Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation - ARISTOTLE

Contribution To Literature:

The ARISTOTLE trial showed that apixaban was superior to warfarin in reducing stroke and systemic embolism in patients with AF, with a better bleeding profile.


Results of the AVERROES trial demonstrated superiority of apixaban, an oral Xa inhibitor, over aspirin in preventing strokes in patients with atrial fibrillation (AF). The current trial sought to investigate the efficacy of apixaban versus warfarin in these patients.

Study Design

  • Blinded
  • Parallel
  • Randomized
  • Placebo Controlled

Patient Populations:

  • Males and females ≥18 years with AF or atrial flutter (AFL) at enrollment (or two or more documented episodes of AF/AFL at least 2 weeks apart in the 12 months before enrollment) and one or more of the following risk factors for stroke:
    • Age ≥75, previous stroke
    • TIA or systemic embolism
    • Symptomatic CHF within 3 months or left ventricular dysfunction with left ventricular ejection fraction ≤40%
    • Diabetes mellitus or hypertension requiring pharmacological treatment


  • AF or atrial flutter due to reversible causes (e.g., thyrotoxicosis, pericarditis)
  • Clinically significant (moderate or severe) mitral stenosis
  • Increased bleeding risk believed to be a contraindication to oral anticoagulation (e.g., previous intracranial hemorrhage)
  • Conditions other than AF that require chronic anticoagulation (e.g., prosthetic mechanical heart valve)
  • Persistent uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg)
  • Active infective endocarditis
  • Planned major surgery
  • Planned AF or atrial flutter ablation procedure
  • Use of unapproved investigational drug or device in past 30 days
  • Required aspirin >165 mg/day
  • Simultaneous treatment with both aspirin and a thienopyridine (e.g., clopidogrel, ticlopidine)
  • Severe comorbid condition with life expectancy ≤1 year
  • Active alcohol or drug abuse or psychosocial reasons that make study participation impractical
  • Recent stroke (within 7 days)
  • Severe renal insufficiency (serum creatinine level >2.5 mg/dl or calculated creatinine clearance <25 ml/min)
  • ALT or AST >2 × upper limit of normal (ULN) or a total bilirubin ≥1.5 × ULN (unless an alternative causative factor [e.g., Gilbert's syndrome] is identified)
  • Platelet count ≤100,000/mm3
  • Hemoglobin level <9 g/dl
  • Inability to comply with INR monitoring

Primary Endpoints:

  • Primary efficacy: Stroke (ischemic or hemorrhagic) or systemic embolism (noninferiority)
  • Primary safety: Major bleeding (per ISTH definition)

Secondary Endpoints:

  • Superiority of apixaban over warfarin for primary outcome
  • Major bleeding + clinically relevant nonmajor bleeding
  • All cause-mortality

Drug/Procedures Used:

Patients were randomized to receive either apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) or dose-adjusted warfarin (titrated to a target international normalized ratio [INR] range of 2.0-3.0). The 2.5 mg dose was used in patients with at least two of the following criteria: age ≥80 years, body weight ≤60 kg, and/or serum creatinine ≥1.5 mg/dl (approximately 4.8% of the total population).

Concomitant Medications:

Aspirin (31%), amiodarone (11%), nonsteroidal anti-inflammatory drugs (NSAIDs) (8%), statins (45%), clopidogrel (2%), and beta-blockers (63%)

Principal Findings:

A total of 18,201 patients were randomized, 9,120 to apixaban and 9,081 to warfarin. Preliminary results indicate that apixaban is noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Key secondary endpoints for efficacy and ISTH (International Society on Thrombosis and Haemostasis) major bleeding demonstrated superiority, as compared with warfarin.

Baseline characteristics were fairly similar between the two arms. About a quarter of the patients were recruited in North America. Hypertension was noted in 88% of the patients, prior myocardial infarction (MI) in 14%, diabetes in 25%, congestive heart failure (CHF) in 35%, 19% had prior stroke, and about 31% of the patients were at least 75 years of age. The mean CHADS2 score was 2.1, with about 34% with a score of ≤1. About 57% had been on a vitamin K antagonist prior to randomization. In the patients on warfarin, the median time in therapeutic range was 66%.

