The Quandary of Oral Anticoagulation in Patients With Atrial Fibrillation and Chronic Kidney Disease

The Quandary of Oral Anticoagulation in Patients With Atrial Fibrillation and Chronic Kidney Disease

Accepted Manuscript The Quandary of Oral Anticoagulation in Patients with Atrial Fibrillation and Chronic Kidney Disease Shmuel Schwartzenberg, MD, El...

298KB Sizes 0 Downloads 56 Views

Accepted Manuscript The Quandary of Oral Anticoagulation in Patients with Atrial Fibrillation and Chronic Kidney Disease Shmuel Schwartzenberg, MD, Eli I. Lev, MD, Alik Sagie, MD, Asher Korzets, MB, BS, Ran Kornowski, MD PII:

S0002-9149(15)02258-4

DOI:

10.1016/j.amjcard.2015.10.065

Reference:

AJC 21534

To appear in:

The American Journal of Cardiology

Received Date: 9 September 2015 Revised Date:

25 October 2015

Accepted Date: 30 October 2015

Please cite this article as: Schwartzenberg S, Lev EI, Sagie A, Korzets A, Kornowski R, The Quandary of Oral Anticoagulation in Patients with Atrial Fibrillation and Chronic Kidney Disease, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.10.065. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1

The Quandary of Oral Anticoagulation in Patients with Atrial Fibrillation and Chronic

RI PT

Kidney Disease

Shmuel Schwartzenberg1, MD, Eli I. Lev1, MD, Alik Sagie1, MD,

SC

Asher Korzets2, MB, BS, and Ran Kornowski1, MD

The Departments of Cardiology1 and Nephrology2, Rabin Medical Center,

M AN U

Beilinson & Hasharon Hospitals, Petach Tikva, Israel

Disclosures: no conflict of interest or disclosure

TE D

Address for Correspondence: Shmuel Schwartzenberg, MD Department of Cardiology,

Jabotinsky 39 St.

EP

Rabin Medical Center, Beilinson Hospital,

AC C

Petach Tikva 4941492, Israel Tel: 972-3-9377056

Fax: 972-3-9377055

e-mail: [email protected]

ACCEPTED MANUSCRIPT 2

Abstract Compared to patients with normal renal function, the prevalence of atrial fibrillation (AF) in

RI PT

chronic kidney disease (CKD) is increased, as is consequently the stroke prevalence in these patients. This increased risk of stroke in CKD patients is caused not only by the increased prevalence of AF, but also by associated comorbidities, and inherent platelet and vascular

SC

dysfunction. Paradoxically, imbalance in the same factors also increases the bleeding risk,

imposing a dilemma as to whether anticoagulation should be prescribed or deferred, particularly

M AN U

in patients with end stage renal disease (ESRD), in whom the bleeding diathesis and thromboembolic predisposition are most recalcitrant. Unfortunately, it is in this vulnerable population, in whom therapeutic options are most limited, that evidence-based studies relating to stroke prophylaxis are scarce, discordant, and based only on registry observations. Pending randomized-controlled studies on this issue, we will review important epidemiologic data and

TE D

major recent registry-based studies that the clinician has to weigh when making the best decision on the issue of the prophylactic use of warfarin in CKD patients with AF, focusing on ESRD

EP

patients.

AC C

Key words: chronic renal failure, end-stage renal disease, atrial fibrillation, warfarin, NOACs, anticoagulation

ACCEPTED MANUSCRIPT 3

Introduction In the current review, we will examine relevant epidemiologic data and considerations in an

RI PT

attempt to help the clinician make the best decision on the issue of the prophylactic use of anticoagulation in CKD patients with AF. We will focus the discussion on patients with ESRD (dialysis-dependent and non-dialysis dependent patients with glomerular filtration rate (GFR) ≤

SC

15 ml/min) and patients with severe CKD (with GFR 15-30 ml/min). CKD and atrial fibrillation

M AN U

The prevalence of AF in CKD patients is 15-20% in various studies, and it increases with age, markedly exceeding that of the general population in all age groups1. Indeed, 13% of US HD patients aged 65–75 years; 19% of those aged 75–85 years; and 23% of those over 85 years have a history of AF2. In a large meta-analysis, the overall prevalence of AF in patients with

