Antikoagulation bei VHF und CKD - Robert-Bosch-Hospital...bei Vorhofflimmern und CKD Mark Dominik Alscher Robert-Bosch-Krankenhaus Email: [email protected]. Agenda • Bedeutung

1

Antikoagulation bei Vorhofflimmern und CKD

Mark Dominik Alscher

Robert-Bosch-Krankenhaus Email: [email protected]

Agenda

• Bedeutung und Häufigkeit VHF bei CKD

• Unterschiede CKD 2-4 und 5D

• Antikoagulation

• Phenprocoumon versus NOAKs

• Empfehlung Vorgehen

2

CKD G2-4

Mediasklerose • Nicht-entzündlich • Keine Lipid-Ablagerung • Meist asymptomatisch • Pseudohypertonie

Atherosklerose • Entzündlich • Lipid Ablagerung • Ischämie, Okklusion

- Pathophysiologie des sekundären Hyperparathyreoidismus -

GFR

Ca x HP04

Weichteil-verkalkungen

1α-Hydroxylase

1,25(OH)2D3 = Calcitriol

Ca++

PTH

P04

Parenchym

25(OH)2D3

Calcium-Phosphat-Haushalt bei Niereninsuffizienz

AJKD 1998;32:391

Kalzifizierende urämische Arteriolopathie

Überleben in Abhängigkeit vom vaskulären Kalzifizierungsscore

Blacher J et al. Hypertension 2001;38:938–42

Follow-up (Monate)

0

p<0,0001

0

0,25

0,5

0,75

1

0 20 40 60 80

Übe

rlebe

nsw

ahrs

chei

nlic

keit 1

2

3

4

Kalzifizierungsscore

• 110 Dialyse-Patienten •Mittlere Follow-up-Dauer: 53 ± 21 Monate

CKD G5D

Induktoren (+) und Inhibitoren (-) der vaskulären Kalzifizierung

VitaminK-dependentcarboxyla4on

Matrix Gla Protein (MGP) wird durchCarboxylierung und Phosphorylierung aktiviert

Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation Validation of the R2CHADS2 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;127:224-232

Piccini et al Predictors of Stroke in Nonvalvular AF Patients 229

model shown in Table 2. In this population, the R2CHADS2 score improved net stroke risk reclassification 8.2% (95% CI, 2.5%–14%) over the CHADS2 score (P=0.005) and 6.2% (95% CI, 0.9%–11.6%) over CHA2DS2VASc (P=0.023; Table 6). The low-, intermediate-, and high-risk categories

used when calculating the net reclassification index are shown in Table 7 with the corresponding Kaplan-Meier rates at 2 years. Compared with the simplified risk score based only on prior stroke/TIA and CrCl <60 mL/min, net reclassification was not augmented by the R2CHADS2 score (P=0.499).

Validation of the R2CHADS2 Risk ScoreThese models were applied to assessment of the risk of stroke and systemic embolism in the ATRIA study cohort taking and not taking warfarin. For all patients, the R2CHADS2 risk score exhibited discriminant power for stroke similar to the CHADS2 score (respective C statistics 0.672 and 0.673), but net stroke risk reclassification improved 17.4% (95% CI, 12.1%–22.5%) with the R2CHADS2 score. The findings were similar when applied to patients not taking warfarin (C statistics 0.696 ver-sus 0.704 for the R2CHADS2 and CHADS2 scores, respec-tively; net reclassification index improved with R2CHADS2 by 22.6% [95% CI, 14.5%–30.7%]; Tables 6 and 8).

DiscussionThis post hoc analysis of outcomes in the ROCKET AF trial found that impaired renal function and prior stroke or TIA are independently associated with the occurrence of stroke or sys-temic embolism during follow-up of patients with a relatively high risk of stroke (mean CHADS2 score 3.5) taking warfarin

Table 6. Discriminatory Capacity of Stroke Prediction Models at 2-Year Follow-Up

Risk Stratification Model

ATRIA

ROCKET AF Not Taking Warfarin at Baseline Taking Warfarin at Baseline Overall

C-Index (95% CI)*

% NRI With R2CHADS2 (95% CI)†

C-Index (95% CI)*


C-Index (95% CI)*


C-Index (95% CI)*

%NRI With R2CHADS2 (95% CI)†

CHADS2 0.575 (0.55–0.60)

8.2 (2.5–14.0)

0.704 (0.676–0.732)

22.6 (14.5–30.7)

0.648 (0.618–0.678)

12.7 (6.0–19.5)

0.673 (0.652–0.694)

17.4 (12.1–22.5)

CHA2DS2VASc 0.578 (0.55–0.60)

6.2 (0.9–11.6)

R2CHADS2 0.587 (0.56–0.61)

… 0.696 (0.667–0.726)

… 0.650 (0.621–0.679)

… 0.672 (0.651–0.692)

…

Sum of CrCl <60 mL/min and prior stroke/TIA‡

0.590 (0.57–0.61)

1.5 (−2.8 to 5.7)

0.625 (0.594–0.656)

2.4 (−2.9 to 7.7)

0.610 (0.581–0.640)

1.4 (−6.6 to 3.8)

0.617 (0.595–0.638)

0.4 (−3.4 to 4.1)

Nomogram for R2CHADS2§

0.622 (0.60–0.65)

−7.9 (−13.5 to −2.3)

Model selected using continuous variables and components of the CHADS2 score ‖

0.635 (0.61–0.66)

−11.3 (−17.1 to −5.6)

ATRIA indicates AnTicoagulation and Risk factors In Atrial fibrillation; CHADS2, risk stratification system that awards 1 point each for the presence of congestive heart failure, hypertension, age ≥75 years, and diabetes and 2 points for prior stroke or transient ischemic attack; CHADS2VASc, risk stratification system that awards 1 point each for the presence of congestive heart failure, hypertension, vascular disease history, diabetes, and female sex, 2 points for prior stroke or transient ischemic attack, and 0, 1, or 2 points depending on age; CI, confidence interval; CrCl, creatinine clearance; NRI, net reclassification index; R2CHADS2, CHADS2 + 2 points if creatinine clearance <60 mL/min; 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 TIA, transient ischemic attack.

*C statistic comes from the univariable model containing the risk stratification score.†Positive NRI values (NRI= event NRI + non-event NRI) indicate improvement with R2CHADS2. The NRI component for events (stroke and non-central nervous system

embolism) is 44.1 for R2CHADS2 versus CHADS2 and 16.6 for R2CHADS2 versus CHA2DS2VASc. The NRI component for non-events is –35.8 for R2CHADS2 versus CHADS2 and –10.4 for R2CHADS2 versus CHA2DS2VASc.

‡ATRIA analysis includes stroke only (not prior TIA).§Where nomogram values ≤45 are considered low risk, values 46–55 are medium, and values >55 are classified as high risk.‖Where predicted values 0% to 3.9% are considered low risk, values 3.9% to 5.5% are medium, and predicted probabilities >5.5% are classified as high risk.

Figure 2. Cumulative incidence of stroke or non–central ner-vous system systemic embolism according to R2CHADS2 scores (R2CHADS2 indicates CHADS2 [risk stratification system that awards 1 point each for the presence of congestive heart failure, hypertension, age ≥75 years, and diabetes and 2 points for prior stroke or transient ischemic attack] + 2 points if creatinine clear-ance <60 mL/min). The vertical axis is the cumulative incidence by percent. The horizontal axis represents the follow-up in days after randomization.

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Cumulative incidence of stroke or non–central nervous system systemic embolism according to R2CHADS2 scores (R2CHADS2 indicates CHADS2 [risk stratification system that awards 1 point each for the presence of congestive heart failure, hypertension, age ≥75 years, and diabetes and 2 points for prior stroke or transient ischemic attack] + 2 points if creatinine clearance <60 mL/min). The vertical axis is the cumulative incidence by percent.

CKD G2-4

The Increasing Prevalence of Atrial Fibrillation among Hemodialysis Patients

JASN 2011;22: 349–357

tions) attenuated this finding, but a 70% (RR: 1.70; 95% CI:1.64 to 1.75) increase in AF prevalence from 1992 to 2006 re-mained (Figure 3).

One-Year MortalityIn all study patients, 1-year mortality was 19.3% among pa-tients without AF and 38.9% among those with prevalent AF,with 1-year mortality rates for each annual cohort presented inFigure 4. One-year mortality rates were more than double inpatients with AF compared with those without it (hazard ratio[HR]: 2.32; 95% CI: 2.30 to 2.34) and 72% higher after adjust-ment for demographic information (age, gender, and race-adjusted HR: 1.72; 95% CI: 1.70 to 1.73). Multivariate adjust-

ment for all other variables attenuated this estimate further(HR: 1.45; 1.44 to 1.46). We tested for any changes in the de-mographic-adjusted HRs associated with AF over time, but theinteraction term between prevalent AF and calendar year didnot indicate that any temporal trends were present (P ! 0.50).

DISCUSSION

In this most comprehensive study of the prevalence of AF inthe U.S. hemodialysis population to date, we described threelandmark findings. The overall prevalence of AF in this patientpopulation was high, exceeding 10% in 2006. Although the prev-

Figure 1. Trends in the prevalence of AF in U.S. patients receiving hemodialysis, 1992 to 2006. (A) Prevalence of AF among allprevalent hemodialysis patients on December 31 of 15 consecutive years: comparison of three different algorithms to ascertain AF.Prevalence of AF, defined by more than two diagnosis codes in the same calendar year, among prevalent hemodialysis patients onDecember 31 of 15 consecutive years by (B) age group, (C) gender, (D) race, (E) dialysis vintage, and (F) diabetes.

CLINICAL EPIDEMIOLOGY www.jasn.org

352 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 349–357, 2011

CKD G5D

Dilemmas in the Management of Atrial Fibrillation in Chronic Kidney Disease

JASN 2009;20:705–71

population (Figure 1A). Fibrillation ishighly correlated with the diagnosis ofstructural heart disease in these pa-tients, particularly coronary artery dis-ease, degenerative valvular disease as aresult of accelerated calcifications,and left ventricular hypertrophy.19 –22

Fluctuating levels of electrolytes dur-ing hemodialysis as well as sympatheticnervous system activation and mod-ulation of the renin-angiotensinsystem represent additional predispos-ing factors for atrial fibrillation inCKD.18,22–24

CKD, ATRIAL FIBRILLATION, ANDRELATED MORBIDITY ANDMORTALITY

Because of the strong relationship ofatrial fibrillation to structural heartdisease, the direct impact of atrial fi-brillation on morbidity and mortalityis problematic to assess. It is difficult todetermine whether patients have com-plications related to atrial fibrillationor to advanced structural heart diseaseaccompanied by atrial fibrillation.

