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ARISTOTLE: Efficacy of apixaban as compared with warfarin in relation to renal function in patients with atrial fibrillation - Insights from the ARISTOTLE Trial

Atrial Fibrillation

Presenter: Stefan H Hohnloser | see Discussant report 




Atrial fibrillation (AF) is common among patients with impaired renal function. Apixaban, a novel oral anticoagulant with partial renal excretion, was compared to warfarin and reduced the rate stroke, death and bleeding in the ARISTOTLE trial. We evaluated these outcomes in relation to renal function.

Methods and results
Baseline glomerular filtration rate (GFR) was estimated at base-line using the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations as well as cystatin C measurements.
According to baseline Cockcroft-Gault there were 7518 patients (42%) with eGFR >80ml/min, 7587 (42%) between >50 and 80 ml/min, and 3017 (15%) with eGFR ≤50 ml/min. The rate of cardiovascular events and bleeding was higher at impaired renal function (≤80 ml/min). Apixaban was more effective than warfarin in preventing stroke or systemic embolism and reducing mortality irrespective of renal function. These results were consistent, regardless of methods for GFR estimation. Apixaban was associated with less major bleeding events across all ranges of eGFRs. The relative risk reduction in major bleeding was greater in patients with eGFR ≤ 50 ml/min using Cockcroft-Gault (HR 0.50 [95% CI 0.38-0.66], interaction-p=0.005) or CKD-EPI equations (HR 0.48 [95% CI 0.37-0.64], interaction-p=0.003).

In patients with atrial fibrillation, renal impairment was associated with increased risk of cardiovascular events and bleeding. As compared to warfarin, apixaban treatment reduced the rate of stroke, death and major bleeding, regardless of renal function. Patients with impaired renal function seemed to have the greatest reduction in major bleeding with apixaban.

Discussant: Keith Fox | see Presenter abstract 




In this clinical trial update the authors report the findings of the ARISTOTLE trial in relation to renal function in the ARISTOTLE patient population.  15% had an eGFR ≤50ml/min and 42% had an eGFR of ≥50-80ml/min.
What is already known is that renal dysfunction is common among patients with atrial fibrillation and that it increases the risk of stroke and of major and minor haemorrhage.  From the main report of the ARISTOTLE trial the findings indicated that apixaban reduced the risk of stroke and of major bleeding compared with warfarin.
To put the trial in context, data from the ATRIA study (Circ 2009; 119: 1363-69) will be mentioned briefly.  From that study the prevalence of an eGFR of 45 – 59ml/min is approximately 20% and an eGFR <45ml/min 10%.  The ATRIA study found a close relationship between eGFR and the rate of thrombo-embolic stroke.
What is unknown is whether the findings of the study, overall, are consistent in those in patients with renal dysfunction and the impact on stroke and major haemorrhage.
What was found, in keeping with the literature, was the rate of ischaemic stroke was two-fold higher and mortality three-fold higher in patients with impaired renal function (eGFR <50 versus eGFR > 80).  Similarly, major bleeding was increased three-fold.
When the findings were analysed according to renal function there was broadly consistent findings, with overlap of the confidence intervals and the statistical test for interaction was non-significant.  In  other words the findings were broadly similar for the categories eGFR >80, 50-80 and <50ml/min.  However, these confidence intervals are wide and as the sample sizes are limited for those with renal dysfunction so the findings do not exclude modest differences in effect.
In relation to major bleeding the findings were surprising.  Those with eGFR of 50-80 ml/min and <50 ml/min had lower rates of bleeding than for warfarin (consistent with the main trial) but there was a significant value for the statistical test for interaction, indicating that those with eGFR<50 had the most marked benefit (approximately 50% of the hazard).  This explanation for this remains unexplained.

In the study (also to be reported in a fast track manuscript in the European Heart Journal) three methods of analysing renal function were evaluated.  However, the study was not designed, nor was it sufficiently powered, to test for superiority or inferiority of the respective methods.  The most widely used current method is the Cockcroft-Gault method for estimating eGFR.  Using this method, data to be presented to show that the curves for warfarin and apixaban appear to be super-imposable for higher GFRs (above approximately 80ml/min). However, in those with more markedly impaired renal function (below approximately 60ml/min) there is separation of the curves in favour of apixaban).  However, the findings using cystatin C the findings were inconsistent with those of the Cockcroft-Gault method. In addition, the influence of the reduced dose of apixaban (2.5mg bd) on the reduced rate of major bleeding is not clear. Also, the definitions of major bleeding differ from trial to trial (for example in ARISTOTLE an Hb drop of >2gm was required within a 24hrs period.  Am Heart J
2010; 159:331-9).
Overall, the study confirms renal dysfunction is highly prevalent in patients with ACS and associated with both stroke and bleeding risk.  In ARISTOTLE, the overall findings of the trial are consistent with those seen in patients with moderate renal dysfunction.  The benefits of apixaban over warfarin, in terms of reduced bleeding, appear to be more marked in those with moderate renal dysfunction.  The trial was not designed to test for superiority of one of the three methods of measuring renal function.
Finally, ARISTOTLE provides a treatment option, and advantages over warfarin, for patients with moderate dysfunction and this is a group where the current management of patients with stroke risk is sub-optimal.


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Clinical Trial & Registry Update III: Updates on Atrial Fibrillation and Valves

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.