1 Department of Nephrology, Sahlgrenska University Hospital, Göteborg and 2 AstraZeneca R&D, Mölndal, Sweden
Correspondence and offprint requests to: Per-Ola Attman, Department of Nephrology, Sahlgrenska University Hospital, SE 41345 Göteborg, Sweden. Email: per-ola.attman{at}vgregion.se
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Abstract |
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Methods. During two 4 h haemodialysis sessions, 10 adult patients were administered i.v. dalteparin. During two subsequent sessions, melagatran was administered as an i.v. bolus before dialysis, and in the dialysis fluid. The pharmacokinetics of melagatran administered as a bolus before dialysis, and of i.v. melagatran during a dialysis-free day, were studied. Dialysis performances were evaluated from clinical criteria including clot formation in the dialyzer and bloodlines, pre-post dialyzer pressures and iohexol clearance. Anticoagulant efficacy was evaluated from dialysis success.
Results. All dialysis sessions were successful, with no apparent difference in clot formation between the two treatments. Median iohexol clearance was similar with dalteparin (99103 ml/min) and melagatran in the dialysis fluid (98100 ml/min). There was no difference in pre- and post-dialyzer bloodline pressures between the two treatments. During dialysis sessions with melagatran in dialysis fluid, melagatran concentrations in plasma rapidly equilibrated to 70% of those in dialysis fluid. While the clearance of melagatran was low in patients with renal failure (mean±SD, 0.93±0.36 l/h), haemodialysis provided efficient clearance of melagatran (7.20±0.76 l/h). Melagatran clearance by dialysis (104±10 ml/min) was comparable to iohexol clearance.
Conclusions. The DTI melagatran administered via dialysis fluid may provide sufficient anticoagulation for haemodialysis. Melagatran is rapidly cleared from plasma by haemodialysis, suggesting that this method may be used to decrease drug levels in patients with renal impairment.
Keywords: anticoagulant; chronic uraemia; haemodialysis; melagatran; thrombosis; ximelagatran
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Introduction |
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Arteriovenous (A-V) fistulas and central venous catheters, used to connect the extracorporeal circuit to the blood circulation, tend to clot and require intermittent acute fibrinolytic therapy or even chronic anticoagulation between dialysis sessions when they clot frequently.
In the coagulation cascade, thrombin proteolytically cleaves fibrinogen to generate fibrin, which polymerizes to form the thrombus network. Thrombin is also a potent platelet activator and this may lead to the formation of platelet-rich arterial thrombi. Hence, pharmacologic inhibition of thrombin may prevent development of thrombosis and clotting of extracorporeal blood circuits.
Melagatran is a novel, low-molecular-weight (430 Da) thrombin inhibitor with predictable pharmacokinetics and pharmacodynamics for parenteral use [7]. Melagatran is the active form of the oral direct thrombin inhibitor ximelagatran. After oral administration, ximelagatran is rapidly absorbed and bioconverted via two intermediates to its active form, melagatran [7,8]. Ximelagatran has been shown to have predictable and stable pharmacokinetics with low intra- and inter-individual variability [9]. In young healthy volunteers, about 80% of systemically available melagatran is excreted as unchanged compound via the kidneys [8] and the clearance of melagatran correlates to the renal function [10]. Melagatran and ximelagatran have been approved in several European countries for the prevention of thrombosis in conjunction with orthopaedic surgery. Potential side-effects of melagatran include those expected from inhibition of thrombin, i.e. bleeding tendency. There is no known antidote to reverse the action of melagatran.
Studies in surgical and non-surgical patients have shown that treatment with ximelagatran or melagatran carries a low frequency of bleeding complications not different from that of other anticoagulant regimes, i.e. low molecular weight heparin (LMWH) or vitamin K antagonists [11].
Previous in vitro experiments confirmed that melagatran passes efficiently across dialysis membranes (unpublished observations). These results demonstrate that it should be possible to obtain anticoagulation in patients undergoing dialysis by addition of melagatran to the dialysis fluid and, more specifically, to the electrolyte-containing concentrate. Predictable diffusion across the membrane would rapidly provide suitable steady-state concentrations in these patients during dialysis.
In a preliminary study in anaesthetized anuric (by renal arteriovenous ligation) pigs, 1 µmol/l melagatran was provided in the dialysis fluid during haemodialysis for 3 h [12]. The dialysis procedures were successful and there were no visible clots in the saline-perfused tubing and dialyzer after dialysis. Pressures in the dialysis circuit measured before and after the dialyzer together with iohexol clearance remained constant during the dialysis. This suggests that melagatran efficiently prevented clot formation in this model of haemodialysis.