Compared with patients with eGFR!59 ml/min, those with eGFR between45 and 59 ml/min have a 1.2-foldhigher adjusted hazard ratio for deaththat increases to a 5.9-fold increase inthose with eGFR "15 ml/min. Further-more, the hazard ratios for hospitaliza-tion are 1.1-fold higher in patients witheGFR between 45 and 59 ml/min andrise to 3.1-fold in those with ESRD.11

Regarding atrial fibrillation, cross-sectional data from the USRDS showedthat patients who have ESRD and haveknown atrial fibrillation have an annualmortality rate of 5% compared with only2% in those without it.16 The 3-yr mor-tality rates for patients who had ESRDand had been hospitalized for atrial fi-brillation were also significantly higher(53%; n # 123) than in control subjects(45%; n # 3245).21 Moreover, one longi-tudinal, single-center study (n # 190) re-ported 4-yr mortality rates of 81% in pa-tients with ESRD and atrial fibrillationcompared with only 29% in those with-out.25 There are no data about the impactof atrial fibrillation on the mortality ofpatients in other stages of CKD besidesESRD; therefore, regardless of whetheratrial fibrillation is an independent riskfactor for mortality or represents only a

PREVALENCE OF ATRIAL FIBRILATION, %

RELATIVE RISK OF STROKE INDIFFERENT SUBGROUPS OF CKD

CUMULATIVE 2-YEAR MORTALITY RATES, %

General population <60 years

eGFR>70 ml/mineGFR 40–70 ml/min Nakayama et al.26

USRDS 20061

USRDS 200516

Vasquez et al.25

eGFR<40 ml/min

No CKDCKD

HemodialysisPatients on hemodialysis with

atrial fibrilation comparedto those without

Patients without stroke/TIA

Patients afterTIA

Patients after stroke

0

18

7

1316

825

48

4162

28

74

27

10 20 30

General population <80 years

Patients on peritoneal dialysis

Patients on chronic hemodialysis(various studies)

0 2 4 6 8

0 20 40 60 80 100

No CKDCKDHemodialysis

A

B

C

15

55

Figure 1. Synopsis of atrial fibrillation in CKD. Various stages of CKD are displayed bythe same colors in all panels (blue, no CKD; green, CKD without hemodialysis; red,hemodialysis; purple, peritoneal dialysis). (A) The prevalence of atrial fibrillation in pa-tients on hemodialysis is 10- to 20-fold higher than in the general population, whereaspatients with peritoneal dialysis were less frequently affected.15–19 (B) Risk for stroke isincreased by each stage of CKD, with the highest risk in the patients who are onhemodialysis and have atrial fibrillation.1,16,25,26 (C) Cumulative 2-yr mortality rates afterstroke or transient ischemic attacks (TIA) demonstrate the dramatic death rates in patientswho have CKD or are on hemodialysis.1

Table 1. Classification of various stages of CKDa

CKD Stage eGFRPrevalence

(%)Affected Patients Definition

1 !90 ml/min 3.3 Approximately 5,900,000 Renal injury (e.g., proteinuria) without reduced eGFR2 89 to 60 ml/min 3.0 Approximately 5,300,000 Mildly decreased eGFR3 59 to 30 ml/min 4.3 Approximately 7,600,000 Moderately decreased eGFR4 29 to 15 ml/min 0.2 Approximately 400,000 Severely decreased eGFR5 (almost identical

to ESRD, see Appendix)"15 ml/min 0.3 Approximately 500,000 Kidney failure, mostly indication

for renal replacement therapyaThe estimation of affected patients refers to the US population. Adapted from references.1,8

BRIEF REVIEW www.jasn.org

706 Journal of the American Society of Nephrology J Am Soc Nephrol 20:705–711, 2009

CKD G5D

Risk of Thromboembolic Events in Atrial Fibrillation With Chronic Kidney Disease

Stroke 2015;46:157-163

160 Stroke January 2015

328 889 patients and 21 307 incident outcomes recorded dur-ing a weighted mean follow-up duration of ≈2 years. Studies reported findings in relation to thromboembolic risk discrimina-tion as AUC or C-statistic. The pooled AUCs of the CHADS2, CHA2DS2-VASc, and CHADS2-CKD scores in predicting thromboembolic events were 0.66 (95% CI, 0.62–0.70), 0.68 (95% CI, 0.64–0.71), and 0.69 (95% CI, 0.65–0.73), respectively. There was a slightly significant improvement of CHADS2 score by the addition of CKD (pooled AUC difference, 0.03 [95% CI, 0.01–0.05]), but the AUC for CHADS2-CKD and CHA2DS2-VASc scores were not statistically different (Table 3).

DiscussionThe present meta-analysis, involving >500 000 patients and >40 000 patients with thromboembolic events from 18 stud-ies, found a significantly increased risk of thromboembolic events associated with renal impairment in patients with AF, even after reported adjustment for CHADS2 risk factors. The association seemed to be similar in patients taking or

not taking OACs. Incidence of thromboembolic events was inversely associated with renal function, and the addition of renal impairment to CHADS2 scores yielded a slight improve-ment in risk discrimination (0.03 point estimate).

Recent studies have suggested that nonvalvular AF patients with heart failure (RR=1.4), hypertension (RR=1.6), older age (RR=1.4), diabetes mellitus (RR=1.7), and previous ischemic stroke (RR=2.5) were at risk of developing thromboembolic events, whereas conflicting results were reported for renal impairment.35 This meta-analysis is the first to our knowledge to confirm CKD to be an independent risk factor for thromboem-bolism in patients with nonvalvular AF. Although the risk mag-nitude seems to be less robust than previous ischemic stroke, it is at least as strong as other well-established major risk factors, such as heart failure, hypertension, older age, diabetes mellitus.35 However, CKD is common in AF patients, and the combination of end-stage renal disease and AF in patients treated with chronic hemodialysis may confer significantly greater thromboembolic risk. For example, Vazquez et al demonstrated that approximately

Figure 1. Forrest plot showing relative risk of thromboembolic events associated with renal impairment in atrial fibrillation (AF) patients. The size of each square is proportional to the study’s weight (inverse of variance). AMADEUS indicates Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; CI, confidence interval; J-ROCKET, Japanese Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; NHI, national health insurance; ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; RR, relative risk; and SWEDEHEART, Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies.


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Risiko für ischämischen Apoplex bei CKD Faktor 1,6!

CKD G2-4

Risk of Thromboembolic Events in Atrial Fibrillation With Chronic Kidney Disease

Stroke 2015;46:157-163

162 Stroke January 2015

renal dysfunction further increases the risk of ischemic stroke significantly after accounting for other known thromboembolic risk factors. In addition, our study demonstrated that adding renal dysfunction to the CHADS2 score yields a small but sta-tistically significant improvement in c-statistic. Given these findings, further studies are warranted to elucidate the additive predictive value of renal dysfunction to CHA2DS2-VASc score.

Strengths of this meta-analysis include the strict inclusion crite-ria, the large number of patients analyzed, the robustness of the find-ings in sensitivity analyses, and the fact that all subgroup analyses

were prespecified a priori. The absence of important publication bias supports the robustness of the study findings. A possible limita-tion of our study is the heterogeneity of the studies with regard to adjustment of the estimates for potential confounders. Although dif-ferences in number of events and the outcomes of interest, at least in part, explain this finding, the specific mechanism remains unclear. Inclusion of different types of studies into one meta-analysis may also introduce heterogeneity into the results. Despite this, the con-sistency of the finding of an increased thromboembolic risk among cohort studies and randomized controlled trials suggests that the association is valid. Another limitation was the lack of individual participant data, which precluded determining the independent associations of individual variables with study outcomes. Instead, we used between-study meta-regressions, when possible.

In conclusion, impaired renal function is a predictor of incident stroke and systemic embolism in patients with non-valvular AF taking and not taking OACs, independent of conventional thromboembolic risk factors. Adding CKD to the CHADS2 stroke risk scores slightly improved the risk dis-crimination, and consideration of renal function may improve stroke risk stratification in patients with AF.

DisclosuresNone.

References 1. Albertsen IE, Rasmussen LH, Overvad TF, Graungaard T, Larsen TB,

Lip GY. Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis. Stroke. 2013;44:1329–1336.

2. Kokubo Y, Nakamura S, Okamura T, Yoshimasa Y, Makino H, Watanabe M, et al. Relationship between blood pressure category and incidence of stroke and myocardial infarction in an urban Japanese population with and without chronic kidney disease: the Suita Study. Stroke. 2009;40:2674–2679.

3. Di Angelantonio E, Chowdhury R, Sarwar N, Aspelund T, Danesh J, Gudnason V. Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. BMJ. 2010;341:c4986.

4. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–1305.

5. Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L, et al. Impact of proteinuria and glomerular filtration rate on risk of throm-boembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119:1363–1369.

6. Soliman EZ, Prineas RJ, Go AS, Xie D, Lash JP, Rahman M, et al. Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC). Am Heart J. 2010;159:1102–1107.

7. Baber U, Howard VJ, Halperin JL, Soliman EZ, Zhang X, McClellan W, 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 Electrophysiol. 2011;4:26–32.

8. Tonelli M, Muntner P, Lloyd A, Manns B, Klarenbach S, Pannu N, et al. Impact of age on the association between CKD and the risk of future coronary events. Am J Kidney Dis. 2014;64:375–382.

9. Friberg L, Benson L, Lip GY. Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study [publishead online ahead of print April 10, 2014]. Eur Heart J. doi: 10.1093/eurheartj/ehu139. http://eurheartj.oxfordjournals.org/content/early/2014/04/09/eurheartj.ehu139.long. Accessed July 4, 2014.

10. Reinecke H, Engelbertz C, Schäbitz WR. Preventing stroke in patients with chronic kidney disease and atrial fibrillation: benefit and risks of old and new oral anticoagulants. Stroke. 2013;44:2935–2941.

11. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JJ, Cigarroa JE, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the american

Table 3. AUC Analysis for 3 Risk Stratification Models in Predicting Thromboembolic Events in AF Patients

CHADS2 CHA2DS2−VASc CHADS2+CKD

Study AUC (95% CI)c AUC (95% CI) AUC (95% CI)

Swedish Atrial Fibrillation Cohort study

0.72 (0.72–0.73) 0.71 (0.71–0.72) 0.72 (0.71–0.72)

Roldan V 0.65 (0.62–0.68) 0.62 (0.59–0.65) 0.64 (0.61–0.67)

Chao TF NA 0.83 (0.73–0.93) 0.87 (0.79–0.95)

ROCKET AF 0.57 (0.55–0.60) 0.58 (0.55–0.60) 0.59 (0.56–0.61)

Leipzig Heart Center AF Ablation Registry

0.72 (0.70–0.74) 0.74 (0.72–0.75) 0.74 (0.72–0.75)

AMADEUS Trial 0.64 (0.56–0.73) 0.67 (0.60–0.75) 0.69 (0.62–0.76)

The Loire Valley Atrial Fibrillation Project

0.64 (0.61–0.67) 0.64 (0.62–0.67) 0.64 (0.61–0.67)

ATRIA Study 0.66 (0.62–0.70) 0.69 (0.67–0.71) 0.71 (0.69–0.74)

Pooled AUC estimates 0.66 (0.62–0.70) 0.68 (0.64–0.71) 0.69 (0.65–0.73)

AF indicates atrial fibrillation; AMADEUS, Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; AUC, area under the curve; CHADS2, congestive heart failure, hypertension, age, diabetes mellitus, stroke/transient ischemic attack; CHA2DS2-VASc, congestive heart failure, hypertension, age (>75 y), diabetes mellitus, stroke/transient ischemic attack, vascular disease, age (65–74 y), sex (female); and ROCKET, Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

Figure 3. Annual rates of stroke or systemic embolism accord-ing to renal function estimated by Cockcroft–Gault. The solid line represents point estimates of rate of thromboembolic events; dashed lines are 95% confidence interval (CIs). Circles pres-ent the estimated glomerular filtration rate (eGFR)–specific rate estimates reported in each study. The area of each circle is pro-portional to the sample size. The dotted line represents the null hypothesis of no association.


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CKD G2-4

Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation

AJKD 2017;69(6):734-743

Background: The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain.

Study Design: Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada.

Setting & Participants: 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded.

Predictor: Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis.

Outcomes: Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding.

CKD G2-4

Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation

AJKD 2017;69(6):734-743

risk associated with warfarin therapy was not modi-fied by eGFR category (P 5 0.8). Similarly, whenassessed as individual outcomes, warfarin use wasassociated with lower risk for ischemic stroke or TIAacross eGFR categories, although statistical signifi-cance was not reached in 2 categories (Fig 4). Themagnitude of this relative risk with warfarin treatmentwas again not modified by eGFR (P5 0.8).

HRs for Major Bleeding

The risk for major bleeding associated withwarfarin therapy was not significantly increased byeGFR category except for those with eGFRs of 60 to89 mL/min/1.73 m2, for whom, compared to nonuse,warfarin therapy was associated with 36% higher riskfor major bleeding (HR, 1.36; 95% CI, 1.13-1.64;P 5 0.001; P for interaction 5 0.02; Fig 4).