TE D

ESRD treated with HD or peritoneal dialysis was 11.6% and the overall incidence was 2.7/100 patient-years3. In a large survey comprising almost 2.5 million US outpatients with AF aged 65 years old or above, CKD was an associated comorbidity in 32% of the subjects (see

EP

http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-

AC C

Reports/Chronic-Conditions/Downloads/2012Chartbook.pdf). CKD and Thromboembolism CKD is associated with low-grade inflammation, endothelial dysfunction, and platelet

activation, all of which confer an increased thromboembolic risk4. Vascular calcification, arterial stiffness and hypertension, which are all associated with CKD, appear to play an additional role in the increased risk for stroke5. Indeed, multiple studies have confirmed CKD as an independent risk factor for stroke after adjustments for conventional risk factors1,6,7. A recent

ACCEPTED MANUSCRIPT 4

large meta-analysis comprising 63 cohort studies and 20 randomized control studies found an inverse linear relationship between GFR and stroke risk, with risk of stroke increasing 7% (RR:

RI PT

1.07, CI: 1.04-1.09) for every 10 mL/min/1.73 m2 decrease in GFR8. CKD and Bleeding

The risk of bleeding in CKD is clearly increased as a result of thrombocytopathy, caused

SC

by uremic toxins that inhibit release of platelet factors including serotonin and thromboxane resulting in inhibition of their adhesion and aggregation ability, and impaired glycoprotein IIb-

M AN U

IIIa receptor activation and its binding to fibrinogen and von Willebrand factor9. Enhanced production of nitric oxide and prostacyclin due to endothelial dysfunction also act to inhibit platelet adhesion and aggregation respectively10. Bleeding has been reported in 40–50% of patients with chronic renal failure or on haemodialysis (HD)11. Clinically, there is an increased

TE D

risk of gastrointestinal bleeding and intracerebral hemorrhage in CKD patients6,12,13,14. “Net clinical benefit” of warfarin anticoagulation in atrial fibrillation and ESRD The concept of “net clinical benefit” aims to balance the risks of ischemic stroke and

EP

bleeding on oral anticoagulation (OAC) therapy and has been facilitated by registry data. The

AC C

latest 2012 focused update of the ESC Guidelines for the management of atrial fibrillation15 advocates using the CHA2DS2-VASc score (Congestive heart failure/left ventricular dysfunction, Hypertension, Age ≥75 [doubled], Diabetes, Stroke [doubled] – Vascular disease, Age 65–74, and Sex category [female]) for determining thromboembolic risk in AF patients, with a score threshold ≥ 2 for administering anticoagulation, but makes no definitive recommendation for ESRD patients. Of note, this score was derived from non-renal patients and may not be valid in ESRD16. The ESC Guidelines also recommend a formal bleeding risk assessment for all patients

ACCEPTED MANUSCRIPT 5

with AF, and in patients with a HAS-BLED17 [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (e.g. age .65, frailty, etc.), Drugs/alcohol concomitantly], score ≥3, caution is appropriate, and efforts to correct potentially

RI PT

reversible risk factors for bleeding are warranted. This recommendation is all the more pertinent in most of the elderly ESRD patients as they will have a high HAS-BLED score. The latest 2014 AHA/ACC Guidelines for the management of atrial fibrillation18 state that “for patients with

SC

nonvalvular AF with a CHA2DS2-VASc score ≥ 2 and who have end-stage CKD (creatinine clearance [CrCl] <15 mL/min) or are on HD, it is reasonable to prescribe warfarin (INR 2.0 to

M AN U

3.0) for oral anticoagulation”. This recommendation in the AHA/ACC Guidelines is based solely on a medium-sized prospective cohort study published in 2011 by Winkelmayer et al19. The cohort consisted of 2313 HD patients > 65 years old with new AF who survived 30 days after hospital discharge. Comparing 237 warfarin users and 948 propensity-matched nonusers over

TE D

2287 person-years of follow-up, the occurrence of ischemic stroke was similar (HR=0.92; 95% CI, 0.61 to 1.37), whereas warfarin users experienced twice the risk of hemorrhagic stroke (HR=2.38; 95% CI, 1.15 to 4.96). The risks of stroke, gastrointestinal hemorrhage, and mortality

EP

did not differ between groups. Analyses restricted to patients with CHADS2 score ≥2 yielded similar findings. The recommendation accorded to warfarin use in these patients is surprising

AC C

considering that the results of this particular study on which it was based do not indicate that warfarin-treated HD patients fared any better and considering the fact that additional large registry-based studies were published in recent years looking at this issue which were not accounted for in the AHA/ACC AF guidelines1,6,7,12,13,20,21. The study populations and number of patients in each of these studies is detailed in tables1 and 2. Mortality, ischemic stroke risk

ACCEPTED MANUSCRIPT 6

and overall stroke risk (ischemic and hemorrhagic) with warfarin treatment in patients with ESRD are presented in Figures 1-3 for these studies when respective data was available.