The primary objective of this exploratory and feasibility study was to investigate if intravenous anticoagulation can be successfully replaced by melagatran administered in the dialysis fluid for the prevention of clot formation in the extracorporeal circuit during haemodialysis in uraemic patients. A secondary objective was to characterize melagatran pharmacokinetics in uraemic patients undergoing haemodialysis and to assess its elimination during dialysis, as this may potentially be used in the event that reversal of anticoagulation is necessary in patients with renal insufficiency.
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Subjects and methods |
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Signed informed consent to participate was obtained from all patients. The study was carried out according to the Declaration of Helsinki and approved by the Swedish Medical Products Agency and the Göteborg Ethics Committee.
Ten patients completed the study according to protocol (Table 3). Eight of these patients agreed to participate in the optional pharmacokinetic session between dialyses (Visit 4). One 61-year-old man with past history of rheumatoid arthritis and amyloidosis withdrew from the study after the initial two dialyses with dalteparin and before any administration of melagatran because of septic arthritis in a prosthetic knee joint. He received long-term antibiotic therapy and was discharged from hospital after 13 days but without recovery at follow-up 11 weeks later. A causal relationship to the study drug was assessed as unlikely.
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Before connection of the patient to the efferent and afferent bloodlines, 20 ml (300 mg/ml) iohexol was given intravenously to monitor dialyzer clearance during Visits 2, 3, 6 and 7.
After completion of the dialysis session, the cannulae were removed from the A-V fistulas according to standard procedures and the duration of bleeding from puncture sites was recorded during compression. Permanent central venous catheters were disconnected and heparinized according to routine procedure. The investigator made an overall assessment whether or not the session had been successful and without complications. The disconnected bloodlines and dialyzer were cleared from blood by perfusion with saline and searched for visible clots. The results were reported separately for tubing and dialyzer and graded as no clot, suspected clot, evident clot or obstruction.
Measurement of dialyzer clearance
For the determination of iohexol in plasma, arterial blood (6 ml) was drawn from efferent (arterial) tubing into heparinized test tubes every 30 min after the iohexol administration. Plasma was recovered after centrifugation (10 000 g for 5 min) and stored at 20°C until analysis. Iohexol in plasma was determined at the Laboratory of the Department of Nephrology (Sahlgrenska University Hospital, Göteborg, Sweden) using a Renalyser PRX 90 (Provalid AB, Lund, Sweden). Iohexol clearance, used as a marker of dialyzer function, was estimated as dose/area under the plasma concentration-versus-time curve (AUC) of iohexol, where the AUC of iohexol was calculated using the log-linear trapezoidal rule as described below for the pharmacokinetic evaluation of melagatran.
Pharmacokinetic assessments
Blood samples (2.7 ml) were obtained in citrate buffer (Venoject©; Terumo Europe N.V, Leuven, Belgium) for determination of plasma concentrations of melagatran. On Visit 4, when patients were administered melagatran as an i.v. bolus while not undergoing dialysis, venous blood samples (2.7 ml) were obtained predose and 10 and 30 min; and 1, 2, 3, 4, 6, 8, 10, 12 and 22 h postdose. During dialysis sessions on Visits 5, 6 and 7, the same blood samples (2.7 ml) were taken from the efferent (arterial) dialysis blood tubing predose and 10 and 30 min; and 1, 2, 3, and 4 h postdose. Catheters were flushed with physiological saline after each sampling, while the use of heparin was prohibited.
Melagatran concentrations were determined at Bioanalytical Chemistry, AstraZeneca Research and Development, Mölndal, Sweden, using liquid chromatography-mass spectrometry with a limit of quantification of 0.010 µmol/l [13]. A dilution factor of 1.185 was used to adjust for the dilution of blood with citrate buffer in the sampling tubes.
Noncompartmental methods were used to estimate pharmacokinetic variables of melagatran for the data obtained between dialysis sessions (Visit 4) and during dialysis (Visit 5). The AUC was calculated using the log-linear trapezoidal rule to the last measurable plasma concentration and extrapolated to infinity. Maximum plasma concentration (Cmax) was the observation at the first sampling time (10 min) after i.v. injection. The elimination half-life (t1/2) was calculated as 0.693/k, where k is the elimination rate constant estimated by linear least-squares regression of plasma concentrations versus time in the terminal phase of decline. Clearance of melagatran (CL) was calculated as dose/AUC. The clearance by dialysis (CLD) was estimated as (CL during the dialysis at Visit 5) (CL between the dialysis sessions). The volume of distribution for steady-state condition (Vss) was calculated as (dose/AUC) x (AUMC/AUC), where AUMC is the area under the first-moment curve calculated using the log-linear trapezoidal rule up to Clast and extrapolated to infinity.
