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Editorial |

Treatment of Atrial Fibrillation in Patients With Chronic Kidney Disease: Is Stroke Prevention Worth the Risk? FREE TO VIEW

Farhan Shahid, MRCP; Eduard Shantsila, PhD; Gregory Y.H. Lip, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: G. Y. H. L. has participated in guideline membership/reviewing for various guidelines and position statements from ESC, EHRA, NICE etc; steering committees/trials, including steering committees for various phase II and III studies, Health Economics & Outcomes Research, etc; investigator in various clinical trials in cardiovascular disease, including those on antithrombotic therapies in atrial fibrillation, acute coronary syndrome, lipids, etc; consultant for Bayer/Jensen J&J, Astellas, Merck, Sanofi, BMS/Pfizer, Biotronik, Medtronic, Portola, Boehringer Ingelheim, Microlife and Daiichi-Sankyo; speaker for Bayer/Jensen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche, and Daiichi-Sankyo. None declared (F. S., E. S.).

CORRESPONDENCE TO: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, United Kingdom


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(4):891-892. doi:10.1016/j.chest.2015.09.026
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Atrial fibrillation (AF) and chronic kidney disease (CKD) commonly coexist in the same patient, and presence of AF does increase the relative risk of stroke in patients with CKD at least to the same extent as in those with normal renal function. Based on these considerations, stroke prevention with oral anticoagulation (OAC) appears essential in patients with AF and CKD. However, patients with CKD also have a higher risk of both intracranial and extracranial haemorrhage. A delicate balance is therefore needed to shift the overall risk-to-benefit ratio toward stroke prevention with minimal possible risk of harm from serious bleeding with OAC use. However, do we have sufficient evidence to suggest best practice in these settings? Unfortunately, there are no clinical trials to unambiguously answer this important question and insight from observational studies and meta-analyses are important.

FOR RELATED ARTICLE SEE PAGE 951

In this issue of CHEST (see page 951), Dahal et al provide a meta-analysis of studies that assessed the safety and efficacy of warfarin in patients with AF and with or without end-stage CKD. The analysis excluded subjects treated by nonvitamin K OACs (NOACs). In patients with mild-moderate CKD, administration of warfarin was associated with a reduced mortality rate without any significant excess in bleeding events. However, no obvious benefits were seen in patients with end-stage CKD and paralleled an increased incidence of bleeding complications. The last observation accords well with a prior meta-analysis conducted by Zimmerman et al.

The study by Dahal is well designed and includes standardization of renal function in the included participants aiming for minimization of heterogeneity of the study population. However, the study does not account for the time in therapeutic range (TTR) for warfarin users, which leaves a widely open question of whether patients with very severe CKD genuinely do not benefit from OAC or whether the treatment’s efficacy was hampered by suboptimal international normalized ratio (INR) control. In addition, there was a prominent heterogeneity among the patient cohorts that had data being extrapolated from nonrandomized studies, thus introducing a risk of bias.

From these data, what can we implement for the treatment of patients with AF and CKD? Admittedly, optimal antithrombotic management of patients with advanced CKD remains to be established. Patients with severe CKD have been excluded from the key randomized clinical trials of oral anticoagulation in AF. In fact, all NOACs are currently contraindicated in end-stage CKD, with limited information also provided by “real-world” observational studies. Appropriate use of warfarin mandates meticulous INR control, and suboptimal TTR has major implications for warfarin efficacy and safety.,, Careful INR control is particularly important in severe CKD. These patients seem to have reduced tolerance to INR fluctuations and possibly even a narrower therapeutic range. This is perhaps expected given the prominent disturbances in pro- and antithrombotic branches of the hemostatic system evident in severe CKD. Given that a typical patient with CKD has uncontrolled hypertension and is of an advanced age, it is not surprising that many subjects with renal dysfunction are placed into the category of patients with a high risk of bleeding.

Does it mean that OACs should not be used for stroke prevention in AF in individuals with CKD? Although robust evidence from randomized trials is lacking in this regard, observational data from health-care systems with efficient INR control do support OAC utilization. A large retrospective study from Sweden covering more than 13,000 patients with AF and CKD showed significant benefits of warfarin despite a higher bleeding risk, and the net benefit was lower than expected in patients with normal renal function. Despite a higher propensity for bleeding reflected by a hypertension, abnormal renal function, stroke, bleeding, labile INRs, elderly, drug therapy score of > 3, patients with renal failure still had a statistically significant reduction in ischemic stroke or death when warfarin was used. Of note, well-managed warfarin was associated with a low risk of intracranial bleeding, the most feared complication of OAC.

NOACs have not been specifically tested in severe renal dysfunction because the randomized trials excluded AF patients with creatinine clearance < 30 mL/min (< 25 mL/min for apixaban). Based on clinical pharmacology, some of the NOACs have been licensed for stroke prevention in AF in patients with a creatinine clearance of 15 to 30 mL/min, but because these patients were not included in randomized trials, NOACs’ efficacy and safety remain uncertain. In the large Food and Drug Administration Medicare analysis by Graham et al, dabigatran 75 mg bid (licensed in United States for patients with creatine clearance 15-30 mL/min) showed similar relative efficacy and safety outcomes in relation to dabigatran 150 mg bid when compared with warfarin. Of interest, indirect comparisons of NOACs in patients with moderate CKD were suggestive of apixaban and edoxaban having a more favorable safety profile in this category of patients.

