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1 Antonio González Pérez contributed to the study design, the acquisition and analysis of data, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
Antonio González Pérez
Correspondence
Corresponding author at: Spanish Centre for Pharmacoepidemiologic Research, c/ Almirante 28, 2°. 28004, Madrid, Spain.
1 Antonio González Pérez contributed to the study design, the acquisition and analysis of data, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
Affiliations
Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, SpainAndalusian Bioinformatics Research Centre (CAEBi), Seville, SpainPharmacoepidemiology Research Group, Institute for Health Research (IRYCIS), Madrid, Spain
2 Yanina Balabanova contributed to the study concept, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
2 Yanina Balabanova contributed to the study concept, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
3 María E Sáez contributed to the study concept, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication
3 María E Sáez contributed to the study concept, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication
Affiliations
Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, SpainAndalusian Bioinformatics Research Centre (CAEBi), Seville, Spain
4 Gunnar Brobert contributed to the study concept, the study design, the acquisition of data, the analysis and interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
4 Gunnar Brobert contributed to the study concept, the study design, the acquisition of data, the analysis and interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
Affiliations
Integrated Evidence Generation, Bayer AB, Stockholm, Sweden
5 Luis A Garcia Rodriguez contributed to the study concept, the study design, the acquisition of data, the analysis and interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
5 Luis A Garcia Rodriguez contributed to the study concept, the study design, the acquisition of data, the analysis and interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
Affiliations
Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain
1 Antonio González Pérez contributed to the study design, the acquisition and analysis of data, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication. 2 Yanina Balabanova contributed to the study concept, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication. 3 María E Sáez contributed to the study concept, the interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication 4 Gunnar Brobert contributed to the study concept, the study design, the acquisition of data, the analysis and interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication. 5 Luis A Garcia Rodriguez contributed to the study concept, the study design, the acquisition of data, the analysis and interpretation of the data, the revision of manuscript drafts and the decision to submit the final approved manuscript for publication.
In AF, rivaroxaban users had ~30% lower risk of adverse renal events (vs warfarin).
•
This finding was also seen in subgroups of patients with diabetes or heart failure.
•
Rate of renal decline was also faster in users of warfarin vs rivaroxaban (p = 0.03).
Abstract
Background
Reports suggest that renal decline is greater among patients with non-valvular atrial fibrillation (NVAF) treated chronically with warfarin vs. some non-vitamin K antagonist oral anticoagulants.
Methods and results
Using primary care electronic health records from the United Kingdom we followed adults with NVAF and who started rivaroxaban (20 mg/day, N = 5338) or warfarin (N = 6314), excluding those with estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2, end-stage renal disease (ESRD) or no eGFR or serum creatinine (SCr) values recorded in the previous year. Outcomes were: doubling SCr levels, ≥30% decline in eGFR and progression to ESRD. We calculated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome. Average eGFR slope was estimated using mixed model regression. After a mean follow-up 2.5 years, the number of incident cases of adverse renal events within the two cohorts was: doubling SCr (n = 322), ≥30% decline in eGFR (n = 1179), and progression to ESRD (n = 22). Adjusted HRs (95% CIs) for the renal outcomes among rivaroxaban vs. warfarin users were: doubling SCr, 0.63 (0.49–0.81); ≥30% decline in eGFR, 0.76 (0.67–0.86); ESRD, 0.77 (0.29–2.04). Similar results were observed among patients with diabetes or heart failure. Estimated mean decline in renal function over the study period was 2.03 ml/min/1.73 m2/year among warfarin users and 1.65 ml/min/1.73 m2/year among rivaroxaban users (p = 0.03).
Conclusions
We found clear evidence that patients with NVAF, preserved renal function at baseline and treated with rivaroxaban had a markedly reduced risk and rate of renal decline compared with those treated with warfarin.
2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: clinical significance and implications for decision making-a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society.
