Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment
Abstract
AIMS: Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages. METHODS AND RESULTS: We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban. CONCLUSION: Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Rivaroxaban has 35% renal clearance.
“Renal clearance”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [426]
Cites
Prediction of Creatinine Clearance from Serum Creatinine
Cockcroft, D. W., & Gault, H. (2008) · The Nephron journals/Nephron journals · doi:10.1159/000180580 · Cited by 15,291 · see citing works
Dabigatran versus warfarin in patients with atrial fibrillation
Connolly, S. J., Ezekowitz, M. D., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., Pogue, J., Reilly, P. A., Themeles, E., Varrone, J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0905561 · Cited by 11,215 · see citing works
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation
Patel, 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., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1009638 · Cited by 9,430 · see citing works
Self-citationSchulman, S., & Kearon, C. (2005) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2005.01204.x · Cited by 5,025 · see citing works
Pisters, R., Lane, D. A., Nieuwlaat, R., de Vos, C. B., Crijns, H. J. G. M., & Lip, G. Y. H. (2010) · CHEST Journal · doi:10.1378/chest.10-0134 · Cited by 4,517 · see citing works
Schulman, S., Angerås, U., Bergqvist, D., ERIKSSON, B., Lassen, M. R., & FISHER, W. (2009) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2009.03678.x · Cited by 3,761 · see citing works
Apixaban in patients with atrial fibrillation
Connolly, S. J., Eikelboom, J., Joyner, C., Diener, H.-C., Hart, R., Golitsyn, S., Flaker, G., Avezum, A., Hohnloser, S. H., Diaz, R., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1007432 · Cited by 2,483 · cited 1× · see citing works
“3) and seen in unselected clinical practice.(10,11,30) Those with moderate renal insufficiency have higher CHADS2 values than patients without renal dysfunction (Table 1), hence the importance of testing the randomized comparison of rivaroxaban and warfarin in a population that included a substantial cohort with moder…”
BackgroundEffect of clopidogrel added to aspirin in patients with atrial fibrillation
The ACTIVE Investigators (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0901301 · Cited by 2,102 · see citing works
Hylek, E. M., Evans‐Molina, C., Shea, C., Henault, L. E., & Regan, S. (2007) · Circulation · doi:10.1161/circulationaha.106.653048 · Cited by 1,054 · see citing works
Underuse of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review
Ogilvie, I. M., Newton, N., Welner, S. A., Cowell, W., & Lip, G. Y. H. (2010) · The American Journal of Medicine · doi:10.1016/j.amjmed.2009.11.025 · Cited by 925 · see citing works
A New Risk Scheme to Predict Warfarin-Associated Hemorrhage
Fang, M. C., Go, A. S., Chang, Y., Borowsky, L. H., Pomernacki, N. K., Udaltsova, N. V., & Singer, D. E. (2011) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2011.03.031 · Cited by 853 · see citing works
Self-citationXimelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation
Albers, G. W., Diener, H., Frison, L., Grind, M., Nevinson, M., Partridge, S., Halperin, J. L., Horrow, J. C., Olsson, S. B., Petersen, P., et al. (2005) · JAMA · doi:10.1001/jama.293.6.690 · Cited by 674 · see citing works
Self-citationKubitza, D., Becka, M., Voith, B., Zuehlsdorf, M., & Wensing, G. (2005) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2005.06.011 · Cited by 646 · see citing works
Kubitza, D., Becka, M., Wensing, G., Voith, B., & Zuehlsdorf, M. (2005) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-005-0043-5 · Cited by 639 · see citing works
The Executive Steering Committee, O. B. O. T. R. A. S. I. (2010) · American Heart Journal · doi:10.1016/j.ahj.2009.11.025 · Cited by 476 · see citing works
Soliman, E. Z., Prineas, R. J., Go, A. S., Xie, D., Lash, J. P., Rahman, M., OJO, A. O., Teal, V. L., Jensvold, N. G., Robinson, N. L., et al. (2010) · American Heart Journal · doi:10.1016/j.ahj.2010.03.027 · Cited by 451 · see citing works
Kubitza, D., Becka, M., Mueck, W., Halabi, A., Maatouk, H., Klause, N., Lufft, V., Wand, D. D., Philipp, T., & Bruck, H. (2010) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2010.03753.x · Cited by 434 · see citing works
Waldo, A. L., Becker, R. C., Tapson, V. F., & Colgan, K. J. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.06.077 · Cited by 378 · see citing works
Self-citationAgnelli, G., Gallus, A., Goldhaber, S. Z., Haas, S., Huisman, M. V., Hull, R. D., Kakkar, A. K., Misselwitz, F., & Schellong, S. (2007) · Circulation · doi:10.1161/circulationaha.106.668020 · Cited by 337 · see citing works
Eriksson, B. I., Borris, L. C., Dahl, O. E., Haas, S. K., Huisman, M. V., Kakkar, A. K., Muehlhofer, E., Dierig, C., Misselwitz, F., & Kälebo, P. (2006) · Circulation · doi:10.1161/circulationaha.106.642074 · Cited by 333 · see citing works
Mueck, W., Lensing, A. W. A., Agnelli, G., Decousus, H., Prandoni, P., & Misselwitz, F. (2011) · Clinical Pharmacokinetics · doi:10.2165/11595320-000000000-00000 · Cited by 325 · see citing works
Kubitza, D., Becka, M., Roth, A., & Mueck, W. (2008) · Current Medical Research and Opinion · doi:10.1185/03007990802361499 · Cited by 268 · see citing works
