JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 23, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.09.052
EDITORIAL COMMENT
Chronic Anticoagulation in Chronic Kidney Disease* Timothy Ball, MD,yz Kevin Wheelan, MD,yz Peter A. McCullough, MD, MPHyzxk
B
leeding in patients with chronic kidney
and the lack of adequately powered, randomized
disease (CKD) or “uremic bleeding” is a
controlled trials help to explain the equipoise in
well-recognized complication. It has been
recommendations on anticoagulation in patients with
described as far back as 1907 by Reisman (1), classi-
atrial fibrillation (AF) and CKD. In 2011, the Kidney Dis-
cally as a complication of Bright disease. The
ease Outcomes Quality Initiative committee changed
continued debate over the mechanism of this disease
from recommending anticoagulation for hemodialysis
only highlights the complicated biochemical milieu
patients with AF to recommending anticoagula-
that is present in the blood of patients with CKD.
tion only as secondary prevention and with close
SEE PAGE 2471
In this issue of the Journal, Bonde et al. (2) use the Danish national registries to explore which direction benefit risk is tipped in patients with CKD receiving chronic anticoagulation. There are at least 92 known uremic retention solutes (3), all of which likely play some role in the body’s essential biochemical functions, and many of which may play a role in the coagulation cascade and platelet function. A number of factors have been identified in CKD patients that promote as well as inhibit coagulation. The untreated patient with CKD is generally more prone to thrombosis; however, when treated with antiplatelet agents, heparin, warfarin, and novel anticoagulants, the same patient is more prone to bleed than is a patient with normal renal function. Figure 1 is a detailed, but not comprehensive list of the commonly identified processes involved (4–7). This complex biologic balance
monitoring (8). The investigators use an individual-level linkage of data from several Danish national patient registries to examine the outcomes of all patients discharged with nonvalvular AF from 1997 to 2011. A total of 154,259 patients were identified; 4,419 with pre-dialysis CKD, and 1,142 receiving renal replacement therapy. They examined 4 endpoints: composite of death or hospitalization from stroke or bleeding; composite of fatal stroke or fatal bleeding; cardiovascular death; and all-cause mortality. The study found anticoagulation in patients with CHA 2DS2-VASc (Congestive heart failure;
Hypertension;
Age
$75
years;
Diabetes
mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) score >2 to be associated with better outcomes at all levels of renal function. In predialysis patients, there was a reduction in composite endpoints of fatal stroke or fatal bleeding, cardiovascular death, and all-cause mortality. In renal replacement therapy patients, however, there was only a reduction in all-cause mortality, suggesting
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the yBaylor University Medical Center, Dallas, Texas; zBaylor Heart and Vascular Institute, Dallas, Texas; xBaylor Jack and Jane Hamilton
possible confounding by indication and not a therapeutic effect of stroke prevention. Whereas this work has significant limitations inherent to cohort studies, it is among the largest and
Heart and Vascular Hospital, Dallas, Texas; and kThe Heart Hospital,
most complete datasets analyzing this complex man-
Plano, Texas. Dr. Wheelan owns stock in Medtronic and Johnson &
agement question. The investigators acknowledge
Johnson; receives lecturing fees from Medtronic, Pfizer, and Boehringer Ingelheim; and receives research support from Medtronic and Boston
that even with rigorous review of the population to
Scientific. All other authors have reported that they have no relationships
ensure the cohorts were matched, it is impossible to
relevant to the contents of this paper to disclose.
eliminate some confounding factors. Interestingly, the
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Ball et al.
JACC VOL. 64, NO. 23, 2014 DECEMBER 16, 2014:2483–5
Chronic Anticoagulation in Chronic Kidney Disease
F I G U R E 1 Effects of CKD on the Coagulation Cascade
CKD related pro-coagulation CKD related anticoagulation
TF Trauma XII
TFPI
XIIa
TF
XIa
XI IX
VII
Heparin Cofactor II
VIII IXa VIIIa
VIIa X
X Xa
Prothrombin
Stabilized Clot
Fibrin
Fibrinogen
XIIIa
Activated Protein C PF3
Protein S Protein C + Thrombomodulin
tPA
Thrombin
Va V
PAI-1
Antithrombin
XIII
GSA ADP
Activated Platelets
PGl2
TxA2 GPIb/IX Receptor
vWF
TF
Platelets
The classic coagulation cascade with the dashed red lines demonstrating a negative effect of chronic kidney disease (CKD)-related factors, and the dashed slate lines demonstrating a positive effect on the indicated reaction or activation. The factors written in red are decreased in CKD, whereas the factors in slate are increased. ADP ¼ adenosine diphosphate; GPIb ¼ glycoprotein Ib; GSA ¼ guanidinosuccinic acid; PAI-1 ¼ plasminogen activator inhibitor-1; PGI2 ¼ prostacyclin; TF ¼ tissue factor; TFPI ¼ tissue factor pathway inhibitor; tPA ¼ tissue plasminogen activator; TxA2 ¼ thromboxane A2; vWF ¼ Von Willebrand factor.
