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Meta-Analysis of Renal Function on the Safety and Efficacy of Novel Oral Anticoagulants for Atrial Fibrillation
Am J Cardiol. 2016;117(1):69-75
Novel oral anticoagulants (NOACs) are safe and effective for the prevention of stroke or systemic embolism (S/SE) in atrial fibrillation. The efficacy and safety of NOACs compared with warfarin has not been systematically assessed in subjects with mild or moderate renal dysfunction. We performed a meta-analysis of the randomized clinical trials that compared efficacy and safety (major bleeding) outcomes of NOACs compared to warfarin for the treatment of nonvalvular atrial fibrillation and had available data on renal function. We estimated the pooled relative risk (RR) of S/SE and major bleeding in relation to renal function (assessed by baseline estimated glomerular filtration rate divided in 3 groups: normal [estimated glomerular filtration rate >80 ml/min], mildly impaired [50 to 80 ml/min], and moderate impairment [<50 ml/min]). We included 4 randomized clinical trials enrolling a total of 58,338 subjects. The RRs of S/SE and major bleeding were higher in subjects with renal impairment compared to normal renal function, independent of type of anticoagulant therapy. In subjects with normal renal function, no difference in the risk of S/SE was observed, whereas the risk of major bleeding was slightly lower for subjects taking NOACs (RR 0.87, 95% confidence interval [CI] 0.76 to 0.99). In subjects with mild or moderate renal impairment, NOACs were associated with a reduced risk of S/SE (RR 0.75, 95% CI 0.66to 0.85 and RR 0.80, 95% CI 0.68 to 0.94, respectively) and major bleeding (RR 0.87, 95% CI 0.79 to 0.95 and RR 0.80, 95% CI 0.71 to 0.91, respectively) compared to warfarin. The pooled analysis for major bleeding demonstrated significant heterogeneity. In conclusion, the use of NOACs was associated with a reduced risk of S/SE and reduced risk of major bleeding compared to warfarin in subjects with mild or moderate renal impairment suggesting a favorable risk profile of these agents in patients with renal disease.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with fivefold increased risk of cardioembolic stroke. Warfarin reduces the risk of stroke or systemic embolism (S/SE) by approximately two-thirds 1 and recent large-scale clinical trials have demonstrated that the novel oral anticoagulants (NOACs) are associated with a similar reduction in stroke with a favorable risk profile. 2 3 4 5 Advantages of the NOACs over warfarin include the predictable pharmacokinetics, rapid onset of action, fewer drug–drug interactions and dietary restrictions, and convenience due to the lack of need for ongoing monitoring. 6 Renal impairment is common in patients with AF and has an important impact on clinical outcomes. Patients with AF and renal dysfunction are at particularly high risk of thromboembolic complications as well as an increased risk of bleeding. 7 8 Each of the NOACs has some degree of renal metabolism or excretion and their efficacy and safety across the range of mild-to-moderate renal impairment have not been fully studied. We performed a systematic review and meta-analysis of the safety and efficacy of the 4 Food and Drug Administration (FDA)–approved NOACs compared to warfarin in nonvalvular AF in relation to renal function.
We searched for randomized clinical studies that compared the risk of S/SE events in subjects with nonvalvular AF randomized to any of the 4 NOACs (dabigatran, rivaroxaban, apixaban, or edoxaban) versus warfarin and that reported outcomes in relation to renal function. We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Database using keywords: “atrial fibrillation,” “dabigatran,” “rivaroxaban,” “apixaban,” “edoxaban,” “warfarin,” “new oral anticoagulant,” “oral factor Xa inhibitor,” and “oral thrombin inhibitor.” Studies were restricted to English language in peer-reviewed journals until January 2014. We searched the US FDA databases ( www.fda.gov ) to obtain data from the respective drug (NOACs) sponsor's application pursuing FDA approval. Finally, principal investigators and/or sponsors of the trials were also contacted.
Data were independently reviewed and extracted. Studies considered in the present study were: (1) randomized clinical trials evaluating the safety and efficacy of any new oral anticoagulant compared to oral anticoagulation with therapeutic dose-adjusted warfarin, for prevention of S/SE in patients with nonvalvular AF, (2) evaluated renal function at baseline, and (3) reported outcomes in relation to renal function. For trials reporting more than one publication, data were extracted from the most complete publication, using the other reports to clarify or complement the information obtained. To assess the agreement between reviewers for study selection, we used the κ statistic (κ = 0.78).
