ARISTOTLE TRIAL

Dr R Nyabadza

GPST1

Ward 32

Structure

• AF, stroke and CHA2-DS2VASC

• 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• CHA2-DS2VASC Score recommended in new

ESC guidelines (2010)

CHA2-DS2VASC ScoreCondition Points

C CCF or LV systolic dysfunction 1

H BP >140/90mmHg (or treated) 1

A2 Age ≥75 years 2

D Diabetes mellitus 1

S2 Previous stroke/TIA 2

V Vascular disease (PVD, MI) 1

A Age 65-74 years 1

Sc Sex category (Female) 1

Annual stroke riskCHA2-DS2VASC Score Stroke risk %

0 0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 9.6

8 6.7

9 15.2

New ESC RecommendationsScore Risk Anticoagulant

0 Low None or Aspirin(none preferable)

1 Moderate New OAC or Warfarin

≥2 Moderate to High New 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

ARISTOTLEApixaban 5mg bd vs Warfarin Supported by Bristol-Myers Squibb and Pfizer

• 18 201 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, 0.66-0.95; 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 prevented8 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: £102.90 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. 2011 Sep 15;365(11):981-92

• Stroke and systemic embolism (prevention, non-valvular atrial fibrillation) - apixaban [ID500]. www.nice.org.uk

• The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin.Camm AJ. Eur Heart J. 2009 Nov;30(21):2554-5.

• Apixaban in patients with atrial fibrillation. Connolly SJ et al. N Engl J Med. 2011 Mar 3;364(9):806-17.