overall rates of warfarin use were surprisingly low.
roughly double that of non-CKD patients. In all
Among those with no CKD, the rate of warfarin use was
groups there was a large (4-fold or more) increase in
23.6% despite 79.2% having a CHA 2 DS2-VASc score of 2
the rate of bleeding in those in CHA 2DS2 -VASc $2 with
or higher. For those with CKD and end-stage renal
a smaller step up for CKD and end-stage renal disease.
disease, warfarin was prescribed in fewer than 20% of
Thus, one would conclude on balance that there is a
patients. It is not known how many patients were
greater opportunity for benefit than harm when the
taking dabigatran, rivaroxaban, or apixaban, and thus
stroke risk is higher in AF in patients with background
a treatment effect from these agents cannot be
renal disease. This study provides powerful data
excluded. Certain assumptions were made due to
about the role of anticoagulation in CKD; however,
incomplete data. Elements of the CHA2DS2 -VASc score,
additional data are needed in CKD patients with AF to
including hypertension, diabetes, and heart failure,
better understand the role of antiplatelet agents,
were compiled based on available filled prescription
warfarin, and the novel anticoagulants. In addition,
data. Because as little as a 1-point difference in the
the optimal approach to AF and stroke prevention
CHA2DS 2-VASc score can change treatment recom-
with end-stage renal disease is still yet to be defined.
mendations, these assumptions carry great weight in
For now, these data are helpful to physicians in
the analysis. It is likely that this method un-
choosing warfarin in both advanced CKD patients and
derestimates patients’ risk and lowers the CHA 2DS2-
those on dialysis when the CHA2DS2 -VASc score is
VASc score in the database. With this limitation in
calculated.
mind, doctors must be very cautious in their interpretation of the reported mortality benefit found in pre-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
dialysis patients with a CHA 2DS2-VASc of >1.
Peter A. McCullough, Baylor Heart and Vascular
The results of this study suggest that at any CHA2DS 2-VASc score, the risk of stroke or embolism is
Institute, 621 North Hall Street, H030, Dallas, Texas 75226. E-mail:
[email protected].
Ball et al.
JACC VOL. 64, NO. 23, 2014 DECEMBER 16, 2014:2483–5
Chronic Anticoagulation in Chronic Kidney Disease
REFERENCES 1. Reisman D. Hemorrhages in the course of Bright’s disease, with especial reference to the occurrence of a hemorrhage diathesis of nephritic origin. Am J Med Sci 1907;134:709–12.
4. Adams MJ, Irish AB, Watts GF, Oostryck R, Dogra GK. Hypercoagulability in chronic kidney disease is associated with coagulation activation but not endothelial function. Thromb Res 2008;123:374–80.
coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study. J Am Soc Nephrol 2005;16: 529–38.
2. Bonde AN, Lip GYH, Kamper A-L, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study.
5. Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 2007;3:138–53.
8. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011;80:
J Am Coll Cardiol 2014;64:2471–82.
6. Sica D. The implications of renal impairment among patients undergoing percutaneous coronary
3. Vanholder R, De Smet R, Glorieux G, et al., for the European Uremic Toxin Work Group. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 2003;63: 1934–43.
intervention. J Invasive Cardiol 2002;14 Suppl B: 30B–7B. 7. Muntner P, He J, Astor BC, Folsom AR, Coresh J. Traditional and nontraditional risk factors predict
572–86.
KEY WORDS arrhythmia, atrial fibrillation, CHA2DS2-VASc score, chronic kidney disease, thromboprophylaxis, warfarin
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