The primary efficacy outcome of stroke or systemic embolism was significantly reduced in the apixaban arm as compared with warfarin (1.27%/year vs. 1.6%/year, hazard ratio 0.79, 95% confidence interval 0.66-0.95, p < 0.001 for noninferiority, p = 0.01 for superiority). All strokes (1.19%/year vs. 1.51%/year, p = 0.01), hemorrhagic strokes (0.24%/year vs. 0.47%/year, p < 0.001), and all-cause mortality (3.52%/year vs. 3.94%/year, p = 0.047) were similarly reduced in the apixaban arm. The rates of systemic embolism (0.09%/year vs. 0.10%/year, p = 0.7), ischemic strokes (0.97%/year vs. 1.05%/year, p = 0.42), and MI (0.53%/year vs. 0.61%/year, p = 0.37) were similar between the two arms. No evidence of heterogeneity for the primary endpoint was noted for any of the subgroups tested.

The primary safety outcome of ISTH major bleeding was significantly reduced in the apixaban arm (2.13%/year vs. 3.09%/year, p < 0.001). Other forms of bleeding such as intracranial bleeding (0.33%/year vs. 0.80%/year, p < 0.001), major or clinically relevant bleeding (4.07%/year vs. 6.01%/year, p < 0.001), GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding (0.52%/year vs. 1.13%/year, p < 0.001), TIMI (Thrombolysis In Myocardial Infarction) major bleeding (0.96%/year vs. 1.69%/year, p < 0.001), and any bleeding (18.1%/year vs. 25.8%/year, p < 0.001) were all reduced with apixaban, as compared with warfarin. On subgroup analysis, there were two significant interactions: patients with diabetes and normal renal function did not demonstrate a significant difference in ISTH major bleeding with apixaban, as compared with warfarin.

Drug discontinuation was lower with apixaban: 25.3% vs. 27.5% (p = 0.001). Rates of liver function abnormalities were similar between the two arms.

Results based on renal function: Stroke, systemic embolism, and bleeding rates all trended higher in both arms as renal function declined. The efficacy of apixaban as compared with warfarin appeared to be similar irrespective of renal function. However, a significant reduction in major bleeding was noted in patients with impaired renal function with apixaban as compared with warfarin. Annual bleeding rates were 1.46% vs. 1.84% for glomerular filtration rate (GFR) ≥80, 2.45% vs. 3.21% for GFR 50-80, and 3.21% vs. 6.44% for GFR ≤50, respectively (p for interaction = 0.03).

In patients with worsening of renal function over time during 12 months, apixaban, compared  with warfarin, had numerically lower rates of stroke or systemic embolism (HR 0.80, 95% CI 0.51-1.24; p = 0.86), ischemic or unspecified stroke (HR 0.88, 95% CI 0.52-1.48, p = 0.94), and major bleeding (HR 0.76, 95% CI 0.54-1.07, p = 0.73).

Individual time in therapeutic range (TTR) was calculated for each warfarin-treated patient by the Rosendaal method, excluding the first 7 days after randomization and treatment interruptions until 2 days after the last dose of warfarin. The center’s TTR was calculated as the median of the individual TTRs during the whole study in its warfarin patients. The center’s TTR was assigned as a proxy for centers’ quality of INR control for all of its patients. Centers in the lowest quartile (TTR <58: 32.6%) had more patients with CHADS2 scores of 3-6 versus those in the other quartiles (58-65.7: 31.1%, 65.7-72.2: 30%, ≥72.2: 27%; p < 0.0001). They also had more patients with prior strokes, CHF, and were less likely to be on statin therapy. There was no difference for the primary efficacy outcomes between the four quartiles of TTR (p for interaction = 0.29). The primary safety endpoint was also similar (p for interaction). Major and clinically relevant bleeding was highest in the subgroup with TTR ≥72.2/highest quartile (p for interaction = 0.005). These results suggest that the benefits of apixaban over warfarin in preventing strokes and reducing bleeding were independent of the centers' TTR (i.e., quality of INR control).