Types of Bleeding

Of the 1,023 major bleeding events, 43 (0.3%), 547(3.7%), and 433 (2.9%) were due to intracranial,gastrointestinal, and other bleeds, respectively.Warfarin therapy was not associated with increasedrisk in intracranial bleeding across eGFR categories(adjusted HRs [95% CI] and event numbers [warfarinusers vs nonusers] for eGFR categories 60-89,

45-59, and 30-44 mL/min/1.73 m2: 1.43 [0.61-3.33],13/4,105 vs 9/4,105; 0.58 [0.14-2.42], 3/2,010 vs5/2,010; and 0.11 [0.01-0.84], 1/870 vs 9/870,respectively; models for $90 (0/195 vs 3/195)and ,30 (0/266 vs 0/266) mL/min/1.73 m2 did notconverge due to zero or small event counts). Warfarintherapy was associated with greater risk for other andgastrointestinal bleeding among patients in the eGFRcategory of 60 to 89 mL/min/1.73 m2 (adjusted HRs[95% CI] were 1.46 [1.12-1.91] and 1.25 [0.96-1.64],respectively; event numbers [warfarin users vs non-users] were 133/4,105 vs 90/4,105 and 119/4,105 vs94/4105, respectively). Twenty-nine patients with ableeding episode (12 warfarin users and 17 nonusers)died in the hospital or within 7 days of beingdischarged.

Ascertainment of Subsequent Warfarin ExposureStatus After Index Date

Among 7,446 warfarin users, 5,009 (67.3%) hadINR information available. There were 3,758 (75.0%)who were considered to have had continuous warfarinuse based on dispensed warfarin prescriptions andINR measurements during the study follow-up period.Among 7,446 nonusers, 1,580 (21.2%) subsequentlyhad 1 or more dispensed warfarin prescription after

Figure 3. Incidence (number of events and rates per 100 person-years) of study outcomes by warfarin use and estimated glomer-ular filtration rate (eGFR) category. (A) All-cause death, ischemic stroke, or transient ischemic attack (TIA); (B) ischemic stroke or TIA;(C) all-cause death; and (D) major bleeding. Bars represent 95% confidence intervals (per 100 person-years) for incidence rates.

Am J Kidney Dis. 2017;69(6):734-743 739

Kidney Function and Warfarin Effectiveness/Safety

CKD G2-4

Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF

JACC 2016;67:2888

with patients on warfarin without renal disease(Table 1) (17).

NOACs

Currently, there are 4 FDA-approved NOACs forstroke prevention in patients with AF: apixaban,rivaroxaban, dabigatran, and edoxaban. Table 2summarizes the renal clearance, effect of dialysis,and reversal agents for these medications; in addi-tion, it outlines the hazard ratios (HRs) for stroke andbleeding from the pivotal phase 3 trials among sub-jects with CrCl <50 ml/min (referent to warfarin).

APIXABAN. Apixaban is a direct factor Xa inhibitorwith 27% renal elimination (Figure 4A). In theAVERROES (Apixaban Versus Acetylsalicylic Acid toPrevent Stroke in Atrial Fibrillation Patients WhoHave Failed or Are Unsuitable for Vitamin K Antago-nist Treatment) trial (n ¼ 5,599 subjects withcreatinine <2.5 mg/dl), subjects with AF who wereunable to take warfarin were randomized to apixaban5 mg twice per day or aspirin. A reduced dose ofapixaban 2.5 mg twice per day was given to patientswho met at least 2 of the following criteria: serumcreatinine between 1.5 and 2.5 mg/dl, age $80 years,and body weight #60 kg. The study showed thatapixaban was superior to aspirin in preventing strokeor systemic embolization (HR: 0.32; 95% CI: 0.19 to0.56), and the trial was stopped prematurely by theData and Safety Monitoring Board because of over-whelming efficacy (23). No significant difference inthe rate of major bleeding between the groups wasobserved (HR: 1.06; 95% CI: 0.58 to 1.93). The supe-riority of apixaban over aspirin in stroke preventionand a similar incidence of major bleeding were pre-served among patients with CrCl of 25 to 50 ml/min inthe study.

In the ARISTOTLE (Apixaban for Reduction inStroke and Other Thromboembolic Events in AtrialFibrillation) trial (n ¼ 18,201 subjects withcreatinine <2.5 mg/dl), patients were randomized toapixaban 5 mg twice per day or warfarin. Because

they met the same criteria used in the AVERROES trialfor dose reduction, 4.7% of apixaban patientsreceived a lower dose of 2.5 mg twice per day. Overall,apixaban significantly decreased the risk for strokeand systemic embolism (HR: 0.79; 95% CI: 0.66 to0.95) and major bleeding (HR: 0.69; 95% CI: 0.60 to0.80) compared with warfarin (2). These trends per-sisted in post hoc analyses among patients with CrClof 25 to 50 ml/min, in whom apixaban demonstrated anonsignificantly decreased risk for stroke (HR: 0.79;95% CI: 0.55 to 1.14) and a significantly decreased riskfor bleeding (HR: 0.50; 95% CI: 0.38 to 0.66) referentto warfarin (24,25). Because of multiple criteria fordose reduction, it is uncertain how many patientswith CrCl of 25 to 50 ml/min received the 2.5-mgversus the 5-mg apixaban dose and whether doseaffects these HR estimates.

Apixaban was FDA approved in December 2012 forthe prevention of stroke and systemic embolism inpatients with nonvalvular AF at a dose of 5 mg twiceper day and with a 2.5-mg twice-daily dose in patientswith 2 of the following: serum creatinine between1.5 and 2.5 mg/dl, age $80 years, and body weight#60 kg. In the original labeling, the drug was notrecommended for patients with CrCl <25 ml/min.

The drug label was amended in January 2014 forpatients with renal impairment, including those withESRD maintained on hemodialysis. For these pa-tients, no dose reduction (5 mg twice daily) wassuggested unless patients were also $80 years of ageor had body weight #60 kg, in which case the reduceddose of 2.5 mg twice per day could be used. Patientswith creatinine >2.5 mg/dl, with CrCl <25 ml/min, oron long-term dialysis were excluded from theARISTOTLE trial; therefore, these dosing suggestionswere based partially on a single-dose (not multidose)PK study in 8 hemodialysis subjects matched to8 subjects with normal renal function (26). In thisstudy, the post-hemodialysis administration of 5 mgapixaban resulted in 36% higher drug exposurecompared with healthy subjects with normal renalfunction. In another 10-mg single-dose PK study of 24subjects with mild and moderate CKD compared with8 subjects with normal kidney function, total apix-aban exposure was estimated via regression modelsto be 44% greater in subjects with CrCl of 15 ml/minthan in subjects with normal kidney function (27).Thus, under current dosing suggestions on the apix-aban label, patients with advanced and end-stagekidney disease could be exposed to 40% more drug.Further studies are needed to establish the optimalapixaban dose in this population.

In terms of dialysis clearance, only 6.7% of apix-aban is cleared by a 4-h hemodialysis session

TABLE 1 Estimated Major Bleeding Rates for Patients onWarfarin by Creatinine Clearance

Kidney FunctionMajor Bleeding

(Events per 100 Patient-Years)

CrCl $60 ml/min 6.2 (4.1–8.9)

CrCl 30–59 ml/min 8.3 (5.1–12.8)

CrCl <30 ml/min 30.5 (17.0–50.3)

Dialysis 54–100

Data from Limdi et al. (17) and Elliott et al. (64).

CrCl ¼ creatinine clearance.

Chan et al. J A C C V O L . 6 7 , N O . 2 4 , 2 0 1 6

NOACs in Advanced CKD and Dialysis J U N E 2 1 , 2 0 1 6 : 2 8 8 8 – 9 9

2892

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CKD G3CKD G4

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The association of anticoagulation, ischemicstroke, and hemorrhage in elderly adults with chronic kidney disease and atrial fibrillation

KI 2017;91:928–936

mortality, and no reduction in the risk of ischemic stroke.These findings were demonstrated after propensity scorematching on multiple variables and after multiple sensitivityanalyses, including examining anticoagulation in a time-varying manner and accounting for the competing risk of

mortality. Our findings suggested the administration of an-ticoagulants in patients with advanced CKD significantlyincreased the risk of hemorrhage and might lower all-causemortality, but there was no clear demonstrable reduction inthe risk of ischemic stroke.

Table 1 | Baseline characteristics of anticoagulant users and non-users pre- and post-propensity score match

Prematch Postmatch

Anticoagulant:No

Anticoagulant:yes St Diff* (%)

Anticoagulant:no


Total, no. (%) 5069 (77) 1475 (23%) 1417 1417Age (mean ! SD) 83.0 ! 7.4 81.5 ! 6.9 21 82.0 ! 7.7 81.7 ! 6.8 4Sex (male), no. (%) 2147 (42.7) 615 (41.7) 1 580 (40.9) 586 (41.4) 1Income quintile, no. (%)

Quintile 1 (lowest) 1,202 (23.7) 306 (20.7) 7 298 (21.0) 300 (21.2) 0Quintile 2 1,123 (22.2) 356 (24.1) 5 324 (22.9) 337 (23.8) 2Quintile 3 1037 (20.5) 311 (21.1) 2 297 (21.0) 299 (21.1) 0Quintile 4 891 (17.6) 256 (17.4) 1 249 (17.6) 247 (17.4) 1Quintile 5 (highest) 816 (16.1) 246 (16.7) 2 249 (17.6) 234 (16.5) 3

Rural,† no. (%) 730 (14.4) 211 (14.3) 0 226 (15.9) 203 (14.3) 4Long-term care, no. (%) 453 (8.9) 107 (7.3) 6 98 (6.9) 104 (7.3) 2eGFR, (mean ! SD) (ml/min/1.73m2) 33.1 ! 9.0 34.5 ! 8.1 17 34.3 ! 8.2 34.6 ! 8.0 4<15, no. (%) 222 (4.4) 35 (2.4) 11 32 (2.3) 32 (2.3) 015–29, no. (%) 1443 (28.5) 354 (24.0) 10 334 (23.6) 334 (23.6) 030–45, no. (%) 3404 (67.2) 1086 (73.6) 14 1051 (74.2) 1051 (74.2) 0

AF hospitalization LOS (mean ! SD days) 10.5 ! 17.3 5.0 ! 9.7 39 5.5 ! 9.9 5.1 ! 9.9 4Time from AF to prescription (d) (mean ! SD) 10.7 ! 8.5 9.2 ! 8.0 19 9.3 ! 7.7 9.2 ! 8.1 0Comorbidities, no. (%)

Diabetes 2120 (41.8) 688 (46.6) 10 642 (45.3) 650 (45.9) 1Hypertension 4558 (89.9) 1334 (90.4) 2 1287 (90.8) 1279 (90.3) 2Ischemic stroke 371 (7.3) 107 (7.3) 0 99 (7.0) 102 (7.2) 1TIA 103 (2.0) 29 (2.0) 0 30 (2.1) 29 (2.0) 1Hemorrhage 653 (12.9) 103 (7.0) 20 100 (7.1) 102 (7.2) 0CHF 2762 (54.5) 771 (52.3) 4 739 (52.2) 737 (52.0) 0Myocardial infarction 1067 (21.0) 200 (13.6) 20 187 (13.2) 198 (14.0) 2CAD 2840 (56.0) 808 (54.8) 2 757 (53.4) 769 (54.3) 2CABG 384 (7.6) 81 (5.5) 8 65 (4.6) 80 (5.6) 5PVD 309 (6.1) 67 (4.5) 7 50 (3.5) 66 (4.7) 6COPD 790 (15.6) 174 (11.8) 11 162 (11.4) 172 (12.1) 2Cancer 1054 (20.8) 243 (16.5) 11 257 (18.1) 242 (17.1) 3

