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Published ahead of print on September 27, 2006
Clin J Am Soc Nephrol 1: 1357-1359, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.01700506
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Diagnostic & Therapeutic Corner

Should Dialysis Patients Ever Receive Warfarin and for What Reasons?

William M. Bennett

Northwest Renal Clinic, Portland, Oregon

Address correspondence to: Dr. William M. Bennett, Northwest Renal Clinic, Transplant Services, Legacy Good Samaritan Hospital, 1040 NW 22nd Avenue, Suite 480, Portland, OR 97210. Phone: 503-413-7349; Fax: 503-413-6563; E-mail bennettw{at}lhs.org


   Introduction
Top
 Introduction
Conclusion
 References
 
It has been common practice for dialysis patients with problematic vascular access to receive warfarin for the purposes of keeping the access functional. This, of course, increases the risk for bleeding. Also, in light of new knowledge, vascular calcification may be enhanced by warfarin (1). Therefore, a reexamination of this common practice seems warranted because the efficacy of anticoagulation for access maintenance has never been established. The available evidence does not allow an evidence-based approach. Therefore, this article is an opinion, based on what is published. The issue obviously warrants a prospective study because the clinical practice is widespread.

The most common indication for prescribing warfarin in hemodialysis patients is to maintain vascular access. In dialysis patients with comorbid rhythm disturbances such as atrial fibrillation or patients with prosthetic valves, warfarin may be indicated to prevent stroke. The benefit/harm ratio for this indication needs to be considered separately because the efficacy of warfarin to prevent thromboembolism is well established. A small percentage of warfarin use in ESRD is in patients who have documented hypercoagulable states.

The major risk of warfarin in dialysis patients obviously is bleeding, adding to the already present uremic platelet dysfunction that accompanies progressive chronic renal disease. Another major issue regarding warfarin use in dialysis patients is potential bleeding in the event of unplanned or emergency surgery, such as in patients who are awaiting deceased-donor renal transplant. In these cases, surgery may be necessary before the warfarin can be withdrawn. In this situation, even fresh-frozen plasma and vitamin K do not fully reverse the patient’s anticoagulation. In the general population, a rare complication of warfarin is dramatic skin necrosis, presumably as a result of vitamin K deficiency. Risk factors for this adverse reaction are proteins C and S deficiencies and diffuse vascular disease. Because protein S frequently is reduced in patients chronic kidney disease (stage 5) or in protein-losing states such as nephrotic syndrome, the risk for this rare complication of warfarin may be enhanced.

Warfarin is rapidly absorbed from the gastrointestinal tract. It is 99% bound to protein, specifically albumin. It has a half-life of approximately 40 h, although certain factors such as factor VII are inhibited more rapidly (half-life of 5 h), whereas factors IX, II, and X have half-lives of 24 to 48 h. When the shorter acting coagulation factors are inhibited, the international normalized ratio (INR) is abnormal but the patient needs an additional 4 to 5 d to become fully anticoagulated because of the slower effect of warfarin on other coagulation factors. Common variables that affect warfarin anticoagulation are the amount of vitamin K in the diet, the acuity of illness, and, of course, liver function. In addition, the effects of vitamin K that are generated by intestinal bacteria can be markedly reduced by concomitant antibiotics. Warfarin has many drug–drug interactions usually via albumin binding/displacement or liver clearance effects. An INR of 2 to 3 is considered low-intensity anticoagulation, and 3 to 4.5 is considered high-intensity anticoagulation.

Warfarin inhibits a vitamin K epoxide reductase enzyme. This prevents {gamma} carboxylation of glutamic acid residues (2) (Figure 1). Warfarin’s activity on the epoxide enzyme reduces the number of residues added to 7 to 8 as opposed to the normal 10 to 13 per clotting factor molecule (2,3). Anticoagulation with warfarin represents a complex interaction of known procoagulant and anticoagulant proteins. It is beyond the scope of this article to review coagulation in detail except to say that protein C, antithrombin III, and protein S are major procoagulant stimuli that when deficient as a result of loss in the urine, failure of synthesis, or a lack of activity in various disease states can promote clotting.


Figure 1
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  		Figure 1. Interaction of warfarin and vitamin K. Illustration by Josh Gramling—Gramling Medical Illustration.

