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Peripheral Artery Disease: causes and consequences

Coronary Artery Disease: causes and consequences

Patients with Renal Impairment

This section looks at the epidemiology of renal impairment in patients with AF and examines how the presence of renal impairment affects prognosis and treatment

Atrial fibrillation: A patient’s journey

Follow the story of John, who has been newly diagnosed with atrial fibrillation (AF) and subsequently develops co-morbidities. Find out about the associated risk factors during the course of his disease and the impact on his and his family’s life.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting more than 30 million people worldwide, and a major cause of stroke.1-3 AF is frequently accompanied by co-morbid conditions such as hypertension, diabetes, heart failure or chronic kidney disease (CKD)4, with CKD present in one-third of all outpatients with AF.5 CKD is defined by impaired renal structure or function that lasts for more than 3 months.6


The severity of CKD is classified based on estimated glomerular filtration rate (eGFR) and can be categorized as renal injury without reduced renal function (stage I), mild renal impairment (stage II), moderate renal impairment (stage III), severe renal impairment (stage IV) or end-stage renal disease or renal failure (stage V).5,6

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Classification of various stages of CKD.5,6

In patients with AF worldwide, 10.4% also have moderate-to-severe renal impairment, as observed in the global GARFIELD-AF registry.7 Similar percentages were reported for patient populations in Spain and France;8,9 however, the prevalence rates of patients with AF and co-morbid renal impairment were substantially higher in other countries such as Germany, Italy, the Netherlands and the USA.

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Prevalence of moderate-to-severe renal impairment in patients with AF.7-13

This high prevalence of co-morbid CKD in patients with AF is important, because CKD is associated with a 50% increase in the risk of stroke or systemic embolism, and a more than twofold increase in the risk of bleeding events.14 More than 30% of patients with AF have moderate-to-severe renal impairment, and increasing severity of renal impairment is associated with worsening outcomes such as stroke in patients with AF.5

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Frequency of the stages of CKD in patients with AF.5

Compared with patients with normal renal function or mild renal impairment (eGFR ≥60 ml/min), the risk of death is increased 1.2-fold and 5.9-fold in patients with moderate renal impairment (eGFR 30–59 ml/min) and end-stage renal disease or renal failure (eGFR <15 ml/min), respectively.15 Similarly, the risk of hospitalization is increased with the severity of renal impairment; patients with moderate or severe renal impairment have a 1.1-fold and 3.1-fold increased risk, respectively, of being hospitalized compared with those with normal renal function.15


An important cause of CKD is diabetes, which occurs in 15−30% of patients with AF. As with CKD, diabetes is a significant risk factor for ischaemic stroke in patients with AF.16 More information on the impact of diabetes on the outcomes of patients with AF can be found here.

The incidence of stroke in patients with AF can be reduced using antithrombotic prophylaxis with an oral anticoagulant.1 Four pivotal phase III clinical trials compared the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin in patients with AF (ARISTOTLE for apixaban; RE-LY for dabigatran; ENGAGE AF-TIMI 48 for edoxaban; ROCKET AF for rivaroxaban).17-20

The trials were similar in design, although they differed in the proportions of patients with renal impairment recruited, with ROCKET AF including the largest proportion of patients with moderate renal impairment, followed by ENGAGE AF-TIMI 48, RE-LY then ARISTOTLE.17-21 There was also variation in the mean CHADS2 scores across the four trials for the subgroup of patients with renal impairment. The ROCKET AF study enrolled the highest proportion of high-risk patients (91% of patients with renal impairment had a CHADS2 score ≥3), followed by the ARISTOTLE and RE-LY trials; in the ENGAGE AF-TIMI 48 trial, the proportion of patients with renal moderate impairment and CHADS2 score ≥3 was not reported.17-24

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Patients with AF and moderate renal impairment in pivotal phase III NOAC trials.
CHADS2 scores are shown for patients with moderate renal impairment.17-20,22-24

Another key difference across the four trials was the criteria used to allocate reduced NOAC doses in patients with renal impairment. The ROCKET AF study was the only trial where dosing, based solely on renal function, was studied prospectively.17 Patients with moderate renal impairment (creatinine clearance [CrCl] 30–49 ml/min) in this study received a reduced rivaroxaban dose of 15 mg once daily (od).17 However, in the RE-LY trial, both dabigatran doses (110 mg or 150 mg twice daily [bid]) and warfarin were tested randomly in all predefined renal function subgroups without any predetermined dose adjustment.23 This differed from the ARISTOTLE and ENGAGE AF-TIMI 48 trials, where a reduced dose was tested in 24% and 84% of patients with renal impairment, respectively.20,24 In ARISTOTLE, patients with renal impairment (serum creatinine ≥1.5 mg/dl) had to be either aged ≥80 years or have a body weight ≤60 kg (or both) to receive the apixaban 2.5 mg bid dose.24 In the ENGAGE AF-TIMI 48 trial, a reduced dose was used in patients if any of the following criteria were present: estimated CrCl of 30–50 ml/min; body weight ≤60 kg; or concomitant use of verapamil or quinidine.20