Data included design, randomization protocol, allocation concealment, number of participants, mean age, gender, therapeutic interventions, type of drug, duration of treatment, and baseline renal function. Primary efficacy outcome: stroke (ischemic or hemorrhagic) or systemic embolism. Primary safety outcome: major bleeding as defined by the International Society of Thrombosis and Hemostasis criteria (bleeding causing a decrease in hemoglobin levels of >2 g/dl, bleeding leading to transfusion of >2 units of blood, symptomatic bleeding in a critical area [intracranial, intraspinal, intraocular, retroperitoneal, intrarticular, pericardial, or intramuscular with compartment syndrome], or bleeding events leading to death). Secondary outcomes: total mortality, cardiovascular mortality, ischemic stroke, intracranial bleeding, gastrointestinal bleeding, and myocardial infarction.
Information about these outcomes was stratified by renal function, according to baseline estimated glomerular filtration rate (eGFR) using the Cockcroft–Gault formula and classified in the following groups: eGFR <50 ml/min (moderate renal impairment), eGFR 50 to 80 ml/min (mild renal impairment), and eGFR >80 ml/min (normal renal function). Two reviewers independently assessed the quality of the included studies using the checklist of the Cochrane Database of Systematic Reviews that assesses the risk of bias in sequence generation, allocation concealment, blinding, attrition, selection, and other biases.
We calculated pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) for the primary efficacy (S/SE), safety (major bleeding), and when available for the secondary outcomes in relation to the 3 groups according to renal function. When possible, we did analysis with the intention-to-treat population. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, 2 doses of dabigatran were tested; we only included the higher dose. In the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, 2 doses of edoxaban were tested and we included data from the higher dose (60 mg/30 mg). A separate sensitivity analysis was carried out including only factor Xa inhibitors. Outcomes were then pooled and compared with a fixed effects model (Mantel–Haenszel method). A value of p <0.05 was considered statistically significant. All analyses were performed using Review Manager software (RevMan, version 5.2, from the Cochrane Collaboration). The appropriateness of pooling data across studies was assessed using Cochran Q and the I 2 test for heterogeneity.
Of the 43 full-text studies reviewed, 36 studies were excluded (see study flow diagram, Figure 1 ), and of the excluded studies, 3 were randomized studies (1 study was excluded because it had no warfarin comparison group, 1 used different doses of dabigatran, and 1 randomized study was not blinded and not reporting outcomes in renal function subgroups). 9 10 11 Six phase II trials were excluded because of no reporting baseline renal function and/or no outcomes in relation to renal function. 12 13 14 15 16 17 Four phase III RCTs were included, 2 3 4 5 information from 3 substudies reporting outcomes in relation to renal function were extracted to complete the information from the primary trials. 18 19 20 Furthermore, data from the 4 drug sponsor's application to the FDA were reviewed 21 22 23 24 and used to complement other sources. All investigators of the primary trials and substudies were contacted but were not able to provide more detailed data about their studies.
The 4 included studies enrolled a total of 58,076 subjects. Of them, 29,066 subjects were randomized to an NOAC and 29,010 to warfarin. The studies characteristics are listed in Table 1 . All 4 trials were phase III randomized, 3 of them (ARISTOTLE, 4 ROCKET-AF, 3 and ENGAGE AF-TIMI 58 5 ) were double-blind and double-dummy studies. The RE-LY trial 2 had the dabigatran arm blinded and the warfarin arm unblinded. The RELY and ARISTOTLE studies enrolled subjects at lower risk of stroke (CHADS 2 score of 2.1 both), whereas the ENGAGE AF-TIMI 58 trial enrolled subjects with CHADS 2 scores average of 2.8, and the ROCKET-AF trial had the subjects at highest risk (CHADS 2 score of 3.5 with no subjects with scores of 0 or 1). The number of subjects with previous warfarin use ranged from 50% to 60%. The time in therapeutic range in the warfarin arms was the lowest in the ROCKET-AF trial (mean 58%) and was similar in the other 3 trials (66% to 68%). All 4 studies had small fraction of subjects lost to follow-up (<0.1%). According to the Cochrane Database of Systematic Reviews assessment of the risk of bias, all 4 studies were deemed of high quality ( Table 2 ).