At present, it is recommended that anticoagulation is beneficial in patients with AF and mild-moderate CKD. In those with severe CKD, warfarin may still be beneficial, providing that very meticulous attention to TTR is given and a TTR > 70% is maintained. NOACs should be used with caution in patients with CKD, given the lack of trial outcome data in those with creatinine clearance < 25 to 30 mL/min. The best practice of NOAC use in end-stage CKD on dialysis is still to be established, and the meta-analysis by Dahal highlights existence of a “gray area” in this regard. Although apixaban 5 mg bid is licensed by the Food and Drug Administration in such patients, further evidence in needed to support routine use of apixaban for this indication. Dabigatran is removed by hemodialysis, which provides a mechanism of fast drug removal in case of bleeding, but this possibly reduces stroke protection in the peridialysis period. All other NOACs are contraindicated in patients with creatine clearance < 15 mL/min. We should remember that all the NOACs have a degree of renal excretion, with the highest seen for dabigatran; regular monitoring of renal function and clinical follow-up are necessary. Further research on anticoagulation strategies in patients with AF and severe (or end-stage) CKD is essential.

References

Marinigh R. .Lane D.A. .Lip G.Y. . Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol. 2011;57:1339-1348 [PubMed]journal. [CrossRef] [PubMed]
 
Olesen J.B. .Lip G.Y. .Kamper A.L. .et al Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367:625-635 [PubMed]journal. [CrossRef] [PubMed]
 
Dahal K. .Sumit K. .Jharendra R. .Schulman P. .Lee J. . Stroke, major bleeding and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease: a meta-analysis of observational studies. Chest. 2016;149:951-959 [PubMed]journal. [CrossRef] [PubMed]
 
Zimmerman D. .Sood M.M. .Rigatto C. .Holden R.M. .Hiremath S. .Clase C.M. . Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis. Nephrol Dial Transplant. 2012;27:3816-3822 [PubMed]journal. [CrossRef] [PubMed]
 
De Caterina R. .Husted S. .Wallentin L. .et al Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;110:1087-1107 [PubMed]journal. [CrossRef] [PubMed]
 
Gallego P. .Roldan V. .Marin F. .et al Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost. 2013;110:1189-1198 [PubMed]journal. [CrossRef] [PubMed]
 
Sjogren V. .Grzymala-Lubanski B. .Renlund H. .et al Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula. Thromb Haemost. 2015;113:1370-1377 [PubMed]journal. [CrossRef] [PubMed]
 
Friberg L. .Benson L. .Lip G.Y. . Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J. 2015;36:297-306 [PubMed]journal. [CrossRef] [PubMed]
 
Hylek E.M. .Ko D. .Cove C.L. . Gaps in translation from trials to practice: non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost. 2014;111:783-788 [PubMed]journal. [CrossRef] [PubMed]
 
Graham D.J. .Reichman M.E. .Wernecke M. .et al Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015;131:157-164 [PubMed]journal. [CrossRef] [PubMed]
 
Nielsen P. .Lane D. .Rasmussen L. .Lip G.H. .Larsen T. . Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol. 2015;104:418-429 [PubMed]journal. [CrossRef] [PubMed]
 
Turagam M.K. .Addepally N.S. .Velagapudi P. . Novel anticoagulants for stroke prevention in atrial fibrillation and chronic kidney disease. Expert Rev Cardiovasc Ther. 2013;11:1297-1299 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Marinigh R. .Lane D.A. .Lip G.Y. . Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol. 2011;57:1339-1348 [PubMed]journal. [CrossRef] [PubMed]
 
Olesen J.B. .Lip G.Y. .Kamper A.L. .et al Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367:625-635 [PubMed]journal. [CrossRef] [PubMed]
 
Dahal K. .Sumit K. .Jharendra R. .Schulman P. .Lee J. . Stroke, major bleeding and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease: a meta-analysis of observational studies. Chest. 2016;149:951-959 [PubMed]journal. [CrossRef] [PubMed]
 
Zimmerman D. .Sood M.M. .Rigatto C. .Holden R.M. .Hiremath S. .Clase C.M. . Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis. Nephrol Dial Transplant. 2012;27:3816-3822 [PubMed]journal. [CrossRef] [PubMed]
 
De Caterina R. .Husted S. .Wallentin L. .et al Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;110:1087-1107 [PubMed]journal. [CrossRef] [PubMed]
 
Gallego P. .Roldan V. .Marin F. .et al Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost. 2013;110:1189-1198 [PubMed]journal. [CrossRef] [PubMed]
 
Sjogren V. .Grzymala-Lubanski B. .Renlund H. .et al Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula. Thromb Haemost. 2015;113:1370-1377 [PubMed]journal. [CrossRef] [PubMed]
 
Friberg L. .Benson L. .Lip G.Y. . Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J. 2015;36:297-306 [PubMed]journal. [CrossRef] [PubMed]
 
Hylek E.M. .Ko D. .Cove C.L. . Gaps in translation from trials to practice: non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost. 2014;111:783-788 [PubMed]journal. [CrossRef] [PubMed]
 
Graham D.J. .Reichman M.E. .Wernecke M. .et al Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015;131:157-164 [PubMed]journal. [CrossRef] [PubMed]
 
Nielsen P. .Lane D. .Rasmussen L. .Lip G.H. .Larsen T. . Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol. 2015;104:418-429 [PubMed]journal. [CrossRef] [PubMed]
 
Turagam M.K. .Addepally N.S. .Velagapudi P. . Novel anticoagulants for stroke prevention in atrial fibrillation and chronic kidney disease. Expert Rev Cardiovasc Ther. 2013;11:1297-1299 [PubMed]journal. [CrossRef] [PubMed]
 
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