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the acute DVT event, while 31% of the patients still had an abnormal CUS examination. This study indicates that MRDTI may potentially be an accurate method to distinguish a new recurrent event from an old thrombus in patients with acute suspected RDVT. However, this has to be evaluated in prospective management studies. In conclusion, this study showed that the use of the established diagnostic criteria of CUS is less clinically applicable in the daily diagnostic work-up of suspected ipsilateral RDVT. The associated high percentage of non-diagnostic CUS and related overdiagnosis and overtreatment indicates the urgent need for more accurate diagnostic methods and strategies in patients presenting with suspected ipsilateral RDVT. Acknowledgements This study has been funded by the Netherlands Heart Foundation. Grant number 2007B146. Disclosure of Conict of Interests The authors state that they have no conict of interest. References
1 Koopman MM, Buller HR, Ten Cate JW. Diagnosis of recurrent deep vein thrombosis. Haemostasis 1995; 25: 4957.

2 Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. Ann Intern Med 1998; 128: 66377. 3 Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, Noventa F, Benedetti L, Girolami A. A simple ultrasound approach for detecting of recurrent proximal-vein thrombosis. Circulation 1993; 88: 173035. 4 Prandoni P, Lensing AW, Bernardi E, Villalta S, Bagatella P, Girolami A. The diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis. Thromb Haemost 2002; 88: 40206. 5 Linkins LA, Stretton R, Probyn L, Kearon C. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous ow in patients with previous venous thrombosis. Thromb Res 2006; 117: 24147. 6 Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Perrier A, White RH, Vickars L, Rodger M. Validation of a diagnostic approach to exclude recurrent venous thromboembolism. J Thromb Haemost 2009; 7: 75259. 7 Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial. Ann Internl Med 2004; 141: 83945. 8 Westerbeek RE, Van Rooden CJ, Tan M, Van Gils AP, Kok S, De Bats MJ, De Roos A, Huisman MV. Magnetic resonance direct thrombus imaging of the evolution of acute deep vein thrombosis of the leg. J Thromb Haemost 2008; 6: 108792.

Prospective observational cohort study of bioaccumulation of dalteparin at a prophylactic dose in patients with peritoneal dialysis
P . S C H M I D , * 1 D . B R O D M A N N , 1 A . G . F I S C H E R and W . A . W U I L L E M I N *
*Division of Hematology and Central Hematology Laboratory, Department of Medicine, Luzerner Kantonsspital, Luzern; Division of Nephrology, Department of Medicine, Luzerner Kantonsspital, Luzern; and University of Bern, Bern, Switzerland

To cite this article: Schmid P, Brodmann D, Fischer AG, Wuillemin WA. Prospective observational cohort study of bioaccumulation of dalteparin at a prophylactic dose in patients with peritoneal dialysis. J Thromb Haemost 2010; 8: 8502. See also Schmid P, Brodmann D, Odermatt Y, Fischer AG, Wuillemin WA. Study of bioaccumulation of dalteparin at a therapeutic dose in patients with renal insufciency. J Thromb Haemost 2009; 7: 162932. Correspondence: Pirmin Schmid, Division of Hematology and Central Hematology Laboratory, Department of Medicine, Luzerner Kantonsspital, CH-6000 Luzern 16, Switzerland. Tel.: +41 41 205 51 47; fax: +41 41 205 21 97. E-mail: pirmin.schmid@gmx.net
1

Both authors contributed equally to this study.

DOI: 10.1111/j.1538-7836.2010.03749.x Received 18 November 2009, accepted 5 January 2010

Low-molecular weight heparins (LMWH) have been shown to be eective, safe and convenient for anticoagulation [1]. However, because of their pharmacokinetics, LMWH tend to accumulate in patients with renal insuciency (RI) [1,2], which results in an increased risk of bleeding [3,4]. Many LMWH have been shown to be safe for intermittent anticoagulation during haemodialysis [5,6]. Despite this, LMWH have not been well studied in patients with peritoneal dialysis (PD) [2]. In a
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Letters to the Editor 851

A Adjusted anti-Xa level ( 103) B 16 14 12 10 8 6 4 2 0 1 C 0.8 Peak anti-Xa level (U mL1) 4 7 10 13 Time (days) 16 19 * Adjusted anti-Xa level ( 103) 16 14 12 10 8 6 4 2 0 1 4 7 10 13 Time (days) 16 19