|RE-LY 2 19||ROCKET-AF 3 18||ARISTOTLE 4 20||ENGAGE-AF TIMI 48 5|
|Dabi 150||Warf||Riva||Warf||Apixa||Warf||Edo 60||Warf|
|Study design||RCT phase III, unblinded warfarin||RCT phase III, double blind, double dummy||RCT phase III, double blind, double dummy||RCT phase III, double blind, double dummy|
|Population||NVAF and ≥1 risk factor (stroke or TIA, CHF, age >75yo or 65-74 yo + DM or HTN or CAD||NVAF, CHADS score ≥2||NVAF, ≥1 risk factor (age ≥75 y, stroke or TIA, CHF, DM, HTN||NVAF, CHADS ≥2|
|Number of randomized subjects||6076||6022||7131||7133||9120||9081||7035||7036|
|Age||71 (mean)||73 (median)||70 (median)||72 (median)|
|Previous warfarin use||50%||49%||62%||63%||57%||57%||59%||59%|
|Concomitant Aspirin use||39%||41%||36%||37%||31%||31%||29%||30%|
|Median follow-up (years)||2.0||1.9||1.8||2.8|
|Warfarin group time in therapeutic range||67 (54-78)||58 (43-71)||66 (52-77)||68 (57-77)|
|Random sequence generation (selection bias)||Allocation concealment (selection bias)||Blinding of participants and personnel (performance bias)||Blinding of outcome assessment (detection bias)||Incomplete outcome data (attrition bias)||Selective reporting (reporting bias)||Other bias|
|ENGAGE AF-TIMI 48||Low||Low||Low||Low||Low||Low||Low|
As presented in Table 3 , the residual risk of S/SE in subjects receiving NOACs ranged from 2.16% for subjects with normal renal function to 3.8% for subjects with moderate renal impairment. Compared to subjects with normal renal function, the odds ratio of residual stroke was 1.3 times (95% CI 1.1 to 1.5) greater in subjects with mild renal impairment and 1.79 times (95% CI 1.5 to 2.2) greater in subjects with moderate renal impairment. In subjects receiving warfarin, the risk of residual S/SE was highest in the group with moderate renal function; in comparison to subjects with normal renal function, the residual risk of stroke was greater in subjects with moderate and mild renal impairment.
|Stroke or Systemic Embolism||Risk of Stroke||Odds Ratio||95% CI||P value|
|Normal Renal Function||229/10,603||2.16%||Ref||Ref||NA|
|Mild Renal Impairment||352/12,952||2.72%||1.27 ∗||1.07-1.5||<0.01|
|Moderate Renal Impairment||210/5,511||3.81%||1.79 ∗||1.48-2.17||<0.001|
|Normal Renal Function||235/10,515||2.23%||Ref||Ref||NA|
|Mild Renal Impairment||505/13,098||3.86%||1.75 ∗||1.50-2.06||<0.0001|
|Moderate Renal Impairment||261/5,397||4.84%||2.22 ∗||1.86-2.66||<0.0001|
∗ Compared to normal renal function.
Similarly, the risk of bleeding was greater in subjects with renal impairment ( Table 4 ). In the group receiving NOACs, compared with subjects with normal renal function, the odds of major bleeding were greater in subjects with mild or moderate renal impairment. In subjects receiving warfarin, we observed greater risk of major bleeding in subjects with renal impairment.
|Major Bleeding||Risk of Major Bleed||Odds Ratio||95% CI||P value|
|Normal Renal Function||397/10,606||3.74%||Ref||Ref||NA|
|Mild Renal Impairment||734/12,957||5.66%||1.54 ∗||1.36-1.75||<0.0001|
|Moderate Renal Impairment||397/5,514||7.20%||2.00 ∗||1.73-2.30||<0.0001|
|Normal Renal Function||457/10,512||4.35%||Ref||Ref||NA|
|Mild Renal Impairment||840/13,096||6.41%||1.51 ∗||1.34-1.70||<0.0001|
|Moderate Renal Impairment||486/5,411||8.98%||2.17 ∗||1.90-2.48||<0.0001|
∗ Compared to normal renal function.
In subjects with moderate renal impairment, S/SE occurred in 3.8% of subjects treated with NOACs and 4.8% of subjects treated with warfarin ( Figure 2 ). The use of NOACs was associated with a significant reduction of S/SE (RR 0.79, 95% CI 0.66 to 0.94). In subjects with mild renal impairment, S/SE occurred in 2.7% of subjects receiving NOACs and in 3.9% of subjects taking warfarin; the use of NOACs was associated with a significant reduction of S/SE (RR 0.71, 95% CI 0.62 to 0.81). In subjects with normal renal function, there was no difference in the risk of S/SE between NOACs or warfarin treatment (RR 0.96, 95% CI 0.81 to 1.15). When analyzing the differences among the groups, the test for interaction was significant (p = 0.02) with moderate degree of heterogeneity among the groups (I 2 = 54%).
