Discussion
The results of our cohort analysis provided several insights of relevance to clinical practice. Firstly, DOAC prescription increased substantially over time, whereas warfarin prescription fell concomitantly. Nevertheless, over 10% of AF patients with stage III CKD were still being prescribed warfarin in 2017. Secondly, relative to warfarin, rivaroxaban appears to be effective and safe in AF patients with stage III CKD, but if creatinine clearance rate (CrCl) is between 30–49 mL/min, we need to reduce the dose at 15 mg. Apixaban 2.5 mg might even have better safety profiles than warfarin; and for apixaban 5.0 mg, this difference in effectiveness was mainly driven by a reduction in deaths.
The increase in DOAC prescription is in line with the latest AF guidelines from the Canadian Society of Cardiology and European Society of Cardiology, which recommend DOAC therapy over warfarin for patients with NVAF and stage III CKD.7,41 This recommendation is based on a sub-analysis of AF RCTs, which demonstrated that along with the DOACs’ logistic advantages vs. dose-adjusted warfarin, these drugs are no worse or even better than warfarin in reducing the risk of AF-associated stroke or SE in AF patients with stage III CKD, with a lower or similar major bleeding risk.10-13 A meta-analysis of RCTs and observational trials of AF patients with CKD showed that DOACs are associated with a significant reduction in stroke/SE (HR 0.81; 95% CI 0.68–0.97) and a nonsignificant reduction in major bleeding (HR 0.87; 95% CI 0.69–1.05) in stage III CKD, when compared with warfarin.14
There are few data on the effectiveness and safety of each individual DOAC and the impact of dose selection in patients with stage III CKD specifically, and mostly of the available information has been derived from observational studies.15-21 A sub-analysis of the ARISTOLE trial’s data showed that apixaban reduced the rate of stroke and mortality relative to warfarin (regardless of the patient’s level of renal function); however, the safety and effectiveness of apixaban vs. warfarin were not assessed specifically in stage III CKD patients.13 Wetmore et al . examined Medicare data from 22,739 AF patients with stage III-IV CKD and found that apixaban was associated with a reduction in stroke/SE (HR 0.70; 95% CI 0.51–0.96) and in the major bleeding risk (HR 0.47; 95% CI 0.37–0.59).23 Using electronic health record data, Fuet al . examined the safety and effectiveness of rivaroxaban vs. warfarin in 555 stage III CKD AF patients and found a similar risk of stroke (HR 0.60; 95% CI 0.23–1.56) and major bleeding (HR 0.73; 95% CI 0.38–1.41).42 A sub-analysis of the ROCKET-AF trial found that rivaroxaban 20 mg daily had a better efficacy profile in patients with a CrCl of 50 mL/min or more but that rivaroxaban 15 mg daily had a similar efficacy profile in patients with a CrCl of 30–49 mL/min; the safety profile was similar for both CrCl categories.43 Nonetheless, dose adjustment yielded results consistent with the overall trial, when compared with dose-adjusted warfarin.11 Wetmore et al . found that in AF patients with stage III-IV CKD, rivaroxaban was associated with similar risks of stroke/SE (HR 0.80; 95% CI 0.54–1.17) and major bleeding (HR 1.05; 95% CI 0.85–1.30).23 However, the investigators did not report data on the effectiveness and safety of each dose level of DOAC vs. warfarin in stage III CKD AF patients specifically.
Likewise, there are few published data on the impact of DOAC therapy vs. warfarin on mortality, and also per specific dose. Makani et al.examined electronic health record data on 21,733 AF patients with CKD and found that DOACs reduce the risk of all-cause mortality for all CKD classes.17 When examining individual DOACs in an on-treatment analysis, Wetmore et al. found a reduction in mortality for apixaban (HR 0.90; 95% CI 0.84–0.96) but not for rivaroxaban (HR 0.95; 95% CI 0.88–1.02) or dabigatran (HR 0.92; 95% CI 0.84–1.01).23 This results might be explained by the fact that DOACs are associated with a lower incidence of renal adverse outcomes in patients with mild-to-moderate CKD, including a decline renal function, a doubling in the serum creatinine level, or acute kidney injury.44 Moreover, warfarin treatment is associated with an elevated risk of vascular and cardiac valve calcification,45-47 which in turn is associated with greater cardiovascular morbidity and mortality rates.48
The present study had several strengths. Firstly, it is one of the few large, real-world comparative studies of the effectiveness, safety and mortality rates associated with individual DOACs and dose levels vs. warfarin. Secondly, we analyzed the province-wide, single-payer Quebec healthcare claims database. Given that (i) most important clinical events would have resulted in an administrative claim and (ii) few patients seek medical services outside of the Quebec province, it is likely that nearly all clinically significant events were captured; this might not have been the case in previous single-hospital or single-insurer studies. Thirdly, we performed IPTW cohorts to account for confounding effects in our primary analysis and we provided several sensitivity analyses.
Our study also had some limitations. Firstly, this observational study of administrative data might have been subject to confounding bias by unadjusted factors (e.g. the severity of AF, the exact eGFR, the international normalized ratio, body weight, over-the-counter prescriptions, and ethnicity). Secondly, administrative claims data depend on the exhaustive, accurate recording and coding of diagnoses, procedures, and drugs. Thirdly, it might not be possible to generalize our results to younger patients, patients treated with other DOACs (dabigatran and edoxaban). Fourthly, the effect sizes for individual safety and effectiveness outcomes were small. Fifthly, time spent in the therapeutic range could not be used to assess the appropriateness of warfarin dosing, since the international normalized ratio was not recorded in our database. Lastly, we did not have the exact eGFR value; however, the algorithm used to estimate the eGFR is known to be valid in older adults.31