Meta-Analysis of the Influence of Chronic Kidney Disease on the Risk of Thromboembolism Among Patients With Nonvalvular Atrial Fibrillation
2014; Elsevier BV; Volume: 114; Issue: 4 Linguagem: Inglês
10.1016/j.amjcard.2014.05.048
ISSN1879-1913
AutoresRui Providência, Éloi Marijon, Serge Bovéda, Sérgio Barra, Kumar Narayanan, Jean‐Yves Le Heuzey, Bernard J. Gersh, Lino Gonçalves,
Tópico(s)Acute Ischemic Stroke Management
ResumoChronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist. However, the extent to which CKD increases the risk of thromboembolism in patients with nonvalvular AF and the benefits of anticoagulation in this group remain unclear. We addressed the role of CKD in the prediction of thromboembolic events and the impact of anticoagulation using a meta-analysis method. Data sources included MEDLINE, EMBASE, and Cochrane (from inception to January 2014). Three independent reviewers selected studies. Descriptive and quantitative information was extracted from each selected study and a random-effects meta-analysis was performed. After screening 962 search results, 19 studies were considered eligible. Among patients with AF, the presence of CKD resulted in an increased risk of thromboembolism (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.20 to 1.76, p = 0.0001), particularly in case of end-stage CKD (HR 1.83, 95% CI 1.56 to 2.14, p <0.00001). Warfarin decreased the incidence of thromboembolic events in patients with non–end-stage CKD (HR 0.39, 95% CI 0.18 to 0.86, p <0.00001). Recent data on novel oral anticoagulants suggested a higher efficacy of these agents compared with warfarin (HR 0.80, 95% CI 0.66 to 0.96, p = 0.02) and aspirin (HR 0.32, 95% CI 0.19 to 0.55, p <0.0001) in treating non–end-stage CKD. In conclusion, the presence of CKD in patients with AF is associated with an almost 50% increased thromboembolic risk, which can be effectively decreased with appropriate antithrombotic therapy. Further prospective studies are needed to better evaluate the interest of anticoagulation in patients with severe CKD. Chronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist. However, the extent to which CKD increases the risk of thromboembolism in patients with nonvalvular AF and the benefits of anticoagulation in this group remain unclear. We addressed the role of CKD in the prediction of thromboembolic events and the impact of anticoagulation using a meta-analysis method. Data sources included MEDLINE, EMBASE, and Cochrane (from inception to January 2014). Three independent reviewers selected studies. Descriptive and quantitative information was extracted from each selected study and a random-effects meta-analysis was performed. After screening 962 search results, 19 studies were considered eligible. Among patients with AF, the presence of CKD resulted in an increased risk of thromboembolism (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.20 to 1.76, p = 0.0001), particularly in case of end-stage CKD (HR 1.83, 95% CI 1.56 to 2.14, p <0.00001). Warfarin decreased the incidence of thromboembolic events in patients with non–end-stage CKD (HR 0.39, 95% CI 0.18 to 0.86, p <0.00001). Recent data on novel oral anticoagulants suggested a higher efficacy of these agents compared with warfarin (HR 0.80, 95% CI 0.66 to 0.96, p = 0.02) and aspirin (HR 0.32, 95% CI 0.19 to 0.55, p <0.0001) in treating non–end-stage CKD. In conclusion, the presence of CKD in patients with AF is associated with an almost 50% increased thromboembolic risk, which can be effectively decreased with appropriate antithrombotic therapy. Further prospective studies are needed to better evaluate the interest of anticoagulation in patients with severe CKD. Thromboembolic events are one of the most feared complications of atrial fibrillation (AF).1Lin H.J. Wolf P.A. Kelly-Hayes M. Beiser A.S. Kase C.S. Benjamin E.J. D'Agostino R.B. Stroke severity in atrial fibrillation. The Framingham Study.Stroke. 