Comorbidity scores, no. (%)CHADS2VaSc

‡ (mean ! SD) 4.3 ! 1.2 4.3 ! 1.2 3 4.3 ! 1.3 4.3 ! 1.2 4Index year, no. (%)

2002–2006 1355 (26.7) 361 (24.5) 2 337 (23.8) 341 (24.1) 02007–2010 1976 (39.0) 565 (38.3) 1 554 (39.1) 548 (38.8) 02011–2014 1738 (34.3) 549 (37.2) 3 526 (37.1) 528 (37.3) 0

Health care useHospitalizations (mean ! SD) 1.5 ! 1.2 1.0 ! 1.1 43 1.0 ! 1.0 1.0 ! 1.1 4ED visits (mean ! SD) 2.3 ! 2.2 2.2 ! 1.8 8 2.2 ! 1.8 2.2 ! 1.8 1GP/FP visits (mean ! SD) 17.6 ! 15.0 16.2 ! 13.1 10 16.4 ! 13.8 16.3 ! 13.1 1Nephrology visit, no. (%) 1547 (30.5) 528 (35.8) 11 477 (33.7) 494 (34.9) 3Cardiology visit, no. (%) 4088 (80.6) 1233 (83.6) 8 1162 (82.0) 1180 (83.3) 3

Medications,§, no. (%)NSAIDs 1154 (22.8) 316 (21.4) 3 335 (23.6) 304 (21.5) 5Antiplatelet agents 877 (17.3) 189 (12.8) 13 181 (12.8) 185 (13.1) 1Statins 2460 (48.5) 798 (54.1) 11 750 (52.9) 758 (53.5) 1b blockers 2811 (55.5) 805 (54.6) 2 765 (54.0) 769 (54.3) 1ACE inhibitor 2123 (41.9) 614 (41.6) 1 580 (40.9) 589 (41.6) 1ARB 1232 (24.3) 421 (28.5) 10 407 (28.7) 394 (27.8) 2

ACE, angiotensin converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF,congestive heart failure; COPD, chronic obstructive pulmonary disease; ED, emergency department; eGFR, estimated glomerular filtration rate; GP/FP, general practitioner/family physician; LOS, length of stay; NSAIDs, nonsteroidal anti-inflammatory drugs; PVD, peripheral vascular disease; TIA, transient ischemic attack.*Standardized differences were used to compare anticoagulant use to no anticoagulant use. Standardized differences are less sensitive to sample size than traditional hy-pothesis tests. They provide a measure of the difference between groups divided by the pooled SD; a value >10% is interpreted as a meaningful difference between groups.†Rural defined as residing in a location with population of <10, 000.‡Risk score Birmingham 2009.§Data on dispensed prescriptions only available for individuals age 66 years or older.

c l i n i ca l i nves t iga t i on V Keskar et al.: Anticoagulation and atrial fibrillation in elderly with CKD

930 Kidney International (2017) 91, 928–936

mortality, and no reduction in the risk of ischemic stroke.These findings were demonstrated after propensity scorematching on multiple variables and after multiple sensitivityanalyses, including examining anticoagulation in a time-varying manner and accounting for the competing risk of

mortality. Our findings suggested the administration of an-ticoagulants in patients with advanced CKD significantlyincreased the risk of hemorrhage and might lower all-causemortality, but there was no clear demonstrable reduction inthe risk of ischemic stroke.

Table 1 | Baseline characteristics of anticoagulant users and non-users pre- and post-propensity score match

Prematch Postmatch

Anticoagulant:No


Anticoagulant:no


Total, no. (%) 5069 (77) 1475 (23%) 1417 1417Age (mean ! SD) 83.0 ! 7.4 81.5 ! 6.9 21 82.0 ! 7.7 81.7 ! 6.8 4Sex (male), no. (%) 2147 (42.7) 615 (41.7) 1 580 (40.9) 586 (41.4) 1Income quintile, no. (%)

Quintile 1 (lowest) 1,202 (23.7) 306 (20.7) 7 298 (21.0) 300 (21.2) 0Quintile 2 1,123 (22.2) 356 (24.1) 5 324 (22.9) 337 (23.8) 2Quintile 3 1037 (20.5) 311 (21.1) 2 297 (21.0) 299 (21.1) 0Quintile 4 891 (17.6) 256 (17.4) 1 249 (17.6) 247 (17.4) 1Quintile 5 (highest) 816 (16.1) 246 (16.7) 2 249 (17.6) 234 (16.5) 3

Rural,† no. (%) 730 (14.4) 211 (14.3) 0 226 (15.9) 203 (14.3) 4Long-term care, no. (%) 453 (8.9) 107 (7.3) 6 98 (6.9) 104 (7.3) 2eGFR, (mean ! SD) (ml/min/1.73m2) 33.1 ! 9.0 34.5 ! 8.1 17 34.3 ! 8.2 34.6 ! 8.0 4<15, no. (%) 222 (4.4) 35 (2.4) 11 32 (2.3) 32 (2.3) 015–29, no. (%) 1443 (28.5) 354 (24.0) 10 334 (23.6) 334 (23.6) 030–45, no. (%) 3404 (67.2) 1086 (73.6) 14 1051 (74.2) 1051 (74.2) 0

AF hospitalization LOS (mean ! SD days) 10.5 ! 17.3 5.0 ! 9.7 39 5.5 ! 9.9 5.1 ! 9.9 4Time from AF to prescription (d) (mean ! SD) 10.7 ! 8.5 9.2 ! 8.0 19 9.3 ! 7.7 9.2 ! 8.1 0Comorbidities, no. (%)

Diabetes 2120 (41.8) 688 (46.6) 10 642 (45.3) 650 (45.9) 1Hypertension 4558 (89.9) 1334 (90.4) 2 1287 (90.8) 1279 (90.3) 2Ischemic stroke 371 (7.3) 107 (7.3) 0 99 (7.0) 102 (7.2) 1TIA 103 (2.0) 29 (2.0) 0 30 (2.1) 29 (2.0) 1Hemorrhage 653 (12.9) 103 (7.0) 20 100 (7.1) 102 (7.2) 0CHF 2762 (54.5) 771 (52.3) 4 739 (52.2) 737 (52.0) 0Myocardial infarction 1067 (21.0) 200 (13.6) 20 187 (13.2) 198 (14.0) 2CAD 2840 (56.0) 808 (54.8) 2 757 (53.4) 769 (54.3) 2CABG 384 (7.6) 81 (5.5) 8 65 (4.6) 80 (5.6) 5PVD 309 (6.1) 67 (4.5) 7 50 (3.5) 66 (4.7) 6COPD 790 (15.6) 174 (11.8) 11 162 (11.4) 172 (12.1) 2Cancer 1054 (20.8) 243 (16.5) 11 257 (18.1) 242 (17.1) 3

Comorbidity scores, no. (%)CHADS2VaSc

‡ (mean ! SD) 4.3 ! 1.2 4.3 ! 1.2 3 4.3 ! 1.3 4.3 ! 1.2 4Index year, no. (%)

2002–2006 1355 (26.7) 361 (24.5) 2 337 (23.8) 341 (24.1) 02007–2010 1976 (39.0) 565 (38.3) 1 554 (39.1) 548 (38.8) 02011–2014 1738 (34.3) 549 (37.2) 3 526 (37.1) 528 (37.3) 0

Health care useHospitalizations (mean ! SD) 1.5 ! 1.2 1.0 ! 1.1 43 1.0 ! 1.0 1.0 ! 1.1 4ED visits (mean ! SD) 2.3 ! 2.2 2.2 ! 1.8 8 2.2 ! 1.8 2.2 ! 1.8 1GP/FP visits (mean ! SD) 17.6 ! 15.0 16.2 ! 13.1 10 16.4 ! 13.8 16.3 ! 13.1 1Nephrology visit, no. (%) 1547 (30.5) 528 (35.8) 11 477 (33.7) 494 (34.9) 3Cardiology visit, no. (%) 4088 (80.6) 1233 (83.6) 8 1162 (82.0) 1180 (83.3) 3

Medications,§, no. (%)NSAIDs 1154 (22.8) 316 (21.4) 3 335 (23.6) 304 (21.5) 5Antiplatelet agents 877 (17.3) 189 (12.8) 13 181 (12.8) 185 (13.1) 1Statins 2460 (48.5) 798 (54.1) 11 750 (52.9) 758 (53.5) 1b blockers 2811 (55.5) 805 (54.6) 2 765 (54.0) 769 (54.3) 1ACE inhibitor 2123 (41.9) 614 (41.6) 1 580 (40.9) 589 (41.6) 1ARB 1232 (24.3) 421 (28.5) 10 407 (28.7) 394 (27.8) 2

ACE, angiotensin converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF,congestive heart failure; COPD, chronic obstructive pulmonary disease; ED, emergency department; eGFR, estimated glomerular filtration rate; GP/FP, general practitioner/family physician; LOS, length of stay; NSAIDs, nonsteroidal anti-inflammatory drugs; PVD, peripheral vascular disease; TIA, transient ischemic attack.*Standardized differences were used to compare anticoagulant use to no anticoagulant use. Standardized differences are less sensitive to sample size than traditional hy-pothesis tests. They provide a measure of the difference between groups divided by the pooled SD; a value >10% is interpreted as a meaningful difference between groups.†Rural defined as residing in a location with population of <10, 000.‡Risk score Birmingham 2009.§Data on dispensed prescriptions only available for individuals age 66 years or older.

c l i n i ca l i nves t iga t i on V Keskar et al.: Anticoagulation and atrial fibrillation in elderly with CKD

930 Kidney International (2017) 91, 928–936

CKD G2-4


KI 2017;91:928–936

Figure 1 | Plot of the cumulative incidence function of exposure to anticoagulation for (a) ischemic stroke, (b) hemorrhage, and (c)mortality.

V Keskar et al.: Anticoagulation and atrial fibrillation in elderly with CKD c l i n i ca l i nves t iga t ion

Kidney International (2017) 91, 928–936 931

Ischämischer Schlaganfall

CKD G2-4


KI 2017;91:928–936

Figure 1 | Plot of the cumulative incidence function of exposure to anticoagulation for (a) ischemic stroke, (b) hemorrhage, and (c)mortality.



Blutungen

CKD G2-4


KI 2017;91:928–936Figure 1 | Plot of the cumulative incidence function of exposure to anticoagulation for (a) ischemic stroke, (b) hemorrhage, and (c)mortality.



Mortalität

CKD G2-4

Effectiveness and Safety of Warfarin in Dialysis Patients With Atrial Fibrillation

Medicine 2015;94:e2233

FIGURE 2. Combined estimate of hazard ratios (HRs) and 95% confidence intervals (CIs) of warfarin use associated with stroke risk.Squares represent the HRs (size of square reflects the study’s weight), and lines represent the 95% CIs for individual studies. The diamondrepresents the pooled HR and 95% CI. CI¼ confidence intervals, HRs¼ hazard ratios.

FIGURE 3. Combined estimate of hazard ratios (HRs) and 95% confidence intervals (CIs) of warfarin use associated with bleeding risk.Squares represent the HRs (size of square reflects the study’s weight), and lines represent the 95% CIs for individual studies. The diamondrepresents the pooled HR and 95% CI. CI¼ confidence intervals, HRs¼ hazard ratios.

Liu et al Medicine " Volume 94, Number 50, December 2015

6 | www.md-journal.com Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved.

Combined estimate of hazard ratios (HRs) and 95% confidence intervals (CIs) of warfarin use associated with stroke risk. Squares represent the HRs (size of square reflects the study’s weight), and lines represent the 95% CIs for individual studies. The diamond represents the pooled HR and 95% CI. CI = confidence intervals, HRs = hazard ratios.