BULLER, H., DEITCHMAN, D., PRINS, M., & SEGERS, A. (2008) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2008.03054.x · Cited by 252 · see citing works
Outcomes and predictors of very stable INR control during chronic anticoagulation therapy
Witt, D. M., Delate, T., Clark, N. P., Martell, C., Tran, T. S., Crowther, M. A., Garcia, D. A., Ageno, W., & Hylek, E. M. (2009) · Blood · doi:10.1182/blood-2009-02-207928 · Cited by 132 · see citing works
Quality of Care for Atrial Fibrillation Among Patients Hospitalized for Heart Failure
Piccini, J. P., Hernandez, A. F., Zhao, X., Patel, M. R., Lewis, W. R., Peterson, E. D., & Fonarow, G. C. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.091 · Cited by 130 · see citing works
Self-citationUse of anticoagulants in elderly patients: practical recommendations
Righini, M. (2009) · Clinical Interventions in Aging · doi:10.2147/cia.s4308 · Cited by 114 · see citing works
Heuzey, J. L., BREITHARDT, G. E., Camm, A. J., Crijns, H. J. G. M., Dorian, P., Kowey, P. R., Merioua, I., Prystowsky, E. N., Schwartz, P. J., Torp-Pedersen, C. T., et al. (2009) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2009.10.012 · Cited by 109 · see citing works
Johnston, J. A., Cluxton, R. J., Heaton, P. C., Guo, J. J., Moomaw, C. J., & Eckman, M. H. (2003) · Archives of Internal Medicine · doi:10.1001/archinte.163.14.1705 · Cited by 72 · see citing works
Rivaroxaban, an oral direct factor Xa inhibitor
Piccini, J. P., Patel, M. R., Mahaffey, K. W., Fox, K. A. A., & Califf, R. M. (2008) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.17.6.925 · Cited by 48 · see citing works
Self-citationKubitza, D., Becka, M., Wensing, G., et al. (2003) · Blood · Cited by 21 · see citing works
The HAS-BLED Score and Renal Failure
Vázquez, E., & Sánchez-Perales, C. (2011) · CHEST Journal · doi:10.1378/chest.10-2961 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
2013 ACCF/AHA Guideline for the Management of Heart Failure
Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Drazner, M. H., Fonarow, G. C., Geraci, S. A., Horwich, T., Januzzi, J. L., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.05.019 · Cited by 12,536 · see citing works
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
Kirchhof, P., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., Castella, M., Diener, H.-C., Heidbuchel, H., Hendriks, J., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw210 · Cited by 6,418 · see citing works
Meschia, J. F., Bushnell, C., Boden-Albala, B., Braun, L. T., Bravata, D. M., Chaturvedi, S., Creager, M. A., Eckel, R. H., Elkind, M. S. V., Fornage, M., et al. (2014) · Stroke · doi:10.1161/str.0000000000000046 · Cited by 2,650 · see citing works
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
Kirchhof, P., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., Castella, M., Diener, H.-C., Heidbuchel, H., Hendriks, J., et al. (2016) · European Journal of Cardio-Thoracic Surgery · doi:10.1093/ejcts/ezw313 · Cited by 1,403 · see citing works
Heidbuchel, H., Verhamme, P., Alings, M., Antz, M., Hacke, W., Oldgren, J., Sinnaeve, P., Camm, A. J., & Kirchhof, P. (2013) · Europace · doi:10.1093/europace/eut083 · Cited by 792 · see citing works
Hohnloser, S. H., Hijazi, Z., Thomas, L., Alexander, J. H., Amerena, J., Hanna, M., Keltai, M., Lanas, F., Lopes, R. D., Lopez-Sendon, J., et al. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehs274 · Cited by 574 · see citing works
Hijazi, Z., Hohnloser, S. H., Oldgren, J., Andersson, U., Connolly, S. J., Eikelboom, J. W., Ezekowitz, M. D., Reilly, P. A., Siegbahn, A., Yusuf, S., et al. (2014) · Circulation · doi:10.1161/circulationaha.113.003628 · Cited by 396 · see citing works
Goodman (2014) · doi:10.1016/j.jacc.2013.11.013 · Cited by 228 · see citing works
Albertsen, I. E., Rasmussen, L. H., Overvad, T. F., Graungaard, T., Larsen, T. B., & Lip, G. Y. H. (2013) · Stroke · doi:10.1161/strokeaha.113.000883 · Cited by 101 · see citing works
- Authors
- Fox, K. A. A., Piccini, J. P., Wojdyla, D., Becker, R. C., Halperin, J. L., Nessel, C. C., Paolini, J. F., Hankey, G. J., Mahaffey, K. W., Patel, M. R., Singer, D. E., & Califf, R. M.
- Affiliations
- University of Edinburgh (GB)
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-08-28
- Volume
- 32
- Issue
- 19
- Pages
- 2387-2394
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- OpenAlex
- W2148984742
- Cited by
- 608
- References
- 31
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 19 · 2023: 13 · 2022: 24 · 2021: 37 · 2020: 33 · 2019: 40 · 2018: 61 · 2017: 45 · 2016: 54 · 2015: 54 · 2014: 56 · 2013: 89 · 2012: 58
- FWCI
- 46.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Keywords
- rivaroxaban, warfarin, non-valvular atrial fibrillation, renal dysfunction, stroke prevention, systemic embolism, factor Xa inhibitors, intracranial hemorrhage, bleeding risk, creatinine clearance, anticoagulation, renal dose adjustment, RE-LY trial, ROCKET AF trial, PARAGON-HF trial
- MeSH terms
- Rivaroxaban, Aged, Aged, 80 and over, Anticoagulants, Atrial Fibrillation, Double-Blind Method, Embolism, Female, Hemorrhage, Humans, Male, Morpholines, Thiophenes, Warfarin, Treatment Outcome, Stroke, Renal Insufficiency
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