] Most patients with AF are at increased risk of thromboembolism and require life-long anticoagulant (OAC) therapy. Comorbid CKD further increases the risk of thromboembolism as well as the risk of major bleeding and mortality, which can make decisions around anticoagulation in those patients more complicated. [
Management and 1-year outcomes of patients with newly diagnosed atrial fibrillation and chronic kidney disease: results from the prospective GARFIELD - AF registry.
For patients with non-valvular AF (NVAF), international guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) as the preferred therapy [
2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
2021 european heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
] Recent years have seen reports of anticoagulant-related nephropathy (ARN), especially in patients using warfarin, and this is important because ARN accelerates the progression of CKD, which is associated with increased risks of systemic embolic events and bleeding. [
] Previous observational studies based on the secondary data have found that patients with NVAF treated with NOACs have significantly lower risks of long-term adverse renal outcomes compared with those treated with a VKA. [
P4746Worsening of renal function in atrial fibrillation patients with stage 3 or 4 chronic kidney disease treated with warfarin or rivaroxaban - evidence from the real-world CALLIPER study in the US claims.
P4749Renal function worsening in factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study.
] However, limitations such as the absence of relevant demographic or lifestyle data in the claims databases used in some of these studies, hinders interpretation of the observed associations. Furthermore, findings from sub-studies of randomized controlled trials (RCTs) on this topic have been mixed but suggest there could be a differential influence between individual NOACs and warfarin on adverse renal outcomes. [
Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
] As renal decline increases with ageing per se, and prophylactic OAC therapy should be life-long, this further underscores the need to better understand its effects on renal function.
We aimed to evaluate the incidence of adverse renal outcomes among patients with NVAF with preserved renal function receiving rivaroxaban 20 mg/day or warfarin in the United Kingdom (UK) primary care setting. The primary objective was to compare progressive renal decline between OAC treatment groups. The secondary objective was to repeat this comparison among patients with diabetes or heart failure – common comorbidities among patients with AF. [
We performed a population-based cohort study using data from the IQVIA Medical Research Data-UK (IMRD-UK) database of anonymised primary care electronic health records (EHRs), formerly known as The Health Improvement Network. The database holds clinical and prescribing information entered by primary care practitioners (PCPs) as part of routine patient care, covering approximately 6% of the UK population. [
] and a free text field enables manual data entry to add additional details. Demographics, lifestyle factors and results of laboratory tests, including those for renal function (e.g. serum creatinine [SCr] values) are also recorded. Data received from secondary care are entered into the patient's EHR retrospectively, and all prescriptions are automatically recorded upon issue. The study protocol was approved by an independent scientific research committee (reference SRC-20SRC023). Data collection for IMRD-UK was approved by the South East Multicentre Research Ethics Committee in 2003 and individual studies using IMRD-UK data do not require separate ethical approval if only anonymized data are used.
2.2 Source population and cohort identification
Fig. 1 illustrates the identification of the study cohorts. The source population included individuals with NVAF aged ≥18 years with a first prescription for rivaroxaban or warfarin between 1 January 2014 and 31 March 2019. Individuals in the source population were also required to have been registered in the database and with a first recorded prescription for any drug at least a year before the start of the study, and with no previous prescription for any OAC (all patients were therefore OAC naïve). The date of the first rivaroxaban/warfarin prescription was the start of follow-up (start date). As there is no Read code for NVAF, we identified all patients with a code for AF any time before the start date or within the 2 weeks after, and excluded those with a code indicative of valvular AF (i.e. heart valve replacement or mitral stenosis) during this time period. We restricted the cohort to those with preserved renal function due to the potential for rivaroxaban dosing to be different in those with pre-existing CKD of a certain stage. To do this, we excluded those with a history of end-stage renal disease (ESRD), or baseline estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2. We also excluded patients with a record of deep vein thrombosis, pulmonary embolism, or hip/knee surgery in the 3 months before the start date (because these are all alternative reasons for NOAC initiation), and those with no eGFR or SCr values recorded in the year before the start date.
Fig. 1Flowchart depicting the identification of the rivaroxaban and warfarin new user cohorts.