In subjects with moderate renal impairment, major bleeding occurred in 7.20% of subjects receiving NOACs and in 8.98% patients receiving warfarin ( Figure 3 , Supplementary Figure 1 ). The use of NOACs was associated with a significant reduction in the risk of major bleeding compared to warfarin (RR 0.80, 95% CI 0.70 to 0.91). In subjects with mild renal impairment, major bleeding occurred in 5.66% of patients taking NOACs and in 6.41% of subjects taking warfarin. Treatment with NOACs was associated with a significant reduction of major bleeding compared to the use of warfarin (RR 0.88, 95% CI 0.80 to 0.97). In subjects with normal renal function, major bleeding occurred in 3.74% of subjects taking NOACs and in 4.35% of patients taking warfarin. The use of NOACs was associated with a significant reduction in the risk of major bleeding (RR 0.86 95% CI 0.75 to 0.98). There was a significant degree of heterogeneity (p = 0.03).
Data for total mortality in relation to renal function were available from only 2 studies ( Supplementary Figure 2 ): RELY and ARISTOTLE trials. In subjects with moderate renal impairment, the use of NOACs was not associated with mortality reduction in comparison with the use of warfarin (RR 1.05, 95% CI 0.91 to 1.20). In subjects with moderate renal impairment, the use of NOACs was associated with a trend to reduced mortality compared to the use of warfarin (RR 0.89 95% CI 0.79 to 1.01). In subjects with normal renal function, the use of NOACs was also associated with a trend toward less mortality compared to the use of warfarin (RR 0.85, 95% CI 0.73 to 1.01).
Data for intracranial bleeding were available from 3 trials and only for subjects with moderate renal impairment and a single group of subjects with mild impairment and normal renal function (eGFR >50 ml/min; Supplementary Figure 3 ). In subjects with moderate renal impairment, intracranial bleeding occurred in 0.90% of subjects taking NOACs and in 1.62% of patients taking warfarin. In subjects with eGFR >50 ml/min, intracranial bleeding occurred in 0.58% of patients taking NOACs and in 1.15% of patients taking warfarin. Independent of renal function there was a lower risk of intracranial bleeding associated with the use of NOACs compared to the use of warfarin.
We performed a sensitivity analysis of primary efficacy and safety outcomes in relation to renal function; including only Factor Xa inhibitors ( Supplementary Figures 4 and 5 ). In subjects with moderate renal impairment, the use of Factor Xa inhibitors was associated with a trend to lower risk of S/SE (RR 0.85, 95% CI 0.70 to 1.03), in subjects with mild renal impairment, the use of Factor Xa inhibitors was associated with a significant reduction in the risk of S/SE (RR 0.71, 95% CI 0.61 to 0.83), whereas in subjects with normal renal function, the use of Factor Xa inhibitors was not associated with a reduction in the primary efficacy end point (RR 1.02 95% CI 0.84 to 1.24) compared to warfarin. There was a differential response among the groups (test for interaction p = 0.01). Compared to the primary analysis, it seems apparent that the benefit or lack of, associated with the use of NOACs is not related significantly with the underlying mechanism of the NOACs.
In terms of major bleeding, in subjects with moderate renal impairment, the use of Factor Xa inhibitors was associated with a significant reduction in the risk of major bleeding (RR 0.73, 95% CI 0.62 to 0.84). In subjects with mild renal impairment, the use of Factor Xa inhibitors was associated with a reduction of major bleeding compared to warfarin use (RR 0.87, 95% CI 0.78 to 0.98). Although in subjects with normal renal function, the use of Factor Xa inhibitors was associated with a trend to less risk of major bleeding compared to the use of warfarin (RR 0.86, 95% CI 0.74 to 1.00). Similar to the principal analysis, there was significant heterogeneity in the groups of moderate impairment and normal renal function.
A funnel plot of the included studies was not informative given the small number of studies included. Supplementary Figure 6 shows the funnel plot S/SE.
This meta-analysis of large phase III RCTs demonstrated that in patients with nonvalvular AF receiving anticoagulation: (1) the residual risks of S/SE and bleeding are higher in subjects with mild or moderate renal impairment compared to subjects with normal renal function, (2) the risk of S/SE is lower with the use of NOACs compared to warfarin in subjects with mild or moderate renal impairment, but that risk is not different in subjects with normal renal function, and (3) the risk of bleeding is lower with the use of NOACs compared to warfarin, independently of renal function.
