AVERROES - Apixaban versus ASA in patients with AF not suitable for warfarin

In patients with non-valvular AF, apixaban is more effective at reducing stroke risk than ASA (relative risk reduction 55%; NNT ~46/year), with a small increase in minor bleeding (NNH 84/year) but no significant increase in major bleeding;
This favorable benefit/risk profile of apixaban over ASA was present even in patients with a CHADS2 score of 0-1.

Included:
- 50+ y/o
- AF (documented within 6 months before enrolment or by 12-lead EKG)
- At least 1 stroke risk factor (any CHADS2 criteria or PAD):
  - HF (NYHA class 2-4 symptoms or LVEF 35% or less), HTN, Age 75+, diabetes (on treatment), prior stroke/TIA, or documented PAD
- Not receiving a warfarin because previously demonstrated to be "unsuitable" or expected to be unsuitable
Excluded:
- Additional indication for anticoagulation other than AF
- Serious bleeding within 6 months
- High risk of bleeding (eg active peptic ulcer, plt <100, Hb <100 g/L, stroke within 10 days, blood dyscrasias)
- Serum creatinine >221 umol/L or CrCl <25 mL/min
Baseline characteristics:
- Age 70, male 59%
- AF type: Paroxysmal (27%), persistent (21%), permanent (52%)
- CHADS2 mean 2 (0 or 1 in 36%)
- Stroke risk factors: Clinical HF (40%), LVEF <35% (5%), HTN (86%), diabetes (20%), prior stroke/TIA (14%)
- Most common reason warfarin was "unsuitable" (multiple reasons in 51%):
  - Unable to measure INR frequently enough 43%
  - Patient refused to take warfarin 38% (the only reason in 15%)
  - CHADS2=1 so warfarin not recommended by physician 21%
  - Unable to keep INR therapeutic 17%
  - Unsure if patient can adhere to instructions to take warfarin 16%

Intervention: Apixaban 5 mg PO BID
- Decreased to 2.5 mg BID if 2/3 of: Age 80+ y, wt <60 kg, SCr >132 umol/L (occurred in 6%)
Control: ASA 81-324 mg/d (64% on 81 mg/d)

Efficacy
- Primary outcome (any stroke or systemic embolism): Apixaban 1.8% versus ASA 4.0%, hazard ratio (HR) 0.45 (0.32-0.62), NNT=46
- Death from any cause: 4.0% vs 5.0%, HR 0.79 (0.62-1.02)
- CV hospitalization: 13.1% vs 16.3%, HR 0.79 (0.69-0.91), NNT=32
Safety
- Major bleed (overt bleed with Hb decrease 20+ g/L over 24h, transfusion 2+ units of RBCs, or bleeding at a critical site [e.g. brain, eyes, pericardium, retroperitoneum): 1.6% vs 1.4%, HR 1.13 (0.74-1.75)
  - Intracranial: 0.4% vs 0.5%, HR 0.85 (0.38-1.90)
  - Extracranial: 1.2% vs 1.0%, HR 1.23 (0.74-2.05)
- Minor bleed: 6.7% vs 5.5%, HR 1.24 (1.00-1.53), NNH=84
- Serious adverse events: 22% vs 27%, NNT=20
Subgroup analysis by baseline CHADS2 score demonstrated consistent relative risk reductions with apixaban over ASA regardless of score, with higher-risk patients deriving greater ABSOLUTE reductions in stroke (NNT=143/year for CHADS2=0 to 1, NNT=23/year for CHADS2=3+)

Representative sample of elderly patients with AF & a wide spectrum of stroke risk who had a difficult time maintaining INRs in the therapeutic range, going to the lab for INR monitoring, or who were expected not to do well with warfarin based on clinical judgement. Results were similar regardless of the reason for being unsuitable for warfarin.

Low risk of allocation, performance, detection, attrition, selective reporting bias
- Central, computerized, automated randomization
- Double-dummy blinding
- Blinded outcome adjudication
- No patients lost to follow-up
- All relevant & important outcomes reported
Trial stopped early after 1st interim analysis for efficacy based on 104 events between groups