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