Vitamin K Antagonists: Beyond Bleeding € ger, and Ju € rgen Floege Thilo Kru Division of Nephrology, Uniklinik RWTH Aachen, Aachen, Germany

ABSTRACT Warfarin is the most widely used oral anticoagulant in clinical use today. Indications range from prosthetic valve replacement to recurrent thromboembolic events due to antiphospholipid syndrome. In hemodialysis (HD) patients, warfarin use is even more frequent than in the nonrenal population due to increased cardiovascular comorbidities. The use of warfarin in dialysis patients with atrial fibrillation requires particular caution because side effects may outweigh the assumed benefit of reduced stroke rates. Besides increased bleeding risk, coumarins exert side effects which are not in the focus of clinical routine, yet they deserve special consideration in dialysis

patients and should influence the decision of whether or not to prescribe vitamin K antagonists in cases lacking clear guidelines. Issues to be taken into consideration in HD patients are the induction or acceleration of cardiovascular calcifications, a 10-fold increased risk of calciphylaxis and problems related to maintaining a target INR range. New anticoagulants like direct thrombin inhibitors are promising but have not yet been approved for ESRD patients. Here, we summarize the nontraditional side effects of coumarins and give recommendations about the use of vitamin K antagonists in ESRD patients.

Use of vitamin K antagonists in CKD and ESRD

and 2005, a rate of 0.7% of all deaths were due to pulmonary embolism compared to 0.5% in the control population representing an age- and sex-standardized mortality rate ratio of 12.2 compared with the general population (4). Third, the incidence of venous thrombosis is also increased, higher by 5.6fold in HD patients compared to healthy individuals (5). Atrial fibrillation (AF), however, is the most frequent reason for VKA treatment in ESRD (6,7). There is a bidirectional relationship between AF and CKD: the incidence of deteriorating kidney function is increased in patients with AF and vice versa. In CKD, AF occurs 2–3 times more often than in nonrenal patients (8,9) with around 20% suffering from AF (10) (and even these 20% may be an underestimation as 7-day ECGs are not routinely performed in HD patients); one-third of the patients with AF exhibits CKD (11). With decreasing GFR, the prevalence of atrial fibrillation gradually increases (10). The risk for stroke in patients with CKD is increased 1.5-fold compared to patients without kidney disease (11), and the annual rate of strokes in HD patients is around 7%, as shown in smaller trials (9,12). Finally, the coincidental occurrence of dialysis and AF influences not only morbidity but also mortality (13–16). In the indications mentioned above—mechanical heart valve and pulmonary embolism as well as recurrent thrombosis—the use of coumarins is still without alternative in ESRD patients. In contrast, in dialysis patients with AF, the indication for cou-

Vitamin K antagonists are still the drug of choice in many indications requiring chronic anticoagulation such as prosthetic cardiac valve replacement, recurrent thromboembolic events and pulmonary embolism as well as atrial fibrillation (AF). In hemodialysis (HD) patients, the use of vitamin K antagonists (VKA) is reported to be up to 37% (1) and is thus higher than in the normal population, likely reflecting the higher incidence of cardiovascular comorbidities requiring anticoagulation, as stated above. For example, valvular calcification is a common feature in HD patients as shown by several observations (2,3). As the incidence of CKD and ESRD increases, the incidence of mechanical valve replacements with the subsequent necessity of VKA is expected to follow an upward trend as well. Second, pulmonary embolism is more frequent in HD patients than in the non-CKD population despite repeated anticoagulation with heparins during HD. In a large cohort of incident dialysis patients from the ERA-EDTA registry, including over 130,000 dialysis patients from 11 countries between 1994 € ger, MD, Division of Address correspondence to: Thilo Kru Nephrology, Uniklinik RWTH Aachen Pauwelsstrasse 30, 52074 Aachen, Germany, Tel.: +49 241 8035425, Fax: +49 241 8082446, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 1 (January–February) 2014 pp. 37–41 DOI: 10.1111/sdi.12175 © 2014 Wiley Periodicals, Inc. 37

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marins is not as clear. The largest trial to date investigating incident dialysis patients with AF and VKA found an almost 2.4-fold higher risk for hemorrhagic stroke without reducing the risk for ischemic stroke compared to those without VKA (17). In contrast, in 2012 a large observational trial from Denmark revealed a reduced risk for strokes in patients with “renal replacement therapy” taking VKA (n = 901); this result may, however, be misleading as the group “renal replacement therapy” included not only HD but also patients on PD and after kidney transplantation (18,19). Finally, cardiologic guidelines recommending VKA in AF may not apply in HD; for example, the commonly used decision basis for anticoagulation in AF, namely the CHA2DS2-VASc score, has never been validated in HD patients. Thus, nephrologists need to balance the individual risk and benefit of whether or not to start vitamin K antagonists. Warfarin and Cardiovascular Calcification Vitamin K antagonists interfere with the vitamin K cycle which restores vitamin K after a carboxylation step by inhibition of the enzymes, DT diaphorase and vitamin K epoxide reductase (VKOR) (Fig. 1). The hepatic effects of VKA include the production of inactive, i.e., noncarboxylated, coagulation factors II, VII, IX and X and protein C, S and Z. Vitamin K-dependent carboxylation steps are also impaired in extrahepatic tissues and targets, amongst others, osteocalcin (OC) and matrix Gla protein (MGP). Matrix Gla protein, an approximately 10-kDa protein, is produced and secreted by osteoclasts and chondrocytes, but mainly by vascular smooth muscle cells of the arterial media. Similar to hepatic coagulation factors, MGP needs to undergo posttranslational gamma-glutamyl carboxylation to achieve full biological activity. If the vitamin K

The vitamin K cycle and its inhibition by vitamin K antagonists (VKA).