1996; 27: 1760-1764Crossref PubMed Scopus (1139) Google Scholar Chronic kidney disease (CKD) is relatively prevalent in patients with AF.2Go A.S. Fang M.C. Udaltsova N. Chang Y. Pomernacki N.K. Borowsky L. Singer D.E. ATRIA Study InvestigatorsImpact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.Circulation. 2009; 119: 1363-1369Crossref PubMed Scopus (354) Google Scholar The extent to which the presence of CKD may increase the risk of thromboembolism in patients with AF has not yet been fully elucidated. Oral anticoagulation is the mainstay of thromboembolic prevention in patients with AF,3Ezekowitz M.D. Bridgers S.L. James K.E. Carliner N.H. Colling C.L. Gornick C.C. Krause-Steinrauf H. Kurtzke J.F. Nazarian S.M. Radford M.J. Rickles F.R. Shabetai R. Deykin D. the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation InvestigatorsWarfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veteran Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.N Engl J Med. 1992; 327: 1406-1412Crossref PubMed Scopus (1261) Google Scholar but data on efficacy and safety in the CKD and dialysis population have been scarce and contradictory.4Chan K.E. Lazarus J.M. Thadhani R. Hakim R.M. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation.J Am Soc Nephrol. 2009; 20: 2223-2233Crossref PubMed Scopus (362) Google Scholar, 5Olesen J.B. Lip G.Y. Kamper A.L. Hommel K. Køber L. Lane D.A. Lindhardsen J. Gislason G.H. Torp-Pedersen C. Stroke and bleeding in atrial fibrillation with chronic kidney disease.N Engl J Med. 2012; 367: 625-635Crossref PubMed Scopus (737) Google Scholar Our aim was to systematically evaluate, through a meta-analysis method, the impact of the presence of CKD in patients with AF as regards risk of thromboembolism and the potential benefit of anticoagulation in that setting. We performed a search in MEDLINE (by way of Ovid and PubMed), EMBASE, and Cochrane (from inception to January 3, 2014) databases using the following search string: “atrial fibrillation” AND (“renal failure” OR “chronic renal disease” OR “dialysis”) AND (“stroke” OR “thromboembolism”). The reference lists of the accessed full-text reports were further researched for sources of potential information relevant to this analysis. The authors of full-text reports and abstracts were contacted by e-mail to retrieve additional information. Only longitudinal studies assessing the occurrence of a composite end point of stroke or systemic embolism (and including transient ischemic attack) during follow-up in patients with AF were considered for inclusion. Both registries and randomized trials were considered eligible for analysis. The methods sections of evaluated studies were reviewed to confirm the suitability and composition of the reported end point. Studies assessing only stroke (either ischemic, hemorrhagic, or a composite of both) and providing no data on systemic embolism were not considered representative of the full spectrum of thromboembolism in AF and were excluded from analysis. Similarly, studies only reporting stroke or systemic embolism in association with myocardial infarction, hospitalization, or death not due to stroke or systemic embolism were not included. To be included in the systematic review, the studies needed to have a design allowing extraction of information concerning at least 1 of the 2 main aims of this study: (1) assessment of the incidence of stroke and systemic embolism in patients with AF according to the presence of CKD (including dialysis treatment) and (2) estimating the impact of anticoagulation in patients with CKD and AF. The population, intervention, comparison, and outcome approach was used for this aim.6Menzies D. Systematic reviews and meta-analyses.Int J Tuberc Lung Dis. 2011; 15: 582-593Crossref PubMed Scopus (30) Google Scholar The population of interest included patients with nonvalvular AF with CKD or treated with dialysis. The term end-stage CKD was used for patients with disease requiring renal replacement therapy, either dialysis or