This information is intended for healthcare professionals based in Ireland.

ARISTOTLE Trial

ELIQUIS® in Stroke Prevention: The ARISTOTLE trial demonstrated superior risk reduction in stroke/systemic embolism in patients with non-valvular atrial fibrillation (NVAF)

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

In this randomised, double-blind trial, ELIQUIS® was compared with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. A 5 mg BD dose was used in 95.3% of ELIQUIS patients.1 A 2.5 mg BD dose of ELIQUIS was used in patients who met two or more of the following criteria: ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dl (133 µmol/l).1 Patients with the exclusive criteria of severe renal impairment (creatinine clearance 15–29 ml/min) should also receive a lower dose of 2.5 mg twice daily.2 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 (according to the criteria of the International Society of Thrombosis and Haemostasis (ISTH))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

Interactions ARISTOTLE

ELIQUIS® Is the only factor Xa inhibitor that demonstrated superior risk reduction in stroke/systemic embolism with significantly less major bleeding vs. warfarin

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

aristotle eliquis (apixaban) trial risk reduction in stroke / systemic embolism image

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)

ELIQUIS® reduced risk of bleeding across several components of major bleeding vs. warfarin in patients with NVAF

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 was defined as acute or sub-acute clinically overt bleeding accompanied at least one of the following:

  • A decrease in haemoglobin level of >2 g/dL
  • A transfusion of >2 U of packed red blood cells
  • Bleeding that was fatal or occurred in the following critical sites: intracranial, intra-spinal, intra-ocular, pericardial, intra-articular, intra-muscular with compartment syndrome, retroperitoneal
  • 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% relative 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 in patients with NVAF: ARISTOTLE trial1

aristotle eliquis (apixaban) trial bleeding profile vs. warfarin in patients with nvaf image

HR=hazard ratio
*Major bleeding (according to the criteria of the International Society of Thrombosis and Haemostasis (ISTH)
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. warfarin

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

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

aristotle eliquis (apixaban) trial reduction in all-cause mortality vs. warfarin image

NOAC = Novel 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)
Note: with improved INR control the observed benefits of ELIQUIS vs warfarin for all-cause death diminish. For patients randomised to warfarin, median TTR (INR 2-3) = 66%

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

Risk Minimisation Materials

The Eliquis (apixaban) Prescriber Guide and Patient Alert Card are risk minimisation materials developed for all indications as an aid to prescribing, in particular they are aimed at increasing awareness about the potential risk of bleeding during treatment with apixaban and providing guidance on how to manage that risk. Printed copies of these educational materials may be obtained by contacting the Bristol-Myers Squibb Medical Information Department (telephone: 1800 749 749; e-mail: medical.information@bms.com). Alternatively, electronic copies can be accessed via the HPRA website at http://www.hpra.ie/homepage/medicines/medicines-information/find-a-medicine.

References:

  1. Granger CB, Alexander JH, McMurray JJ. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011;365:981-992.
  2. ELIQUIS® (apixaban): Summary of Product Characteristics.