Patients in the rivaroxaban and warfarin cohorts were followed from their start date until the earliest of the following: an adverse renal outcome, death, the last date of data collection for their practice or the end of the study period (30 September 2019). We used an intention-to-treat (ITT) approach where patients were followed for their whole observation period irrespective of whether they discontinued their starting OAC or switched OAC. Separate follow-ups were undertaken to identify each adverse renal outcome of interest, which were chosen based on their use in previous RCTs [
Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
P4746Worsening of renal function in atrial fibrillation patients with stage 3 or 4 chronic kidney disease treated with warfarin or rivaroxaban - evidence from the real-world CALLIPER study in the US claims.
P4749Renal function worsening in factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study.
] on this topic, thereby enabling comparison of results. These were doubling of SCr at any point during follow-up, ≥30% decline in eGFR (confirmed by a subsequent measurement), and incident ESRD (code for ESRD, stage 5 CKD, chronic dialysis, or eGFR <15 ml/min/1.73m2 confirmed by a subsequent measurement). We manually reviewed the EHR of a random sample of 100 cases to validate the identified adverse renal events. In addition, to determine the rate of renal decline, we estimated the average eGFR slope among a subset of individuals with at least two eGFR measurements during follow-up, where the first was recorded within 120 days of the start of follow-up, and the last was recorded >180 days after the first eGFR measurement (reflecting sufficient time for a potential change to occur).
2.4 Other patient variables
We obtained data on patient demographics (age, sex and Townsend index score of deprivation), [
] comorbidities and previous clinical events of importance on/any time before the start date, CHA2DS2-VASc score for stroke risk at the start date, frailty, [
] comedications (prescription on/in the year before the start date), polypharmacy, lifestyle factors (using the most recently recorded status/values before the start date), and healthcare use (in the year before the start date). Details can be found in the Appendix Methods. Renal function at baseline was determined using eGFR measurements (expressed as mL/min/1.73m2) using the closest valid SCr value recorded in the year before the start date and applying the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation, [
] but omitting ethnicity because this is not routinely recorded in UK primary care. Coded clinical entries indicating CKD stage, acute or chronic dialysis were also used to determine renal function.
2.5 Statistical analysis
We described baseline characteristics of the study cohorts using frequency counts and percentages for categorical values and mean with standard deviation (SD) for age and eGFR at baseline. Incidence rates of each adverse renal outcome were calculated for both cohorts by dividing the number of incident cases by the total person-years of follow-up, with 95% confidence intervals (CIs) assuming a Poisson distribution. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% CIs to quantify the association with rivaroxaban vs. warfarin use, adjusted for confounders, including the number of eGFR/SCr measurements before follow-up, which could potentially influence the number of measurements during follow-up and likelihood of outcome detection. We did not adjust for the number of eGFR/SCr measurements during follow-up (i.e. after ascertainment of drug exposure) as this could have been influenced by the exposure itself. In subgroup analyses, we repeated this analysis among patients with diabetes, and among those with heart failure. Further, in a post-hoc analysis, we repeated the analysis among patients free of nephropathy (glomerulonephritis, polycystic kidney disease, interstitial or hypertensive nephropathy as well as those with previous acute kidney injury events) at baseline. An additional post-hoc analysis was performed in which follow-up was censored for all individuals after the first two years of follow-up. The average eGFR slopes after OAC initiation was determined using a linear mixed regression model, adjusted for confounders, where the treatment group, time of eGFR measurement, the interaction between treatment group and time were included as fixed factors and each patient was included as a random factor (i.e. random intercept model). We performed several sensitivity analyses. Firstly, we repeated the main analyses after excluding patients with missing data on either lifestyle variables of the Townsend index. Secondly, we repeated the main analyses with the additional exclusion of patients with eGFR <60 ml/min/1.73m2 at baseline, and then those with eGFR <70 ml/min/1.73m2 at baseline (i.e. applying stricter thresholds for preserved renal function). Thirdly, to reflect variability in endpoints used across other studies and guidelines, we repeated the endpoint analyses lowering the threshold for determining SCr increase from 100% to ≥50%, ≥40%, ≥30% and ≥ 20%, respectively, and changing the threshold for determining eGFR decline from the ≥30% cut-off to ≥20%, ≥40% and ≥ 50%, respectively. Fourthly, we performed an ‘on-treatment’ analysis where patients were censored at the date of OAC discontinuation (>30 days after the end of the last consecutive prescription of the starting OAC) or OAC switching, Lastly, we performed an’ as-treated’ analysis where patients contributed person-time to different OAC exposure categories according to their current exposure irrespective of the starting drug. Analyses were undertaken using Stata version 12.1 (Statacorp).