Outcomes in patients with valvular heart disease: The trial included 4,808 patients with valvular heart disease. The benefits of apixaban compared with warfarin in reducing stroke or systemic embolism were consistent in patients with (HR 0.70, 95% CI 0.51-0.97) and without (HR 0.84, 95% CI 0.67-1.04) valvular heart disease (interaction p value = 0.38). Other efficacy outcomes, including stroke, ischemic stroke, hemorrhagic stroke, death from any cause, and several composite outcomes were consistently and similarly reduced with apixaban compared with warfarin. Bleeding rates in patients with (HR 0.79, 95% CI 0.61-1.04) and without (HR 0.65, 95% CI 0.55-0.77) valvular heart disease (interaction p value = 0.23) were similar.

Bleeding score: A bleeding score was developed using the ARISTOTLE cohort (ABC-bleeding score: age, biomarkers [GDF-15, high-sensitivity cardiac troponin, and hemoglobin], clinical history [previous bleeding]). This yielded a c-index of 0.68, compared with 0.61 and 0.65 for the HAS-BLED and ORBIT scores, respectively (p < 0.001 for both). This was then validated in the RE-LY cohort. The c-indices for the three scores were 0.71, 0.62, and 0.68, respectively (p < 0.01 for ABC-bleeding vs. the other two).

Methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA) levels: On multivariable analysis adjusting or established ris factors and treatment, tertile groups of ADMA concentrations were significantly associated with stroke/systemic embolism (p = 0.034) and death (p < 0.0001), whereas tertile groups of SDMA were associated with major bleeding and death (p < 0.001 for both). Neither ADMA nor SDMA predicted differential response to warfarin or apixaban. Disturbances of nitric oxide function may modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF.

Use of apixaban in patients at extremes of body weight: 10.9% had weight ≤60 kg (≤132 lbs) and 5.4% >120 kg (>264.5 lbs). The treatment effect of apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction was consistent across the weight spectrum (interaction p value > 0.05). For major bleeding, apixaban had a better safety profile than warfarin in all weight categories and even showed a greater relative risk reduction in patients in the low (≤60 kg; HR 0.55, 95% CI 0.36-0.82) and midrange (>60-120 kg) weight groups (HR 0.71, 95% CI 0.61-0.83, interaction p value = 0.016).

Concomitant NSAID use: Baseline NSAID use (n = 832 [4.8%]); incident NSAID use (n = 2,185 [13.2%]). During a median follow-up of 1.8 years and when excluding those taking NSAID at baseline, incident NSAID use was associated with an increased risk of major bleeding (HR 1.61, 95% CI 1.11-2.33) and clinically relevant nonmajor bleeding (HR 1.70, 95% CI 1.16-2.48), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome.

Dose adjustment: Dose-adjustment criteria in the trial were age ≥80 years, weight ≤60 kg (≤132 lbs), and creatinine ≥1.5 mg/dl. Patients who received the lower dose of apixaban (2.5 mg BID) compared with the standard dose had lower apixaban exposure. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers and prothrombin fragment 1 + 2 (PF1+2) were consistent with those observed in the standard-dose population. Efficacy and safety were similarly preserved.


Apixaban is a novel anti-Xa oral anticoagulant, with a mechanism of action similar to other agents such as rivaroxaban. Rivaroxaban demonstrated noninferiority compared with warfarin in the ROCKET AF trial in reducing systemic embolism in patients with AF. In the AVERROES trial, apixaban demonstrated superiority compared with aspirin in reducing the risk of strokes in patients with AF. The current trial extends those findings, and demonstrates superiority for stroke/systemic embolism with apixaban compared with warfarin, with a better bleeding profile. In addition, it is a twice-daily oral medication that does not require routine INR or other blood level monitoring, thereby being more convenient to use compared with warfarin.

Results based on renal function are reassuring, and in fact, indicate a superior profile in patients with chronic kidney disease, who have a higher risk for both stroke and bleeding. It should be noted that patients with GFR <25 ml/min and those on dialysis were excluded from this trial; thus, apixaban’s utility in this patient population is unknown.