 
The published efficacy of warfarin anticoagulation in dialysis patients for access maintenance is unimpressive. Mokrzycki et al. (4) followed for 1 yr 105 patients who were randomly assigned to placebo versus minidose warfarin therapy. Eight catheters failed in each group, and there was no effect of warfarin on thrombosis-free survival or time to urokinase manipulation. Crowther et al. (5) in 2002 reported 107 patients who had polytetrafluoroethylene grafts and were randomly assigned to warfarin with INR between 1.4 to 1.9 versus placebo. The likelihood of vascular graft survival was increased in the placebo group, although this value was not statistically significant. There were five major bleeds in the warfarin patients and none in the placebo group. The examples from older literature suggested that anticoagulants in hemodialysis patients were a risk factor for subdural hematoma and other major hemorrhages (6,7). Another, more recent study examined tunneled catheters and compared aspirin versus warfarin versus neither. This was a nonrandomized trial of 63 patients. The number of open catheters at 120 d was 91% with aspirin, 73% with warfarin, and only 29% with neither (8). The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) study of US dialysis patients comprised a cohort of 900 fistula patients and 1944 vascular graft patients. Technical failure within 30 d was excluded from analysis. Taking aspirin after a previous access failure was associated with better secondary graft patency with a relative risk of 0.7 (Figure 2). However, warfarin was worse in maintaining primary vascular grafts, with a relative risk of 1.33 for failure. These studies, of course, may be severely confounded by the selection of patients who were at high risk for the warfarin interventions (9). A recent study by Ziai et al. (10) examined the effect of warfarin on clotting of the dialyzer. This was a randomized, crossover study of 10 warfarin-treated patients that compared low molecular weight heparin versus no additional anticoagulation for the purpose of dialysis. The authors showed that an INR between 2 to 3 was insufficient to prevent dialyzer clotting on the basis of observation and D-dimer measurement.


Figure 2
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  		Figure 2. Secondary (assisted survival) patency for grafts by drug therapy (aspirin [dashed line] versus no aspirin [solid line]). Survival estimates are adjusted for age, gender, race, body mass index, incidence to ESRD, diabetes, hypertension, valvular disease, chronic obstructive pulmonary disease, aortic aneurysm, deep venous thrombosis, and number of previous permanent accesses.

 
For atrial fibrillation and cardiac indications, the literature stratifying dialysis patients for efficacy of warfarin prophylaxis is sparse (11). Wiesholzer et al. (12) assessed retrospectively 430 chronic hemodialysis patients for >1100 patient-years. In the general population, the incidence of stroke in patients with atrial fibrillation is 1 in 100 patient-years. The stroke incidence in hemodialysis patients is approximately 2.8 per 100 patient-years. The risk factors for stroke were age, diabetes, hypertension, weight gain on dialysis, and the use of warfarin. The use of warfarin with or without salicylates increased the risk of stroke 8.3-fold (12). Although not stated, these probably were hemorrhagic strokes.

There have been studies to assess how many patients with recurrent graft vascular access thrombosis have preexisting hypercoagulability disorders. O’Shea et al. (13) observed 31 patients with 199 thrombotic events in the previous year. Of these, 68% had anticardiolipin antibodies and 18% had heparin-induced antibodies. Warfarin was used in 13 of these patients, 10 of whom maintained efficacy of their access for >10 mo at the cost of five serious bleeding episodes. Warfarin also has been used in peritoneal dialysis patients to prevent systemic vascular events. A study by Kim et al. (14) in 2001 showed that in 76 peritoneal dialysis patients who were followed for 1 yr, 2 mg of warfarin daily versus a control group had no difference in cardiovascular deaths or major bleeding. As expected, there was a decrease in coagulation factors.

One of the newer issues that affect the use of warfarin in dialysis patients is the increasing knowledge regarding vascular calcification in these patients (1). It now is known that vascular calcification is a regulated process that is similar to bone formation. There are constitutive inhibitors of calcification such as matrix Gla protein in normal arterial walls. Vascular smooth muscle calcification is inhibited by matrix-bound vesicles that contain these inhibitors. The chronic use of warfarin may inhibit the inhibitors of endogenous mineralization by reducing vitamin K–dependent {gamma} carboxylation of involved proteins. Comparing warfarin and nonwarfarin therapy in patients without chronic kidney disease and with aortic valve disease found increased calcification in the former (15). There is a growing literature on these specific inhibitors of calcification. Suffice it to say that there are many of these, including various vitamin K–dependent secreted proteins such as growth arrest–specific gene 6 protein, which is a growth factor in vascular smooth muscle and mesangial cells (16). Warfarin interferes with the action of this protein at concentrations that are lower than necessary for anticoagulation. Warfarin may even be a risk factor for calciphylaxis (17).

