ARISTOTLE clinical trial

The population analysed in ARISTOTLE covers a broad range of different patients with NVAF.¹

* Stroke or systemic embolism was the primary efficacy endpoint, major bleeding was the primary safety endpoint, and all-cause mortality was a key secondary endpoint.¹ Haemorrhagic stroke and ischaemic or undetermined stroke were components of stroke.¹ Pre-specified hierarchical sequential testing was performed first on stroke / systemic embolism (primary efficacy endpoint) for non-inferiority, then for superiority, then on major bleeding and, finally, on death from any cause (secondary endpoint).¹

Patients were eligible for inclusion in the trial if they met the following criteria:¹

• had [non-valvular] atrial fibrillation or flutter at enrolment or two or more episodes of atrial fibrillation or flutter, as documented by electrocardiography, at least 2 weeks apart in the 12 months before enrolment

Patients also had to have at least one of the following risk factors for stroke:

• age ≥75 years
• previous stroke, TIA, or systemic embolism
• symptomatic heart failure within the previous 3 months of left ventricular ejection fraction of no more than 40%
• diabetes mellitus
• hypertension requiring pharmacologic treatment

Patients were excluded if they met the following criteria:¹

• had atrial fibrillation due to a reversible cause
• had moderate or severe mitral stenosis
• had conditions other than atrial fibrillation that required anticoagulation (e.g. a prosthetic heart valve)
• had experienced a stroke within the previous 7 days
• had a need for aspirin at a dose of >165 mg a day or for both aspirin and clopidogrel
• had severe renal insufficiency (serum creatinine level of >2.5 mg/dl [221 µmol/l] or calculated creatinine clearance of <25 ml/min)

 ELIQUIS has demonstrated superiority on stroke / systemic embolism prevention and superiority on major bleeding vs. warfarin in patients with NVAF¹*

Adapted from Granger et al. 2011.¹
* Stroke or systemic embolism was the primary efficacy endpoint, major bleeding was the primary safety endpoint, and all-cause mortality was a key secondary endpoint.¹ Haemorrhagic stroke and ischaemic or undetermined stroke were components of stroke.¹ Pre-specified hierarchical sequential testing was performed first on stroke / systemic embolism (primary efficacy endpoint) for non-inferiority, then for superiority, then on major bleeding, and finally on death from any cause (secondary endpoint).¹

Primary efficacy endpoint¹*

Fewer strokes / systemic embolism: 21% RRR, 0.33% ARR (1.27% per year [n=212] with ELIQUIS vs. 1.60% per year [n=265] with warfarin; HR=0.79 [95% CI: 0.66–0.95] p=0.01).

• 6 fewer strokes per 1,000 patients treated with ELIQUIS instead of warfarin for 1.8 years

Secondary efficacy endpoints¹*

• Fewer fatal or disabling strokes: 29% RRR, 0.21% ARR (0.50% per year [n=84] with ELIQUIS vs. 0.71% per year [n=117] with warfarin; HR=0.71 [95% CI: 0.54–0.94] p-value not calculated)
• Fewer haemorrhagic strokes: 49% RRR, 0.23% ARR (0.24% per year [n=40] with ELIQUIS vs. 0.47% per year [n=78] with warfarin; HR=0.51 [95% CI: 0.35–0.75] p<0.001)
• Comparable rate of systemic embolism: 0.09% per year (n=15) with ELIQUIS vs. 0.10% per year (n=17) with warfarin; HR=0.87 (95% CI: 0.44–1.75) p=0.70
• Comparable rate of ischaemic / undetermined stroke: 0.97% per year (n=162) with ELIQUIS vs. 1.05% per year (n=175) with warfarin; HR=0.92 (95% CI: 0.74–1.13) p=0.42

Primary safety endpoint¹

ELIQUIS demonstrated fewer major bleeds:^‡ 31% RRR, 0.96% ARR (2.13% per year (n=327) with ELIQUIS vs. 3.09% per year (n=462) with warfarin; HR=0.69 (95% CI: 0.60–0.80) p<0.001).

• 15 fewer major bleeds per 1,000 patients treated with ELIQUIS instead of warfarin for 1.8 years

Secondary safety endpoints¹

• Fewer major or clinically relevant non-major bleeds: 32% RRR, 1.94% ARR (4.07% per year [n=613] with ELIQUIS vs. 6.01% per year [n=877] with warfarin; HR=0.68 [95% CI 0.61–0.75] p<0.001
• Fewer intracranial haemorrhages: 58% RRR, 0.47% ARR (0.33% per year [n=52] with ELIQUIS vs. 0.80% per year [n=122] with warfarin; HR=0.42 [95% CI: 0.30–0.58] p<0.001)
• Comparable rate of gastrointestinal bleeding (0.76% per year [n=105] with ELIQUIS vs. 0.86% per year [n=119] with warfarin; HR=0.89 [95% CI: 0.70–1.15] p=0.37)
• Fewer major bleeds at other locations (including major gastrointestinal bleeding): 21% RRR, 0.48% ARR (1.79% per year [n=275] with ELIQUIS vs. 2.27% per year [n=340] with warfarin; HR=0.79 [95% CI: 0.68–0.93] p=0.004)
• Fatal bleeding (including fatal haemorrhagic stroke) occurred in 10 patients in the ELIQUIS group vs. 37 patients in the warfarin group (0.06% vs. 0.24% per year);^§ p value not reported²

ELIQUIS is the only NOAC that has demonstrated a significant reduction in all-cause mortality vs. warfarin in patients with NVAF^1†

Deaths from any cause were observed in 603 patients treated with ELIQUIS (3.52% per year) and in 669 patients treated with warfarin (3.94% per year); HR=0.89 (95% CI: 0.80–0.99; p=0.047).¹

In patients with NVAF, ELIQUIS is the only factor Xa inhibitor that has demonstrated all of the following:

• Superior risk reduction in stroke / systemic embolism vs. warfarin¹
• Superior risk reduction in major bleeding vs. warfarin¹
• Significant risk reduction in all-cause mortality vs. warfarin¹

432UK1800479-01 – May 2018