CKD G5D

Effectiveness and Safety of Warfarin in Dialysis Patients With Atrial Fibrillation

Medicine 2015;94:e2233

FIGURE 2. Combined estimate of hazard ratios (HRs) and 95% confidence intervals (CIs) of warfarin use associated with stroke risk.Squares represent the HRs (size of square reflects the study’s weight), and lines represent the 95% CIs for individual studies. The diamondrepresents the pooled HR and 95% CI. CI¼ confidence intervals, HRs¼ hazard ratios.

FIGURE 3. Combined estimate of hazard ratios (HRs) and 95% confidence intervals (CIs) of warfarin use associated with bleeding risk.Squares represent the HRs (size of square reflects the study’s weight), and lines represent the 95% CIs for individual studies. The diamondrepresents the pooled HR and 95% CI. CI¼ confidence intervals, HRs¼ hazard ratios.

Liu et al Medicine " Volume 94, Number 50, December 2015

6 | www.md-journal.com Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved.

Combined estimate of hazard ratios (HRs) and 95% confidence intervals (CIs) of warfarin use associated with bleeding risk. Squares represent the HRs (size of square reflects the study’s weight), and lines represent the 95% CIs for individual studies. The diamond represents the pooled HR and 95% CI. CI = confidence intervals, HRs = hazard ratios.

CKD G5D

Apixaban%/Jahr(n)

Warfarin%/Jahr(n)

Hazard-Ratio(KI95%)

p-WertfürdieInteraktion

Schlaganfall/SECockcroft-Gault(eGFRml/min) 0,705

>80 0,99(70) 1,12(79)

>50–80 1,24(87) 1,69(116)

≤50 2,11(54) 2,67(69)

SchwereBlutungCockcroft-Gault(eGFRml/min) 0,030

>80 1,46(96) 1,84(119)

>50–80 2,45(157) 3,21(199)

≤50 3,21(73) 6,44(142)

0,25 0,5 1 2

Apixabanbesser Warfarinbesser

ARISTOTLE:KonsistenterNutzenvonApixabangegenüberWarfarinüberdieverschiedenenNierenfunktionsgradehinweg

KI:Konfidenzintervall;eGFR:geschätzteglomeruläreFiltrationsrate;SE:systemischeEmbolieÜbernommenvonHohnloserSHetal.EurHeartJ.2012;33:2821-2830

HINWEIS:PatientenmiteinerberechnetenKreatinin-Clearancevon<25ml/MinutewurdenausARISTOTLEausgeschlossen.

CKD G2-4

Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Verdict 2

CJASN 2016;11:2095–2096

bench is not persuaded by this line of reasoning. First, thepaucity of robust (i.e., clinical trial) data renders the debate(regarding warfarin) moot. Second, the train has left thestation (or the horse is out of the barn if you live in a ruraldistrict) due to the FDA’s decision to officially sanction twoNOACs in patients on dialysis, effectively trivializing a de-bate focused on warfarin. The difficulty of maintaining pa-tients on dialysis in a therapeutic range with warfarin isparticularly vexing to clinicians; the bar for considering anNOAC over warfarin is low (especially after the FDA’sguidance on apixaban and rivaroxaban). Third, warfarinis a particularly unappealing choice of anticoagulant in apatient population already at risk for accelerated vascularcalcification (or worse, calciphylaxis). Fourth, the data onNOACs in nondialysis-dependent patients with CKD arereasonably robust and of material interest in this debate:NOACs seem to provide better safety and efficacy thanwar-farin in this CKD population (Figure 1). It is not unreason-able to infer that NOACs would be superior (or at leastnoninferior) to warfarin in CKD stage 5D.McCullough et al. (1) and Keskar and Sood (2) have ad-

mirably argued their positions. The reviewer panel laboredover the summer, weighing and massaging the facts andfactoids. Verdict 2 is found in favor of the McCulloughet al. (1) pro counsel team. The bench strongly concurswith both teams regarding the necessity for randomizedclinical trials on anticoagulation in patients on dialysiswith atrial fibrillation (particularly given the scope of theproblem, with small studies using implantable loop re-corders suggesting under-recognition of paroxysmal atrialfibrillation in patients on hemodialysis). It will be chal-lenging to complete a well designed, adequately powered

clinical trial that will provide definitive guidance on thesafety and efficacy of anticoagulation for primary preventionof ischemic stroke and systemic embolism in patients withCKD stage 5D and atrial fibrillation. It should not just be asafety trial on the noninferiority of NOACs versus warfarin,but one that will hopefully inform clinicians (and futureguideline task forces) on the wisdom of anticoagulation inthis challenging patient population.

AcknowledgmentsThisworkwas supportedby theChronicDiseaseResearchGroup,

Minneapolis Medical Research Foundation.

DisclosuresC.A.H. has an equity interest in Johnson & Johnson (New

Brunswick, NJ), and he received an honorarium from BristolMyers Squibb (New York, NY) for participation in an advisoryboard meeting in 2015.

References1. McCullough PA, Ball T, Cox KM, AssarMD:Use of oral anticoagulation

in the management of atrial fibrillation in patients with ESRD: Pro.Clin J Am Soc Nephrol 11: 2079–2084, 2016

2. Keskar V, Sood MM: Use of oral anticoagulation in the manage-ment of atrial fibrillation in patients with ESRD: Con.Clin J Am SocNephrol 11: 2085–2092, 2016

3. K/DOQI Workgroup: K/DOQI clinical practice guidelines forcardiovascular disease in dialysis patients. Am J Kidney Dis 45[Suppl 3]: S1–S153, 2005

4. Herzog CA, Asinger RW, Berger AK, Charytan DM, Dı́ez J, HartRG, Eckardt KU, Kasiske BL, McCullough PA, Passman RS,DeLoach SS, Pun PH, Ritz E: Cardiovascular disease in chronickidney disease. A clinical update from Kidney Disease: ImprovingGlobal Outcomes (KDIGO). Kidney Int 80: 572–586, 2011

5. Qamar A, Bhatt DL: Stroke prevention in atrial fibrillation in pa-tients with chronic kidney disease. Circulation 133: 1512–1515,2016

6. Hart RG, Eikelboom JW, Ingram AJ, Herzog CA: Anticoagulants inatrial fibrillation patients with chronic kidney disease. Nat RevNephrol 8: 569–578, 2012

Published online ahead of print. Publication date available at www.cjasn.org.

Figure 1. | Relative risk reductions in stroke or systemic embolismand major hemorrhage by novel oral anticoagulants versus warfarinin patients with moderate CKD. Patients with CKD had estimatedcreatinine clearances of 30–49 ml/min, except for those treated withapixaban (25–50 ml/min). Risk reductions were statistically signifi-cant for dabigatran (150 mg) on stroke and apixaban on major hem-orrhage. Reprinted from reference 6, with permission.

Figure 2. | Hazard ratios (HRs) for subgroups of patients with CKDstage 3 from two randomized trials comparing anticoagulation withaspirin. For warfarin comparison from the SPAF III Study, the outcomewas ischemic stroke and systemic embolism, and the aspirin groupadditionally received low ineffective doses ofwarfarin. For apixaban, theoutcome was stroke and systemic embolism. 95% CI, 95% confidenceinterval; INR, international normalized ratio SPAF III, Stroke Preventionin Atrial Fibrillation. Reprinted from reference 6, with permission.

2096 Clinical Journal of the American Society of Nephrology

Relative risk reductions in stroke or systemic embolism and major hemorrhage by novel oral anticoagulants versus warfarin in patients with moderate CKD. Patients with CKD had estimated creatinine clearances of 30–49 ml/min, except for those treated with apixaban (25–50 ml/min). Risk reductions were statistically significant for dabigatran (150 mg) on stroke and apixaban on major hemorrhage.

CKD G5D

Comparative effectiveness of novel oral anticoagulants in UK patients with nonvalvular atrial brillation and chronic kidney disease: a matched cohort study

BMJ Open 2018;8:e019638

8 Loo SY, et al. BMJ Open 2018;8:e019638. doi:10.1136/bmjopen-2017-019638

Open Access

to the small number of observed outcome events, we obtained wide CIs around many of our point estimates. Although these preclude definitive conclusions, the consistency of our results using different definitions of exposure and their concordance with previous RCTs still allow for informative interpretations of our anal-yses. Third, we were unable to take into consideration certain laboratory tests which may not be systematically recorded in a primary care database such as the CPRD. For example, we did not include changes in haemo-globin in our definition of major bleeding, as stipulated by the ISTH. Nevertheless, we adhered to the ISTH definition in all other regards, and therefore, we expect any outcome misclassification resulting from this limita-tion to be slight. We were further unable to use time in therapeutic range to assess the degree of achieved anticoagulation among new users of VKAs; in addition, comparable information would have not been available for new users of NOAC. Finally, our cohort size did not allow for an analysis of individual NOACs.

To conclude, our results suggest that NOACs are overall effective and safe alternatives to VKAs for the preven-tion of ischaemic stroke/SE in NVAF, including NVAF patients with CKD. Nevertheless, despite our reasonably large cohort, we lack the statistical power to make a defin-itive conclusion. Moreover, the effectiveness and safety of these medications may vary from one NOAC to the next, and therefore, further large observational studies should be conducted to evaluate individual NOAC compared to VKAs. This would further inform clinicians as to the most appropriate treatment options for their patients.

Contributors SYL contributed to the study design, conducted statistical analyses, interpreted the data, wrote the first draft of the manuscript and revised the manuscript for important intellectual content. JC conducted supplementary statistical analyses, supervised the conduct of the statistical analyses, interpreted the data and revised the manuscript for important intellectual content. SD contributed to the study design, supervised the conduct of the statistical analyses, interpreted the data and revised the manuscript for important intellectual content. JMB contributed to the study design, interpreted the data and revised the manuscript for important intellectual content. SS contributed to the study design, interpreted the data and revised the manuscript for important intellectual content. CR conceived and designed the study, supervised the conduct of the statistical analyses, interpreted the data, revised the manuscript for important intellectual content and provided supervision and funding.

Funding This work was supported by the Canadian Institutes of Health Research (MOP-341510). SYL is the recipient of a Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institutes of Health Research.

Competing interests SS has received research grants, participated in advisory board meetings and/or was a speaker at conferences for Bayer, Boehringer-Ingelheim and Bristol-Myers-Squibb.

Patient consent Not required.

Ethics approval This study protocol (No: 16_271R) was approved by the Independent Scientific Advisory Committee of the CPRD and the Research Ethics Committee of the Jewish General Hospital (Montreal, Canada), and was made available to journal reviewers.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Table 4 As-treated sensitivity analyses of the comparative effectiveness and safety of NOACs, with 30 days added to the end of the continuous use period to account for informative censoring

OutcomeDrug exposure

All patients with NVAF Patients with NVAF and CKD

EventsPerson-time in years

Adjusted* HR(95% CI) Events

Person-time in years

Adjusted† HR(95% CI)

Ischaemic stroke/SE VKA 48 2815.13 1.00 (reference) 18 1095.30 1.00 (reference)NOAC 50 3773.79 0.95 (0.64 to 1.42) 18 1455.21 0.90 (0.47 to 1.75)

Major bleeding VKA 43 2869.60 1.00 (reference) 22 1082.23 1.00 (reference)

NOAC 47 3790.54 0.92 (0.61 to 1.40) 24 1472.19 0.87 (0.48 to 1.56)

Intracranial bleeding VKA 10 2808.32 1.00 (reference) <5‡ 1088.42 1.00 (reference)

NOAC 7 3753.26 0.65 (0.24 to 1.74) <5‡ 1477.20 0.84 (0.12 to 6.07)

GI bleeding VKA 67 2819.65 1.00 (reference) 44 1079.08 1.00 (reference)

NOAC 117 3741.32 1.47 (1.09 to 2.00) 45 1454.48 0.88 (0.58 to 1.34)

Myocardial infarction VKA 30 2867.63 1.00 (reference) 15 1112.88 1.00 (reference)

NOAC 32 3796.18 0.95 (0.57 to 1.57) 15 1474.08 0.92 (0.44 to 1.90)Death VKA 152 2894.39 1.00 (reference) 70 1127.60 1.00 (reference)

NOAC 195 3835.57 1.01 (0.82 to 1.25) 98 1498.09 1.14 (0.83 to 1.55)

*Adjusted for hypertension, diabetes, antiplatelet use and CKD, as time-dependent covariates.†Adjusted for hypertension, diabete, and antiplatelet use, as time-dependent covariates.‡Cells with less than five events were suppressed owing to privacy restrictions, in accordance with CPRD policy. CKD, chronic kidney disease; CPRD, Clinical Practice Research Datalink; GI, gastrointestinal; NOAC, novel oral anticoagulant; NVAF, non-valvular atrial fibrillation; SE, systemic embolism; VKA, vitamin K antagonist.