With these known adverse effects of warfarin in patients with many comorbidities, it is clear that if warfarin is to be used in dialysis patients for the purpose of maintaining vascular access, then efficacy must be shown by a proper prospective, randomized trial. Although the "common sense" practice of using warfarin to prevent access thrombosis seems logical, such anticoagulation has no documented benefit to offset the risks of such therapy.


   Conclusion
Top
 Introduction
 Conclusion
References
 
Warfarin is of little proven benefit in dialysis patients, at least in those without defined hypercoagulable states. Bleeding complications are enhanced, and unplanned emergency surgeries such as deceased-donor renal transplantation are complicated. To answer the question posed in the title, my view is that until efficacy is proved, the answer to the question should be, "Practically never."


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


   References
Top
 Introduction
 Conclusion
 References
 

  1. Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg PL, Shanahan CM: Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: A potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol15 :2857 –2867,2004[Abstract/Free Full Text]
  2. Majerus PW, Tollefsen DM: Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th Ed., edited by Brunton LL, Lazo JS, Parker KL, New York, McGraw-Hill,2006 , pp1467 –1488
  3. Hirsh J: Mechanism of action and monitoring of anticoagulants. Semin Thromb Hemost12 :1 –11,1986[Medline]
  4. Mokrzycki MH, Jean-Jerome K, Rush H, Zdunek MP, Rosenberg SO: A randomized trial of minidose warfarin for the prevention of late malfunction in tunneled, cuffed hemodialysis catheters. Kidney Int59 :1935 –1942,2001[CrossRef][Medline]
  5. Crowther MA, Clase CM, Margetts PJ, Julian J, Lambert K, Sneath D, Nagai R, Wilson S, Ingram AJ: Low-intensity warfarin is ineffective for the prevention of PTFE graft failure in patients on hemodialysis: A randomized controlled trial. J Am Soc Nephrol13 :2331 –2337,2002[Abstract/Free Full Text]
  6. Leonard A, Shapiro FL: Subdural hematoma in regularly hemodialyzed patients. Ann Intern Med82 :650 –658,1975[Medline]
  7. Biggers JA, Remmers AR Jr, Gassford DM, Sarles HE, Lindley JD, Fish JC: The risk of anticoagulation in hemodialysis patients. Nephron18 :109 –113,1977[Medline]
  8. Obialo CI, Conner AC, Lebon LF: Maintaining patency of tunneled hemodialysis catheters. Scand J Urol Nephrol37 :172 –176,2003[CrossRef][Medline]
  9. Saran R, Dykstra DM, Wolfe RA, Gillespie B, Held PJ, Young EW: Association between vascular access failure and the use of specific drugs: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis40 :1255 –1263,2002[CrossRef][Medline]
  10. Ziai F, Benesch T, Kodras K, Neumann I, Dimopoulos-Xicki L, Haas M: The effect of oral anticoagulation on clotting during hemodialysis. Kidney Int68 :862 –866,2005[CrossRef][Medline]
  11. Lo DS, Rabbat CG, Clase CM: Thromboembolism and anticoagulant management in hemodialysis patients: A practical guide to clinical management. Thromb Res118 :385 –395,3006[CrossRef]
  12. Wiesholzer M, Harm F, Tomasec G, Barbieri G, Putz D, Balcke P: Incidence of stroke among chronic hemodialysis patients with nonrheumatic atrial fibrillation. Am J Nephrol21 :35 –39,2001[CrossRef][Medline]
  13. O’Shea SI, Lawson JH, Reddan D, Murphy M, Ortel TL: Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg38 :541 –548,2003[CrossRef][Medline]
  14. Kim SB, Lee SK, Park JS, Chi HS, Hong CD, Yang WS: Effects of fixed low-dose warfarin on hemostatic factors in continuous ambulatory peritoneal dialysis patients. Am J Kidney Dis37 :343 –347,2001[Medline]
  15. Koos R, Mahnken AH, Muhlenbruch G, Brandenburg V, Pflueger B, Wildberger JE, Kuhl HP: Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol96 :747 –749,2005[CrossRef][Medline]
  16. Yanagita M: Gas6, warfarin, and kidney diseases. Clin Exp Nephrol8 :304 –309,2004[CrossRef][Medline]
  17. Coates T, Kirkland GS, Dymock RB, Murphy BR, Brealey JK, Mathew TH, Disney APS: Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis32 :384 –391,1998[Medline]

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