Rivaroxaban, apixaban, edoxaban, and dabigatran are direct oral anticoagulants that are Food and Drug Administration (FDA) approved for use in AF, and have significantly simplified medical management in these patients. Cost-effectiveness analyses, as well as head-to-head comparisons, especially of bleeding risks, are also awaited.

Both rivaroxaban and apixaban are not yet Food and Drug Administration (FDA) approved for use in AF, but have the potential to significantly impact medical management in these patients. Cost-effectiveness analyses, as well as head-to-head comparisons, especially of bleeding risks, are also awaited. Dabigatran 150 mg twice daily, a direct thrombin inhibitor, was recently FDA approved, based on results of the RE-LY trial demonstrating superiority for stroke/systemic embolism compared with warfarin, with a similar bleeding profile.

Findings in patients with valvular heart disease are hypothesis-generating and deserve further investigation.

The bleeding score developed in this population and tested in the RE-LY cohort performed better than contemporary bleeding scores and deserves further attention. GDF-15 is a marker of cellular aging and oxidative stress and is increased in renal failure and CHF. It is not available clinically yet.


Zeitouni M, Giczewska A, Lopes RD, et al. Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial. J Am Coll Cardiol 2020;75:1145-55.

Editorial Comment: Eikelboom J, Wheeler M, Chan N. Optimal Prescription of the Lower Dose of Apixaban. J Am Coll Cardiol 2020;75:1156-8.

Dalgaard F, Mulder H, Wojdyla DM, et al. Patients With Atrial Fibrillation Taking Nonsteroidal Anti-Inflammatory Drugs and Oral Anticoagulants in the ARISTOTLE Trial. Circulation 2020;141:10–20.

Hohnloser SH, Fudim M, Alexander JH, et al. Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight: Insights From the ARISTOTLE Trial. Circulation 2019;139:2292-300.

Editorial: Lip GY, Khan AA, Olshansky B. Short-Term Outcomes of Apixaban Versus Warfarin in Patients With Atrial Fibrillation: Is Body Weight an Important Consideration? Circulation 2019;139:2301-3.

Horowitz JD, De Caterina R, Heresztyn T, et al. Asymmetric and Symmetric Dimethylarginine Predict Outcomes in Patients With Atrial Fibrillation: An ARISTOTLE Substudy. J Am Coll Cardiol 2018;72:721-33.

Editorial Comment: Cooke JP, Sukhovershin RA. Novel Markers for Adverse Events in Atrial Fibrillation. J Am Coll Cardiol 2018;72:734-7.

Hijazi Z, Hohnloser SH, Andersson U, et al. Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time: Insights From the ARISTOTLE Randomized Clinical Trial. JAMA Cardiol 2016;1:451-60.

Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016;387:2302-11.

Avezum A, Lopes RD, Schulte PJ, et al. Apixaban Compared with Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the ARISTOTLE Trial. Circulation 2015;132:624-32.

Wallentin L, Lopes RD, Hanna M, et al,. on behalf of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Investigators. Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation. Circulation 2013;127:2166-76.

Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821-30.

Presented by Dr. Stefan H. Hohnloser at the European Society of Cardiology Congress, Munich, Germany, August 29, 2012.

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.

Presented by Dr. Christopher B. Granger at the European Society of Cardiology Congress, Paris, France, August 2011.

BusinessWire News Release. ELIQUIS® (apixaban) Meets Primary and Key Secondary Endpoints in Phase 3 ARISTOTLE Study. June 22, 2011.

Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: Design and Rationale. Am Heart J 2010;159:331-9.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Acute Heart Failure, Hypertension

Keywords: Vitamin K, North America, Morpholines, Warfarin, Creatinine, Renal Dialysis, beta-Alanine, Benzimidazoles, United States Food and Drug Administration, Thrombosis, Stroke Volume, Pyridones, Hypertension, Stroke, Myocardial Infarction, Body Weight, Pyrazoles, Heart Failure, Glomerular Filtration Rate, Embolism, Ventricular Dysfunction, Left, Diabetes Mellitus, Renal Insufficiency, Chronic, Atrial Flutter, Atrial Fibrillation, Heart Valve Diseases

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