3. Results
3.1 Characteristics of the study cohorts
We identified a total of 11,652 patients with NVAF and preserved renal function; 5338 in the rivaroxaban 20 mg cohort (mean age 72.6 years, SD 10.2; 61% male) and 6314 in the warfarin cohort (mean age 73.2 years, SD 9.5; 58% male). The distribution of other baseline characteristics was very similar between treatment groups (Table 1). Approximately a fifth of the cohorts had diabetes and approximately 10% had heart failure.
Table 1Baseline characteristics of the study cohorts (patients with NVAF and preserved renal function).
Rivaroxaban 20 mg (N = 5338) n (%)
Warfarin (N = 6314)n (%)
Age (years)
18–49
111 (2)
103 (2)
50–59
455 (9)
403 (6)
60–69
1330 (25)
1541 (24)
70–79
2097 (39)
2594 (41)
80–89
1174 (22)
1522 (24)
≥90
171 (3)
151 (2)
Mean (SD)
72.6 (10.2)
73.2 (9.5)
Sex
Male
3253 (61)
3644 (58)
Female
2085 (39)
2670 (42)
Mean eGFR (SD) at baseline
75.7 (56.1)
75.5 (82.6)
Townsend index
Most affluent
1100 (21)
1223 (19)
2nd quintile
1082 (20)
1365 (22)
3rd quintile
995 (19)
1082 (17)
4th quintile
741 (14)
991 (16)
Most deprived
430 (8)
593 (9)
Missing
990 (19)
1060 (17)
Smoking
Non-smoker
2210 (41)
2477 (39)
Smoker
444 (8)
548 (9)
Ex-smoker
2678 (50)
3288 (52)
Missing
6 (0)
1 (0)
BMI
<20
148 (3)
158 (3)
20–24
1053 (20)
1247 (20)
25–29
1914 (36)
2236 (35)
≥30
2029 (38)
2468 (39)
Missing
194 (4)
205 (3)
PCP visits
0–4
44 (1)
41 (1)
5–9
535 (10)
552 (9)
10–19
2330 (44)
2759 (44)
≥20
2429 (46)
2962 (47)
Hospitalisations
0
3041 (57)
3776 (60)
1
1224 (23)
1296 (21)
≥2
1073 (20)
1242 (20)
Ischemic heart disease
1142 (21)
1612 (26)
Cancer
801 (15)
986 (16)
Diabetes
1118 (21)
1362 (22)
Heart failure
519 (10)
710 (11)
Hypertension
3484 (65)
4320 (68)
CHA2DS2VASc score
0–1
894 (17)
825 (13)
2
1166 (22)
1324 (21)
3
1343 (25)
1630 (26)
4
1062 (20)
1415 (22)
5
544 (10)
716 (11)
≥6
329 (6)
404 (6)
Frailty
Fit
1066 (20)
1122 (18)
Mild frailty
2381 (45)
2848 (45)
Moderate frailty
1401 (26)
1776 (28)
Severe frailty
490 (9)
568 (9)
BMI, body mass index; eGFR, estimated glomerular filtration rates; NVAF, non-valvular atrial fibrillation; PCP, primary care practitioner; SD, standard deviation.
