

ARISTOTLE Apixaban 5mg bd vs Warfarin Supported by Bristol-Myers Squibb and Pfizer patients: AF or flutter + 1 stroke RF 1034 sites 39 countries Double blind, double dummy Randomised to apixaban or warfarin Groups well matched

Outcomes 1° safety outcome: Major bleeding 1° efficacy outcome: Stroke/systemic embolism 2° safety outcomes: Clinically relevant non-major bleeding, any bleeding, liver function abnormalities 2° efficacy outcome: All-cause mortality, MI

Results Major bleeding: 2.13% vs 3.09% per year (HR 0.69; 95% CI, 0.60 to 0.80; P<0.001) Intracranial haemorrhage: 0.33% vs 0.8% per year (HR 0.42; 95% CI, 0.30 to 0.58; P<0.001) Stroke/systemic embolism: 1.27% vs 1.6% per year (HR 0.79; 95% CI, ; P<0.001) All-cause mortality: 3.52% vs 3.94% per year (HR 0.89; 95% CI, 0.80 to 0.99; P=0.047) Cardiovascular mortality: 1.8% vs 2.02% (HR 0.89; 95% CI, 0.76 to 1.04) Noncardiovascular mortality: 1.14% vs 1.22% (HR 0.93; 95% CI, 0.77 to 1.13)

Results contd. Reduction in risk of: Systemic embolism by 21% Major bleeding by 31% Death by 11% For every 1000 patients treated for 1.8 years: 6 strokes prevented (4 haemorrhagic, 2 ischaemic or ?) 15 major bleeding prevented 8 deaths prevented Results consistent geographically and between subgroups

Pros and Cons of ARISTOTLE Large trial, multi-centred Adequately powered Intention-to treat analysis 380 (2.1%) of patients withdrew consent/lost to follow up Poor INR control in warfarin group

OACs vs Warfarin VKAs need monitoring High inter- and intra-individual variation in INRs Drug and food interactions In clinical trials target INR achieved 60-65% of time In ‘real-life’ often <50% Below-therapeutic INR for <60% of time may completely offset benefit of VKA No monitoring needed with new OACs No reversal agents Bd dosing

Cost Apixaban: £ for 30 days Warfarin: £35.40 for 30 days NICE currently assessing Guideline due April 2013

References Apixaban versus warfarin in patients with atrial fibrillation. Granger CB et al. N Engl J Med Sep 15;365(11): Stroke and systemic embolism (prevention, non-valvular atrial fibrillation) - apixaban [ID500]. The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin. Camm AJ. Eur Heart J Nov;30(21): Apixaban in patients with atrial fibrillation. Connolly SJ et al. N Engl J Med Mar 3;364(9):