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ORIGINAL ARTICLE
Year : 2023 | Volume
: 24
| Issue : 3 | Page : 136-140
Real-world experience in managing atrial fibrillation in patients with renal impairment; Rivaroxaban versus warfarin
Monirah Abdulrahman Albabtain1, Zaid Dakheel Alanazi1, Nawaf Hamoud Al-Mutairi1, Ola Alyafi2, Raneem Albanyan1, Amr A Arafat3
1 Cardiology Clinical Pharmacy Department, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia
2 Department of Clinical Pharmacy, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
3 Department of Adult Cardiac Surgery, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia; Department of Cardiothoracic Surgery, Tanta University, Tanta, Egypt
Correspondence Address:
Ms. Monirah Abdulrahman Albabtain
Prince Sultan Cardiac Center, Riyadh
Saudi Arabia
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/heartviews.heartviews_117_22
Abstract
Background: The use of rivaroxaban in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) poses the risk of over- or underdosing. We aimed to compare rivaroxaban and warfarin in AF patients with moderate and severe renal impairment.
Methods: This retrospective study was conducted between 2015 and 2016 to compare the use of warfarin (n = 164) and rivaroxaban (n = 149) in patients with AF and moderate or severe CKD. The study outcomes were survival, stroke, and major bleeding events. The median follow-up was 50 months (interquartile range: 23–60).
Results: Thirty-six patients had major bleeding: 24 with rivaroxaban and 12 with warfarin (P = 0.01). The rivaroxaban group had major bleeding in 3 patients with moderate CKD, 4 with severe CKD, and 17 on dialysis. Multivariable analysis of factors affecting major bleeding revealed that warfarin use lowered the risk of bleeding (hazard ratio: 0.34; P = 0.004). Stroke occurred in 14 patients: 6 in the rivaroxaban group and 8 in the warfarin group (P = 0.44). Survival at 1, 3, and 5 years was 89%, 77%, and 71% with warfarin and 99%, 94%, and 88% with rivaroxaban, respectively (P < 0.001). Multivariable analysis showed higher mortality in patients with lower creatinine clearance and those on warfarin.
Conclusions: The safety of warfarin could be better than rivaroxaban in patients with CKD with fewer bleeding complications but similar stroke rates. Further studies on rivaroxaban dosing in patients on dialysis are required.
Keywords: Renal impairment, rivaroxaban, Vitamin K-dependent anticoagulation
Introduction 
The introduction of non-Vitamin K antagonist oral anticogulants (NOACs) has been a major advancement in stroke prevention in patients with atrial fibrillation (AF). Unlike the Vitamin K antagonist (the commonly used anticoagulant for AF), the narrow therapeutic window and drug/food interaction profile limit its use.[1],[2],[3]
Evidence from several studies suggests that the risk of stroke, morbidity, and overall mortality increases in patients with AF and chronic kidney disease (CKD).[4] These two diseases are common in clinical practice and often coexist in patients. There is little evidence of NOAC use in patients with AF and renal insufficiency; however, NOAC use is increasing in patients with advanced CKD with or without dialysis.[5] Moreover, patients with stage 4 and 5 CKD at baseline have an increased risk of bleeding because of several factors, such as anemia, platelet aggregation defects, and the use of heparin during hemodialysis.[6]
Rivaroxaban is a well-tolerated direct oral factor Xa inhibitor that is increasingly used in patients with AF.[7] The use of rivaroxaban in patients with CKD carries the risk of over- or underdosing, which may lead to an increased risk of stroke or bleeding.[8] Since approximately 14%–31% of the drug is excreted unchanged in the urine,[9] dose reduction is necessary if there is moderate or severe renal impairment to ensure a nontoxic rivaroxaban plasma concentration.
However, the efficacy and safety of rivaroxaban in patients with renal impairment have not been thoroughly evaluated. Thus, we aimed to evaluate rivaroxaban use in patients with moderate and severe renal impairment compared with warfarin.
Methods Design and patients
This retrospective single-center study was conducted between 2015 and 2016 at a tertiary referral center. A total of 313 patients who required anticoagulation therapy with rivaroxaban or warfarin for AF were enrolled. All patients had moderate or severe renal impairment.
We excluded patients with normal renal function or mild renal impairment, those on warfarin or NOACs during the study period, those on NOACs other than rivaroxaban, and those with mechanical heart valves. Patients were grouped according to the medications used for anticoagulation in the warfarin group (n = 164) and the rivaroxaban group (n = 149).
The data collection for this study was approved by the local institutional review board (reference number: R17003).
Data and endpoints
Baseline data, including age, sex, body mass index, hypertension, diabetes mellitus, heart failure, and coronary artery disease, were compared between the two groups. Creatinine clearance (CrCl) was estimated using the Cockcroft-Gault equation. All patients had a CrCl below 50 mL/min, which is the threshold required for rivaroxaban dose adjustment.[10]
Study outcomes were survival, stroke, and major bleeding, defined using the Bleeding Academic Research Consortium definition.[11]
Follow-up
Patients on warfarin were followed up in the anticoagulation clinic, and the target international normalization ratio was set between 2 and 3. Follow-up was scheduled every 2–3 months. Patients taking rivaroxaban were followed by their perspective cardiologists only. Any bleeding or stroke was reported to the emergency department.