RI PT

Studies showing net clinical risk for warfarin anticoagulation in AF and ESRD: In a retrospective cohort study of 1671 patients with ESRD and coexisting atrial

fibrillation, warfarin use was associated with a statistically increased incidence of ischemic and

SC

hemorrhagic stroke21. Warfarin users who received no INR monitoring in the first 90 days of dialysis had the highest risk for stroke compared with non-users. Warfarin use did not associate

INR control were not determined.

M AN U

with statistically significant increases in all-cause mortality or hospitalization. Bleeding risk and

Using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS), Wizemann et al. also reported that in HD patients with AF anticoagulation with

TE D

warfarin was associated with an increased incidence of stroke especially in patients older than 75 years of age1. The limitations of this study included data collection exclusively through questionnaires, potentially inducing inaccuracy in AF detection; combining both ischemic and

EP

hemorrhagic stroke for stroke outcome; and lack of bleeding risk assessment.

AC C

Another negative retrospective cohort study was recently published by a Canadian group13. They showed that in 1626 dialysis patients with AF, warfarin use, in comparison with no-warfarin use, did not reduce the risk for stroke but was associated with a 44% higher adjusted hazard ratio for a bleeding event, whereas warfarin use in nondialysis patients with AF was associated with a 13% lower adjusted hazard ratio for stroke and only a 19% higher hazard ratio for bleeding event. Propensity score–adjusted analyses yielded similar results. INR levels were not available in this study.

ACCEPTED MANUSCRIPT 7

Studies showing net clinical benefit for warfarin anticoagulation in AF and ESRD: A large Danish registry study published in 2012 assessed the risk of stroke or systemic

RI PT

thromboembolism and bleeding associated in AF patients with non end-stage CKD and on renalreplacement therapy (i.e. dialysis or kidney transplant patients) versus AF patients without renal disease6. Warfarin treatment was associated with a significantly decreased risk of stroke or

SC

systemic thromboembolism in patients requiring renal-replacement therapy (HR=0.44; 95% CI, 0.26 to 0.74) with a nonsignificantly decreased risk among patients with non–end-stage CKD

M AN U

(HR=0.84; 95% CI, 0.69 to 1.01). The risk of bleeding among both of the CKD groups was significantly increased (HR=1.33, 95% CI 1.16 to 1.53). Criticisms of this study included lack of information on INR control and analyzing all patients with different exposures to heparin and different renal function in the renal-replacement therapy group (i.e. HD, peritoneal dialysis and

TE D

kidney transplant patients) as a homogenous group.

A more extended study based on the same national registry of non-valvular AF patients discharged from Danish hospitals between 1997-2011 was recently published, looking at the

EP

same group categories and using the same design7. In non end-stage CKD patients with CHA2DS2-VASc score ≥ 2, warfarin was associated with a net clinical benefit, as it was

AC C

associated with a lower risk of all-cause mortality (HR=0.64, 95% CI 0.6 to 0.69) , a lower risk of cardiovascular death (HR=0.8, 95% CI 0.74-0.88), and a lower risk of the composite outcome of fatal stroke/fatal bleeding (HR=0.71, 95% CI 0.57 to 0.88), respectively. In renal-replacement therapy patients with CHA2DS2-VASc score ≥ 2, warfarin was associated with a net clinical benefit and with a lower risk of all-cause mortality (HR=0.85, 95% CI 0.72 to 0.99). A nonsignificant trend toward a lower risk of cardiovascular death and a composite outcome of fatal stroke/fatal bleeding was also observed in this later group.