CKD G2-4

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

DOAC versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with CKD

Patient or population: atrial f ibrillat ion pat ients with CKDSetting: Hospital-based sett ing

Intervention: DOAC

Comparison: Dose-adjusted warfarin

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No. of participants

(studies)

Quality of the evidence

(GRADE)

Assumed risk Corresponding risk

Warfarin DOAC

All strokes and

systemic embolic eventsFollow up: 1.8 years to 2.8

years

29 per 1,000 23 per 1,000

(19 to 29)

RR 0.81 (0.65 to 1.00) 12,545 (5) ⊕⊕⊕⃝¹

MODERATE

Major bleeding

Follow up: 1.8 years to 2.8

years

55 per 1,000 43 per 1,000

(32 to 57)

RR 0.79 (0.59 to 1.04) 12,521 (5) ⊕⊕⃝⃝¹ ²

LOW

Myocardial infarction

Follow up: 2.8 years

11 per 1,000 10 per 1,000

(5 to 21)

RR 0.92 (0.45 to 1.90) 2,740 (1) -

Minor bleeding


years

74 per 1,000 72 per 1,000

(43 to 119)

RR 0.97

(0.58 to 1.61)

3,012 (2) ⊕⊕⃝⃝¹ ²

LOW

Gastrointestinal bleeding


years

17 per 1,000 24 per 1,000

(17 to 35)

RR 1.40

(0.97 to 2.01)

5,678 (2) ⊕⊕⊕⃝¹

MODERATE

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Intracranial haemorrhage


years

14 per 1,000 6 per 1,000

(4 to 9)

RR 0.43 (0.27 to 0.69) 12,521 (5) ⊕⊕⊕⃝¹

MODERATE

All- cause mortality


years

78 per 1,000 71 per 1,000

(61 to 82)

RR 0.91 (0.78 to 1.05) 9,595 (4) ⊕⊕⊕⃝¹

MODERATE

*The risk in the intervention group (and its 95%CI) is based on the assumed risk in the comparison group and the relative effect of the intervent ion (and its 95%CI).

AF: atrial f ibrillat ion; CI: conf idence interval; DOAC: direct oral ant icoagulants; RR: risk rat io

GRADE Working Group grades of evidence

High quality: We are very conf ident that the true ef fect lies close to that of the est imate of the ef fect

Moderate quality: We are moderately conf ident in the ef fect est imate: The true ef fect is likely to be close to the est imate of the ef fect, but there is a possibility that it issubstant ially dif f erent

Low quality: Our conf idence in the ef fect est imate is lim ited: The true ef fect may be substant ially dif f erent f rom the est imate of the ef fect

Very low quality: We have very lit t le conf idence in the ef fect est imate: The true ef fect is likely to be substant ially dif f erent f rom the est imate of ef fect

1 Some concerns with imprecision because of the uncertain ef f ect est imate2 Some concerns with inconsistency because of medium heterogeneity

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Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease (Review)

Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No.: CD011373.

Cochrane Database of Systematic Reviews

Direct oral anticoagulants versus warfarin for preventingstroke and systemic embolic events among atrial fibrillationpatients with chronic kidney disease (Review)

Kimachi M, Furukawa TA, Kimachi K, Goto Y, Fukuma S, Fukuhara S

Kimachi M, Furukawa TA, Kimachi K, Goto Y, Fukuma S, Fukuhara S.

Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic

kidney disease.

Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No.: CD011373.

DOI: 10.1002/14651858.CD011373.pub2.

www.cochranelibrary.com

Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with

chronic kidney disease (Review)

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

CKD G2-4


JACC 2016;67:2888

CENTRAL ILLUSTRATION Use of Nonvitamin K-Dependent Oral Anticoagulant Agents in Patients WithAdvanced Chronic Kidney Disease and on Dialysis: Substantial and Growing

Chan, K.E. et al. J Am Coll Cardiol. 2016;67(24):2888–99.

Prevalence of nonvitamin K-dependent oral anticoagulant agent (NOAC) use is rising among patients with advanced chronic kidney disease (CKD) and those on dialysisanticoagulated for atrial fibrillation, despite the most recent American Heart Association, American College of Cardiology, and European Heart Rhythm Society guideline,which discourages the use of NOACs when creatinine clearance (CrCl) is<30 ml/min. There are few randomized trial data on NOACs in this population. All NOACs dependon the kidney for elimination, and it is unclear if severe renal impairment leads to drug bioaccumulation to precipitate inadvertent bleeding.

FIGURE 1 Pharmacokinetic Curves for Renally Cleared Drugs in Patients With Normal and Impaired Kidney Function

100

80

60

40

20

00 6 12 18 24

Time (Hours)

Drug

Con

cent

ratio

n (n

g/m

L)

0 6 12 18 24Time (Hours)

100

80

60

40

20

0

A B

Pharmacokinetic (PK) curves illustrating the peak, trough, and total drug exposure for a renally cleared drug in a patient with normal kidneyfunction (A) and in a patient with impaired kidney function (B). Decreased drug clearance resulted in increased peak level, trough level, andtotal drug exposure. Total drug exposure is quantified by the area under the PK curve, in blue.

Chan et al. J A C C V O L . 6 7 , N O . 2 4 , 2 0 1 6

NOACs in Advanced CKD and Dialysis J U N E 2 1 , 2 0 1 6 : 2 8 8 8 – 9 9

2890

CKD G5D


JACC 2016;67:2888

(Optiflux F180NR dialyzer, dialysate flow rate 500ml/min, blood flow rate 350 to 500 ml/min, no hepa-rin) (26); therefore, in patients who have overdosed orare having life-threatening bleeding, dialysis wouldnot be an effective means to remove apixaban fromthe circulation.

RIVAROXABAN. Rivaroxaban is also a direct factorXa inhibitor, and the kidneys eliminate 36% of theparent drug and the remainder is hepatically metab-olized into an inactive form (Figure 4B) (28). InROCKET-AF (Rivaroxaban Once Daily Oral DirectFactor Xa Inhibition Compared With Vitamin K

TABLE 2 Characteristics of Warfarin and Nonvitamin K-Dependent Oral Anticoagulant Agents

Warfarin Apixaban Rivaroxaban Dabigatran Edoxaban

Renal clearance of parent drug <1% 27% 36% 80% 50%

Removal with 4 h of hemodialysis <1% 7% <1% 50%–60% 9%

Volume of distribution, l (66) 8 21 50 50–10 107

Reversal agent Vitamin K, FFP,4F-PCC

4F-PCC 4F-PCC Idarucizumab 4F-PCC

Lowest CrCl drug can be prescribedper FDA label, ml/min

Can be usedon dialysis

<15* 15 15 15

HR (95% CI) of stroke referentto warfarin, CrCl <50 ml/min

Reference 0.79 (0.55–1.14) 0.88 (0.65–1.19) 0.56 (0.37–0.85) 0.87 (0.65–1.18)†

HR (95% CI) of major bleedingreferent to warfarin, CrCl <50 ml/min

Reference 0.50 (0.38–0.66) 0.98 (0.84–1.14) 1.01 (0.79–1.30) 0.76 (0.58–0.98)†

*A 5-mg twice-daily dose of apixaban is suggested for patients with CrCl <15 ml/min. This dosing suggestion was based on a small single-dose pharmacokinetic and phar-macodynamic (anti-Xa activity) study. Clinical efficacy and long-term safety studies have not been done in this population; therefore, use apixaban with caution in patients withadvanced or end-stage chronic kidney disease. †30–50 ml/min for the comparison of edoxaban versus warfarin (37).

CI ¼ confidence interval; CrCl ¼ creatinine clearance; FDA ¼ U.S. Food and Drug Administration; FFP ¼ fresh-frozen plasma; 4F-PCC ¼ 4-factor prothrombin complexconcentrate; HR ¼ hazard ratio.

FIGURE 4 Pharmacokinetics of Nonvitamin K-Dependent Oral Anticoagulant Agents

A apixaban

parent drug(87% bound)

CYP3A4/5 and6% clearedwith dialysis

P-glycoprotein

27% renal elimination

inactive metabolite

~50% in feces

B rivaroxaban

parent drug(95% bound)

CYP3A4/5 and CYP2J2metabolized


51% inactive metabolite

7% feces

Cdabigatran etexilate

dabigatran active

(35% bound)

50-60% clearedwith dialysis


Dedoxaban

10% metabolite

parent drugCYP3A4

(55% bound)

9% clearedwith dialysis

40% bile50% renal eliminationelimination

(A) Apixaban, (B) rivaroxaban, (C) dabigatran, and (D) edoxaban.

J A C C V O L . 6 7 , N O . 2 4 , 2 0 1 6 Chan et al.J U N E 2 1 , 2 0 1 6 : 2 8 8 8 – 9 9 NOACs in Advanced CKD and Dialysis

2893

Dosierung NOAKs bei Vorhofflimmern in Abhängigkeit von der Kreatinin-Clearance

Aktuelle Fachinformationen: Apixaban, Dabigatran, Edoxaban und Rivaroxaban

CrCl Dabigatran Rivaroxaban Apixaban Edoxaban

>80ml/min 2x150mg* 1x20mg 2x5mg** 1x60mg***

50-80ml/min 2x150mg* 1x20mg 2x5mg** 1x60mg***

30-49ml/min 2x150mg* 1x15mg 2x5mg** 1x30mg

15-29ml/min kontraindiziert 1x15mg 2x2,5mg 1x30mg

<15ml/min kontraindiziert nicht empfohlen nicht empfohlen nicht empfohlen

Dialyse kontraindiziert nicht empfohlen nicht empfohlen nicht empfohlen

*Bei Alter >80 Jahre oder gleichzeitig Verapamil: 2x110mg. Bei Alter 75-80 Jahre, mäßig beeinträchtigter Nierenfunktion, Gastritis /Ösophagitis/Reflux , erhöhtem Blutungsrisiko: individuelle Entscheidung über Dosisreduktion.

**Bei 2 von 3 Kriterien (Alter >80 Jahre, Körpergewicht <60kg, Serumkreatinin >1,5mg/dl): 2x2,5mg

***Bei Körpergewicht <60kg oder gleichzeitiger Gabe von bestimmten P-gp-Inhibitoren: 1x30mg

Primary Prevention of Stroke in Chronic Kidney Disease Patients: A Scientific Update

Primary Prevention of Stroke in CKD 35Cerebrovasc Dis 2018;45:33–41DOI: 10.1159/000486016

CKD patients treated with warfarin have a labile interna-tional normalized ratio with a significantly lower time-in-therapeutic range and a higher adverse events risk [15].

The novel non-vitamin K antagonist oral anticoagu-lants (NOACs) are associated with lower risks for stroke and major bleeding compared to warfarin in patients with mild and moderate renal impairment [16]. Nonetheless, definite dose adjustment is needed as they have variable renal elimination (Table 1) [10]. The 2016 ESC guidelines do not support the use of NOACs in CKD stages 4 and 5 due to the lack of evidence [10], but the European Medi-cines Agency and the Food and Drug Administration also spread the indications to CKD stage 4 based on pharma-cokinetic studies (Table 1) [9].