Figure 1. The vitamin K cycle and its inhibition by vitamin K antagonists.

cycle is blocked, inactive (i.e., undercarboxylated) MGP (ucMGP), accumulates. MGP is the most potent inhibitor of vascular calcification within the walls of large arteries. Absence of MGP in MGP / mice led to disturbed bone mineralization and the animals all died at about 8 weeks after birth because of the rupture of a severely calcified aorta (20). In humans, a loss-of-function mutation of the MGP gene results in Keutel syndrome, which is characterized by abnormal cartilage calcification and accelerated calcification of the aorta as well as coronary and cerebral arteries (21). UcMGP is detected in areas of vascular calcification (VC), whereas bioactive carboxylated (c)MGP is present in intact vessel walls (22). In rodents, functional depletion of vitamin K stores by coumarins resulted in VC of the arterial media (23,24) which in turn could be prevented by the coadministration of vitamin K (24,25). In humans, coumarins also significantly increased the prevalence and extent of aortic valve and coronary calcifications in patients with mild or no CKD (26,27). In HD patients, the long-term use of warfarin was associated with more severe aortic valve calcification (28). Data from our German calciphylaxis registry additionally indicate that treatment with warfarin is a risk factor for calciphylaxis (also termed calcific uremic arteriolopathy, CUA) as approximately half of all patients (180 to date) were treated with coumarins at the onset or immediately before CUA developed (29). Similarly, a Japanese survey reported a 10-fold increased risk for CUA in dialysis patients on VKA (30). Observational data revealed that dialysis patients are significantly more deficient in vitamin K than non-CKD patients (31,32). This observation may be due to the diet of HD patients, which is low in vitamin K (33). In addition, at least in rodents with CKD, we found an impaired activity of the enzyme gamma-carboxylase (Kaesler N et al., under submission), i.e., uremia per se is a “warfarin-like condition”. In these rodents, replenishment of vitamin K was able to increase the diminished enzyme activity and reduced prior increased levels of ucMGP. The latter was confirmed in a prospective pilot trial with dialysis patients. Here, vitamin K supplementation was dose-dependently able to reduce increased levels of the undercarboxylated proteins MGP as well as osteocalcin and PIVKA (prothrombin inactive in vitamin K absence) (32). We also demonstrated that low levels of circulating carboxylated MGP predict an increased mortality in these patients (34). Whether supplementation of vitamin K will indeed retard the progress of vascular calcification is the subject of our recently initiated randomized trial “VitaVasK” (www.clinicaltrials.gov, NCT01742273). Taken together, there is strong evidence that vitamin K antagonism causes and/or accelerates vascular calcification and CUA, especially in HD patients, a population which is per se at high risk of calcification contributing to its high mortality rate.

VITAMIN K ANTAGONISTS

Achieving and Maintaining INR Target Levels in ESRD It seems trivial to stress the importance of achieving the intended INR target. However, in reality, this goal is difficult to maintain: only around 60% of all INR measurements are within the desired range (35). Of note, not all trials assessing bleeding complications report how long their patients remained within the INR target range, and one might speculate that increased hemorrhage, at least in part, resulted from over anticoagulation. Frequent INR monitoring indeed led to a reduced risk of hemorrhages (36). HD patients may be particularly challenging in this respect because CKD affects the warfarin dose requirements and because INR values tend to fluctuate widely (37). One trial including 381 patients showed that patients with an eGFR between 30– 59 ml/minute (n = 300) needed a 9% lower dose of coumarin and those with an eGFR 60 ml/minute, to maintain INR values in the target range (38). This difference persisted after adjustment for clinical and genetic factors (39,40). Conversely, a trial investigating the change in INR values due to HD sessions found reduced INRs after HD indicating a need for higher warfarin dosages (7). However, blood contamination with locking solutions from central dialysis catheters can interfere with INR measurement when samples are collected directly from the catheter (41). All these circumstances render warfarin dosing and maintaining the target INR difficult in the HD population and might predispose to complications. An interesting approach to reduce INR variability resulting from inconsistent vitamin K intake was proposed in 2004. The authors tested whether a constant low vitamin K supplementation would reduce the amplitudes of INR levels. In a placebo-controlled trial including 200 Dutch patients receiving phenprocoumon, half of the patients received an additional supplementation with daily low-dose (100 lg/day) vitamin K. After 24 weeks of INR monitoring, patients with vitamin K coadministration remained within the therapeutic range for a longer period of time than control patients (89.5% vs. 85.5%, both exceptionally long times within target range stressing the value of close INR monitoring) (42). Whether this approach also results in a better INR control in HD patients is unknown. A thrice weekly administration of VKA in HD patients has also been tested (43). Here, 17 patients (487 patient weeks) took warfarin after each dialysis session and were compared with 20 patients (834 patient weeks) with daily warfarin administration. At the one-year follow-up, patients of the thrice weekly regimen showed significantly more weekly INR measurements within the target range (57% vs. 49%) and a slightly higher weekly warfarin dose