ACCEPTED MANUSCRIPT 8

A large observational multicenter cohort study (SWEDEHEART) among 24137 survivors of MI with AF and known creatinine levels discharged between 2003-2010 from Swedish hospitals of whom 21.8% were prescribed warfarin at discharge, was recently

RI PT

published20. In multivariate analysis, warfarin was associated with a lower 1 year composite outcome of death, myocardial infarction, and ischemic stroke without a higher risk of bleeding in strata of patients with moderate, severe, or end-stage CKD (i.e. GFR 30-60, 15-30, and ≤ 15

SC

ml/min respectively). However, since the number of patients with end-stage CKD was low (478 or 3.8% of total patients with CKD), caution in generalization of the results in this later sub-

M AN U

group is warranted.

Finally, another large registry study recently published identified patients with a diagnosis of AF with or without CKD at Swedish hospitals and affiliated clinics12. Ischemic stroke occurred more often in AF patients with CKD, but upon multivariate analysis it was

TE D

determined that this was related to more prevalent concomitant comorbidities. Although CKD was an independent risk factor for intracranial bleeding [adjusted HR: 1.27 (1.09–1.49)], the majority of patients with CKD benefited from warfarin treatment: the incidence of the combined

EP

endpoint (ischaemic or haemorrhagic stroke or death) was lower among those who used warfarin

AC C

than among those who did not use warfarin (adjusted HR: 0.76, CI 0.72–0.80). A major limitation of all the Scandinavian studies that showed a net clinical benefit for

warfarin in CKD patients with AF is lack of information on INR control. A high percentage of time in the therapeutic range (TTR) of at least 70% is critical for achieving stroke prevention with warfarin therapy in atrial fibrillation22. Indeed, in the latest Swedish registry study12, information about TTR values in warfarin-treated patients was available in less than 10% of patients, and for these patients the mean TTR was 66.7%. Patients with renal failure and TTR ≥

ACCEPTED MANUSCRIPT 9

70% suffered fewer strokes and bleedings than patients with lower TTR, but the differences were not statistically significant, due to lack of statistical power. As noted in the SWEDEHEART registry study20, the lack of increase in bleeding risk with warfarin in patients with ESRD and AF

RI PT

versus patients with AF and normal renal function in the Swedish studies12,20, as opposed to the increased bleeding risk in similar patients in other studies6,13,19 can be attributed to the excellent

SC

warfarin titration in Sweden.

New oral anticoagulants as alternatives to warfarin in atrial fibrillation and CKD

M AN U

Recent studies comparing novel oral anticoagulants (NOACs) including a direct thrombin inhibitor (dabigratan) and factor Xa inhibitors (apixaban and rivaroxaban and edoxaban) versus warfarin in patients with AF have demonstrated at least similar, if not greater, risk reductions in stroke and systemic embolic events without increased risk of bleeding, in both the general

TE D

population and in patients with non end-stage CKD in subgroup analysis23,24,25,26,27,28,29. It is important to note that these studies excluded patients with severe CKD: patients with CrCl < 30 ml/min were excluded from the RE-LY trial23 with dabigratan, from the ROCKET AF and J-

EP

ROCKET AF trials with rivaroxaban24,28, from the ENGAGE-AF TIMI 48 trial with endoxaban29 ; and patients with CrCl < 25 ml/min or serum creatinine > 2.5 mg/ml were

AC C

excluded from the ARISTOTLE25 and AVERROES30 trials with apixaban. In addition, patients with mechanical heart valves or hemodynamically significant mitral stenosis were also excluded from all 4 major trials (RE-LY, ROCKET AF, J-ROCKET AF, ARISTOTLE and ENGAGEAF). Table 3 summarizes sub-group analysis of main outcomes in the CKD participants in recent trials of NOACs in patients with AF. A meta-regression analyses on NOACs versus warfarin supplemented with indirect comparisons that included all these trials except AVERROES was

ACCEPTED MANUSCRIPT 10

recently published31. This analyses found that NOACs had similar efficacy and safety compared to warfarin across different levels of renal function.