transplantation. Non–end-stage CKD was used for the remaining patients with renal disease. The intervention was anticoagulation. Comparisons were performed among the following groups: adjusted-dose warfarin (target international normalized ratio of 2 to 3) versus no treatment, aspirin or low dosage non–adjusted-dose warfarin (target international normalized ratio <1.5); warfarin versus novel oral anticoagulants; and novel oral anticoagulants versus aspirin. The outcome has been defined previously. Two independent reviewers (RP and SCB) screened all abstracts and titles to identify potentially eligible studies. The full text of these potentially eligible studies was then evaluated to determine the eligibility of the study for the review and meta-analysis. Disagreements regarding eligibility were resolved by consensus with the help of a third reviewer (SB). Data extraction and presentation for the preparation of this report followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group.7Moher D. Liberati A. Tetzlaff J. Altman D.G. PRISMA GroupPreferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement.Ann Intern Med. 2009; 151: 264-269Crossref PubMed Scopus (18837) Google Scholar The following data were extracted for characterizing each patient sample in the selected studies, whenever available: criteria for defining CKD, number of patients with CKD (and when available, number in each estimated glomerular filtration rate [eGFR] category of the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative classification8IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000.Am J Kidney Dis. 2001; 37: S182-S238Abstract Full Text Full Text PDF PubMed Google Scholar) or on dialysis in each study, and type and frequency of antithrombotic treatment (warfarin or other vitamin K antagonists, novel oral anticoagulants, aspirin, or other antiplatelet agents). Data were pooled using random effects, according to the Mantel-Haenszel model, through Review Manager (RevMan), version 5.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2011, Copenhagen, Denmark). The measurement of treatment effect and AF, CKD, or dialysis exposure was performed using dichotomous adjusted hazard ratios (HR) and 95% confidence intervals (CI). Pairwise comparisons were performed for the primary end point in the settings defined in the third paragraph of the Methods section. Comparison of the treatment effect of adjusted-dose warfarin versus the novel oral anticoagulants was performed through the use of risk ratios (number of events or the incidence in each treatment group) from randomized controlled trials. Additional sensitivity analyses were performed, whenever data were available, regarding end-stage CKD on dialysis treatment. Statistical heterogeneity on each outcome of interest was assessed and quantified using the Cochran Q test and the I2 statistic, respectively. The I2 statistic describes the percentage of total variation across studies due to heterogeneity rather than chance. Values of 50% are by convention classified low, moderate, and high degrees of heterogeneity, respectively. The presence of publication bias was evaluated through the use of funnel plots if the appropriate requisites concerning the minimum number of included studies in a forest plot were met (at least 10 studies).9Higgins J.P.T. Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011www.cochrane-handbook.orgGoogle Scholar Overall, 962 entries were retrieved for title and abstract analysis. Of these, 783 were excluded as they did not meet inclusion criteria for the meta-analysis and 106 were duplicate entries. The remaining 73 studies were carefully evaluated, and after full-text review, only 19 studies (all full-text reports) were finally considered eligible.2Go A.S. Fang M.C. Udaltsova N. Chang Y. Pomernacki N.K. Borowsky L. Singer D.E. ATRIA Study InvestigatorsImpact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.Circulation. 