University of Groningen
Optimal dosing strategy for prothrombin complex concentrate
Khorsand, Nakisa
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Chapter 2
Fixed versus variable dosing of prothrombin
complex concentrate for counteracting
vitamin-K antagonist therapy
Nakisa Khorsand
Nic J.G.M. Veeger
Marcella Muller
Hans W.P.M Overdiek
Wim Huisman
Reinier M. van Hest
Karina Meijer
Transfusion Medicine, 2011; 21: 116-123
Pilot study
ABSTRACT
Background: Although prothrombin complex concentrate (PCC) is often
used to counteract vitamin K antagonist (VKA) therapy, evidence regarding
the optimal dose for this indication is lacking. In Dutch hospitals, either a
variable dose, based on body weight, target INR (international normalised
ratio) and initial INR, or a fixed dose is used.
Aim/objectives: In this observational, pilot study, the efficacy and feasibility
of the fixed dose strategy compared to the variable dosing regimen,
is investigated. Materials and Methods: Consecutive patients receiving
PCC (Cofact®, Sanquin, Amsterdam) for VKA reversal because of a major
noncranial bleed or an invasive procedure were enrolled in two cohorts.
Data were collected prospectively in the fixed dose group, cohort 1, and
retrospectively in the variable dose regimen, cohort 2. Study endpoints were
proportion of patients reaching target INR and successful clinical outcome.
Results: Cohort 1 consisted of 35 and cohort 2 of 32 patients. Target INR
was reached in 70% of patients in cohort 1 versus 81% in cohort 2 (P = 0.37).
Successful clinical outcome was seen in 91% of patients in cohort 1 versus
94% in cohort 2 (P = 1.00). Median INR decreased from 4.7 to 1.8 with a
median dosage of 1040 IU factor IX (F IX) in cohort 1 and from 4.7 to 1.6
with a median dosage of 1580 IU F IX in cohort 2.
Conclusion: This study suggests that a fixed dose of1040 IU of F IX may be an
effective way to rapidly counteract VKA therapy in our patient population
and provides a basis for future research.
28
Chapter 2
Introduction
Approximately 1 - 1.5% of the population of Western countries is treated with
vitamin K antagonists (VKA) for prophylaxis and treatment of thrombosis.
As a serious adverse effect of VKA treatment, major bleeding is seen in 1.43.3% of users each year (Palareti et al., 1996; Veeger et al., 2005). In the
Netherlands, VKA is, after acetylsalicylic acid, the main drug responsible
for medication-related hospital admissions (Leendertse et al., 2008).
Both major bleeding and emergency surgery are indications for rapid reversal
of the action of VKAs. Available strategies are, in addition to withholding VKA
and administration of vitamin K, replacement of the depleted coagulation
factors by administration of prothrombin complex concentrate (PCC) or
fresh frozen plasma (FFP). Generally, PCC is preferred in the Netherlands.
In effectiveness studies, a relationship between the administered PCC
dose and the INR (international normalised ratio) reached has been
indirectly shown (Lubetsky et al., 2004; Lankiewics et al., 2006; Riess
et al., 2007; Pabinger et al., 2008). However, no formal dose finding
studies have been performed to find the lowest effective PCC dose.
In Dutch hospitals, two PCC-dosing strategies are commonly used to reverse
anticoagulation. The first is the dose advised by the manufacturer, depending
on the initial INR, bodyweight and target INR (variable dose regimen). The
second is a fixed dose regimen regardless of the bodyweight and initial
INR. There is little data on the comparison of the effectiveness of both
strategies. One study compared the fixed PCC dose regimen of 520 IE F IX
(factor IX) with the variable dose regimen (van Aart et al., 2006). This study
showed that a fixed dose of 520 IU F IX was insufficient in 57% of cases to
reach the target INR versus 11% in the variable dosing regimen. In the fixed
dose, cohort median dose of 878 and 658 (range not given) IU F IX was found
to be necessary to decrease the INR to ≤1.5 and 2.1, respectively. Of note,
these doses were still much lower than the doses used in the variable dose
regimen (1874 and 1360 IU F IX, respectively). In many Dutch hospitals,
these data formed the basis for a switch of PCC-dosing regimen from the
variable dose regimen to a fixed dose regimen of 1040 IU F IX.
