Doença renal canada oral anticoagulant use in patients with chronic kidney disease how to choose and by Louize Lobato

Canadian Journal of Cardiology 30 (2014) 853e854

Editorial

Oral Anticoagulant Use in Patients With Chronic Kidney Disease: How to Choose, and the Importance of Empiric Human Data Cristopher T. Witt, MD,a,b and Jeff S. Healey, MD, MSca a

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada b

Aarhus University Hospital, Skejby, Denmark

See article by Sardar et al., pages 888-897 of this issue. Atrial fibrillation (AF) and venous thromboembolism are the 2 most common indications for chronic oral anticoagulation. Chronic kidney disease (CKD) of at least moderate severity is present in 15%-25% of patients with these conditions.1-4 The number of affected individuals will likely grow, because of the aging of our population and the growing number of individuals with hypertension and diabetes. The presence of CKD in these patients is associated with an increased risk of thromboembolic events, an increased risk of major bleeding, and important challenges for the selection of appropriate antithrombotic therapy, particularly since the introduction of the new oral anticoagulants (NOACs).5-7 However, large clinical trials provide abundant data regarding the safety and efficacy of NOACs among patients with mild or moderate CKD, which is nicely summarized in a meta-analysis by Sardar and colleagues in this issue of the Canadian Journal of Cardiology.8 Irrespective of the presence of AF, CKD is associated with an increased risk of stroke and death.6,9 In patients with AF, the presence of CKD might be associated with a similar increase in stroke risk as other factors in the Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) scheme.5,6 In addition to its association with AF and stroke, impaired renal function increases bleeding risk,10 and patients with AF or venous thromboembolism associated with CKD often do not receive anticoagulation because of concerns that bleeding risk might outweigh the potential benefits.2,11 This is particularly true among dialysis patients, in whom current AF guidelines do not advocate any oral anticoagulation, because of an unproven benefit for stroke prevention and a major bleeding rate of more than 10% per year with warfarin.7 Because patients with CKD are at high risk of thromboembolism and bleeding, and because of the different renal clearance of individual NOACs, physicians are seeking guidance regarding Received for publication June 9, 2014. Accepted June 12, 2014. Corresponding author: Dr Jeff S. Healey, Room C3-121, DBCVSRI Building, Hamilton Health Sciences, General Site, 237 Barton St East, Hamilton, Ontario L88L 2X2, Canada. Tel.: þ1-905-577-8004. E-mail: Jeff.Healey@phri.ca See page 854 for disclosure information.

the choice of optimal antithrombotic therapy in this large population of patients. There has been an intuitive preference for the use of warfarin in patients with moderate or severe CKD, because < 1% of the drug is excreted by the kidneys; substantially less than the 25% with apixaban, 66% with rivaroxaban, and 80% with dabigatran.12 However, there is evidence that in patients with CKD, smaller initial doses of warfarin and more frequent monitoring are required, and that bleeding rates are also increased.7,13 There is now a wealth of comparative efficacy data between warfarin and NOACs in patients with CKD, which is clearly summarized in the meta-analysis by Sardar et al.8 Somewhat surprisingly, their meta-analysis demonstrates fairly consistent results across studies, showing that in patients with mild or moderate CKD (estimated glomerular filtration rate [eGFR] of 30-50 mL/min), all NOACs are associated with decreased rates of thromboembolism compared with warfarin.8 Among patients with mild CKD (defined as an eGFR of between 50 and 79 mL/min), major bleeding was also significantly decreased in patients who received NOACs; however, in patients with moderate CKD (defined as an eGFR of between 30 and 49 mL/min) the overall bleeding rate was similar to warfarin, except in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, in which the risk was 50% less with apixaban. The results of this meta-analysis provide strong evidence to support the use of NOACs in patients with mild to moderate CKD. The number of patients included in these trials is many times greater than in the earlier warfarin studies,14 and baseline renal function was evaluated in a far more rigourous fashion. As well, in the trials of apixaban and rivaroxaban,1,12,15 the dose of NOAC was adjusted based on patient factors, including renal function. This was likely a significant factor in the observed safety of NOACs in patients with CKD. The large numbers of patients included in this metaanalyses offer the ability to accurately estimate the relative efficacy of NOACs and permits a meaningful evaluation of patient subgroups, such as those with mild and moderate CKD. However, the results might be oversimplified by pooling trials with different patient populations, different