2009; 119: 1363-1369Crossref PubMed Scopus (354) Google Scholar, 5Olesen J.B. Lip G.Y. Kamper A.L. Hommel K. Køber L. Lane D.A. Lindhardsen J. Gislason G.H. Torp-Pedersen C. Stroke and bleeding in atrial fibrillation with chronic kidney disease.N Engl J Med. 2012; 367: 625-635Crossref PubMed Scopus (737) Google Scholar, 10Roldán V. Marín F. Manzano-Fernandez S. Fernández H. Gallego P. Valdés M. Vicente V. Lip G.Y. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation?.Thromb Haemost. 2013; 109: 956-960Crossref PubMed Scopus (97) Google Scholar, 11Roldán V. Marín F. Fernández H. Manzano-Fernández S. Gallego P. Valdés M. Vicente V. Lip G.Y. Renal impairment in a “real-life” cohort of anticoagulated patients with atrial fibrillation (implications for thromboembolism and bleeding).Am J Cardiol. 2013; 111: 1159-1164Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 12Banerjee A. Fauchier L. Vourc'h P. Andres C.R. Taillandier S. Halimi J.M. Lip G.Y. Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.J Am Coll Cardiol. 2013; 61: 2079-2087Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 13Friberg L. Rosenqvist M. Lip G.Y. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.Eur Heart J. 2012; 33: 1500-1510Crossref PubMed Scopus (892) Google Scholar, 14Friberg L. Benson L. Rosenqvist M. Lip G.Y. Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.BMJ. 2012; 344: e3522Crossref PubMed Scopus (210) Google Scholar, 15Eikelboom J.W. Connolly S.J. Gao P. Paolasso E. De Caterina R. Husted S. O'Donnell M. Yusuf S. Hart R.G. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.J Stroke Cerebrovasc Dis. 2012; 21: 429-435Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 16Connolly S.J. Eikelboom J. Joyner C. Diener H.C. Hart R. Golitsyn S. Flaker G. Avezum A. Hohnloser S.H. Diaz R. Talajic M. Zhu J. Pais P. Budaj A. Parkhomenko A. Jansky P. Commerford P. Tan R.S. Sim K.H. Lewis B.S. Van Mieghem W. Lip G.Y. Kim J.H. Lanas-Zanetti F. Gonzalez-Hermosillo A. Dans A.L. Munawar M. O'Donnell M. Lawrence J. Lewis G. Afzal R. Yusuf S. AVERROES Steering Committee and InvestigatorsApixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (2074) Google Scholar, 17Cha M.J. Oh G.C. Hahn S. Choi E.K. Oh S. Thromboembolic risk evaluation in patients with atrial fibrillation using a modified CHADS(2) scoring system.J Cardiovasc Electrophysiol. 2012; 23: 155-162Crossref PubMed Scopus (8) Google Scholar, 18Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7476) Google Scholar, 19Piccini J.P. Stevens S.R. Chang Y. Singer D.E. Lokhnygina Y. Go A.S. Patel M.R. Mahaffey K.W. Halperin J.L. Breithardt G. Hankey G.J. Hacke W. Becker R.C. Nessel C.C. Fox K.A. Califf R.M. ROCKET AF Steering Committee and InvestigatorsRenal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R2CHADS2 index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts.Circulation. 2013; 127: 224-232Crossref PubMed Scopus (443) Google Scholar, 20Hart R.G. Pearce L.A. Asinger R.W. Herzog C.A. Warfarin in atrial fibrillation patients with moderate chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 2599-2604Crossref PubMed Scopus (171) Google Scholar, 21Granger C.B. Alexander J.H. McMurray J.J. Lopes R.D. Hylek E.M. Hanna M. Al-Khalidi H.R. Ansell J. Atar D. Avezum A. Bahit M.C. Diaz R. Easton J.D. Ezekowitz J.A. Flaker G. Garcia D. Geraldes M. Gersh B.J. Golitsyn S. Goto S. Hermosillo A.G. Hohnloser S.H. Horowitz J. Mohan P. Jansky P. Lewis B.S. Lopez-Sendon J.L. Pais P. Parkhomenko A. Verheugt F.W. Zhu J. Wallentin L. ARISTOTLE Committees and InvestigatorsApixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6991) Google Scholar, 22Hohnloser S.H. Hijazi Z. Thomas L. Alexander J.H. Amerena J. Hanna M. Keltai M. Lanas F. Lopes R.D. Lopez-Sendon J. Granger C.B. Wallentin L. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.Eur Heart J. 2012; 33: 2821-2830Crossref PubMed Scopus (458) Google Scholar, 23Lai H.M. Aronow W.S. Kalen P. Adapa S. Patel K. Goel A. Vinnakota R. Chugh S. Garrick R. Incidence of thromboembolic stroke and of major bleeding in patients with atrial fibrillation and chronic kidney disease treated with and without warfarin.Int J Nephrol Renovasc Dis. 2009; 2: 33-37PubMed Google Scholar, 24Singer D.E. Chang Y. Borowsky L.H. Fang M.C. Pomernacki N.K. Udaltsova N. Reynolds K. Go A.S. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score.J Am Heart Assoc. 2013; 2: e000250Crossref Scopus (274) Google Scholar, 25Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. Pogue J. Reilly P.A. Themeles E. Varrone J. Wang S. Alings M. Xavier D. Zhu J. Diaz R. Lewis B.S. Darius H. Diener H.C. Joyner C.D. Wallentin L. RE-LY Steering Committee and InvestigatorsDabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (9166) Google Scholar, 26Hijazi Z. Hohnloser S.H. Oldgren J. Andersson U. Connolly S.J. Eikelboom J.W. Ezekowitz M.D. Reilly P.A. Siegbahn A. Yusuf S. Wallentin L. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY trial analysis.Circulation. 2014; 129: 961-970Crossref PubMed Scopus (333) Google Scholar The stepwise selection process is illustrated in Figure 1. There was complete agreement between investigators on the inclusion of all the selected trials. Information on risk stratification, study design, number of participants, and the main findings in each study are provided in Table 1. Following the predefined inclusion and exclusion criteria, ≤5 studies were included in each of the traced forest plots. Accordingly, no funnel plots were drawn.Table 1Selected studies for the systematic review: baseline information and main findingsAuthor, RefStudy Design, AcronymSample Size (pts)Intervention or Baseline Anti-thromboticsDialysis pts (%)HD/PDCKD pts (%)eGFR Cutoff (ml/min)Length of FUP (yrs)Association of CKD With Stroke and/or SEAnticoagulation in pts With CKDVariable OutcomeHR95% CIEndpointIntervention OutcomeHR95% CIRoldan10Roldán V. Marín F. Manzano-Fernandez S. Fernández H. Gallego P. Valdés M. Vicente V. Lip G.Y. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation?.Thromb Haemost. 2013; 109: 956-960Crossref PubMed Scopus (97) Google Scholar, 11Roldán V. Marín F. Fernández H. Manzano-Fernández S. Gallego P. Valdés M. Vicente V. Lip G.Y. Renal impairment in a “real-life” cohort of anticoagulated patients with atrial fibrillation (implications for thromboembolism and bleeding).Am J Cardiol. 2013; 111: 1159-1164Abstract Full Text Full Text PDF PubMed Scopus (101) Google ScholarProspectiveSingle-centerObservational978Acenocoumarol 100%NAeGFR 30–59, 28%eGFR <30, 3%Median2.4eGFRNS1.060.69–1.63Stroke or SE——Banerjee12Banerjee A. Fauchier L. Vourc'h P. Andres C.R. Taillandier S. Halimi J.M. Lip G.Y. Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project.J Am Coll Cardiol. 2013; 61: 2079-2087Abstract Full Text Full Text PDF PubMed Scopus (99) Google ScholarRetrospectiveRegional(4 hospitals)Observational5,912VKA 52.5%Antiplatelet 30.8%None 26.0%Baseline or FUP2.2%eGFR 30–59, 20.2%eGFR <30, 5.8%Mean2.5Renal impairmentNSeGFRNS1.060.75–1.491.090.84–1.41Stroke or SEStroke or SE——Olesen5Olesen J.B. Lip G.Y. Kamper A.L. Hommel K. Køber L. Lane D.A. Lindhardsen J. Gislason G.H. Torp-Pedersen C. Stroke and bleeding in atrial fibrillation with chronic kidney disease.N Engl J Med. 2012; 367: 625-635Crossref PubMed Scopus (737) Google ScholarRetrospectiveNationwideObservational132,372W 28.3%A 18.9%W + A 8.4%Baseline RRT 0.7%FUP RRT 1.0%(78%HD/15% PD)NAMaximum 12CKD (non-endstage)↑RRT↑1.491.38–1.591.831.57–2.14Stroke or SEStroke or SEWNS ↓ trendW↓0.840.69–1.010.440.26–0.76Friberg13Friberg L. Rosenqvist M. Lip G.Y. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.Eur Heart J. 2012; 33: 1500-1510Crossref PubMed Scopus (892) Google Scholar, 14Friberg L. Benson L. Rosenqvist M. Lip G.Y. Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.BMJ. 2012; 344: e3522Crossref PubMed Scopus (210) Google ScholarRetrospectiveNationwideObservational170,291W baseline 40%W baseline/FUP 47%NARenal disease≈6.0%Mean1.5Renal failure↑1.161.05–1.28Ischemic stroke/US/TIA/SE——Eikelboom15Eikelboom J.W. Connolly S.J. Gao P. Paolasso E. De Caterina R. Husted S. O'Donnell M. Yusuf S. Hart R.G. