Novel Oral Anticoagulants in Chronic Kidney Disease: Ready for Prime Time?

Justin Ashley; Manish M. Sood

Disclosures

Curr Opin Nephrol Hypertens. 2018;27(3):201-208. 

In This Article

Real-world Safety and Effectiveness of Novel Oral Anticoagulants in Chronic Kidney Disease

Randomized control trials (RCTs) are useful for assessing the safety and efficacy of medications for the purposes of regulatory approval. However, the rigors of RCTs can sometimes limit their generalizability to the larger population that would benefit from a therapy. This is particularly true for NOACs as patients with CKD were underrepresented in the major trials.[11,14,30] Postmarketing surveillance or observational studies offer rigorous and complementary evidence to RCTs[53,54] as they provide real-world data on prescribing practices and safety. They also identify real-world concerns that could not be identified within the confines of an RCT.[30] These studies have been particularly important for NOACs[30] to establish as alternatives to VKAs[28–32] for patients with CKD and atrial fibrillation or VTE.

As the only Food and Drug Administration (FDA)-approved NOAC for use with CrCl less than 15 ml/min, apixaban is the only NOAC studied in the hemodialysis population.[55] A retrospective cohort study assessing multidose apixaban in patients with ESRD on hemodialysis identified a weak correlation (correlation coefficient <0.4) between higher cumulative apixaban exposure (P = 0.03), number of hemodialysis sessions (P < 0.01), and hospital length of stay (P < 0.01).[55] These results challenge the FDA guidelines and encourage prudence in the use of apixaban in patients with ESRD.

Other observational studies, however, have found apixaban to be similar in efficacy and safety to warfarin. In a small, retrospective cohort study, Stanton et al.[56] identified that patients with ESRD and NVAF had equal rates of ischemic stroke (7.5% in both groups). No recurrent VTEs occurred between either group. Further, apixaban was associated with a lower rate of bleeding (9.6 versus 17.8% in the VKA group). Investigators[57] compared apixaban and warfarin in patients with ESRD undergoing chronic hemodialysis for the treatment or prevention of VTE. Again, there was no statistically significant difference between apixaban and warfarin regarding major bleeding, clinically relevant nonmajor bleeding; or minor bleeding. These studies are limited by their small sample size and clinical context making the generalizability of these studies difficult.[56,57]

Recent observational studies have continued to demonstrate rivaroxaban and dabigatran as similar or superior alternatives to VKAs in the CKD population. In a study of patients with nonvalvular atrial fibrillation (NVAF) either on rivaroxaban or warfarin, investigators[58] found that rivaroxaban had significantly lower rates of stroke (1.9/100 person-years) versus warfarin (4.2/100 person-years; hazard ratio 0.41, 95% CI 0.21–0.80) as well as lower composite events of stroke, VTE, and myocardial infarction (hazard ratio 0.64, 95% CI 0.44–0.91). In a subgroup analysis of different creatinine clearances (<50 ml/min; >50–80 ml/min; ≥80 ml/min), only CrCl less than 50 ml (876 participants total; 429 randomized to rivaroxaban) was statistically superior to warfarin (hazard ratio 0.09, 95% CI 0.01–0.72). There was no difference in outcomes between rivaroxaban (7.3/100 person-years) and warfarin (7.4/100 person-years; hazard ratio 0.64, 95% CI 0.44–0.91) with regard to major bleeding.

A recent population-based nested case–control study focusing on the safety of dabigatran and rivaroxaban versus warfarin in moderate CKD (median eGFR 38 ml/min per 1.73m2) in Ontario, Canada[59] could not find a statistical different risk of major hemorrhage compared with warfarin (dabigatran: OR 1.15, 95% CI 0.91–0.45; rivaroxaban: OR 1.22, 95% CI 0.83–1.79).[59]

The investigators[60] conducted a nationwide cohort study of the rates of stroke prevention in dose-reduced NOACs versus in the CKD population with NVAF versus warfarin and included a reduced dose subgroup analysis based patients on age (age ≥80) and/or renal disease. Notably, researchers did not have access to eGFR or creatinine clearance at the time of treatment initiation. A 'reasonable clinical assumption' was made as to why the NOAC was dose-reduced participants (an assumption that would likely lead to significant misclassification).

Apixaban was associated with higher 1-year rates of ischaemic stroke or systemic embolism compared with warfarin (hazard ratio 1.24, 95% CI 1.00–1.55). Rivaroxaban was associated with a significant decrease in rates (hazard ratio 0.63, 95% CI 0.69–1.24) of stoke or systemic embolism. Dabigatran and apixaban had lower rates of composite bleeding in comparison with warfarin (dabigatran: hazard ratio 078, 95% CI 0.61–0.99; apixaban: hazard ratio 0.81, 95% CI 0.69–0.94). Rivaroxaban had similar bleeding rates to warfarin (hazard ratio 1.00, 95% CI 0.81–1.24). The results of Nielsen et al.[60] continues to demonstrate NOACs, and in particular, rivaroxaban as well tolerated alternatives to warfarin.

In conjunction with post hoc analyses of major trials and meta-analyses, real-world observational studies provides another layer of complimentary evidence that NOACs are efficacious and well tolerated options in the management of NVAF and VTE in CKD compared with warfarin.

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