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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting upwards of 30 million people globally, and is a major cause of stroke (Figure 1). One third of all patients with AF also have chronic kidney disease (CKD), a condition characterised by impaired renal function (Figure 1). In patients with AF, concomitant CKD is associated with a 50% increase in the risk of stroke or systemic embolism (SE), and more than double the risk of bleeding events. An important cause of CKD is diabetes, which occurs in 15−30% of patients with AF. Up to 40% of patients with diabetes will develop CKD, and diabetic kidney disease is the primary cause of end-stage kidney disease (ESKD) in the Western world.
Preventing stroke and bleeding events in this particularly vulnerable group of patients is vital, but what are the best practices for managing patients with AF and renal impairment?
There have been four pivotal phase III clinical trials comparing the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin in patients with AF (ROCKET AF for rivaroxaban; ARISTOTLE for apixaban, ENGAGE AF for edoxaban; and RE-LY for dabigatran). These four trials, though qualitatively similar in design, recruited varying proportions of patients with renal impairment; ROCKET AF included the largest proportion of patients with moderate renal impairment (Figure 2). In addition, the ROCKET AF trial included the highest risk population; 91% of patients with renal impairment had a CHADS2 score ≥3 (Figure 2). ROCKET-AF was also the only trial to prospectively study dosing based solely on renal function. Only patients with moderate renal impairment (creatinine clearance [CrCl] 30−49 ml/min) enrolled in the ROCKET AF trial received a reduced dose of 15 mg once daily (od). The RE-LY trial design randomly tested both dabigatran doses (110 mg or 150 mg twice daily) and warfarin in all predefined renal function subgroups without any predefined dose adjustment. The ARISTOTLE and ENGAGE AF trials tested a reduced renal dose in 24% and 84% of patients with renal impairment respectively.
By combining data from all four pivotal phase III clinical trials, a meta-analysis demonstrated a favourable benefit–risk profile for the use of NOACs over warfarin in patients with AF and renal impairment (Figure 3).
Figure 3. Meta-analyses containing pooled results from pivotal phase III NOAC trials in patients with AF, highlighting the benefit of NOACs over warfarin in patients with AF and moderate renal impairment (CrCl<50 ml/min). (A) Stroke or SE events and (B) major bleeding.
European and American guidelines list all four NOACs as the preferred treatment option for reducing the risk of stroke in patients with AF. However, based on pharmacokinetic data, dose reductions are required in patients with renal impairment, and the use of certain NOACs in patients with severe renal impairment is cautioned (see info boxes on renal clearance and reduced dosing).
The clinical trials provide evidence in support of NOAC use in patients with AF and renal impairment, but have NOACs proved effective in reducing the risk of stroke in patients with AF and renal impairment in routine clinical practice?
The XANTUS trial was the first international, prospective, observational study to investigate the safety and effectiveness of a NOAC (rivaroxaban) in the real-world setting. The trial included 6784 patients, 9.4% of whom had severe or moderate renal impairment (CrCl <50 ml/min), and the effectiveness and safety results complemented the outcomes of the ROCKET AF trial.
A more recent real-world analysis assessed the impact of renal function on ischaemic stroke and major bleeding in 3758 patients with NVAF treated with rivaroxaban compared with warfarin. The rate of ischaemic stroke was statistically significantly lower for rivaroxaban than for warfarin (0.8 versus 6.0 per 100 patient-years for patients receiving rivaroxaban and warfarin, respectively: HR=0.09; 95% CI 0.01−0.72; p=0.02). Across all categories of renal function, rivaroxaban was found to have a comparable safety profile to warfarin, with no statistically significant difference in the risk of major bleeding events.
When making treatment decisions regarding the management of patients with AF, it is important to consider the negative outcomes associated with renal impairment. Concomitant renal impairment puts the patient at increased risk of stroke, SE and bleeding events. However, pivotal clinical trials have demonstrated that the risk of stroke can be addressed using NOACs. There has also been an emergence of real-world evidence complementing the effectiveness and safety findings of these clinical trials. Therefore, if used as indicated in the relevant prescribing guidance, NOACs have an acceptable safety profile and offer effective protection from thromboembolic events to patients with renal impairment and a need for anticoagulation.
NOAC prescription is not always consistent with approved drug labelling in routine clinical practice. This is significant as underdosing can potentially place patients at increased risk of stroke, and overdosing can lead to bleeding and/or worsening renal function. A study assessed NOAC dosing patterns and associated outcomes in 14,865 patients and of the 1473 patients with a renal indication for reduced dosing, 43% were potentially overdosed. Overdosing in patients with renal impairment was accompanied by a statistically significant increase in the risk of bleeding events compared with patients receiving the reduced renal dose (HR=2.19; 95% CI 1.07−4.46; p=0.03) without any decrease in the risk of stroke (HR=1.66; 95% CI 0.4−6.88; p=0.48). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed, with outcomes in favour of the standard dose. Use of a reduced NOAC dose in patients with no renal indication for dose reduction can be associated with an increased risk of stroke without a decrease in risk of bleeding (Figure 4).
Figure 4. Rates of stroke/SE and major bleeding events in patients without a renal indication for dose reduction; comparing reduced versus standard dose of NOAC (potential underdosing effect) favoured the standard dose.
All NOACs have some degree of renal clearance (Figure 5) and dose reduction is indicated in patients with clinically significant renal impairment. For apixaban, edoxaban and rivaroxaban, drug exposure increases only slightly as renal function decreases, whereas exposure to dabigatran, which is 85% renally cleared, increases more dramatically (Figure 5). Correspondingly, dabigatran is contraindicated in patients with CrCl <30 ml/min, and the other NOACs are not recommended in patients with CrCl <15 ml/min.