RI PT

Until recently, the only approved anticoagulant in patients with ESRD was warfarin, but in 2014 the FDA approved a labeling change for apixaban to include dosing and pharmacokinetics in subjects with end-stage renal disease maintained on HD

SC

(www.accessdata.fda.gov/drugsatfda_docs/label/2014/202155s009lbl.pdf). By extrapolation of pharmacokinetic data, the FDA has approved low dose dabigatran for patients with CKD stage 4

M AN U

(GFR 15-30 ml/min); although it bears emphasis that there is lack of clinical evidence to support this dose (http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm250657.htm). Catheter-based Left Atrial Appendage Occlusion Devices A detailed discussion of these devices is beyond the scope of this review. In the recent

TE D

past years, left atrial appendage (LAA) mechanical occlusion has emerged as a potential alternative to OAC to reduce the risk of AF-related stroke without a concomitant increase in bleeding risk. In particular, the European Heart Rhythm Association (EHRA) has recently

EP

published a consensus statement advocating the use of LAA occlusion in patients with ESRD after performance of an individualized risk/benefit analysis for OACs32. Currently, the most

AC C

popular devices are the WATCHMAN device (Boston Scientific) and the Amplatzer Cardiac Plug (ACP). The WATCHMAN device remains the only device studied in randomized trials33,34. It has been approved in the US in 2013 by the Food and Drug Administration (FDA) as an alternative to OAC-eligible patients. A recent large European multicenter study has shown high procedural success and a favorable outcome for prevention of ischemic stroke with the ACP device35, but this device has not been approved yet in the US.

ACCEPTED MANUSCRIPT 11

Conclusion Given the multiple considerations involved in CKD patients with AF, it is best to follow

RI PT

the advice of Hippocrates: “It is more important to know what sort of person has a disease than to know what sort of disease a person has”. When deciding on prescribing warfarin in CKD patients with AF, we should separate between those patients with an absolute indication for

SC

warfarin usage besides the presence of AF (such as having a mechanical heart valve) or

prohibitive contraindications (i.e. very high bleeding risk) in whom there is a consensus

M AN U

regarding warfarin treatment, and CKD patients with a CHA2DS2-VASC score ≥ 2. In the latter group, particularly when renal function is severely reduced, the clinical dilemmas should be worked out through close collaboration between the treating cardiologist and nephrologist. Shared decision-making taking into account the patient’s preferences in such cases is strongly advocated. Based on the different studies we have hereby reviewed, we believe that warfarin

TE D

should be strongly considered in these patients at high thromboembolic risk and acceptable

AC C

EP

bleeding risk, aiming at an optimal TTR as defined as > 70% if achievable.

ACCEPTED MANUSCRIPT 12

1. Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young EW, Robinson BM. Atrial fibrillation in hemodialysis patients: clinical features and associations with

RI PT

anticoagulant therapy. Kidney Int 2010;77:1098–1106.

2. Winkelmayer WC, Patrick AR, Liu J, Brookhart MA, Setoguchi S. The increasing prevalence of atrial fibrillation among hemodialysis patients. J Am Soc Nephrol 2011;22:349–357.

SC

3. Zimmerman D, Sood MM, Rigatto C, Holden RM, Hiremath S, Clase CM. Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on

M AN U

dialysis. Nephrol Dial Transplant 2012;27:3816–3822.

4. Landray MJ, Wheeler DC, Lip GYH, Newman DJ, Blann AD, McGlynn FJ, Ball S, Townend JN, Baigent C. Inflammation, endothelial dysfunction, and platelet activation in patients with

Dis 2004;43:244–253.

TE D

chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study. Am J Kidney

5. Ohishi M, Tatara Y, Ito N, Takeya Y, Onishi M, Maekawa Y, Kato N, Kamide K, Rakugi H.

EP

The combination of chronic kidney disease and increased arterial stiffness is a predictor for

AC C

stroke and cardiovascular disease in hypertensive patients. Hypertens Res 2011;34:1209–1215.

6. Olesen JB, Lip GYH, Kamper A-L, Hommel K, Køber L, Lane D a., Lindhardsen J, Gislason GH, Torp-Pedersen C. Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease. N Engl J Med 2012;367:625–635.

7. Bonde AN, Lip GYH, Kamper A-L, Hansen PR, Lamberts M, Hommel K, Hansen ML, Gislason GH, Torp-Pedersen C, Olesen JB. Net Clinical Benefit of Antithrombotic Therapy

ACCEPTED MANUSCRIPT 13

in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Nationwide Observational Cohort Study. J Am Coll Cardiol 2014;64:2471–2482.

RI PT

8. Masson P, Webster AC, Hong M, Turner R, Lindley RI, Craig JC. Chronic kidney disease and the risk of stroke: a systematic review and meta-analysis. Nephrol Dial Transplant 2015;30:1162-1169.