After a mean follow-up of 2.5 years, the number of incident cases experiencing adverse renal events within the two cohorts was as follows: doubling SCr (n = 322), ≥30% decline in eGFR (n = 1179), and progression to ESRD (n = 22). Cumulative estimates and incidence rates per 10,000 person-years by study cohort are shown in Table 2. After adjusting for age, sex, baseline renal function and comorbidities, we found strong evidence for a significantly reduced risk of SCr doubling and a ≥ 30% decline in eGFR with use of rivaroxaban vs. warfarin; HR 0.63 (95% CI: 0.49–0.81) for SCr doubling, and HR 0.76 (95% CI: 0.67–0.86) for ≥30% decline in eGFR. Evidence for a reduced risk of ESRD with use of rivaroxaban vs. warfarin was virtually absent; HR 0.77 (95% CI: 0.29–2.04) (Table 2). The complete results from these models, including all predictors, are available in the supplementary tables (Tables A.1–A.3). Similar results were observed among patients with diabetes or heart failure (Tables A.4 and A.5), after exclusion of patients with nephropathy at baseline (Table A.6), or when truncating follow-up after two years (Table A.7).
Table 2HRs (95% CI) for risk of renal decline among users of rivaroxaban 20 mg vs. warfarin.
Adjusted for age, sex, baseline eGFR, number of previous measurements at baseline, Townsend index, polymedication, smoking, body mass index, health service use (PCP visits, referrals and hospitalisations) in the year before the start date, ischaemic heart disease, cancer, diabetes, heart failure, hypertension, previous acute kidney injury, frailty and CHA2DS2VASc score.
Adjusted for age, sex, baseline eGFR, number of previous measurements at baseline, Townsend index, polymedication, smoking, body mass index, health service use (PCP visits, referrals and hospitalisations) in the year before the start date, ischaemic heart disease, cancer, diabetes, heart failure, hypertension, previous acute kidney injury, frailty and CHA2DS2VASc score.
A total of 2054 patients on rivaroxaban and 2464 on warfarin were included in the slope analysis; time from the start date to the last available eGFR value for individuals was, on average, 2.7 years (2.4 years for patients on rivaroxaban and 3.0 years for those on warfarin). After adjustment for confounders, there was clear evidence that the rate of eGFR decline was significantly slower in the rivaroxaban cohort than the warfarin cohort. The mean decline in renal function over the study period was 2.03 ml/min/1.73 m2 per year in the warfarin cohort (95% CI: 2.23 to 1.84), and 1.65 ml/min/1.73 m2 per year in the rivaroxaban cohort (95% CI: 1.94 to 1.35), a difference of 0.39 (95% CI: 0.04–0.74; p = 0.03) (Table 3). The slower rate of renal decline in the rivaroxaban cohort was observed over most of the first 5 years of follow-up (Fig. A.1, Table A.8).
Table 3Mean eGFR slope (ml/min/1.73m2/year) in the rivaroxaban 20 mg and warfarin cohorts.
Estimated using linear mixed regression models, where the treatment group, time of eGFR measurement, and the interaction between treatment group and time, were included as fixed factors and each individual was included as a random factor (i.e. random intercept model). The following variables were included as additional fixed factors in the model: age, sex, baseline eGFR, Townsend index, polymedication, smoking, body mass index, health service utilisation in the year before baseline (PCP visits, referrals and hospitalisations), comorbidity (ischemic heart disease, cancer, diabetes, heart failure, and prior acute kidney injury), frailty and CHA2DS2VASc score.
Estimated using linear mixed regression models, where the treatment group, time of eGFR measurement, and the interaction between treatment group and time, were included as fixed factors and each individual was included as a random factor (i.e. random intercept model). The following variables were included as additional fixed factors in the model: age, sex, baseline eGFR, Townsend index, polymedication, smoking, body mass index, health service utilisation in the year before baseline (PCP visits, referrals and hospitalisations), comorbidity (ischemic heart disease, cancer, diabetes, heart failure, and prior acute kidney injury), frailty and CHA2DS2VASc score.
Estimated using linear mixed regression models, where the treatment group, time of eGFR measurement, and the interaction between treatment group and time, were included as fixed factors and each individual was included as a random factor (i.e. random intercept model). The following variables were included as additional fixed factors in the model: age, sex, baseline eGFR, Townsend index, polymedication, smoking, body mass index, health service utilisation in the year before baseline (PCP visits, referrals and hospitalisations), comorbidity (ischemic heart disease, cancer, diabetes, heart failure, and prior acute kidney injury), frailty and CHA2DS2VASc score.