29
Pilot study
On the basis of experience in other hospitals and the above study, our
hospital also changed the PCC-dosing regimen to a fixed dose regimen
(Fig. 1). This change created the opportunity to perform an observational
cohort pilot study to prospectively analyse the efficacy and feasibility of
the fixed dose regimen. A comparison was made with a historical cohort in
which PCC dose regimen was based on initial INR and patients bodyweight
(variable dose regimen, Table 1).
MATERIALS AND METHODS
Patients and study design
In October 2006, the hospital was switched to a fixed dose regimen
(Fig. 1). Thereafter, during a period of 6 months, dosing practice
and outcome was evaluated prospectively in all patients (cohort 1).
In
the
historical
cohort,
data
from
consecutive
patients
who
required reversal of VKA treatment using PCC between December
2005
and
May
2006
were
retrospectively
evaluated
(cohort
2).
In both cohorts, patients were eligible for inclusion if reversal of VKA
treatment was indicated for major or clinically relevant non-cranial bleeding
or for an emergency invasive procedure. The indication for PCC infusion
as well as the target INR was at the discretion of the physician involved.
The definition for major or clinically relevant bleed used by our hospital
is any obvious bleed accompanied by a systolic blood pressure <90 mm
Hg, or haemoglobin <65 g L−1 (4 mmol L−1 ), or a haemoglobin decrease
of >20 g L−1 (1.24 mmol L−1 ) in 24 h, or transfusion requirements ≥2
units of red blood cells, or retro-peritoneal bleeding, or intra-ocular
bleeding, or any bleeding that requires an invasive procedure to stop the
bleeding. This definition resembles the one proposed by the International
Society of Thrombosis and Haemostasis (Schulman et al., 2005).
Because all patients included in cohort 1 were to receive the fixed PCC
dose regardless of this study, according to the local standard, the need for
informed consent was waived by the institutional ethics committee.
30
Chapter 2
PCC regimen
The PCC used in this study was Cofact® (Sanquin, Amsterdam, The
Netherlands). The range of concentration of the vitamin K-dependent
factors (F) in PCC batches used during the period of evaluation was 2326 IU F IX, 10-14 IU F VII, 19-24 IU F II and 18-23 IU F X mL−1 . Each vial
was reconstituted with 10 mL of water prior to infusion. According to
the manufacturer, there were neither activated factors nor heparin
present in Cofact®. The adopted fixed dose regimen (Fig. 1) consisted
of an initial fixed dose of 1040 IU F IX per patient for major or clinically
relevant non-cranial bleeding, or an initial fixed dose of 520 IU F IX prior
to an emergency invasive procedure (cohort 1). The dosing of PCC in the
historical cohort was variable according to the manufacturer’s algorithm
(Table 1) based on the initial and the target INR and bodyweight
(cohort 2). In both cohorts, all patients received 10 mg vitamin K intravenously along with the PCC infusion. After the initial fixed dose infusion,
the attending physician judged each patient. It was to the discretion of the
physician to administer more PCC at any moment, e.g. in case of a high INR
after treatment, deterioration, or an ongoing active bleeding.
Study endpoints
The primary endpoint was the proportion of patients who achieved the
target INR within 20 min after PCC infusion. For major bleeds, target INR
was <1.5. For invasive procedures using epidural anesthesia, target INR
was <1.8. For all other bleeds and invasive procedures, the target INR was
<2.0. Secondary endpoints were the proportion of patients who reached
their target INR in each target INR category, the number of patients in
cohort 1 needing an extra PCC infusion after the initial fixed dose, and
proportion of patients with successful clinical outcome as judged by the
attending physician. Successful clinical outcome was assessed when visual
bleeding had stopped, and/or haemoglobin decrease stopped, and/or blood
pressure normalised and/or there was no need for further transfusion. For
invasive procedures, successful clinical outcome was defined as an invasive
procedure without bleeding complications.
