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Manesh Patel, MD
Most patients who suffer from a chronic condition have multiple co-morbidities, making it difficult to manage the benefits and risks of multiple recommended treatments. The treatment and management of renal impairment is complex due to risk factors and co-morbidities such as old age, diabetes, hypertension, smoking, cardiovascular disease and obesity. Renal impairment is of special interest for cardiologists because cardiovascular disease accounts for more than 50% of all mortality in patients with renal impairment.
One of the most common co-morbidities in patients with renal impairment is atrial fibrillation (AF), and a significant bidirectional association between renal impairment and AF has been shown. AF exacerbates the risk of mortality in patients with renal impairment and increases the relative risk of death by 66%. However, despite being a common co-morbidity of AF, patients with renal impairment are sometimes excluded from or underrepresented in AF clinical trials.
Despite the increased prevalence of AF in patients with renal impairment, renal failure was not shown to improve the predictive ability of the CHA2DS2-VASc scoring system and thus is not classified as a clinical risk factor for AF-related stroke. However, renal impairment is included as a dichotomous variable in the HAS-BLED scoring system which is designed to measure the risk of bleeding in patients receiving anticoagulation.
Anticoagulant therapy for stroke prevention in patients with AF is generally recommended, although its use in patients with renal impairment varies greatly due to limited efficacy data and concerns over the potential for increased risk of bleeding. Currently, four non-vitamin K antagonist oral anticoagulants (NOACs) are approved for stroke prevention in AF: apixaban, dabigatran, edoxaban and rivaroxaban. These agents are at least partially cleared through the kidneys, meaning that impaired renal function may be associated with exposure to increased plasma concentrations. In turn, this may affect the safety and efficacy of the anticoagulation regimen.
Four key phase III NOAC studies of stroke prevention in AF (ARISTOTLE, RE-LY, ENGAGE AF and ROCKET AF) included 15–21% of NOAC-treated patients with moderate renal impairment (creatinine clearance [CrCl] 30–≤50 ml/min). ROCKET AF was the only major phase III trial to prospectively assess a pre-specified analysis of rivaroxaban dose reduced from 20 mg to 15 mg once daily in patients with moderate renal impairment (CrCl 30–49 mL/min; ~21% of all patients receiving rivaroxaban. ARISTOTLE and ENGAGE AF used dose reduction regimens based on risk factor criteria including renal impairment (4.7% and 25% of patients received reduced doses of apixaban and edoxaban, respectively). In RE-LY, other than the exclusion of patients with severe renal impairment (when CrCl range <30 ml/min), renal impairment was not considered when selecting doses and patients were randomized to receive either dabigatran 110 mg twice daily (bid) or dabigatran 150 mg bid. Treatment effects with NOACs and warfarin were consistent between patients with and without renal impairment. However, overall event rates were higher in patients with renal impairment versus those without.
Evidence from controlled clinical trials may not translate completely into clinical practice, for example, patients with severe renal impairment are often excluded from these studies due to concerns over renal clearance. An observational cohort study by Nielsen et al, for the Danish population of unselected patients with AF, reported higher rates of ischaemic stroke or systemic embolism for patients receiving low dose apixaban (2.5 mg bid) compared with warfarin; however, this trend was not significantly different. Dabigatran 110 mg bid and rivaroxaban 15 mg once daily were both associated with lower, but not statistically significant, thromboembolic event rates compared with warfarin. Rates of bleeding were not significantly different for apixaban and rivaroxaban compared with warfarin, but were significantly lower for dabigatran. In a second observational study by Yao et al, of a large US administrative database of patients with AF receiving a NOAC, it was observed that 43% of patients with a renal indication for dose reduction were potentially overdosed. The use of these higher than recommended doses of NOACs were associated with an increased risk of major bleeding, but no statistically significant difference in stroke rate compared with those receiving the reduced dose. Of the 13% of patients that had no renal indication for a dose reduction but received a lower than standard NOAC dose, a higher risk of stroke, but no significant difference in major bleeding, was observed in patients receiving apixaban, compared with the standard dose. These findings illustrate the importance of appropriate dosing of NOACs for patients with AF and renal impairment in clinical practice.
Renal impairment is a predisposing factor for increased anticoagulant-related bleeding. As such, NOAC dose adjustments are recommended in these patients. Guidance recommendations vary according to the severity of renal impairment. With the exception of dabigatran, which is contraindicated in patients with CrCl <30 ml/min, NOACs are not recommended for use in patients with CrCl <15 ml/min (refer to individual SmPCs). For optimal management of NOAC treatment, the 2018 European Heart Rhythm Association guidelines for patients with non-valvular AF advise annual monitoring of renal function. More frequent renal monitoring is recommended in patients who are elderly (>75–80 years), frail, have acute conditions affecting renal function (e.g. infections, acute heart failure), or when patients have a CrCL ≤60 ml/min.
The growing evidence for the efficacy and safety of NOACs in a broad range of patients with renal impairment, together with increased convenience offered by the NOACs versus standard therapies, will help to optimize the management of this clinically challenging patient group.
Table 1. Patients with renal impairment in the key phase III studies of NOACs for stroke prevention in AF.
|Specific renal dose studied to support safety||✔||✘||✘||✘|
|Proportion of patients with moderate renal impairment||21%*||17%#||19%‡||20%§|
|Number of patients studied with low dose||15 mg od:|
|2.5 mg bid:|
|30 mg bid**:|
|110 mg bid:|
|Number of patients on low dose with moderate renal impairment (% of NOAC arm of study)||1474|
*CrCl 30–49 ml/min; #eGFR ≤50 ml/min (Cockcroft–Gault); ‡CrCl ≤50 ml/min; §eGFR <50 ml/min (Cockcroft–Gault); ¶renal impairment defined as serum creatine levels ≥1.5 mg/dl; **data given for dose adjusted arm of ‘high-dose’ (60/30) group.
AF, atrial fibrillation; bid, twice daily; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; NOAC, non-vitamin K antagonist oral anticoagulant; od, once daily.