SC

9. Benigni A, Boccardo P, Galbusera M, Monteagudo J, Marco L De, Remuzzi G, Ruggeri ZM.

Am J Kidney Dis 1993;22:668–676.

M AN U

Reversible activation defect of the platelet glycoprotein IIb-IIIa complex in patients with uremia.

10. Kyrle PA, Stockenhuber F, Brenner B, Gössinger H, Korninger C, Pabinger I, SunderPlassmann G, Balcke P, Lechner K. Evidence for an increased generation of prostacyclin in the microvasculature and an impairment of the platelet alpha-granule release in chronic renal failure.

TE D

Thromb Haemost 1988;60:205–208.

11. Lutz J, Menke J, Sollinger D, Schinzel H, Thürmel K. Haemostasis in chronic kidney

EP

disease. Nephrol Dial Transplant 2014;29:29–40.

AC C

12. Friberg L, Benson L, Lip GYH. Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J 2014:297–306.

13. Shah M, Tsadok MA, Jackevicius C a., Essebag V, Eisenberg MJ, Rahme E, Humphries KH, Tu J V., Behlouli H, Guo H, Pilote L. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014;129:1196–1203.

ACCEPTED MANUSCRIPT 14

14. Jun M, James MT, Manns BJ, Quinn RR, Ravani P, Tonelli M, Perkovic V, Winkelmayer WC, Ma Z, Hemmelgarn BR. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational

RI PT

study. BMJ 2015;350:h246.

15. Camm a J, Lip GYH, Caterina R De, Savelieva I, Atar D, Hohnloser SH, Hindricks G,

SC

Kirchhof P. 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

M AN U

the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719– 2747.

16. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk

TE D

factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–272.

17. Pisters R, Lane DA, Nieuwlaat R, Vos CB de, Crijns HJGM, Lip GYH. A novel user-

EP

friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093–1100.

AC C

18. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC, Cigarroa JE, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–e76.

ACCEPTED MANUSCRIPT 15

19. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol

RI PT

2011;6:2662–2668.

20. Carrero JJ, Evans M, Szummer K, Spaak J, Lindhagen L, Edfors R, Stenvinkel P, Jacobson SH, Jernberg T. Warfarin, kidney dysfunction, and outcomes following acute myocardial

SC

infarction in patients with atrial fibrillation. JAMA 2014;311:919–928.

21. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk

M AN U

for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009;20:2223–2233.

22. Morgan CL, McEwan P, Tukiendorf A, Robinson PA, Clemens A, Plumb JM. Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of

TE D

INR control. Thromb Res 2009;124:37–41.

23. 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,

EP

Diener H-C, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial

AC C

fibrillation. N Engl J Med 2009;361:1139–1151.

24. 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 KAA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.

25. Granger CB, Alexander JH, McMurray JJ V, 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

ACCEPTED MANUSCRIPT 16

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 FWA, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med

RI PT

2011;365:981–992.

26. Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, Ezekowitz

SC

MD, Reilly PA, 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

M AN U

(Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014;129:961–970.

27. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L. Efficacy of apixaban when compared

TE D

with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821–2830.

EP

28. Hori M, Matsumoto M, Tanahashi N, Momomura S-I, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iekushi K, Yamanaka S, Tajiri M. Rivaroxaban vs.

AC C

warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age. Circ J 2014;78:1349–1356.

29. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–2104.

ACCEPTED MANUSCRIPT 17

30. Connolly SJ, Eikelboom J, Joyner C, Diener H-C, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim K-H, Lewis BS, Mieghem W Van, Lip GYH, Kim JH, Lanas-

RI PT

Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S. Apixaban in Patients with Atrial Fibrillation. N Engl J Med 2011;364:806–

SC

817.

31. Nielsen PB, Lane DA, Rasmussen LH, Lip GYH, Larsen TB. Renal function and non-

M AN U

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.

32. Meier B, Blaauw Y, Khattab a. a., Lewalter T, Sievert H, Tondo C, Glikson M, Document

TE D

Reviewers, Lip GYH, Lopez-Minguez J, Roffi M, Israel C, Dudek D, Savelieva I. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion. Europace

EP

2014;16:1397–1416.

33. Reddy VY, Doshi SK, Sievert H, Buchbinder M, Neuzil P, Huber K, Halperin JL, Holmes D.

AC C

Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients With Atrial Fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) Trial. Circulation 2013;127:720–729.

