Hindricks, Gerhard

Steffel, Jan

RERO DOC Digital Library

ESC CLINICAL TRIAL &REGISTRY UPDATE COMMENTARYApixaban in renal insufficiency: successfulnavigation between the Scylla and CharybdisJan Steffel1* and Gerhard Hindricks21Cardiac Arrhythmia Unit, Department of Cardiology, University Hospital Zurich, CH-8091 Zurich, Switzerland; and 2Department of Electrophysiology, University of Leipzig–HeartCenter, Leipzig, GermanyOnline publish-ahead-of-print 29 August 2012This editorial refers to ‘Efficacy of apixaban as comparedwith warfarin in relation to renal function in patients witha trial fibrillation: insights from the ARISTOTLE trial’†, byS.H. Hohnloser et al., on page 2821A changing landscape ofanticoagulationAnticoagulation for stroke prevention in atrial fibrillation has tradition-ally been performed by vitamin K antagonists. Although effectiveunder optimal conditions, the imminent risk of severe haemorrhageis a major cause for substantial underutilization of these drugs, evenin patients at high risk of thrombo-embolic events. The recent intro-duction of the direct thrombin inhibitor dabigatran, as well as the oralfactor Xa inhibitors rivaroxaban and apixaban (Figure 1) has resultedin a paradigm shift regarding the treatment of these patients. Whilelarge-scale clinical trials including Re-LY, ROCKET-AF, and ARIS-TOTLE have (essentially) all indicated superiority of the respectivesubstance compared with warfarin in stroke prevention, theseagents were equally shown to be superior with respect to bleedingevents, especially major, life-threatening, and intracranial haemor-rhage.1–3 The initial enthusiasm associated with these novel agentswas, however, dampened shortly after their introduction whenreports of major haemorrhages surfaced, indicating that an unre-stricted and injudicious use may put certain patients at an elevatedrisk for adverse events. Indeed, it quickly became clear thatespecially dabigatran, which is 80% renally cleared, has a significantpotential for severe bleeding in patients with reduced renal function.Anticoagulation in renalinsufficiency: caught betweenthe Scylla and CharybdisPatients with renal insufficiency, however, are problematic for anykind of anticoagulant treatment due to the increased risk for boththrombo-embolic and bleeding events in this situation.4 A recentcohort study once more identified reduced renal function as an in-dependent predictor of cerebral ischaemic events, with a continu-ous increase in risk with decreasing kidney function.5 This is evenfurther potentiated in patients with end-stage renal disease aswell as those on dialysis. In addition to the high prevalence ofco-morbidities predisposing for thrombo-embolic complicationssuch as hypertension, congestive heart failure, left atrial enlarge-ment, and diabetes, the inflammatory state of chronic kidneydisease as well as alterations of blood constituents and endothelialprotein expression collectively result in a prothrombotic state.6 Atthe same time, however, bleeding risk is equally increased in thesepatients, probably due to poorly or non-functional platelets,altered von Willebrand factor, and the presence of uraemictoxins.4,6 As such, the treating physician is even more than normal-ly caught between the Scylla and Charybdis when having to decidewhether or not—and if yes, how—to anticoagulate patients withatrial fibrillation and renal insufficiency. With the rising incidenceand prevalence of both diseases, this scenario is encounteredwith increasing frequency. Indeed, the co-prevalence of chronickidney disease and atrial fibrillation is reported to be as high as20%, and is likely to increase even further.7 To make things evenmore confusing, several studies have suggested that use ofvitamin K antagonists is even associated with an increased riskfor stroke in the extreme case of end-stage renal diseasepatients.8,9Apixaban in renal insufficiencyHohnloser and colleagues have now reported the pre-specifiedsubgroup analysis of the ARISTOTLE trial for patients withimpaired renal function.10 In the overall trial, apixaban was asso-ciated with a 22% reduction in stroke as well as a 31% reductionin major bleeding.3 Importantly, a reduced dose of apixaban (2 ×2.5 mg instead of the usual 2 × 5 mg) was given to patients withtwo of the following criteria: age ≥ 80 years, weight ≤ 60 kg, and* Corresponding author. Tel: +41 44 255 11 11, Fax: +41 44 255 42 51, Email: jan.steffel@usz.ch† doi:10.1093/eurheartj/ehs274.The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.comEuropean