Direct oral anticoagulants for prevention of stroke in atrial fibrillation patients with chronic kidney disease

What is the issue?


Chronic kidney disease (CKD) patients have an increased risk of atrial fibrillation (AF), which can often lead to stroke or systemic embolism. The conventional therapy for preventive AF is dose-adjusted warfarin, but this can increase the risk of bleeding, which necessitates regular therapeutic monitoring. Recently, direct oral anticoagulants (DOAC) have been developed as alternatives to warfarin. We reviewed the evidence on DOAC compared to warfarin for preventing stroke and systemic embolic events in AF patients with CKD.

What did we do?

We found five studies that compared the effects of DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) and dose-adjusted warfarin. The 12,545 participants in these five studies had non-valvular AF and moderate kidney impairment. These studies presented data on all composite outcomes of stroke and systematic embolic events as the primary efficacy outcome, with major bleeding events as the primary safety outcome. The median follow-up period ranged from 1.8 to 2.8 years. The evidence is accurate as of August 2017.

What did we find?

DOAC probably reduced the incidence of stroke and systemic embolic events as a primary efficacy outcome, compared to warfarin. Further, DOAC might slightly reduce the incidence of major bleeding events as a primary safety outcome, compared to warfarin.

Conclusions

This review demonstrated that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing major bleeding events among AF patients with CKD. According to GRADE, the quality of the evidence was moderate for the primary efficacy outcome because of concerns with imprecision and low for the primary safety outcome because of concerns with inconsistency and imprecision. The results of this study chiefly apply to CKD stage G3 patients, since we could not assess those with CKD stage G4 or G5.

Authors' conclusions: 

Our findings indicate that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. These findings should encourage physicians to prescribe DOAC in AF patients with CKD without fear of bleeding. The major limitation is that the results of this study chiefly reflect CKD stage G3. Application of the results to CKD stage G4 patients requires additional investigation. Furthermore, we could not assess CKD stage G5 patients. Future reviews should assess participants at more advanced CKD stages. Additionally, we could not conduct detailed analyses of subgroups and sensitivity analyses due to lack of data.

Read the full abstract...
Background: 

Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF causes stroke or systemic embolism, leading to increased mortality. The conventional antithrombotic prophylaxis agent warfarin is often prescribed for the prevention of stroke, but risk of bleeding necessitates regular therapeutic monitoring. Recently developed direct oral anticoagulants (DOAC) are expected to be useful as alternatives to warfarin.

Objectives: 

To assess the efficacy and safety of DOAC including apixaban, dabigatran, edoxaban, and rivaroxaban versus warfarin among AF patients with CKD.

Search strategy: 

We searched the Cochrane Kidney and Transplant Specialised Register (up to 1 August 2017) through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria: 

We included all randomised controlled trials (RCTs) which directly compared the efficacy and safety of direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) with dose-adjusted warfarin for preventing stroke and systemic embolic events in non-valvular AF patients with CKD, defined as creatinine clearance (CrCl) or eGFR between 15 and 60 mL/min (CKD stage G3 and G4).

Data collection and analysis: 

Two review authors independently selected studies, assessed quality, and extracted data. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for the association between anticoagulant therapy and all strokes and systemic embolic events as the primary efficacy outcome and major bleeding events as the primary safety outcome. Confidence in the evidence was assessing using GRADE.

Main results: 

Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or dose-adjusted warfarin. Four studies used a central, interactive, automated response system for allocation concealment while the other did not specify concealment methods. Four studies were blinded while the other was partially open-label. However, given that all studies involved blinded evaluation of outcome events, we considered the risk of bias to be low. We were unable to create funnel plots due to the small number of studies, thwarting assessment of publication bias. Study duration ranged from 1.8 to 2.8 years. The large majority of participants included in this study were CKD stage G3 (12,155), and a small number were stage G4 (390). Of 12,545 participants from five studies, a total of 321 cases (2.56%) of the primary efficacy outcome occurred per year. Further, of 12,521 participants from five studies, a total of 617 cases (4.93%) of the primary safety outcome occurred per year. DOAC appeared to probably reduce the incidence of stroke and systemic embolism events (5 studies, 12,545 participants: RR 0.81, 95% CI 0.65 to 1.00; moderate certainty evidence) and to slightly reduce the incidence of major bleeding events (5 studies, 12,521 participants: RR 0.79, 95% CI 0.59 to 1.04; low certainty evidence) in comparison with warfarin.

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