31
Pilot study
2 N. Khorsand et al.
VKA user for invasive procedure (IP)
VKA user presents with bleeding
Major or clinically relevant bleed?
yes
Emergency IP (planned within 12 hours)?
no
yes
Intracranial?
yes
Initial PCC
dosage is
up to
neurologist
involved.
no
no
Stop VKA,
Vitamin k 10mg
intravenously.
Initial PCC
dosage: 1040 IU F
IX,
INR check
immediately after
initial dose and
within 4 hours *
Stop VKA, Vit.
k 10mg Orally
or
intravenously.
INR check after
6 and 12 hours
Stop VKA Vit.
k 10mg
intravenously.
INR check 2 hours
prior to IP. INR>2→
initial PCC dose 520
IU F IX, or in case of
a bleed & IP initial
PCC dose
1040 IU F IX,
INR check
immediately after
initial dose *
Stop VKA
Vit. k 10 mg orally or
intravenously.
INR check after
6 and 12 hours,
and 2 hours
prior to IP.
Extra PCC dosages can be administered if judged so by the
physician involved.
Figure 1: Fixed dose regimen, cohort 1.
Hospital’s algorithm for the PCC-fixed dose regimen. The indication for PCC treatment
was at the discretion of the attending physician as well as the decision to administer any
additional PCC. *Patients treated according to these parts of the algorithm are included
in the present study.
Furthermore, the achieved INR after PCC infusion, and the PCC dose per
patient in each cohort were analysed. A distinction is made in reporting
the achieved INR for baseline INR below and above 5, directly before PCC
treatment. Lastly, information regarding complications during hospitalization
was recorded. This included mortality, bleeding complications, deep vein
thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and
ischemic cerebrovascular accidents.
32
© 2010 The Authors
Transfusion Medicine © 2010 British Blood Transfusion Society, Transfusion Medicine, 21, 116 – 123
Chapter 2
Data collection
PCC is distributed and registered by our hospital’s blood bank when needed
for an individual patient. Therefore, patients for whom PCC was requested,
were identified using the blood bank record. The administration of PCC
was confirmed by the medical chart data in the historical group. In the
prospective fixed dose cohort, the attending physician, who also filled
out the research forms, confirmed the administration. Baseline status
and patient characteristics were evaluated using medical chart data at
admission. These included age, gender, concomitant drugs, indication for
VKA therapy, reason for reversal, initial INR, target INR, administration of
vitamin K and admission to intensive care unit (ICU). Level of anticoagulation
was assessed by INR measurement before PCC treatment, and 20 min
after PCC administration, using Stacompact© (Roche diagnostics, Almere,
The Netherlands) and Hepatoquick© reagens (Diagnostica Stago, Taverny,
France) with an instrument-specific ISI value of 0.92. The INR is expressed
in numbers up to a value of 9. All INRs above 9 are reported as >9 according
to the hospital protocol. Information regarding complications during
hospitalization was collected by a medical chart review.
Statistical analysis
Baseline as well as endpoint data are presented as mean plus standard
deviation or median plus range for continuous variables, depending on
normality of distribution, and as percentages with counts for categorical
variables. Differences between cohorts were evaluated using the Student
t-test or Mann-Whitney U-test, depending on normality, for continuous
data and the Fisher’s exact test for categorical data. A P value <0.05 (two
sided) was used to indicate statistical significance. Commercially available
computer software (prism 5 for Windows, Version 5.00, 1992-2007 GraphPad©
Software, Inc.) was used for all analyses.