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(26  19 vs. 23  12 mg/week) than patients in the daily regimen. Despite the better INR control, the number of bleeding events, however, did not differ between both groups. A Personal Opinion on When to use Coumarins in ESRD Due to the unique situation of HD patients with uremic platelet dysfunction (44,45) and the thrice weekly anticoagulation during HD sessions, special attention is needed regarding VKA. Some indications in the general population for long-term VKA treatment, such as mechanical heart valves or recent pulmonary embolism, are without a doubt also valid in patients with CKD as well as ESRD, as stated above. In ESRD patients with persistent or intermittent atrial fibrillation, current guidelines from the European Society of Cardiology (ESC) provide little guidance and simply state that “CKD may increase the risk of thromboembolism in atrial fibrillation, although such patients are also at increased mortality and bleeding risk and have not been studied in prospective clinical trials” (46). Similarly, the 2005 K/DOQI (Kidney Disease Outcomes Quality Initiative) guideline states that “patients on dialysis exert an increased bleeding risk and require special attention” (47). Given this lack of guidance, we suggest separating the use of VKA in CKD and HD patients into three categories (also see Fig. 2): 1. Pro coumarins: As in the nonrenal population, we recommend VKA in CKD or ESRD patients for cases of pulmonary embolism, deep vein thrombosis (in both cases especially with an underlying antiphospholipid antibody syndrome) and prosthetic heart valve replacement. Whether single, idiopathic thromboembolic events require VKA—and for how long—is, however, unclear. 2. Contra coumarins: We do not recommend VKA for acute or recurrent fistula occlusions or dialysis catheter dysfunction. Although there

Figure 2. Suggested coumarin indications in patients with atrial fibrillation and ESRD. Boxes with solid frames: indications/benefit for coumarins, Boxes with dotted frames: contraindication/risk for coumarins.

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are reports of a benefit of this treatment (48,49), several trials indicate that systemic anticoagulation fails to reduce catheter complications or even show reduced patency rates (50,51), and even increases the risk of bleeding complications (52–54). Adequately designed trials addressing this topic are still needed. 3. Unclear evidence: We suggest dissecting the situation of VKA into two categories: First, in CKD patients not on HD, and especially in early CKD, the indications for coumarins are probably similar to those in the nonrenal population (11,18). In patients on dialysis and with atrial fibrillation, the evidence base for a benefit from coumarins is very limited (see above), INR targeting is difficult and the bleeding risk is increased (55–57). With the unknown riskbenefit ratio and definite increases in calcification progress and CUA risk, we currently do not use vitamin K antagonists in dialysis patients with atrial fibrillation. Conclusion VKA is still the mainstay of oral anticoagulation for several indications in both CKD and non-CKD patients. However, the loss of kidney function and dialysis entail specific complications in these patients. The challenges in maintaining INR target levels in patients with advanced CKD imply that if VKA are used in these patients, frequent INR monitoring will be necessary. Whether a simultaneous supplementation of VKA with vitamin K may reduce the time outside the INR target range, and possibly the burden of vascular calcification, needs to be addressed in larger clinical trials. However, in some common situations like fistula problems and particularly in dialysis patients with AF, we no longer use VKA. Conflicts of interest None declared. References 1. Winkelmayer WC, Levin R, Avorn J: Chronic kidney disease as a risk factor for bleeding complications after coronary artery bypass surgery. Am J Kidney Dis 41:84–89, 2003 2. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 1996;27:394–401. 3. Wang AY, Woo J, Wang M, Sea MM, Ip R, Li PK, Lui SF, Sanderson JE: Association of inflammation and malnutrition with cardiac valve calcification in continuous ambulatory peritoneal dialysis patients. J Am Soc Nephrol 12:1927–1936, 2001 4. Ocak G, van Stralen KJ, Rosendaal FR: Mortality due to pulmonary embolism, myocardial infarction, and stroke among incident dialysis patients. J Thromb Haemost 10:2484–2493, 2012 5. Ocak G, Vossen CY, Rotmans JI: Venous and arterial thrombosis in dialysis patients. Thromb Haemost 106:1046–1052, 2011 6. Thomson BK, MacRae JM, Barnieh L: Evaluation of an electronic warfarin nomogram for anticoagulation of hemodialysis patients. BMC Nephrol 12:46, 2011

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