D Adjusted anti-Xa level ( 103) n = 14 5 1 Day 14 4 5

10

0.6

6 4

0.4

0.2

2 n = 14 0 1 Day 4 5 14 5

0.0

Fig. 1. The adjusted anti-Xa levels over time in the patients with peritoneal dialysis, n = 6 (A) and with normal renal function, n = 14 (B). All patients received prophylactic daily doses of dalteparin. One patient with peritoneal dialysis, marked with an asterisk, was excluded from further analysis because of the erroneous level observed on day 1, and so could not be used for comparison. However, the further course of anti-Xa levels shows no bioaccumulation. (C) Measured peak anti-Xa levels and (D) peak anti-Xa levels adjusted to applied dose and body weight on days 1 and 4. The group of patients with normal renal function is shown with continuous lines; the group of patients with peritoneal dialysis is shown with dashed lines.

rst case report, Schrader et al. [7] demonstrated the feasibility of therapeutic anticoagulation with dalteparin given intraperitoneally. Another case report of intraperitoneal treatment of venous thromboembolism (VTE) with enoxaparin in a child was published by Kleta et al. [8]. Enoxaparin has been studied in two single-dose pharmacokinetic studies [9,10], which reported similar anti-Xa levels in subjects with normal renal function and with PD. Single-dose studies have limited power in predicting bioaccumulation of LMWH in patients with RI undergoing long-term treatment. Generally, such studies underestimate LMWH bioaccumulation [11,12]. Furthermore, bioaccumulation data cannot be extrapolated from one LMWH to another because of their dierent pharmacokinetic properties [2]. To the best of our knowledge, there is no report of subcutaneous use of dalteparin in PD patients. The aim of the present study was to evaluate the pharmacokinetics of dalteparin at a prophylactic dose in PD patients. The method of this prospective observational cohort study has previously been described in detail [11]. Briey, patients treated with PD were included for the present study. The
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indication for prophylaxis with dalteparin was left to the treating physician. Dalteparin was injected subcutaneously once daily at a prophylactic dose. Patients with a glomerular ltration rate 60 mL min)1 1.73 m)2 and on prophylaxis for at least 4 days were used as a control group from the previous study [11]. Peak anti-Xa levels 4 1 h post LMWH administration were measured after the rst dose, and thereafter, every third day. Peak anti-Xa levels were adjusted to applied dose and body weight (adjusted anti-Xa). Bioaccumulation factor R was calculated as a quotient of the adjusted anti-Xa after the fourth and the rst day. Results are shown as median (interquartile range). Wilcoxons rank sum test was used for paired samples of values on day 1 and 4. MannWhitney U-test was used for independent samples. A P-value < 0.05 was considered significant. Statistical analysis was done with MedCalc (Mariakerke, Belgium). The study was approved by the local ethics committee and registered at clinicaltrials.gov, NCT00264693. Five patients (four men; anticoagulated for median 4 days, range 419) with PD and 14 patients (nine men; median 7 days, range 419) with normal renal function were analyzed on day 1