Renal impairment is associated with an increased risk of stroke, bleeding and death in patients with AF.25 However, subgroup analyses of the ARISTOTLE, ENGAGE AF-TIMI 48, ROCKET AF, J-ROCKET AF and RE-LY trials demonstrated numerically fewer strokes and systemic embolic events and fewer major bleeding events with NOACs compared with warfarin in patients with mild-to-moderate renal impairment.6

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Subanalyses for patients with mild-to-moderate renal impairment in pivotal phase III trials showing results for all stroke and systemic embolic events (A) and major bleeding events (B).6

A meta-analysis of the ARISTOTLE, RE-LY, ENGAGE AF-TIMI 48, ROCKET AF, and trials demonstrated a favourable benefit–risk profile for the use of NOACs over warfarin in patients with AF and renal impairment.21

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Meta-analyses containing pooled results from pivotal phase III NOAC trials in patients with AF for stroke or systemic embolic (A) and major bleeding (B) events, categorized by CrCl. 21

The XANTUS trial investigated the safety and effectiveness of a NOAC (rivaroxaban) in a real-world setting and was the first international, prospective, observational study to do so.26 To be eligible for inclusion in the study, patients needed to have had a diagnosis of non-valvular AF, be aged ≥18 years and have been initiated on rivaroxaban to reduce the risk of stroke or systemic embolism.26 A total of 6784 patients were included in the trial, of whom 9.4% had severe or moderate renal impairment (CrCl<50 ml/min).26 The overall results observed in XANTUS complemented the outcomes of ROCKET AF with respect to effectiveness and safety.17,26


More recently, the impact of renal function on ischaemic stroke and major bleeding in 3758 patients with non-valvular AF treated with rivaroxaban compared with warfarin was assessed in a real-world study.27 Rates of ischaemic stroke were significantly lower in rivaroxaban-treated patients compared with warfarin-treated patients (0.8 versus 6.0 per 100 patient-years, respectively: hazard ratio [HR]=0.09; 95% confidence interval [CI] 0.01–0.72; p=0.02).27 In addition, rivaroxaban was found to be as safe as warfarin, with no statistically significant difference in the risk of major bleeding events across all categories of renal function.27

European and American guidelines list all four NOACs as the preferred treatment option for reducing the risk of stroke in patients with AF.28-30 However, all NOACs have some degree of renal clearance, and, based on pharmacokinetic data, dose reductions are required in patients with moderate renal impairment.28,31-35 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.31-34 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.31-34 However, it is important to note that NOACs (particularly dabigatran and rivaroxaban) may be associated with a lower risk of adverse renal outcomes than warfarin in patients with AF.28 More information on this topic can be found here.


For patients with severe CKD or ESRD, warfarin remains the anticoagulant of choice due to the paucity of available randomized controlled trial data for the NOACs.28 For patients on haemodialysis, warfarin use has been deemed acceptable.36 American guidelines recommend the evaluation of renal function prior to the initiation of a NOAC, with renal function to be re-evaluated annually during NOAC use.28 For patients with a CrCl ≤60 ml/min, European guidelines stipulate assessment of renal functioning ‘x’-monthly, with the interval frequency ‘x’ calculated based on the patients level of CrCl (‘x’=CrCl/10).29

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The Kidneys Matter in Patients with Atrial Fibrillation and Diabetes
The importance of preserving renal function in patients with atrial fibrillation and diabetes
Approval number PP-M_RIV-ALL-0084-1

The relevance of NOAC dosing, considering treatment guidelines

In routine clinical practice, NOAC prescription is not always consistent with the approved drug labelling. Inconsistent dosing in the real world is an important issue, because under-dosing can potentially place patients at increased risk of stroke, with over-dosing potentially leading to an increased risk of bleeding or worsening renal function.37 In a study assessing NOAC dosing patterns and associated outcomes in 14,865 patients with AF, of the 1473 patients with a renal indication for reduced dosing, 43% were potentially over-dosed.37 When assessing pooled NOAC dosing patterns in this study, the risk of bleeding events in patients with renal impairment who were over-dosed was significantly increased compared with those receiving the reduced renal dose (HR=2.19; 95% CI 1.07–4.46; p=0.03). The increased risk of bleeding events associated with over-dosing was not accompanied by any decrease in the risk of stroke (HR=1.66; 95% CI 0.4–6.88; p=0.48).37 Of the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially under-dosed. In these patients, outcomes were numerically in favour of the standard dose. In patients with no renal indication for dose reduction, and who were treated with apixaban, under-dosing was associated with a higher risk of stroke (HR=4.87; 95% CI 1.30–18.26; p=0.02) and a numerically higher risk of major bleeding events. There were no statistically significant associated outcomes in patients without a renal indication for dose reduction who were treated with dabigatran or rivaroxaban.37

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Rates of stroke/systemic embolism and major bleeding events in patients without a renal indication for dose reduction receiving a reduced dose of NOAC versus a standard dose of NOAC.37


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