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Results |
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There were few adverse events (AEs) during the study, especially when considering the uraemic condition of the study population and the average study duration of 3 months. Most AEs were of mild or moderate intensity. There were no serious AEs during or after administration of melagatran. Two serious AEs were reported in the periods after the first and the second baseline dialysis with dalteparin, respectively. Nine out of a total of 32 AEs started during treatment with melagatran. These were hypotension (n = 3, different patients and treatment periods), headache (n = 1), dyspepsia (n = 1), hypoglycemia (n = 1, diabetic patient), polyuria (n = 1), parosmia (n = 1) and taste perversion (n = 1).
For each one of the 10 patients who completed this study the individual dalteparin dose was kept constant throughout the study, whereas melagatran was provided at fixed doses via i.v. injection and dialysis fluid only at Visit 6 (cf Subjects and methods). At the last dialysis with melagatran (Visit 7), it was judged suitable by the investigator to maintain the i.v. bolus at 2 mg in six cases, to change to 1 mg in three cases, and to change to 3 mg in one case (Table 2). The melagatran concentration in dialysis fluid was increased to 1 µmol/l in six cases, decreased to 0.25 µmol/l in three cases and maintained at 0.5 µmol/l in one case (Table 2). Presence or absence of clots in tubing and dialyzers after Visit 6 provided reasons for the dose decision at Visit 7 (vide infra).
Dialyzer clearance
The plasma concentrations of iohexol versus time are shown in Figure 1 for the two dialysis sessions with dalteparin and the first dialysis session with melagatran in the dialysis fluid (Visit 6). Comparable observations were made at the second dialysis session with melagatran (7; data not shown). The (mean±SD) iohexol clearance values during the two dialysis sessions with melagatran in the dialysis fluid were similar to those observed during the two dialysis sessions with dalteparin (Table 3).
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Suspected and/or evident clots were observed in tubing and/or dialyzers in eight of 10 patients after dialysis with fixed melagatran doses (Visit 6). Visually evident clots in dialyzers (n = 4) or suspected clots in both tubing and dialyzers (n = 2) at Visit 6 explained the increase in melagatran in the dialysis fluid during Visit 7. Three patients, who were given reduced melagatran bolus and dialysis fluid doses at Visit 7, had no clots in the tubing or in the dialyzer (n = 2) or only suspected clots in the dialyzer (n = 1) at Visit 6. In the tenth case, the melagatran concentration in dialysis fluid was maintained but the bolus dose of melagatran at Visit 7 was increased to 3 mg because of suspected clots in tubing and dialyzer at Visit 6.
After dose adjustment at Visit 7, six patients showed suspected clots in tubing (n = 3) and/or dialyzers (n = 6). In the three patients with suspected clots in the tubing, one had evident and the other two suspected clots in the dialyzer.
Bleeding after percutaneous puncture of A-V fistulas
The duration of bleeding at the dialysis access site (the puncture site in the A-V fistula) after removal of the fistula needle at the end of dialysis session was assessed in all patients, except for patients with a central venous catheter (patient nos 8, 10 and 11). Patient no. 2 had a central venous catheter at Visits 2 and 3 before his newly prepared A-V fistula could be used. On Visits 2 and 3 when the patients received dalteparin alone, the range of bleeding times was 39 min (Table 4). A similar range was observed on Visit 5 when the patients received an i.v. bolus of melagatran just after the start of the dialysis session in combination with pre-dialysis dalteparin. For Visits 6 and 7, when melagatran treatment was given, the bleeding times were within 49 min for the majority of the patients. Patient 4 had a longer bleeding time of 17 min on Visit 7 (melagatran concentration in dialysis fluid 1 µmol/l). Patient 7 had longer bleeding times of 11 and 12 min for Visits 6 and 7, respectively (melagatran concentration in dialysis fluid 0.5 and 1 µmol/l).
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Discussion |
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None of the small clots, suspected or evident, that were observed during dalteparin and melagatran dialyses sessions influenced the dialysis efficiency, dialyzer clearance of iohexol or extracorporeal pressures. The duration of bleeding at the dialysis access site in A-V fistulas following melagatran treatment was comparable to the results with dalteparin treatment in most patients. These results suggest that melagatran may be administered via the dialysis fluid to prevent clot formation during haemodialysis.