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.J Stroke Cerebrovasc Dis. 2012; 21: 429-435Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarConnolly16Connolly S.J. Eikelboom J. Joyner C. Diener H.C. Hart R. Golitsyn S. Flaker G. Avezum A. Hohnloser S.H. Diaz R. Talajic M. Zhu J. Pais P. Budaj A. Parkhomenko A. Jansky P. Commerford P. Tan R.S. Sim K.H. Lewis B.S. Van Mieghem W. Lip G.Y. Kim J.H. Lanas-Zanetti F. Gonzalez-Hermosillo A. Dans A.L. Munawar M. O'Donnell M. Lawrence J. Lewis G. Afzal R. Yusuf S. AVERROES Steering Committee and InvestigatorsApixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (2074) Google ScholarRCTAVERROES5,599Apixa vs A (1:1)5mg∗Apixa (from 5 mg bid to 2.5 mg bid) and Riva (from 20 mg od to 15 mg od) presented dose adjustment for patients with a certain degree of CKD. bid vs 81–324 mg odExclusion criteriaeGFR 30–60, 30.3%eGFR ≤30, 0.4%Mean1.1Stage III CKD↑1.6NA (p <0.01)Stroke or SEApixa vs A↓0.320.18–0.55Cha17Cha M.J. Oh G.C. Hahn S. Choi E.K. Oh S. Thromboembolic risk evaluation in patients with atrial fibrillation using a modified CHADS(2) scoring system.J Cardiovasc Electrophysiol. 2012; 23: 155-162Crossref PubMed Scopus (8) Google ScholarRetrospectiveSingle-centerObservational695W 26.0%A 61.4%None 12.5%NAeGFR <60, 20.8%Median5.5eGFR <60↑3.631.57–8.42Ischemic stroke/TIA/SEW↓0.390.16–0.99Patel18Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7476) Google ScholarPiccini19Piccini J.P. Stevens S.R. Chang Y. Singer D.E. Lokhnygina Y. Go A.S. Patel M.R. Mahaffey K.W. Halperin J.L. Breithardt G. Hankey G.J. Hacke W. Becker R.C. Nessel C.C. Fox K.A. Califf R.M. ROCKET AF Steering Committee and InvestigatorsRenal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R2CHADS2 index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts.Circulation. 2013; 127: 224-232Crossref PubMed Scopus (443) Google ScholarRCTROCKET-AF14,264Riva vs W (1:1)20 mg∗Apixa (from 5 mg bid to 2.5 mg bid) and Riva (from 20 mg od to 15 mg od) presented dose adjustment for patients with a certain degree of CKD. odExclusion criteriaeGFR <50, 20.7%Median1.9eGFR↑1.121.07–1.16Stroke or SERiva vs WNS0.880.65–1.19Hart20Hart R.G. Pearce L.A. Asinger R.W. Herzog C.A. Warfarin in atrial fibrillation patients with moderate chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 2599-2604Crossref PubMed Scopus (171) Google ScholarRCTSPAF-III1,936Low riskA 46.1%High risk 1:1W vs low W + A†Target INR in all RCT was 2.0 to 3.0, except in the A + low dose W arm of the SPAF-III trial, where a mean INR of 1.3 was achieved as a result of the daily 1 to 3 mg warfarin alongside with A 325 mg od. 53.9%NAeGFR 30–59, 41.6%eGFR ≤30, 1.5%Low riskMean 2High riskMean 1.1Stage III CKD(pts treated with A)↑2.01.2–3.3Ischemic stroke or SEW vs A + low W↓0.240.10–0.38Granger21Granger C.B. Alexander J.H. McMurray J.J. Lopes R.D. Hylek E.M. Hanna M. Al-Khalidi H.R. Ansell J. Atar D. Avezum A. Bahit M.C. Diaz R. Easton J.D. Ezekowitz J.A. Flaker G. Garcia D. Geraldes M. Gersh B.J. Golitsyn S. Goto S. Hermosillo A.G. Hohnloser S.H. Horowitz J. Mohan P. Jansky P. Lewis B.S. Lopez-Sendon J.L. Pais P. Parkhomenko A. Verheugt F.W. Zhu J. Wallentin L. ARISTOTLE Committees and InvestigatorsApixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6991) Google ScholarHohnloser22Hohnloser S.H. Hijazi Z. Thomas L. Alexander J.H. Amerena J. Hanna M. Keltai M. Lanas F. Lopes R.D. Lopez-Sendon J. Granger C.B. Wallentin L. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.Eur Heart J. 2012; 33: 2821-2830Crossref PubMed Scopus (458) Google ScholarRCTARISTOTLE18,201Apixa vs W (1:1)Exclusion criteriaeGFR ≤50, 16.6%eGFR ≤30, 1.5%Median1.8——Stroke or SEApixa vs WNS0.790.55–1.14Lai23Lai H.M. Aronow W.S. Kalen P. Adapa S. Patel K. Goel A. Vinnakota R. Chugh S. Garrick R. 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