Overview of the ARISTOTLE Trial

ARISTOTLE was a phase III, double-blind, double-dummy, active-controlled trial of ELIQUIS^® compared with warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke.¹

ARISTOTLE Study Design

In this randomised, double-blind trial, ELIQUIS^® (apixaban 5 mg twice daily) was compared with warfarin (target international normalised ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischaemic or haemorrhagic stroke or systemic embolism.¹
The trial was designed to test for non inferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.¹

• Inclusion Criteria
  Eligible patients had atrial fibrillation or flutter at enrollment or two or more episodes of atrial fibrillation or flutter, as documented by electrocardiography, at least 2 weeks apart in the 12 months before enrollment.¹
  In addition, at least one of the following risk factors for stroke was required: an age of at least 75 years; previous stroke, transient ischaemic attack, or systemic embolism; symptomatic heart failure within the previous 3 months or left ventricular ejection fraction of no more than 40%; diabetes mellitus; or hypertension requiring pharmacologic treatment.¹

• Exclusion Criteria
  Patients with atrial fibrillation due to a reversible cause, moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), stroke within the previous 7 days, a need for ASA (Acetylsalicylic Acid) at a dose of >165 mg a day or for both ASA and clopidogrel, and severe renal insufficiency (serum creatinine level of >2.5 mg per deciliter [221 μmol per litre] or calculated creatinine clearance of <25 ml per minute were excluded).¹

• Baseline Characteristics
  The baseline characteristics are representative of the general non-valvular atrial fibrillation (NVAF) population.¹

Baseline Characteristics

ARISTOTLE Results

1. ELIQUIS^® demonstrated superior risk reduction in stroke/systemic embolism with significantly less major bleeding vs. warfarin¹

For every 1000 patients treated for 1.8 years, ELIQUIS^®;, as compared with warfarin, prevented a stroke in 6 patients, major bleeding in 15 patients, and death in 8 patients.¹

Superior risk reduction in stroke / systemic embolism with significantly less major bleeding vs. warfarin*¹

RRR = Relative Risk Reduction
*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)

2. ELIQUIS^® reduced risk of bleeding across several components of major bleeding vs. warfarin¹

The primary safety outcome of the ARISTOTLE trial was major bleeding, according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH).

• Major bleeding event was seen in 327 patients receiving ELIQUIS^® (2.13% per year) as compared with 462 patients in the warfarin group (3.09% per year)(HR 0.69; with ELIQUIS^®, 95% CI [0.60-0.80], p < 0.001)¹

In the ARISTOTLE trial compared with warfarin, ELIQUIS^® resulted in:

• A 58% reduction in the risk of intracranial haemorrhage (0.33% vs. 0.80% per year; p<0.001)¹

• No increase in major GI bleeding (0.76% vs. 0.86% per year; p=0.37)¹

• Fatal bleeding occured in 10 patients (0.06% per year) in the ELIQUIS^® group and 37 patients (0.24% per year) in the warfarin group²

ELIQUIS^® bleeding profile vs. warfarin: ARISTOTLE trial¹

HR=hazard ratio
NS = NOT SIGNIFICANT
^†Fatal bleeding (including haemorrhagic stroke): the rate of death from non cardiovascular causes includes fatal bleeding other than that from haemorrhagic stroke.

ELIQUIS^®: Superior reduction in all-cause mortality vs. warfarin¹

The median duration of follow-up was 1.8 years.¹

3. ELIQUIS^® is the only NOAC that demonstrated superior reduction in all cause mortality vs. warfarin*¹

NOAC = non-vitamin K antagonist oral anticoagulant
RRR = Relative Risk Reduction
*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

Conclusion

In patients with atrial fibrillation, ELIQUIS^® was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.¹

*95.3% of ELIQUIS patients received a 5 mg BD dose. A 2.5 mg BD dose was used in a subset of ELIQUIS patients (4.7%) who met two or more of the following criteria: an age of 80 years or older, a body weight of 60 kg or less, or a serum creatinine level of 133 μmol per litre or more.¹

Absorption, distribution and metabolism

The pharmacodynamic effects of ELIQUIS^® are reflective of the mechanism of action (factor Xa inhibition).

• The absolute bioavailability^® of Eliquis is approximately 50% for doses up to 10 mg. ELIQUIS^® is rapidly absorbed with maximum concentrations (C_max) appearing 3 to 4 hours after tablet intake. Intake with food does not affect ELIQUIS^® AUC or C_max at the 10 mg dose. ELIQUIS^® can be taken with or without food.¹

• ELIQUIS^® demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥25 mg ELIQUIS^® displays dissolution limited absorption with decreased bioavailability. ELIQUIS^® exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV* and ~30% CV, respectively.¹

• ELIQUIS^® has multiple routes of elimination. Of the administered ELIQUIS^® dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of ELIQUIS^® accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.¹

• ELIQUIS^® has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.¹

Multiple routes of elimination of ELIQUIS^®

Multiple routes of elimination of ELIQUIS^®

Drug-drug interactions

ELIQUIS^® has a low potential for drug interactions¹
No doses adjustment is necessary with many common concomitant therapies¹

• Amoidarone

• Atenolol

• Digoxin

• Diltiazem

• Famotidine

• Naproxen

• Quinidine

• Verapamil

• ELIQUIS^® is not recommended in patients receiving strong inhibitors** of both CYP3A4 and P-gp,

  • such as azole antimycotics (e.g. ketoconazole) and HIV protease inhibitors (e.g. ritonavir).¹

• Strong inducers*** of both CYP3A4 and P-gp should be co-administered with caution (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort), but no dose adjustment of ELIQUIS^® is required.¹

Interactions with medicinal products affecting haemostasis¹

For full information on drug interactions, please visit ELIQUIS Approved Product Information

^† E.g. unfractionated heparin, low molecular weight heparins, heparin derivatives.
^# E.g. warfarin, rivaroxaban, dabigatran.

Food Interactions

• ELIQUIS^® is rapidly absorbed with maximum concentrations (C_max) appearing 3 to 4 hours after tablet intake.¹

• Intake with food does not affect ELIQUIS^® AUC or C_max at the 10 mg dose.¹

• ELIQUIS^® can be taken with or without food.¹

PK according to age and gender

• Age or gender alone do not require dosage adjustments of ELIQUIS^®.¹

• Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in C_max.¹

• Exposure to ELIQUIS^® was approximately 18% higher in females than in males.¹

* coefficient of variation
**Strong inhibitors may increase ELIQUIS exposure
***Strong inducers may reduce ELIQUIS exposure