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active and control therapies, and different methodologies for ascertaining outcomes. As such, the pooled estimates for the relative stroke and bleeding risks are perhaps less important than simply the simultaneous presentation of the results from all of the trials, which show a consistent trend. Current guidelines support the use of apixaban, dabigatran, and rivaroxaban among patients with mild or moderate CKD, provided that the appropriate dose is selected and renal function is monitored at least annually.7,16,17 However, apart from a small amount of data on apixaban,1,15 there is little evidence to support their use in patients with an eGFR of < 30 mL/min. The US Food and Drug Administration has approved dabigatran 75 mg twice per day for patients with an eGFR of 15-30 mL/min, and more recently, apixaban (2.5-5.0 mg twice per day) for endstage renal disease with hemodialysis, based on the pharmacokinetic and pharmacodynamic profiles.18,19 However, we should remain cautious about the use of these agents in patients with severe CKD, until there is published empiric human data to confirm their safety. We have seen the shortcomings of relying on pharmacokinetic data in the case of warfarin use in hemodialysis patients.7,13 We also must remember that hemodialysis patients are a very high-risk group for bleeding and thromboembolism, thus the risk-benefit ratio is critical for selecting the best therapy. Because of the paucity of data among hemodialysis patients with AF, current guidelines do not recommend any specific antithrombotic therapy for these patients. Sardar and colleagues have done us a good service, with their summary of the empiric evidence regarding anticoagulant use in patients with mild and moderate CKD.8 They show that in patients with mild CKD, all NOACs showed superior safety compared with warfarin and for patients with AF, superior efficacy. Thus, in patients with mild CKD, there is a clear benefit for NOACs compared with warfarin. For patients with moderate CKD and AF, there is a similar overall benefit for NOACs compared with warfarin for the prevention of thromboembolism. However; in terms of major bleeding, the NOACs appear to pose a similar risk as warfarin, with the exception of apixaban in the ARISTOTLE trial, which had a significantly decreased rate of major bleeding. Data like these will be the key for guiding therapy among the large and growing population of individuals with CKD. Similar data are urgently needed for patients with severe CKD, for whom no meaningful recommendations can be made at the present time. Disclosures J.S.H has received research grants and speaking fees from Boehringer-Ingelheim, Bristol-Meyers-Squibb, and Bayer. C.T.W. has no conflicts of interest to disclose. References 1. Granger CB, Alexander JH, McMurrary JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.

Canadian Journal of Cardiology Volume 30 2014 4. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) 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;127:224-32. 5. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol 2011;6:2599-604. 6. Go AS, Fang MC, Udaltsova N, et al. Impact 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;119:1363-9. 7. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36. 8. Sardar P, Chatterjee S, Herzog E, Nairooz R, Mukherjee D, Halperin JL. New oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials. Can J Cardiol 2014;30:888-97. 9. Di Angelantonio E, Chowdhury R, Sarwar N, et al. Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population-based cohort study. BMJ 2010;341:c4986. 10. Pavord S, Meyers B. Bleeding and thrombotic complications of kidney disease. Blood Rev 2011;25:271-8. 11. Genovesi S, Pogliani D, Faini A, et al. Prevalence of atrial fibrillation and associated factors in a population of long-term hemodialysis patients. Am J Kidney Dis 2005;46:897-902. 12. Patel MR, Mahaffey W, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. 13. Limdi NA, Limdi MA, Cavallari L, et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010;56:823-31. 14. Hart RG. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501. 15. Connolly SJ, Eieklboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17. 16. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the Amercian College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation, in press. 17. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.

2. Cook LM, Kahn SR, Goodwin J, Kovacs MJ. Frequency of renal impairment, advanced age, obesity and cancer in venous thromboembolism patients in clinical practice. J Thromb Haemost 2007;5:937-41.

18. U.S. Department of Health and Human Services. U.S. Food and Drug Administration. FDA Drug Safety Communication: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate). Available at: http://www.fda.gov/ Drugs/DrugSafety/ucm282724.htm. Accessed June 6, 2014.

3. Baber U, Howard VJ, Halperin JL, et al. Association of chronic kidney disease with atrial ﬁbrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circ Arrhythm Electrophsiol 2011;4:26-32.

19. U.S. Department of Health and Human Services. U.S. Food and Drug Administration. Eliquis (apixaban) 2.5 and 5 mg Tablets. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/ucm384790.htm. Accessed June 6, 2014.