Heart Journal (2012) 33, 2766–2768doi:10.1093/eurheartj/ehs267serum creatinine ≥ 133 mmol/L (1.5 mg/dL). Baseline creatinineclearance was calculated according to the Cockcroft–Gault andChronic Kidney Disease Epidemiology Collaboration (CKD-EPI)equations as well as based on cystatin C measurements. Whencompared with warfarin, apixaban was superior in reducingstroke or systemic embolism, major bleeding, and mortality irre-spective of kidney function. As already indicated in the primarypublication, apixaban was associated with less major bleedingcompared with warfarin across all categories of renal dysfunction,but this reduction was significantly greater in patients with an esti-mated glomerular filtration rate (eGFR) ≤ 50 mL/min (as deter-mined by the Cockcroft–Gault equation of CKD-EPI, albeit notwhen based on cystatin C eGFR). The reason for the inconsistenteffects with the (in practice much less frequently used) cystatin-based eGFR calculation is not clear, but may be related toconfounding variables such as age. Importantly, the finding of astatistically significant greater reduction in major bleeding inpatients with impaired renal function implies a particularlypronounced benefit of apixaban compared with warfarin in thispatient population. Indeed, due to their iatrogenic nature, majorbleeding events are the single most prevalent reason why properanticoagulation is withheld in patients with atrial fibrillation,especially those with impaired renal function.Implications for daily clinicalpracticeShould every patient with atrial fibrillation and renal insufficiencyhence be anticoagulated with apixaban? How does apixabancompare with rivaroxaban and dabigatran in these patients? Unfor-tunately, comprehensive cross-trial comparisons with the othernovel anticoagulants are impossible to perform given—amongothers—the different study designs, different patient populations,and (partly) different bleeding definitions. Since all three trialscompared the respective novel agent with warfarin, it would beinteresting to compare matched subsets of patients from eachtrial; such data, however, are not yet available. Chronic kidneydisease certainly appears to be the ‘Achilles heel’ of dabigatran,as accumulation is likely to occur due to mainly renal elimination.Hence, in view of the available data, apixaban would probably bethe preferred agent over dabigatran in these patients. For rivarox-aban, a solid and valid comparison is virtually impossible given theabove-mentioned limitations. Data from large registries and fromreal-world use will provide additional evidence for further guid-ance. For the time being, the current data with apixaban certainlylook very promising for patients with renal impairment.The latter is particularly true for patients with moderatelyreduce renal function. It should be kept in mind, however, thatonly 1.5% of the included patients presented with an eGFR of ≤30 mL/min, and patients with a creatinine clearance ,25 mL/minor a serum creatinine .2.5 mg/dL (221 mmol/L) were a prioriexcluded from the study.3 The amount of data to support theuse of apixaban in patients with severe renal insufficiency ishence scarce. The problem, of course, in these patients is thelack of alternatives, as vitamin K antagonist treatment is equallyproblematic in this situation and subject to inherent limitationsand risks. Nevertheless, resorting to a familiar medication suchas the latter in the treatment of these particularly challengingFigure 1. Point of action of novel oral anticoagulants in the coagulation cascade. See text for details. VKA, vitamin K antagonist. Adapted fromSteffel and Braunwald.Commentary 2767patients is probably not the most unreasonable practice, especiallyuntil some familiarization has occurred during treatment of themany patients that otherwise qualify for apixaban. It should alsobe kept in mind that the results of Hohnloser et al. are based onbaseline creatinine/GFR, whereas serial measurements are not pro-vided. In contrast, in the real world and during longer treatmentperiods, renal function frequently worsens over time, especiallyin patients with various co-morbidities, necessitating individualadaptation of risk assessment and therapies.A key factor for the successful use of the novel anticoagulants istheir judicious application, especially in high-risk individuals. One ofthe most important aspects in this regard is to withstand the temp-tation to prescribe them in a ‘fill and forget’ manner, which is par-ticularly true for patients with reduced renal function. As expected,and consistent with previous studies, Hohnloser et al. found a gen-erally increased risk for events in these patients (stroke, majorbleeding, all-cause mortality) as compared with those withnormal kidney function. Hence, physicians are likely to see moreevents in their patients with renal dysfunction, independent ofthe way they are treated, just by virtue of them being at highrisk for any kind of event. Data from the study of Hohnloseret al. provide reassurance that patients with moderately reducedrenal function have a lower risk of major haemorrhage if treatedwith apixaban as compared with warfarin. Nevertheless, alsowith apixaban, regular follow-up of these high-risk patients, includ-ing early detection of renal function deterioration and adaptationof treatment, is crucial to successfully navigate between theScylla and Charybdis.In summary, this substudy of the ARISTOTLE trial provides solidevidence for the superiority of apixaban in patients with atrial fib-rillation and chronic kidney disease. In the light of these data, apix-aban appears to be a very appealing option for these individuals,potentially leading to a substantial increase in the numbers ofappropriately anticoagulated patients. Judicious use and vigilantfollow-up will be key to fully exploit the benefits of this therapy.Conflict of interest: J.S. has received consulting and/or speakers’fees from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim,Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis, and researchsupport from Bayer Healthcare.References1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A,Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D,Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabi-gatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.2. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G,Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF,Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxabanversus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.3. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M,Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD,Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S,Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS,Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; AR-ISTOTLE Committees and Investigators. Apixaban versus warfarin in patients withatrial fibrillation. N Engl J Med 2011;365:981–992.4. Marinigh R, Lane DA, Lip GY. Severe renal impairment and stroke prevention inatrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am CollCardiol 2011;57:1339–1348.5. Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L, Singer DE;ATRIA Atudy Investigators. Impact of proteinuria and glomerular filtration rate onrisk of thromboembolism in atrial fibrillation: the anticoagulation and risk factorsin atrial fibrillation (ATRIA) study. Circulation 2009;119:1363–1369.6. Reinecke H, Brand E, Mesters R, Schabitz WR, Fisher M, Pavenstadt H,Breithardt G. Dilemmas in the management of atrial fibrillation in chronickidney disease. J Am Soc Nephrol 2009;20:705–711.7. Soliman EZ, Prineas RJ, Go AS, Xie D, Lash JP, Rahman M, Ojo A, Teal VL,Jensvold NG, Robinson NL, Dries DL, Bazzano L, Mohler ER, Wright JT,Feldman HI, Chronic Renal Insufficiency Cohort Study Group. Chronic kidneydisease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort(CRIC). Am Heart J 2010;159:1102–1107.8. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates withincreased risk for stroke in hemodialysis patients with atrial fibrillation. J Am SocNephrol 2009;20:2223–2233.9. Niblett CL, Zagula KR, Calvert LA, Kendall TL, Stark DM, Smith CE, Beachy RN,Lommel SA. cDNA cloning and nucleotide sequence of the wheat streak mosaicvirus capsid protein gene. J Gen Virol 1991;72:499–504.10. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M,Lanas F, Lopes RD, Lopez-Sendon J, Granger GB, Wallentin L. Efficacy of apixabanwhen compared with warfarin in relation to renal function in patients withatrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821–2830.11. Steffel J, Braunwald E. Novel oral anticoagulants: focus on stroke prevention andtreatment of venous thrombo-embolism. Eur Heart J 2011;32:1968–1776,1976a.Commentary2768

Apixaban in renal insufficiency: successful navigation between the Scylla and Charybdis

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library