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and day 4 of prophylactic dalteparin treatment. One additional sixth PD patient was excluded from further analysis as a result of an erroneous outlying adjusted anti-Xa level on day 1 (shown in Fig. 1A). The median age of the patients was 65 years (interquartile range 5574); the median applied daily dose was 5000 U (50005000) in both groups; the weight adjusted daily dose was 60 U kg)1 (5374) for PD patients and 71 U kg)1 (5579) for patients with normal renal function (P = 0.71). Three PD patients had no residual renal function; two had residual renal functions of 2.5 and 4.1 mL min)1. The individual courses of adjusted anti-Xa levels are shown in Fig. 1A,B. Peak anti-Xa levels and adjusted anti-Xa levels on days 1 and 4 are shown in Fig. 1C,D. For patients with normal renal function, there was no difference in adjusted anti-Xa levels on day 1 [3.7 10)3 (3.24.5)] and day 4 [3.6 10)3 (2.9 4.6; P = 0.95)]. For patients with PD, there was a clear trend to increase from day 1 [4.7 10)3 (3.75.0)] to day 4 [5.8 10)3 (4.66.5; P = 0.0625)]. While the values of both groups were similar on day 1 (P = 0.21), the values of the PD group were signicantly higher on day 4 (P = 0.016). Calculated R was 1.23 (1.101.47) for PD patients and 0.96 (0.811.27) for control patients (P = 0.14). There were no bleeding events and no thromboembolic complications. The present study reports pharmacokinetic data of prophylactically dosed subcutaneous dalteparin in PD patients and shows a mild tendency of dalteparin to bioaccumulate over 4 days in patients with renal failure treated with peritoneal dialysis. The median applied dose was 5000 U per day, which is the standard prophylactic dose for patients with 50100 kg body weight. Residual renal function of the patients studied was minimal, which indicates that subcutaneously administered LMWH is nally cleared through the peritoneal dialysate as expected. The peritoneum has been shown to be permeable to LMWH as intraperitoneally applied dalteparin [7] and enoxaparin [8] resulted in adequate plasma anti-Xa levels. The study period was limited because of short hospitalization time of the investigated patients, which represents current practice. Nevertheless, the present results represent the longest study period of subcutaneously administered LMWH in patients with PD. The reported range of bioaccumulation suggests control of anti-Xa at least after 4 days to allow dose adjustments. The present data show, however, that a stable steady state may be maintained up to 19 days. In conclusion, dalteparin may be a suitable alternative to standard unfractionated heparin in patients with PD for prophylaxis of VTE although available data are still limited. Control of anti-Xa is recommended for dalteparin in PD patients. A dose reduction based on anti-Xa levels should be considered. A dose reduction scheme should be evaluated in a larger prospective study powered to evaluate clinical endpoints.

Acknowledgements We are indebted to all participating patients. We appreciate the professional support of the laboratory and nursing sta of the Luzerner Kantonsspital. This study was supported by unrestricted grants from Pzer Switzerland and the Luzerner Kantonsspital. Disclosure of Conict of Interests W.A. Wuillemin reports receiving lecture honoraries and consulting fees from GlaxoSmithKline, Pzer and SanoAventis. There is no other potential conict of interest relevant to this article. Registration at clinicaltrials.gov (ID: NCT00264693). References
1 Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 141S59S. 2 Schmid P, Fischer AG, Wuillemin WA. Low-molecular-weight heparin in patients with renal insuciency. Swiss Med Wkly 2009; 139: 438 52. 3 Sohal AS, Gangji AS, Crowther MA, Treleaven D. Uremic bleeding: pathophysiology and clinical risk factors. Thromb Res 2006; 118: 417 22. 4 Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: lowmolecular-weight heparin and bleeding in patients with severe renal insuciency. Ann Intern Med 2006; 144: 67384. 5 Lim W, Cook DJ, Crowther MA. Safety and ecacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol 2004; 15: 3192206. 6 Fischer KG. Essentials of anticoagulation in hemodialysis. Hemodial Int 2007; 11: 17889. 7 Schrader J, Tonnis HJ, Scheler F. Long-term intraperitoneal application of low molecular weight heparin in a continuous ambulatory peritoneal dialysis patient with deep vein thrombosis. Nephron 1986; 42: 834. 8 Kleta R, Frund S, Kuwertz-Broking E, Bulla M. Intraperitoneal application of low-molecular-weight heparin in continuous ambulatory peritoneal dialysis in a child. Nephron 2000; 86: 545. 9 Sil A, Mermut C, Yenicerioglu Y, Cavdar C, Gumustekin M, Celik A, Yuksel F, Camsari T. Intraperitoneal and subcutaneous pharmacokinetics of low molecular weight heparin in continuous ambulatory peritoneal dialysis patients. Adv Perit Dial 2003; 19: 2830. 10 Brophy DF, Carr ME Jr, Martin EJ, Venitz J, Gehr TW. The pharmacokinetics of enoxaparin do not correlate with its pharmacodynamic eect in patients receiving dialysis therapies. J Clin Pharmacol 2006; 46: 88794. 11 Schmid P, Brodmann D, Fischer AG, Wuillemin WA. Study of bioaccumulation of dalteparin at a prophylactic dose in patients with various degrees of impaired renal function. J Thromb Haemost 2009; 7: 5528. 12 Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105: 22531.

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