Statistical analysis
Descriptive analysis was used to compare the preoperative data and study outcomes. Continuous data were described as median and interquartile range or mean and standard deviation, and binary data as absolute numbers and percentages. The Wilcoxon test was used for continuous data, and the Chi-squared or Fisher's exact test was used for binary data. Kaplan–Meier analysis was used to determine the distribution of time-to-event variables, and the log-rank test was used for comparison. Multivariate Cox regression analysis was used to assess the factors associated with major bleeding and survival. Variables with P = 0.15 or less in the univariable analysis were included in the multivariable model. Multivariable stepwise regression was performed with backward elimination and a stay P = 0.1 or less. Stata 16 (Stata Corp., College Station, TX, USA) was used for all the analyses.
Results Baseline data
The patients in the warfarin group had significantly lower CrCl 33.7 (22.73–40.3) and significantly lower hemoglobin. Heart failure was more evident in the rivaroxaban group, and there were no differences in age or sex between the groups [Table 1].
Table 1: Comparison of the baseline data between patients who received warfarin versus rivaroxabanOutcomes
The median follow-up period was 50 (23–60) months and 50 (28–57) months in the rivaroxaban group versus 49.5 (18–62) months in the warfarin group. Thirty-six patients (11.50%) had major bleeding: 24 with rivaroxaban (16.11%) and 12 (7.32%) with warfarin [log-rank P = 0.01, [Figure 1]]. The rivaroxaban group had major bleeding in 3 patients with moderate CKD, 4 with severe CKD, and 17 on dialysis.
Stroke occurred in 14 patients: 6 in the rivaroxaban group and 8 in the warfarin group. There was no difference between the groups in terms of stroke (log-rank P = 0.44). Multivariate analysis of factors affecting major bleeding showed that warfarin use lowered the risk of bleeding [hazard ratio: 0.34; P = 0.004, [Table 2]].
Table 2: Multivariable Cox analysis for factors associated with major bleeding and survivalMortality was observed in 54 patients. The survival rates at 1, 3, and 5 years were 89%, 77%, and 71% in the warfarin group and 99%, 94%, and 88% in the rivaroxaban group, respectively [log-rank P < 0.001, [Figure 2]]. Multivariable analysis showed higher mortality in patients with lower CrCl, heart failure, and warfarin use [Table 2].
Discussion It is evident from real-world data that patients with AF with renal impairment are more likely to be older, male, and have many comorbidities. These patients are at a higher risk of major bleeding and stroke than those with normal renal function.[12],[13] The ideal anticoagulation therapy for patients with AF and renal impairment is still under investigation.
This study compared rivaroxaban and warfarin for patients with AF with a CrCl of <50 mL/min. The study endpoints were major bleeding, stroke, and survival.
Major bleeding occurred significantly more frequently with rivaroxaban use. This could be explained by the higher level of rivaroxaban, 33% of which is excreted by the kidneys. Rivaroxaban elimination is reduced in patients with impaired renal function, which potentially increases the risk of bleeding.
Major bleeding occurred more frequently in patients taking rivaroxaban and dialysis. This finding indicates the need to revise the dose adjustment in these patients.
In a retrospective analysis of 73,989 patients with different NOACs from Japan compared to warfarin, all NOACs were associated with a significantly lower risk of stroke and major bleeding.[14] The median age of our study patients indicates that our population consisted entirely of elderly patients. Although all trials on NOAC treatment for AF included the elderly population, age was not a risk factor affecting the safety and efficacy of anticoagulation.[15]
The comorbidities of these patients should be considered. For instance, dementia can affect medication adherence and increase the risk of bleeding during NOAC therapy.[15] However, these factors also apply to warfarin, for which close monitoring can mitigate the effects of these conditions.
The stroke rate in our patients who received rivaroxaban was 4.03%, which is similar to a previous result of approximately 4%.[13] This rate doubled when compared with data from major clinical trials (ROKET AF, RELY, ARISTOLE, and ENGAGE AF TIMI 48), which reported a stroke rate of 2% in patients with renal impairment.[1],[6],[16],[17],[18]
In a meta-analysis in which NOAC therapy was compared to warfarin in patients with mild-to-moderate renal impairment, ischemic stroke rates were lower in patients with mild renal impairment (relative risk [RR]: 0.79; 95% confidence interval [CI]: 0.68–0.91) and moderate renal impairment (RR: 0.80; CI: 0.69–0.92).[19]
We did not report a difference in stroke rates between rivaroxaban and warfarin. This finding has been documented in previously published meta-analyses and real-world studies.[20],[21]
We reported a survival benefit of rivaroxaban compared to that of warfarin. This finding has not been reported previously, and further large randomized trials are warranted.
Study limitations
This study reflects a single-center experience that may not apply to other centers. More importantly, the study was retrospective and liable to selection and referral biases. Several confounders that might have affected the outcomes were excluded from the analysis.
Conclusions The safety profile of warfarin could be better than that of rivaroxaban in patients with renal impairment with fewer bleeding complications but similar stroke rates. Further studies on rivaroxaban dosing in patients on dialysis are required. Rivaroxaban may have survival benefits over warfarin, which warrants further investigation.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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