ESRD PatientsIn the absence of RCTs regarding stroke prevention in

dialysis patients with AF, the decision to use oral antico-agulants should be made on an individual basis [11]. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) controversies report published in September 2017 is the first official taskforce that discusses the existing observational studies that ex-amine warfarin use and associated stroke and bleeding risks in adults with CKD-5D and AF [17]. Strict monitor-

ing due to the increased bleeding risk is mandatory (the KDOQI clinical practice guidelines for CVD in dialysis patients) [18].

Warfarin was reported to increase the risk of major bleeding by 30% in ESRD without having any effect on the risk of stroke [12]. Since the ESC and the European Med-icines Agency do not support the use of NOACs in ESRD due to lack of sufficient data (Table 1) [9, 10] and there are no RCTs of NOACs in patients with severe CKD, warfarin still remains the only choice for oral anticoagulation [10]. Nonetheless, Food and Drug Administration supple-mented the indications for apixaban and low dose of riva-roxaban usage in dialysis patients based on pharmacoki-netic and pharmacodynamic studies (Table 1) [9, 19].

Ischaemic and Bleeding Risk StratificationThe use of individualized stratification models should

be encouraged as refraining CKD patients from standard therapies (“therapeutic nihilism”) worsens their progno-sis [9, 20].

Reinecke et al. [20] have proposed a stratification algo-rithm for CKD patients (Fig. 2) to better identify those that would mostly benefit from anticoagulation: if [1] CHADS2 score (Congestive heart failure, Hypertension, age ≥75 years, Diabetes mellitus, Stroke [double weight])

Table 1. NOACs use in AF and CKD: dosage and administration according to EMA and FDA

Dabigatran Rivaroxaban Apixaban Edoxaban

eGFR ≥50 mL/min(CKD 1–3A)

EMA 150 mg twice daily 20 mg once daily 5 mg twice daily 60 mg once dailyFDA

eGFR = 15–49 mL/min(CKD 3B–4)

EMA 30–49 mL/min: 150 mg or 110 mg twice daily if high bleeding risk15–29 mL/min: NR

15 mg once daily 30–49 mL/min: Reduce to 2.5 mg twice daily if 2 of: – Creatinine ≥1.5 mg/dL– Age ≥80 years– Body weight ≤60 kg15–29: 2.5 mg twice daily

30 mg once daily

FDA 30–49 mL/min: 150 mg twice daily15–29: 75 mg twice daily

Reduce to 2.5 mg twice daily if 2 of:– Creatinine ≥1.5 mg/dL– Age ≥80 years– Body weight ≤60 kg

eGFR <15 mL/min(CKD 5 and dialysis)

EMA NR NR NR NRFDA 15 mg once daily Reduce to 2.5 mg twice daily if:

– Age ≥80 years or– Body weight ≤60 kg

Adapted from Burlacu et al. [9] and according to prescribing information for dabigatran, rivaroxaban, apixaban and edoxaban avail-able at http://www.ema.europa.eu and www.accessdata.fda.gov.

CKD, chronic kidney disease; EMA, European Medicines Agency; FDA, Food and Drug Administration; NOACs, non-vitamin K antagonist oral anticoagulants, NR, not recommended.

Cerebrovasc Dis 2018;45:33–41

Novel oral anticoagulants in patients with chronic kidney disease and atrial fibrillation

NDT 2017;online

determined by the ESC algorithm [12]. The recommendationregarding a reduced dose of NOACs in CKD is based on sec-ondary analyses of the Phase 3 NOACs trials. TheRandomized Evaluation of Long-term AnticoagulationTherapy (RE-LY) trial assessed two fixed doses of dabigatranversus warfarin. Compared with warfarin, dabigatran 150 mgsignificantly reduced the event rates of stroke and systemicembolism, whereas non-inferiority was shown for the dose of110 mg [13]. Major bleeding episodes were significantlyreduced only at the 110 mg dose. A subgroup analysis of theRE-LY trial, which focused on patients with a GFR of 30–49 mL/min, demonstrated a lower risk of stroke/systemicembolism and a similar risk of major bleeding with dabiga-tran compared with warfarin [14] (Figure 3). In a secondary

analysis of the ROCKET-AF trial among patients with mildor moderate renal impairment, rivaroxaban preserved thebenefit of warfarin in preventing stroke and systemic embo-lism, while bleeding events were similar and fatal bleedingoccurred less often with rivaroxaban [15]. With respect toapixaban, in a secondary analysis of the ARISTOTLE study,where the risk of systemic thromboembolism and bleedingwas evaluated in relation to renal function, apixaban wasmore effective than warfarin in preventing stroke and sys-temic thromboembolism and reducing the incidence of majorbleeding. Patients with a GFR! 50 mL/min demonstratedthe greatest benefit [19] (Figure 3). Finally, Bohula et al. [17]assessed the efficacy and safety of edoxaban (60 mg daily or30 mg daily if GFR< 30–50 mL/min) versus warfarin in the

FIGURE 2: Dose adjustments of NOACs according to renal function.

FIGURE 3: (A) Annual event rate of stroke or systemic embolism at different stages of CKD as reported by the RE-LY trial [14], theROCKET-AF trial [15], the ARISTOTLE trial [16] and the ENGAGE AF-TIMI 48 trial [17]. (B) Annual event rate of major bleeding events atdifferent degrees of renal impairment and in the whole study population based on the RE-LY trial, the ROCKET-AF trial, the ARISTOTLE trialand the ENGAGE AF-TIMI 48 trial. Adapted from Reinecke et al. [18].

Novel oral anticoagulants 3Downloaded from https://academic.oup.com/ndt/advance-article-abstract/doi/10.1093/ndt/gfx322/4682924by Universitaet Heidelberg useron 18 February 2018

Anticoagulation, atrial fibrillation, and chronic kidney disease—whose side are you on?

KI 2017;91:778-80

presumably related to adverse cardio-vascular events and CKD progression.5

The absence of prospective, ran-domized, controlled trials stimulatedseveral groups to conduct retrospectivecohort analyses to assess the benefit(if any) of OAT in nondialysis CKDand end-stage renal disease patients.Focusing on administrative registrydata, these analyses yielded conflictingfindings: some early analyses suggestedno benefits of OAT because the strokerisk was not reduced in the total cohort,and in elderly patients, the stroke inci-dence even increased with OAT. Incontrast, others found a benefit ofanticoagulation in terms of effective riskreduction for strokes.6 In the currentissue of Kidney International, Keskarand colleagues7 place this degree ofconfusion and uncertainty at evenhigher levels. Analyzing data from aCanadian health care database, theauthors claim that among elderly AFpatients with an estimated GFR (eGFR)#45 ml/min per 1.73 m2, OAT (unex-pectedly) did not substantially affect theischemic stroke rate, but (expectedly)induced more hemorrhages. Despitethese sober findings, total mortality waslower with OAT.7 In the absence ofdata on cause-specific death, we canonly hypothesize potential explanationsfor this puzzling finding, which maycomprise a lower rate of severe (life-limiting) strokes with OAT, a lower rateof atherosclerotic events, or pure play ofchance, driven by the relatively shortfollow-up period.

Of note, cohort analyses cannotprovide the same evidence level asrandomized, controlled trials, and datafrom administrative registries areparticularly imprecise and prone tobias. Their quality, which substantiallydepends on the correctness of datainput by health care providers, fallsbehind that of specifically designedprospective cohort studies such as CRIC(Chronic Renal Insufficiency Cohort)study and GCKD (German ChronicKidney Disease) study, let alone inter-ventional trials. As 1 example, inadministrative registries, comorbiditiessuch as vascular disease, hypertension,and diabetes mellitus are not recorded

in a systematic and standardized way bytreating physicians, which precludes areliable calculation of thromboembo-lism (CHA2DS2-VASc) and bleedingrisk scores.

Thus, even with comprehensive andsophisticated adjustments, all these un-controlled data are influenced bypotentially neglected residual con-founders and are unable to present morethan an idea of the safety and efficacy of aparticular treatment. Obviously,although these Canadian registry datafurther question the usefulness of OATfor stroke prevention in AF patients witha GFR <45 ml/min per 1.73 m2, thepotential survival benefits with OATfuels the discussion about the need for arandomized, controlled trial in thissetting.

With the currently limited evidence,clinical practices yield diverse standardoperating procedures, dividing treatingphysicians into “believers” and “non-believers” regarding OAT for the pri-mary prevention of embolism in AFpatients with CKD. In our experience,nephrologists are more cautious andreluctant, whereas cardiologists tend tomore willingly transfer guideline-basedrecommendations from the general

population to the CKD scenario. Thisdiscrepant approach is reflected by theirsociety’s recommendations, which aremore cautious in nephrology8 than incardiology.1

As a second limitation, most pub-lished registry analyses of OAT amongCKD patients with AF collecteddata in an era when few patientsreceived NOACs.6,7 In the meantime,outside the field of nephrology, large-scale clinical trials found NOACs to beat least as efficient as VKA for theprevention of thromboembolic eventsand at least as safe. In particular,the risk of intracerebral bleeding ismuch lower with NOACs than withVKAs.

The benefit-to-risk ratio of NOACsreveals relevant interactions with renalfunction both in the upper and thelower GFR range.9 Fortunately, we nowhave subgroup analyses from all thelarge NOAC trials that prove non-inferiority (partly even superiority) ofall approved NOACs compared withwarfarin in patients with mild to mod-erate CKD (down to patients with acreatinine clearance of 25 to 30 ml/min,roughly corresponding to CKD stagesG3a and G3b).9

Indication for oralanticoagulation as strokeprevention in AF(if risk factor[s] present)

Efficacy and safety ofNOACs versus vitamin Kantagonists (VKA)

Association betweenstroke risk andrenal function in AF

Association betweenbleeding risk andrenal function in AF

RCT(s) in the general population:Broad evidence that OAT reduces

stroke risk

RCT: NOACs noninferior(in some cases superior) to VKAs

RCT initiatedResults not yet available in 2017

Mind potential risk ofaccumulation of NOAC

Risk of stroke and systemic embolism

Bleeding risk

Prevalence of atrial fibrillation

NKDCKD G1CKD G2

CKD G3a CKD G3b CKD G4 CKD G5

Cohort studies:Contradictory data and

potentially more strokes inCKD stage G5 with OAT

Figure 1 | Schematic summary of current evidence on oral anticoagulant therapy (OAT)for patients with atrial fibrillation (AF) across the spectrum of chronic kidney disease(CKD). NKD, no known kidney disease; NOACs, non–vitamin K antagonist oral anticoagulants;RCT(s), randomized controlled trial(s); VKA, vitamin K antagonists.

commenta ry


Recent Advances in Stroke Prevention in Patients with Atrial Fibrillation and End-Stage Renal Disease

Cardiorenal Med 2017;7:207–217

212Cardiorenal Med 2017;7:207–217

DOI: 10.1159/000470856

Ronco et al.: Recent Advances in Stroke Prevention in Patients with Atrial Fibrillation and End-Stage Renal Disease

www.karger.com/crm© 2017 S. Karger AG, Basel

for transcatheter LAA occlusion. The PROTECT-AF [50–52] is a multicenter, prospective randomized clinical trial comparing Watchman device with long-term warfarin therapy. It demonstrated the noninferiority of the Watchman device to traditional medical therapy using stroke, cardiovascular or unexplained death and systemic embolism as the primary end point at 1 year follow-up. The PROTEC-AF trial achieved statistical superiority for the composite primary efficacy end point at 4 years of follow-up. In this trial, the rate of procedure-related serious cardiovascular complications was 8.7%, mainly due to periprocedural pericardial effusion. The number of procedural adverse events was higher in the early period of device implantation. In the PREVAIL [53] study, implant success rate increased to 95% (from 90% of PROTECT) and procedural adverse events at 7 days decreased to 4.4%. A meta-analysis by Holmes et al. [54] included 2,406 patients with 5,931 patient-years of follow-up from the PROTECT-AF and the PREVAIL trials (and their respective continued access registries). They concluded that in patients with nonvalvular AF at increased risk for stroke or bleeding who are candidates for chronic anticoagulation, LAA occlusion with watchman device resulted in decreased rates of hemorrhagic stroke, cardiovascular/unexplained death, and nonproce-dural bleeding compared to warfarin.