34. Holmes DR, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY. Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in

ACCEPTED MANUSCRIPT 18

Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy. J Am Coll Cardiol 2014;64:1–12.

RI PT

35. Tzikas A, Shakir S, Gafoor S, Omran H, Berti S, Santoro G, Kefer J, Landmesser U, NielsenKudsk JE, Cruz-Gonzalez I, Sievert H, Tichelbäcker T, Kanagaratnam P, Nietlispach F, Aminian A, Kasch F, Freixa X, Danna P, Rezzagh M, Vermeersch P, Stock F, Stolcova M, Costa M,

SC

Ibrahim R, Schillinger W, Meier B, Park J-W. Left atrial appendage occlusion for stroke

prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug.

AC C

EP

TE D

M AN U

EuroIntervention 2015;10:1–10.

ACCEPTED MANUSCRIPT 19

Figure legends Figure 1 – Hazard ratio (HR) for mortality according to warfarin use in patients on dialysis or

RI PT

renal replacement therapy (dialysis or kidney transplant). Further details on the study populations can be found in tables 1 and 2.

Figure 2 - Hazard ratio (HR) for ischemic stroke according to warfarin use in patients on dialysis

SC

or renal replacement therapy.

M AN U

Figure 3 - Hazard ratio (HR) for all stroke (ischemic and hemorrhagic) according to warfarin use

Footnote for all figures:

TE D

in patients on dialysis or renal replacement therapy.

for patients aged 66-75 years old

¥

for patients > 75 years old

AC C

*

EP



Renal replacement therapy patients (on dialysis or renal transplantees)

ACCEPTED MANUSCRIPT

Table 1 – Recent large registry studies of net negative clinical outcome in AF patients with ESRD treated with warfarin vs no-

RI PT

warfarin.

Population studied

N

Follow-up period (yrs)

Shah13

Canadian patients on dialysis admitted with AF

1635 N/A

SC

Study

M AN U

(2014)

Winkelmayer19 US Medicare beneficiaries on dialysis with new AF 1185 Median 1.2 (2011)

(2009)

TE D

Chan21

Incident hemodialysis patients with AF

EP

(2010)

Multi-national hemodialysis patients

AC C

Wizeman1

3250 N/A

1671 Mean 1.6

ACCEPTED MANUSCRIPT

Table 2 – Recent large registry studies of net positive clinical outcome in AF patients with ESRD treated with warfarin vs no-

Population studied

N

Bonde7

Danish national registries: patients on dialysis or

1728

(2014)

kidney transplantees from 1997 to 2011 478

M AN U

Carrero20 ESRD Swedish patients admitted with myocardial

SC

Study

RI PT

warfarin.

infarction during 2003-2010

Friberg12

Swedish health registries: all CKD levels including

13,435 patients with CKD, 833 on

(2015)

dialysis and kidney transplantees

dialysis and 314 kidney

TE D

(2014)

Follow-up period (yrs) Median 1.6

N/A

Median 2.1

transplantees

Danish national registries: patients on dialysis or

(2012)

kidney transplantees from 1997 to 2008.

AC C

EP

Olesen6

901

N/A

ACCEPTED MANUSCRIPT

CKD Subjects

CrCl (ml/min)

Drug studied

Follow up time (yrs)

RELY23 (2009)

3505

30-49

D 300 or 220 vs W

Median 2

↓ with D 300

Major Hemorrhage risk

Mortality risk

=

N/A

= with D 220

M AN U

3

Stroke and embolic events risk

SC

Study

RI PT

Table 3 – Sub-group analysis of main outcomes in CKD participants with AF in recent trials of NOACs.

1697

30-59

A 5 or A 10 vs W

Mean 1.1



=

=

ARISTOTLE2 (2011)

3017 with

25-50

A 10 vs W

Median 1.8







ROCKETAF24 (2011)

2950

30-49

R 20 vs W

Median 1.9

=

=

=

ENGAGE AF-TIMI 4829 (2013)

4074

30-49

E 30 or E 15 vs W

Median 2.8

N/A

N/A

N/A

J-ROCKET AF28 (2014)

284

30-49

R 10 vs W

Median 2.5

=

=

N/A

AVERROES 0 (2011)

AC C

EP

TE D

5

D - Dabigratan; A - Apixaban; R - Rivaroxaban; E – Edoxaban; ”=” – no significant difference

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT