Download Prevention of clot formation during haemodialysis using the direct

Nephrol Dial Transplant (2005) 20: 1889–1897
doi:10.1093/ndt/gfh915
Advance Access publication 31 May 2005
Original Article
Prevention of clot formation during haemodialysis using the direct
thrombin inhibitor melagatran in patients with chronic uraemia
Per-Ola Attman1, Pia Ottosson1, Ola Samuelsson1, Ulf G. Eriksson2, Maria Eriksson-Lepkowska2 and
Gunnar Fager2
1
Department of Nephrology, Sahlgrenska University Hospital, Göteborg and 2AstraZeneca R&D, Mölndal, Sweden
Abstract
Background. This study assessed the feasibility of
replacing intravenous (i.v.) dalteparin with the direct
thrombin inhibitor (DTI) melagatran administered via
dialysis fluid in patients undergoing haemodialysis,
and also examined the pharmacokinetics of melagatran
with and without dialysis.
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 (99–103 ml/min) and melagatran in
the dialysis fluid (98–100 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
Correspondence and offprint requests to: Per-Ola Attman,
Department of Nephrology, Sahlgrenska University Hospital, SE
41345 Göteborg, Sweden. Email: [email protected]
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
Introduction
Anticoagulation is a prerequisite for haemodialysis.
Currently, individually titrated doses of heparin
preparations are used to prevent clotting in the
extracorporeal blood circuit. However, chronic administration of various heparins is associated with serious
side effects. Annually, about 1% of uraemic patients
on chronic haemodialysis develop heparin-induced
thrombocytopaenia, which may cause severe bleeding
[1,2]. Heparin, whether fractionated or unfractionated,
activates lipoprotein lipase and this may contribute
to the particular dyslipoproteinaemia and progressive
atherosclerosis of chronic renal failure [3–5]. Long-term
treatment with heparin may also accelerate osteoporosis and contribute to osteodystrophy seen in dialysis
patients [3,6]. Replacement of unfractionated heparin
with fractionated (low molecular weight) heparin may
at most attenuate, but cannot eliminate, the long-term
side effects of repeated heparin administration [3].
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.
ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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1890
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 mmol/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
P.-O. Attman et al.
Table 1. Pre-entry characteristics of 10 patients who completed the
study according to protocol
Age (years)
Body weight (kg)
Haemoglobin (g/l)
Platelets (109/l)
WBC (109/l)
P-APTT (s)
INR
S-albumin (g/l)
S-creatinine (mmol/l)
Median
Range
61
86
123
234
7.8
34
0.9
37
774
41–77
63–115
114–134
164–406
6–11.5
28–42
0.45–1.0
35–42
430–1090
INR, international normalized ratio; P-APTT, plasma activated
partial thromboplastin time; S, serum; WBC, white blood cell
count.
of anticoagulation is necessary in patients with renal
insufficiency.
Subjects and methods
Study design
This was an open-label, fixed-sequence observational study
in 10 uraemic patients on chronic haemodialysis (Table 1).
After inclusion criteria were met (Visit 1), patients underwent two consecutive dialysis sessions (Visits 2 and 3) using
their individually titrated standard dose (mean 5625, range
2500–7500 IU) of intravenous (i.v.) dalteparin (FragminÕ ;
Pharmacia & Upjohn, Stockholm, Sweden) as anticoagulant
immediately before start of dialysis. Between two subsequent
dalteparin dialyses at Visit 4, eight patients agreed to receive
1 mg melagatran i.v. for the determination of melagatran
clearance without dialysis. At the subsequent pharmacokinetic session (Visit 5), all 10 patients were given their
usual dose of dalteparin and in addition an i.v. bolus of 1 mg
(2.3 mmol) melagatran (AstraZeneca R&D, Mölndal,
Sweden), both drugs given at start of dialysis.
During the two last study dialysis sessions (Visits 6 and 7),
melagatran was used as the only anticoagulant drug,
and was provided both as an i.v. bolus just before start of
dialysis to prevent early clotting and via the dialysis fluid to
prevent later clot formation during dialysis. On the first
occasion (Visit 6), doses were fixed to a 2 mg (4.6 mmol)
i.v. bolus and a concentration of 0.5 mmol/l (0.21 mg/l) in
the dialysis fluid. On the subsequent occasion (Visit 7), the
investigator was allowed to decrease, maintain or increase
this bolus dose (1, 2 or 3 mg) of melagatran and/or to
decrease, maintain or increase melagatran in the dialysis
fluid (0.25, 0.5 or 1.0 mmol/l) depending on early or late
bleeding or clotting tendency, or to test if successful dialysis
could be achieved also on a lower dose than previously used
(Table 2).
Patients
Patients with chronic renal failure on chronic (>6 weeks)
haemodialysis were eligible. Patients with significant bleeding
or thrombotic disorder or treatment with drugs known to
Melagatran for prevention of clot formation during haemodialysis
Table 2. Melagatran pharmacokinetic data at the end of each
dialysis session during which melagatran was added to the dialysis
fluid
Patient
i.v. bolus Melagatran concentration
dose (mg)
Plasma at 4 h
Dialysis fluid Plasma at
(mmol/l)
4 h (mmol/l) versus dialysis
fluid (%)
Visit 6: melagatran 0.5 mmol/l in dialysis fluid
2
2
0.5
0.380
3
2
0.5
0.408
4
2
0.5
0.348
7
2
0.5
0.297
10
2
0.5
0.374
11
2
0.5
0.337
1
2
0.5
0.442
5
2
0.5
0.350
9
2
0.5
0.390
8
2
0.5
0.380
76
82
70
59
75
67
88
70
78
76
10
0.371
0.040
0.297
0.377
0.442
11
10
74
8
59
75
88
11
n
Mean
SD
Minimum
Median
Maximum
CV
Visit 7: melagatran 0.25, 0.5 or 1.0 mmol/l in dialysis fluid
2
2
1
0.609
61
3
2
1
0.716
72
4
2
1
0.706
71
7
2
1
0.613
61
10
2
1
0.665
67
11
2
1
0.628
63
1
1
0.25
0.226
90
5
1
0.25
0.175
70
9
1
0.25
0.184
74
8
3
0.5
0.417
42
Mean
SD
Minimum
Median
Maximum
CV
ND
ND
ND
ND
ND
ND
67
12
42
68
90
18
CV, coefficient of variation; ND, not determined because of
different dose levels.
affect the coagulation system were excluded from the study.
Eleven eligible patients (10 men, one woman) were included.
One patient had a residual renal function with glomerular
filtration rate (GFR) of 4 ml/min. The other patients had only
minimal or no residual renal function (24 h urine output
<500 ml). Blood access was obtained by A-V fistulas (n ¼ 8)
or double-lumen central venous catheters (n ¼ 3).
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
1891
Table 3. Dialysis iohexol clearance (ml/min) by Visit
Patient
Ioxehol clearance
Visit 2
Visit 3
Visit 6
Visit 7
1
2
3
4
5
7
8
9
10
11
106.3
93.6
106.5
101.9
104.5
91.0
109.5
103.7
102.9
98.1
116.9
89.0
117.0
98.4
98.7
83.8
108.1
105.1
96.3
99.6
119.2
81.5
98.5
81.1
86.7
83.9
104.1
109.4
101.0
111.3
107.4
71.1
77.5
81.3
97.0
98.3
95.0
113.9
103.5
114.0
n
Mean
SD
Minimum
Median
Maximum
10
101.8
5.9
91.0
103.3
109.5
10
101.3
10.8
83.8
99.2
117.0
10
97.7
13.7
81.1
99.8
119.2
10
95.9
15.0
71.1
97.7
114.0
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.
Dialysis set-up
All study dialyses were 4 h sessions. Before start of dialysis,
the dialyzer was primed on both sides for 15 min with
Biosol A 201.5/301.5 glucose (Pharmalink, Solna, Sweden)
dialysis concentrate diluted 1 þ 34 using Gambro AK-200
haemodialysis equipment (Gambro, Lund, Sweden). The flow
rate was adjusted to 500 ml/min on the dialysis fluid side and
to 250 ml/min on the blood side of a low flux, low efficiency,
biocompatible parallel flow dialyzer (Gambro, Lundia Pro
600) by separate pumps. Pressure in the bloodline was
monitored on both sides of the dialyzer during the dialysis
session using standard transducers (Peter von Berg
Medizintechnik, Kirchsee, GmbH) connected to a batteryoperated
transducer
preamplifier
(Kent
Scientific
Corporation/World Precision Instrument Sarasota, FL).
Before each dialysis session the pressure transducers were
calibrated. The mean pressure was shown on a digital display
and recorded every 10 min.
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.
1892
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
(Venojectß; 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 mmol/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) (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.
Results
Clinical outcomes of dialysis sessions and
dose adjustments
For all 10 patients, dialysis sessions with dalteparin
(Visits 2 and 3) and with melagatran i.v. added
P.-O. Attman et al.
to dialysis fluid (Visits 6 and 7) were judged
by the investigators to be clinically successful.
The two dalteparin dialyses were also regarded as
successful in the eleventh patient, who later developed
a septic gonitis and withdrew from the study
before melagatran administration and completion of
the study.
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 ¼ 3,
different patients and treatment periods), headache
(n ¼ 1), dyspepsia (n ¼ 1), hypoglycemia (n ¼ 1, diabetic
patient), polyuria (n ¼ 1), parosmia (n ¼ 1) and taste
perversion (n ¼ 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 mmol/l
in six cases, decreased to 0.25 mmol/l in three cases
and maintained at 0.5 mmol/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).
Extracorporeal circuit pressure
The pressures before and after the dialyzer during
the two sessions with melagatran in the dialysis fluid
were similar to those observed during the two sessions
with dalteparin, and their pre- to post-dialyzer ratios
remained constant and fully comparable throughout
the 4 h sessions. Figure 2 shows the mean pressure
ratio before/after dialyzer for the two sessions with
dalteparin and for the dialysis sessions with melagatran
Melagatran for prevention of clot formation during haemodialysis
1893
A
A
2.5
400
Mean filter pressure ratio
(before/after)
350
lohexol (mg/l)
300
250
200
150
2.0
1.5
1.0
0.5
100
0
50
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time (hours)
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
B
Time (hours)
2.5
B
2.0
Mean filter pressure ratio
(before/after)
400
350
lohexol (mg/l)
300
250
200
1.5
1.0
0.5
150
0
100
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time (hours)
50
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time (hours)
Fig. 1. Mean concentrations of iohexol in plasma (mg/l) with 95%
CI versus time after: (A) dalteparin i.v. bolus (mean of Visits 2 and
3, n ¼ 10), and (B) melagatran 2 mg i.v. and 0.5 mmol/l in dialysis
fluid (Visit 6, n ¼ 10).
0.5 mmol/l in the dialysis fluid. Similar results were
observed at melagatran concentrations of 0.25 and
1.0 mmol/l (data not shown).
Fig. 2. Dialyzer pressure given as pressure ratio before/after
dialyzer during dialysis with: (A) dalteparin i.v. bolus (mean of
Visits 2 and 3, n ¼ 20 observations for 10 patients), and (B)
melagatran concentration of 0.5 mmol/l in dialysis fluid (Visits 6 þ 7,
n ¼ 11 observations for 10 patients).
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 ¼ 3) and/or dialyzers
(n ¼ 6). In the three patients with suspected clots in
the tubing, one had evident and the other two suspected
clots in the dialyzer.
Evaluation of clot formation during the dialysis sessions
Occluding thrombi were not observed in this study.
Suspected clots in tubing and/or in the dialyzer were
observed after both dalteparin dialyses in four of the
10 patients who completed the study (Visits 2 and 3).
The same outcome was observed for the 10 patients
who received dalteparin and melagatran i.v. during one
dialysis (Visit 5).
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 ¼ 4) or suspected
clots in both tubing and dialyzers (n ¼ 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 ¼ 2) or only suspected clots in the dialyzer
(n ¼ 1) at Visit 6. In the tenth case, the melagatran
concentration in dialysis fluid was maintained but
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
3–9 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 4–9 min for the
majority of the patients. Patient 4 had a longer bleeding
time of 17 min on Visit 7 (melagatran concentration in
1894
P.-O. Attman et al.
Table 4. Mean duration of bleeding (min) after percutaneous
punctures of arteriovenous fistulas in connection with dialysis
A
1.0
1
Duration of bleeding (min)
n
2
3
5
6
7
6
6
7
7
7
Mean
SD
Minimum
Maximum
6
7
6
7
9
1
2
1
2
5
4
3
4
5
4
7
9
8
11
17
Plasma concentration (µmol/l)
2
Visit
3
4
5
0.1
7
8
9
10
0.01
0
2
4
6
8
10
12
14
16
18
20
22
11
Time (hours)
B
A
Patient
Plasma concentration (µmol/l)
1
2
3
4
0.1
5
7
8
9
0.01
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
10
11
1.0
Plasma concentration (µmol/l)
1.0
0.1
0.01
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time (hours)
Time (hours)
Fig. 4. Individual plasma concentrations of melagatran versus time
after (A) a single 1 mg intravenous bolus administered between
dialysis sessions (Visit 4), and (B) a single 1 mg bolus dose
administered just after the start of dialysis (Visit 5).
B
Plasma concentration (µmol/l)
1.0
0.1
0.01
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time (hours)
Fig. 3. Individual plasma concentrations of melagatran versus time
after: (A) a single 2 mg intravenous bolus of melagatran followed by
melagatran administered in dialysis fluid at a concentration of
0.5 mmol/l (Visit 6), and (B) after a single 1, 2 or 3 mg bolus dose of
melagatran followed by melagatran administered in dialysis fluid at
concentrations of 0.25, 0.5 or 1.0 mmol/l (Visit 7).
dialysis fluid 1 mmol/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 mmol/l).
Pharmacokinetics of melagatran
Stable plasma concentrations of melagatran were
observed throughout both of the 4 h dialysis sessions
with melagatran administered in the dialysis fluid
(Figure 3). During Visit 6, when melagatran was
administered in the dialysis fluid at a concentration of
0.5 mmol/l, mean plasma concentrations of melagatran
were maintained between 0.317 and 0.371 mmol/l, a
range that corresponded to 63–74% of the concentrations in the dialysis fluid (Table 2). Similar relationships
between plasma concentrations of melagatran and
melagatran concentrations in the dialysis fluid were
observed during Visit 7, when melagatran was administered at concentrations of 0.25, 0.5 or 1.0 mmol/l
(Figure 3 and Table 2).
Comparison of melagatran plasma concentrations
when melagatran was given as an i.v. bolus between
dialysis sessions (Visit 4) with those when
melagatran was given as an i.v. bolus just after
the start of dialysis on Visit 5 showed that melagatran
was rapidly eliminated via dialysis (Figure 4 and
Table 5). When melagatran was administered intravenously between dialysis sessions, the mean
plasma concentration was 0.494 mmol/l 10 min after
injection. Melagatran plasma concentrations rapidly
declined during the first 30 min after dose during
the distribution phase and thereafter slowly
declined to a mean of 0.043 mmol/l 22 h after injection
(Figure 4). When melagatran was administered just
after the start of dialysis, the mean plasma concentration was 0.169 mmol/l 10 min after injection. By
4 h, at the end of the dialysis session, mean
plasma concentration of melagatran was 0.028 mmol/l
(Figure 4). The fraction of the melagatran plasma
concentration remaining at the end of the dialysis
(mean±SD) was 17±4%.
The clearance of melagatran (mean±SD) between
dialysis sessions was 0.93±0.36 l/h compared with
7.20±0.76 l/h during dialysis (Table 5). The half-life
(mean±SD) was 14.1±3.7 h between dialysis sessions
compared with 2.0±0.3 h during dialysis. The clearance of melagatran by dialysis (mean±SD) for the eight
patients having data both between dialysis sessions
Melagatran for prevention of clot formation during haemodialysis
1895
Table 5. Melagatran pharmacokinetics after a single bolus 1 mg dose between dialyses (Visit 4) and after a single bolus 1 mg dose just after
the start of dialysis (Visit 5)
CLD (l/h)
Vss (l)
t1/2 (h)
0.67
1.09
0.53
0.95
0.95
0.75
0.79
1.71
–
–
–
–
–
–
–
–
14.9
14.9
10.7
20.3
23.9
17.2
15.2
12.5
16.6
10.5
14.7
15.4
17.8
16.0
15.2
6.5
8
0.494
0.284
0.192
0.463
0.962
57
8
0.93
0.36
0.53
0.87
1.71
39
–
–
–
–
–
–
–
8
16.2
4.2
10.7
15.1
23.9
26
8
14.1
3.7
6.5
15.3
17.8
26
Visit 5: Melagatran given at the start of dialysis
1
0.315
0.260
2
0.392
0.156
3
0.304
0.166
4
0.333
0.168
5
0.333
0.153
7
0.317
0.132
8
0.378
0.198
9
0.310
0.179
10
0.269
0.143
11
0.322
0.135
7.39
5.95
7.67
7.01
6.99
7.36
6.17
7.51
8.65
7.25
5.28
6.58
6.48
6.04
6.41
5.42
6.72
6.94
14.1
21.7
20.0
21.1
21.3
20.0
15.4
19.3
21.2
24.0
1.4
2.6
1.9
2.2
2.2
1.9
1.8
1.9
1.7
2.3
10
7.20
0.76
5.95
7.31
8.65
11
8
6.23
0.60
5.28
6.45
6.94
10
10
19.8
3.0
14.1
20.6
24.0
15
10
2.0
0.3
1.4
1.9
2.6
17
Patient
AUC (mmolh/l)
Cmax (mmol/l)
Visit 4: Melagatran given between dialysis sessions
2
3.475
0.496
3
2.145
0.962
4
4.378
0.817
5
2.449
0.280
7
2.460
0.192
8
3.096
0.193
9
2.938
0.430
10
1.363
0.584
n
Mean
SD
Minimum
Median
Maximum
CV
n
Mean
SD
Minimum
Median
Maximum
CV
8
2.788
0.909
1.363
2.699
4.378
33
10
0.327
0.036
0.269
0.320
0.392
11
10
0.169
0.038
0.132
0.161
0.260
22
CL (l/h)
AUC, area under the plasma concentration-versus-time curve; Cmax, maximum plasma concentration observed at the first sampling time
after injection; CL, clearance; CLD, clearance by dialysis; CV, coefficient of variation; Vss, volume of distribution estimated for steady-state
condition; t½ ¼ elimination half-life.
and during dialysis was 6.23±0.60 l/h. Expressed in
the same units as for iohexol clearance, melagatran
clearance during dialysis was 104±10 ml/min; this was
comparable to iohexol clearance, which was used as
the marker for dialyzer function.
Discussion
This feasibility study showed that the low-molecularweight direct thrombin inhibitor melagatran can be
safely administered from the dialysis fluid via the
dialysis membrane to uraemic patients undergoing
haemodialysis. It may successfully prevent thrombotic
obstruction of the extracorporeal circuit to provide
as efficient dialysis as with using conventional anticoagulation with fractionated heparin. More studies
are needed to establish the cost-benefit balance of this
concept. Furthermore, the optimal doses of melagatran
must be explored further, but the overall conclusion
about its usefulness applies to the range of doses used
here. The plasma concentrations of melagatran during
dialysis are strictly determined by the concentration
in the dialysis fluid, with a predictable concentrationdependent degree of anticoagulation making individual
titration unnecessary.
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
1896
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 mmol/l). Clearance of melagatran administered
during dialysis was 7 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 4–5 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.
P.-O. Attman et al.
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.
Acknowledgements. This study was sponsored by AstraZeneca
R&D Mölndal (Mölndal, Sweden). The skilful secretarial assistance
of Ann Stenman is gratefully acknowledged. The study dialysis
sessions were expertly carried out by Margareta Dahlgren RN,
Ulla-Britt Johansson RN and Hussain Quraishi.
Conflict of interest statement. Ulf G. Eriksson, Maria ErikssonLepkowska and Gunnar Fager are employees of AstraZeneca.
[See related Editorial by Flanigan, pp. 1789]
References
1. Warkentin TE, Kelton JG. Heparin and platelets. Hemotol
Oncol Clin North Am 1990; 4: 243–264
2. Samuelsson O, Amiral J, Attman P-O et al. Heparin-induced
thrombocytopenia during continuous hemofiltration. Nephrol
Dial Transplant 1995; 10: 1768–1771
3. Lai KN, Ho K, Cheung RCK et al. Effect of low molecular
weight heparin on bone metabolism and hyperlipidemia in
patients on maintenance hemodialysis. Int J Artif Organs 2001;
24: 447–455
4. Wiemer J, Winkler K, Baumstark M, März W, Scherberich JE.
Influence of low molecular weight heparin compared to
conventional heparin for anticoagulation during haemodialysis
on low density lipoprotein subclasses. Nephrol Dial Transplant
2002; 17: 2231–2238
5. Liu G, Bengtsson-Olivecrona G, Ostergaard P, Olivecrona T.
Low Mr heparin is as potent as conventional heparin in releasing
Melagatran for prevention of clot formation during haemodialysis
6.
7.
8.
9.
10.
11.
12.
lipoprotein lipase, but is less effective in preventing hepatic
clearance of the enzyme. Biochem J 1991; 273: 747–752
Taal MW, Masud T, Green D, Cassidy MJD. Risk factors for
reduced bone density in haemodialysis patients. Nephrol Dial
Transplant 1999; 14: 1922–1928
Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran
and its active metabolite melagatran: a mini-review. Thromb
Res 2003; 109: S9–S15
Eriksson UG, Bredberg U, Hoffmann KJ et al. Absorption,
distribution, metabolism, and excretion of ximelagatran, an
oral direct thrombin inhibitor, in rats, dogs, and humans.
Drug Metab Dispos 2003; 31: 294–305
Eriksson UG, Bredberg U, Gisslén K et al. Pharmacokinetics
and pharmacodynamics of ximelagatran, a novel oral direct
thrombin inhibitor, in young healthy male subjects. Eur J Clin
Pharmacol 2003; 59: 35–43
Johansson LC, Frison L, Logren U, Fager G, Gustafsson D,
Eriksson UG. Influence of age on the pharmacokinetics and
pharmacodynamics of ximelagatran, an oral direct thrombin
inhibitor. Clin Pharmacokinet 2003; 42: 381–392
Bergqvist D. Bleeding profiles of anticoagulants, including
the novel oral direct thrombin inhibitor ximelagatran: definitions, incidence and management. Eur J Haematol 2004; 73:
227–242
Carlsson S, Samuelsson O, Attman P-O, Zachrisson H,
Fager G. Antithrombotic effect and pharmacokinetics of the
1897
13.
14.
15.
16.
17.
18.
direct thrombin inhibitor melagatran administered in dialysate
in a porcine model of haemodialysis. J Am Soc Nephrol 2004;
15: 638A.
Larsson M, Logren U, Ahnoff M et al. Determination of
melagatran, a novel direct thrombin inhibitor, in human
plasma and urine by liquid chromatography-mass spectrometry.
J Chromatogr B Biomed Sci Appl 2002; 766: 47–55
Eriksson UG, Mandema JW, Karlsson MO et al.
Pharmacokinetics of melagatran and the effect on ex vivo
coagulation time in orthopaedic surgery patients receiving
subcutaneous melagatran and oral ximelagatran: A population
model analysis. Clin Pharmacokinet 2003; 42: 687–701
Wolzt M, Wollbratt M, Svensson M, Wahlander K, Grind M,
Eriksson UG. Consistent pharmacokinetics of the oral direct
thrombin inhibitor ximelagatran in patients with nonvalvular
atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol
2003; 59: 537–543
Eriksson UG, Johansson S, Attman P-O et al. Influence of
severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.
Clin Pharmacokinet 2003; 42: 743–753
Brandt P, Jespersen K, Sorenson H. Antithrombin-III and
platelets in haemodialysis patients. Nephron 1981; 28: 1–3
Ota K, Akizawa T, Hirasawa Y, Agishi T, Matsui N. Effects of
argatroban as an anticoagulant for haemodialysis in patients
with antithrombin III deficiency. Nephrol Dial Transplant 2003;
18: 1623–1630
Received for publication: 15.12.04
Accepted in revised form: 22.4.05