The Amulet device (AGA; St Jude Medical, Minneapolis, MN, USA, Fig. 1 b), a newer model of the Amplatzer Cardiac Plug (ACP) device, is a self-expanding nitinol occluder of the LAA consisting of a lobe with fixation barbs (that anchors the prosthesis inside the appendage), a disk that seals the ostium of the appendage and a waist (that connects the lobe to the disk). Most of the clinical evidence for ACP and Amulet devices is from pooled multicenter registry data outside the US. A pooled analysis of 1,047 consecutive patients from 22 centers, reports a procedural success of 97.3% with 5% of periprocedural major adverse events [55] . Santoro et al. [56] reported an ischemic stroke rate of 0.8/100 person-years, an embolic event rate of

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Fig. 1. a The Watchman device (Boston Scientific, Marlborough, MA, USA). b The Amulet device (St Jude Medical, St Paul, MN, USA). c The Ultrasept LAA Occluder (Cardia Inc., Eagan, MN, USA). d The Wavecrest de-vice (Coherex Medical, Salt Lake City, UT, USA). e The Occlutech LAA Occluder (Occlutech International AB, Helsingborg, Sweden). f The Lariat device (SentreHEART, Palo Alto, CA, USA). g The LAmbre LAA closure system (Lifetech Scientific Corp., China).

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Primary Prevention of Stroke in CKD 37Cerebrovasc Dis 2018;45:33–41DOI: 10.1159/000486016

composition changes (less collagen, more calcified) and this explains the 3-fold higher prevalence of remote cerebrovas-cular events in these patients compared to non-CKD [21].

Specific guidelines for the medical treatment of carot-id stenosis (CS) in CKD do not exist. The American Heart

Association/American Stroke Association guidelines al-low the use of aspirin for preventing a first stroke when eGFR is under 45 mL/min/1.73 m2, but not for CKD stag-es 4 and 5 [22]; at the same time, the Kidney Disease Im-proving Global Outcomes (KDIGO) 2012 guidelines sug-

Paroxysmal, persistant or permanent atrialfibrillation in patients with renal disease

(calculated GFR <60 ml/min/1.73 m2)

CHADS2 score

Cardiac failureHypertensionAge ≥75 years

DiabetesStroke (double)

CHADS2 score ≥2 points

Yes

No

No

≥1 point*

CHADS2 score <2 points

Age ≥75 years

Age 65–74 yearsFemale sexVascular heart disease

High bleeding risk

No oral anticoagulation

Use of platelet-inhibitors in patients withCHD or PVD or CVD as recommendedaccording to guidelines

Consider bleeding risk (HAS-BLED score)

HypertensionAbnormal renal and/orliver functionStroke

Previous bleedingsLabile INRsElderly (age >65 years)Drugs or alcohol

Additional factors: recurrent falls, dementia,active malignancies

Low to intermediatebleeding risk

Oral anticoagulation

New oral anticoagulants• Only in patients with eGFR >30 mL/min or >25 mL/min for apixaban, respectively• Consider different dosages depending on CKD stages as indicated in the drug information• Control serum creatinine/eGFR regularlyNo special recommendation for any of the 3drugs could be made in CKD patients at current

Warfarin/phenprocoumon (independant of eGFR)• Target INR 2.0–2.5• No starting dose of more than 5 mg/day• Determine first INR after two doses• During the first month, control INR three times a week• During long-term treatment, control INR at least every 14 days

Fig. 2. Risk stratification algorithm for anticoagulation in CKD ac-cording to Reinecke et al. [20] (reproduced with permission of the publisher. ©Stroke, Lippincott Williams and Wilkins 2013). CKD, chronic kidney disease; CVD, cerebrovascular disease; eGFR, esti-

mated glomerular filtration rate; INR, international normalized ratio; PVD, peripheral vascular disease; NOACs, non-vitamin K antagonist oral anticoagulants; VKAs, vitamin K antagonists.

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Cerebrovasc Dis 2018;45:33–41

Novel oral anticoagulants in patients with chronic kidney disease and atrial fibrillation

NDT 2017;online

vitamin K antagonism with low-dose rivaroxaban (10 mg/day)in haemodialysis patients with non-valvular AF. This trial hasanother very interesting arm of rivaroxaban plus high-dosevitamin K [47]. Unfortunately, none of these trials in dialysispatients included a third arm, namely, no oral anticoagulationor intervention.

C O N C L U S I O N

Decisions on whether and which type of oral anticoagulant touse in patients with CKD and AF are strongly affected by theCKD stage. In CKD Stage 3, there is some, albeit not consistent,evidence that NOACs exhibit greater efficacy and/or bettersafety compared with warfarin. However, this comes at a sub-stantial financial burden given the high price of NOACs com-pared with warfarin and the high numbers needed to treat toprevent one thromboembolic event or one bleeding episode.Importantly, patients receiving NOACs need regular checks oftheir renal function to avoid overdosing on NOACs, in particu-lar in situations prone to acute-on-chronic kidney injury. Insuch patients, apixaban, at least theoretically, should be the saf-est of the licensed NOACs given its relatively low renal elimina-tion. In more advanced CKD, i.e. Stage 4 and particularly inStage 5, NOACs are currently not recommended given the pauc-ity of RCT data [13, 20, 48, 49] and concerns of overdosing withthe risk of bleeding and anticoagulant-related nephropathy. Ifrisk stratification suggests that oral anticoagulation is indicated[26, 50], VKAs should be used instead of NOACs in CKD Stage4 and 5 patients until more clinical data are available. In ouropinion, dialysis-dependent CKD with AF is an exception tothis recommendation, given the conflicting data on the efficacyand major concerns about the safety of vitamin K antagonism indialysis patients (Figure 4).

C O N F L I C T O F I N T E R E S T S T A T E M E N T

None declared.

R E F E R E N C E S

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2. Alonso A, Lopez FL, Matsushita K et al. Chronic kidney disease is associatedwith the incidence of atrial fibrillation: the Atherosclerosis Risk inCommunities (ARIC) study. Circulation 2011; 123: 2946–2953

3. Go AS, Fang MC, Udaltsova N et al. Impact of proteinuria and glomerularfiltration rate on risk of thromboembolism in atrial fibrillation: the anticoa-gulation and risk factors in atrial fibrillation (ATRIA) study. Circulation2009; 119: 1363–1369

4. Reinecke H, Brand E, Mesters R et al. Dilemmas in the management of atrialfibrillation in chronic kidney disease. J Am Soc Nephrol 2009; 20: 705–711

5. Limdi NA, Beasley TM, Baird MF et al. Kidney function influences warfarinresponsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912–921

6. Schlieper G, Westenfeld R, Kruger T et al. Circulating nonphosphorylatedcarboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol2011; 22: 387–395

7. Kooiman J, van der Hulle T, Maas H et al. Pharmacokinetics and pharmaco-dynamics of dabigatran 75 mg b.i.d. in patients with severe chronic kidneydisease. J Am Coll Cardiol 2016; 67: 2442–2444

8. Wilson JA, Goralski KB, Soroka SD et al. An evaluation of oral dabigatranetexilate pharmacokinetics and pharmacodynamics in hemodialysis. J ClinPharmacol 2014; 54: 901–909

9. Olesen JB, Lip GY, Kamper AL et al. Stroke and bleeding in atrial fibrillationwith chronic kidney disease. N Engl J Med 2012; 367: 625–635

10. Providencia R, Marijon E, Boveda S et al. Meta-analysis of the influence ofchronic kidney disease on the risk of thromboembolism among patientswith nonvalvular atrial fibrillation. Am J Cardiol 2014; 114: 646–653

11. Hart RG, Pearce LA, Asinger RW et al. Warfarin in atrial fibrillationpatients with moderate chronic kidney disease. Clin J Am Soc Nephrol 2011;6: 2599–2604

12. Heidbuchel H, Verhamme P, Alings M et al. Updated European HeartRhythm Association practical guide on the use of non-vitamin-K antagonistanticoagulants in patients with non-valvular atrial fibrillation: executivesummary. Eur Heart J 2017; 38: 2137–2149

13. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin inpatients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151

14. Hijazi Z, Hohnloser SH, Oldgren J et al. Efficacy and safety of dabigatrancompared with warfarin in relation to baseline renal function in patientswith atrial fibrillation: a RE-LY (Randomized Evaluation of Long-termAnticoagulation Therapy) trial analysis. Circulation 2014; 129: 961–970

15. Fox KA, Piccini JP, Wojdyla D et al. Prevention of stroke and systemicembolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011;32: 2387–2394

16. Hijazi Z, Hohnloser SH, Andersson U et al. Efficacy and safety of apixabancompared with warfarin in patients with atrial fibrillation in relation to renalfunction over time: insights from the ARISTOTLE randomized clinical trial.JAMA Cardiol 2016; 1: 451–460

17. Bohula EA, Giugliano RP, Ruff CT et al. Impact of renal function on out-comes with edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation 2016;134: 24–36

18. Reinecke H, Engelbertz C, Schabitz WR. Preventing stroke in patients withchronic kidney disease and atrial fibrillation: benefit and risks of old andnew oral anticoagulants. Stroke 2013; 44: 2935–2941

19. Hohnloser SH, Hijazi Z, Thomas L et al. Efficacy of apixaban when com-pared with warfarin in relation to renal function in patients with atrial fibril-lation: insights from the ARISTOTLE trial. Eur Heart J 2012; 33: 2821–2830

20. Giugliano RP, Ruff CT, Braunwald E et al. Edoxaban versus warfarin inpatients with atrial fibrillation. N Engl J Med 2013; 369: 2093–2104

21. Harel Z, Sholzberg M, Shah PS et al. Comparisons between novel oral anti-coagulants and vitamin K antagonists in patients with CKD. J Am SocNephrol 2014; 25: 431–442

22. Nielsen PB, Lane DA, Rasmussen LH et al. Renal function and non-vitaminK oral anticoagulants in comparison with warfarin on safety and efficacyoutcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol 2015; 104: 418–429

23. Del-Carpio Munoz F, Gharacholou SM, Munger TM et al. Meta-analysis ofrenal function on the safety and efficacy of novel oral anticoagulants foratrial fibrillation. Am J Cardiol 2016; 117: 69–75

• NOACs recommended; apixaban possibly safer• Consider increased cost and high number needed to treated

• NOACs not recommended• VKAs recommended

• NOACs not recommended• VKAs recommended in non-dialysis patients

GFR30-60 mL/min

GFR15-30 mL/min

GFR < 15 mL/min

FIGURE 4: Suggested anticoagulation indications in patients withrenal impairment and non-valvular AF.

6 E. Stamellou and J. FloegeDownloaded from https://academic.oup.com/ndt/advance-article-abstract/doi/10.1093/ndt/gfx322/4682924by Universitaet Heidelberg useron 18 February 2018

Zusammenfassung

• Bedeutung und Häufigkeit VHF bei CKD

• Unterschiede CKD 2-4 und 5D

• Antikoagulation

• Phenprocoumon versus NOAKs

• Empfehlung Vorgehen

37

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Antikoagulation bei VHF und CKD - Robert-Bosch-Hospital...bei Vorhofflimmern und CKD Mark Dominik Alscher Robert-Bosch-Krankenhaus Email: [email protected]. Agenda • Bedeutung