Previous observations in acutely anuric pigs showed that they rapidly achieved a steady-state concentration level when melagatran was provided in the dialysis fluid during haemodialysis [10]. Initially no bolus dose of melagatran was given to the pigs before dialysis and we observed that thrombotic obstruction occurred very early in the extracorporeal circuit (unpublished observations). We attributed this to plasma melagatran concentrations having not reached a sufficient level during the very early stages of the dialysis experiments.
With a half-life of 2 h during dialysis it takes 20 min to reach a plasma concentration of 10% of the expected steady state concentration.
Therefore the pigs were given an i.v. bolus of melagatran immediately prior to start of dialysis, which effectively prevented early clotting. Hence, an analogous protocol including a bolus dose of melagatran before start of dialysis was used in this study.
Melagatran added to dialysis fluid rapidly equilibrated across the dialysis membrane and was maintained at a stable level throughout the dialysis sessions. The plasma concentration of melagatran was maintained at 70% of that in the dialysis fluid regardless of its melagatran concentration (i.e., 0.25, 0.5 or 1.0 µmol/l). Clearance of melagatran administered during dialysis was
7x more rapid than that between dialysis sessions in these patients with severe renal failure. The dialysis clearance of melagatran had a low interindividual variability of 10% and was comparable to that of iohexol, which was used to assess dialyzer function as it is rapidly cleared by haemodialysis. These results demonstrate that melagatran was readily cleared during haemodialysis, and this suggests that dialysis may be used when rapid reversal of anticoagulation is necessary (e.g. suspected overdose, accumulation because of renal dysfunction, or bleeding). As the half-life of melagatran is relatively short for patients with normal renal function [14,15], dialysis would have the greatest impact for a patient with severely compromised renal function. For the uraemic patients studied,
80% of the administered i.v. dose of melagatran was eliminated during the 4 h dialysis period.
The low melagatran clearance determined in the uraemic patients was expected, as renal excretion is the predominant route of elimination for systemic melagatran [7]. Compared with young healthy volunteers, the exposure of melagatran has been shown to be higher in older volunteers because of the age-related decrease in renal function [10]. In patients with normal or mildly to moderately impaired renal function receiving parenteral melagatran or oral ximelagatran treatment, renal function is the main determinant of interindividual variability in melagatran exposure [14,15]. In 12 patients with severe renal impairment (median GFR estimated as iohexol clearance: 13 ml/min), the melagatran exposure was increased by 45x compared to with that in healthy control volunteers with normal renal function [16].
For patients with congenital or acquired antithrombin III deficiency, heparin does not provide adequate anticoagulation during haemodialysis. Furthermore, it has been speculated that long-term heparin administration could lead to increased consumption and subsequent depletion of antithrombin III [17]. Ota et al. [18] recently reported successful anticoagulation with argatroban, a synthetic thrombin inhibitor in haemodialysis. In contrast to argatroban, melagatran is efficiently removed by haemodialysis.
A potential advantage of melagatran in the dialysis population is the long half-life between dialysis sessions. This may facilitate maintenance of patency of A-V fistulas and central dialysis catheters, and possibly reduce the need for separate anticoagulation between dialysis treatments. Another, albeit minor, advantage of the treatment modality used is that blood contact when administering anticoagulation is avoided. No serious bleeding complications were observed in this study during dialysis with melagatran or dalteparin. Based on previous studies in non-renal patients it could be expected that the use of melagatran as anticoagulant in haemodialysis should not result in increased frequency of such complications compared to that of conventional regimes including LMWH.
In summary, the results of this exploratory feasibility study suggest that melagatran administration via dialysis fluid can be used for successful anticoagulation during haemodialysis. It can certainly provide a useful alternative for patients with heparin intolerance and a means to avoid long-term negative effects of chronic heparin administration in these patients. Although no serious side-effects were observed, additional studies are needed to establish risks and benefits of the treatment and optimal dosing in haemodialysis. Moreover, even if melagatran is an attractive alternative for dialysis patients with HIT, its use in other dialysis patients will depend on experience from further clinical trials and the costs in comparison with conventional anticoagulation. Finally, the current results indicate that melagatran is eliminated by haemodialysis, which suggests that this method may be used to decrease drug levels in patients with renal impairment.
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Acknowledgments |
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Conflict of interest statement. Ulf G. Eriksson, Maria Eriksson-Lepkowska and Gunnar Fager are employees of AstraZeneca.
[See related Editorial by Flanigan, pp. 1789]
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References |
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