Findings of the sensitivity analyses were broadly consistent with the main findings (see Tables A.9–A.18.
4. Discussion
In this population-based study of patients with NVAF and preserved renal function, we found clear evidence that users of rivaroxaban 20 mg had a significantly reduced risk of renal decline compared with users of warfarin, with a 37% reduction in SCr doubling, and a 24% reduction in ≥30% decline in eGFR. Consistent findings were seen among patients with diabetes or heart failure. The rate of renal decline during the first five years of drug use was slower for users of rivaroxaban 20 mg vs. warfarin, although the clinical relevance of this difference is debatable. Similarly, the point estimate was indicative of a potential benefit effect of rivaroxaban on progression to ESRD, yet statistical power was limited to be able to detect a significant difference between exposure groups.
Our findings are consistent with those from previous claims database studies in the United States (US) [
P4746Worsening of renal function in atrial fibrillation patients with stage 3 or 4 chronic kidney disease treated with warfarin or rivaroxaban - evidence from the real-world CALLIPER study in the US claims.
P4749Renal function worsening in factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study.
P4749Renal function worsening in factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study.
P4749Renal function worsening in factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study.
] found rivaroxaban to be associated with a significant 66% reduction in occurrence of ESRD when compared with phenprocoumon. Also using Marketscan, Vaitsiakhovich and colleagues [
P4746Worsening of renal function in atrial fibrillation patients with stage 3 or 4 chronic kidney disease treated with warfarin or rivaroxaban - evidence from the real-world CALLIPER study in the US claims.
] reported a 47% reduction in progression to stage 5 CKD/kidney failure/dialysis in rivaroxaban vs. warfarin users among patients with stage 3 or 4 CKD at baseline, as well as in those with type 2 diabetes, in line with findings from another Marketscan study restricted to patients with diabetes. [
] reported a lower rate of eGRF worsening when comparing NOACs as a class and VKAs, this effect was partially lost in patients with diabetes.
A differential effect of NOACs and VKAs on renal decline is biologically plausible, and potentially relates to their differential effect on vitamin K inhibition. Warfarin has been shown to decrease carboxylation of the matrix G1a protein, which is an important vitamin K-dependent inhibitor of medial and intimal vascular calcification. [
] However, data on this topic from substudies of AF RCTs have been less consistent although they have indicated potential differential renal effects between individual NOACs. In ROCKET-AF, [
Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
] it was faster in patients treated with apixaban vs. warfarin. In the claims database study by Yao and colleagues, the significantly reduced risks of SCr doubling and the ≥30% decline in eGFR seen with rivaroxaban vs. warfarin, were not seen for apixaban, and there was no suggestion of any difference between apixaban and warfarin on the occurrence of ESRD. In the study by Bonnemeier et al, [
P4749Renal function worsening in factor-xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study.
] both long-term use of rivaroxaban and apixaban were associated with a reduced risk of ESRD occurrence compared with phenprocoumon, yet the reduction was double the magnitude for rivaroxaban (66% vs. 33%).
Impaired renal function is common in patients with AF; 28% of patients with newly diagnosed AF and at high risk of stroke in the GARFIELD-AF (Global Anticoagulant Registry in the FIELD–Atrial Fibrillation registry), [
Management and 1-year outcomes of patients with newly diagnosed atrial fibrillation and chronic kidney disease: results from the prospective GARFIELD - AF registry.
] had some degree of CKD. Of note is that, in our study, renal decline was progressive throughout follow-up in both study cohorts and was likely due to age-related physiological decline as well as OAC therapy. This is clinically meaningful given the life-long nature of OAC therapy in patients with AF. It underscores the importance of continuous monitoring of renal function in this patient population because OAC dose adjustment may be required with time. Managing these patients in a way that mitigates the risks of thromboembolism and bleeding, and limits potential loss of kidney function, is imperative to help reduce their risks of adverse clinical outcomes. Our results show that renal decline is common in patients with NVAF, preserved renal function and requiring OAC therapy. Renal decline was quite pronounced shortly after OAC initiation, irrespective of the starting drug.