Renal impairment is a risk factor for S/SE. 25 The present study adds to the body of report demonstrating that renal impairment is associated with an increased risk of residual S/SE regardless of the use of NOACs or warfarin in subjects with nonvalvular AF. Our analysis was unadjusted for other potential factors known to be associated with greater risk of stroke and renal impairment (older age, diabetes, hypertension, cardiovascular disease including stroke, and heart failure), which can in part explain this greater residual S/SE risk.
We found that subjects with mild or moderate renal impairment have less risk of S/SE when taking NOACs than when taking warfarin, a finding in line with the overall effect favoring NOACs over warfarin. For subjects with normal renal function, the benefits of NOACs and warfarin appear to be similar.
The risk of bleeding was greater in subjects with renal impairment compared to subjects with normal renal function, regardless of the use of NOACs or warfarin. This finding supports previous reports that renal impairment is a marker of greater risk of bleeding complications. 26 Renal impairment is considered in the bleeding prediction schemes for subjects with AF using anticoagulants (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol [HAS-BLED] 27 and Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke [HEMORR 2 HAGES] 28 ). As with the residual risk of S/SE, our analysis for bleeding was not adjusted for other potential factors and a patient-level analysis would better addresses this finding.
In most of the performed comparative analyses regarding bleeding complications, there was significant heterogeneity. Regardless of this heterogeneity, however, all subgroup analyses were in line with the overall trend toward lower bleeding risk with NOACs compared to warfarin. The overall effect of reduced major bleeding associated with NOACs compared to warfarin seems to be applicable to all subjects regardless of renal function. No differential effect was found in relation to different degrees of renal impairment. Potential explanations for the heterogeneity were not readily identified, but most likely are related to different baseline risk of bleeding in the populations studied in the 4 trials.
Our evaluation of secondary outcomes of interest is incomplete. Most secondary outcomes were not reported in relation to renal function in any published or unpublished studies; and the sponsors were not able to release that information. For the only 2 secondary analyses reported, total mortality was assessed for apixaban and dabigatran, and we were not able to show any differential mortality benefit for NOACs or warfarin in relation to renal function. For intracranial bleeding, our analysis reported on dabigatran, rivaroxaban, and edoxaban; in relation to moderate renal impairment and a group including subjects with normal and mild renal impairment. It appears that there is no differential effect between the 2 groups.
Analysis of the benefits and risks of the use of factor Xa inhibitors versus warfarin yielded similar results compared to the primary analysis. Coincidentally, 2 of the potential factors to explain heterogeneity of drug characteristics were accomplished with this sensitivity analysis, because dabigatran is the one NOAC with the highest degree of renal excretion (80%), and it is the only direct thrombin inhibitor. Compared to the primary analysis, there were only minor differences in the effect size for S/SE prevention in the group of moderate renal impairment and similar effect sizes in the group of mild impairment and normal renal function.
Our study has several limitations. First, subgroup analysis according to renal function was not predetermined, and no hypothesis was specified in all the studies included. This is a study-level subgroup meta-analysis; therefore, we could not perform further analyses for other clinical characteristics. Renal function was assessed at baseline using the Cockcroft–Gault equation, a formula that is not recommended by the US Renal Data System. Even further, the accepted classification of chronic renal disease on the basis of GFR uses different cutoffs to classify renal impairment from the one used in the landmark clinical trials. Therefore, there exists the possibility for misclassification of the severity of renal impairment. Renal function was uniformly assessed by the same method in all studies included. This meta-analysis included 4 large RCTs on NOACs and excluded all phase II RCTs because of not reporting outcomes in relation to renal function. Because these phase II trials had short follow-up, relatively small sample sizes, and small number of efficacy and safety events, we believe that the final pooled analysis would not have changed by including these studies. However, our analysis has several strengths. The number of events in each subgroup was large, and this analysis represents the largest subgroup analysis performed on this topic. Our meta-analysis specified a priori hypothesis. Our findings are consistent with previous evidence that subjects with renal impairment are at greater risk of stroke and bleeding. Finally, there are plausible biological mechanisms to explain the greater risk of stroke. Our data collection was as complete as possible and included FDA drug sponsor's applications.
The authors have no conflicts of interest to disclose.
This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
See page 75 for disclosure information.
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