Our study has several strengths. The large sample size from a database representative of the UK as a whole supports the external validity of our findings. The validity of the renal decline outcomes was increased by the manual review of EHRs to confirm recorded events, and the requirement to have a confirmatory eGFR measurement after the initial recorded value during follow-up for determining eGFR decline and ESRD. Also, we captured the vast majority of OAC prescriptions due to the UK's healthcare system of managing chronic disease largely in primary care.
4.1 Study limitations
We did not evaluate international normalized ratio levels in the warfarin cohort, thus were unable to take into account potential overdosing that could lead to renal damage in these patients. Some non-differential exposure misclassification will have occurred when patients discontinued or switched OAC during follow-up, potentially biasing risk estimates towards the null. However, this was likely minimal as shown from the ‘on-treatment’ and ‘as-treated’ sensitivity analyses where results were consistent with the main findings. Non-differential outcome misclassification may have occurred from unrecorded/incorrect laboratory measurements or coding errors. Furthermore, the CKD-EPI formula has been reported to slightly overestimate eGFR, particularly in patients of advanced age. [
] The database enabled the control of many variables in the analyses, including lifestyle factors (e.g. body mass index, smoking, alcohol use), that are not recorded in claims databases. Notwithstanding this, and despite the similarity in the baseline characteristics of the comparison groups, other clinical factors influencing decisions to prescribe rivaroxaban over warfarin (or vice versa), and not captured in the database due to being unmeasurable or unknown, could have resulted in residual confounding.
In conclusion, we found strong evidence that patients with NVAF and preserved renal function using rivaroxaban have a markedly reduced risk and rate of renal decline compared with those using warfarin. Further evidence to support a causal association from RCTs and well-designed observational studies in other settings would help prescribers make more informed benefit–risk decisions regarding choice of long-term OAC therapy for their patients.
Funding
This work was supported by Bayer AG (grant number, not applicable).
Role of the sponsor
YB (an employee of Bayer) and GB (a former employee of Bayer and current paid consultant for Bayer) were involved in the study concept, study design, review of manuscript drafts and the decision to submit the article for publication. The sponsor had no other roles in the study.
CRediT authorship contribution statement
Antonio González Pérez: Conceptualization, Software, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – review & editing, Visualization. Yanina Balabanova: Conceptualization, Methodology, Writing – review & editing. María E. Sáez: Conceptualization, Software, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – review & editing. Gunnar Brobert: Conceptualization, Methodology, Writing – review & editing. Luis A. García Rodríguez: Conceptualization, Funding acquisition, Resources, Software, Data curation, Formal analysis, Investigation, Methodology, Supervision, Project administration, Writing – review & editing.
Declaration of Competing Interest
AGP, MES and LAGR work for CEIFE, which has received research funding from Bayer AG. LAGR has also received honoraria for serving on advisory boards for Bayer AG. YB is an employee of Bayer AG. GB was an employee of Bayer AG at the time the study was carried out.
Acknowledgements
We thank Susan Bromley, EpiMed Communications Ltd., Abingdon, UK, for medical writing assistance, funded by Bayer AG and in accordance with Good Publication Practice. We also thank IQVIA for providing the IMRD-UK incorporating data from THIN, a Cegedim Database. THIN is a registered trademark of Cegedim SA in the United Kingdom and other countries. Reference made to THIN is intended to be descriptive of the data asset licensed by IQVIA. This work uses de-identified data provided by patients as a part of their routine primary care.
2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: clinical significance and implications for decision making-a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society.
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2021 european heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
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Adjusted for age, sex, baseline eGFR, number of previous measurements at baseline, Townsend index, polymedication, smoking, body mass index, health service use (PCP visits, referrals and hospitalisations) in the year before the start date, ischaemic heart disease, cancer, diabetes, heart failure, hypertension, previous acute kidney injury, frailty and CHA2DS2VASc score.
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