33
34
2600
2600
2600
90
100
Dosage of PCC (IU of factor IX per patient)
2600
2600
2600
2080
1820
1560
1560
1560
1560
1300
1300
1040
2600
2600
2340
2080
1820
1560
1560
1560
1560
1300
1040
1040
2600
2340
2340
1820
1560
1300
1560
1560
1300
1300
1040
780
2600
2340
2340
1820
1560
1300
1560
1300
1300
1040
780
780
2340
2340
2080
1820
1560
1300
1300
1300
1040
1040
780
780
2340
2080
2080
1560
1300
1040
1040
1040
1040
780
780
520
2080
2080
1820
1560
1300
1040
1040
780
780
780
520
520
1820
1820
1560
1300
1040
780
X
X
X
X
X
X
Initial
Initial
Initial
Initial
Initial
Initial
Initial
Initial
INR 5•9 INR 4•8 INR 4•2 INR 3•6 INR 3•3 INR 3•0 INR 2•8 INR
2•6
1820
1560
1300
1040
1040
780
X
X
X
X
X
X
1560
1300
1300
1040
1040
780
X
X
X
X
X
X
1300
1040
1040
1040
780
780
X
X
X
X
X
X
Initial
Initial
Initial
INR 2•5 INR 2•3 INR
2•2
The dosage is shown as International Units of Factor IX, based on a Cofact® batch with 26 IU of F IX mL−1 as used for this study. This table
is based on manufacturer’s algorithm (Sanquin, Amsterdam, The Netherlands) (van Aart et al., 2006).
2340
80
100
70
1560
90
2080
1560
80
60
1560
70
1560
1560
60
50
1300
50
≤2.1
≤1.5
1040
Body
weight
(kg)
Target INR
Initial
INR
≥7•5
Table 1: PCC variable dosing regimen, cohort 2
Pilot study
Chapter 2
RESULTS
Patient characteristics
In cohort 1, 35 patients were enrolled in the fixed dose PCC regimen cohort
1. In cohort 2, 32 patients were retrospectively identified, who were treated
according to the variable dose regimen (Table 1). Phenprocoumon was used
by 86 and 78% of patients in cohort 1 and 2, respectively. Both cohorts
were comparable regarding age, gender and relevant co-medication. Table
2 shows the main patient characteristics.
Table 2: Patient characteristics
Cohort 1 (N = 35) Cohort 2 (N = 32) P value
Age in years median (range)
76 (28 - 93)
74 (43 - 93)
0.85
Male N (%)
16 (46%)
18 (56%)
0.47
VKA
0.53
-- Phenprocoumon N (%)
30 (86%)
25 (78%)
-- Acenocoumarol N (%)
5 (14%)
6 (19%)
-- Warfarin N (%)
0 (0%)
1 (3%)
3 (8.6%)
6(18.8%)
-- Major non-cranial bleeding
18 (51%)
19 (59%)
-- Invasive procedure
17 (49%)
13 (41%)
4.7 (2.0 to >9.0)
4.7 (1.8 to >9.0)
17 (49%)
15 (47%)
4 (11.4%)
7 (21.9%)
Concomitant antiplatelet
agents N (%)
Indication for PCC
Baseline INR median (range)
-- Baseline INR >5 N (%)
ICU admissions N (%)
0.29
0.62
0.54
0.33
Concomitant anti-platelet drugs: acetyl salicylic acid and clopidogrel. For P value
calculation the Mann - Whitney U -test is used for age and baseline INR, and the Fisher’s
exact test for all other data in this table. Cohort 1: fixed dose, cohort 2: variable dose
regimen. No statistical significant differences in patient characteristics are found
between both cohorts.
35
Pilot study
Table 3: Results
Results
Cohort 1 (N = 35)
Cohort 2 (N = 32)
P value
Target INR reached/total (%)
21/30 (70%)
22/27 (81%)
0.37
Successful clinical outcome/
total (%)
32/35 (91%)
30/32 (94%)
1.0
Cohort 1: fixed dose, cohort 2: variable dose regimen. The INR after PCC administration
was missing in 10 patients because of successful clinical outcome followed by a prompt
discharge (four patients in cohort 1), urgency to proceed to invasive procedure (four patients
in cohort 2) and mortality (one patient in cohort 1 and one in cohort 2).The clinical outcome
was judged by the attending physician. Fisher’s exact test is used for P value calculation.
Figure 2: INR before and after PCC treatment.
INR at baseline and 20 min after PCC treatment. Boxes span the interquartile range.
Horizontal lines bisecting the boxes indicate median values and lower and upper error
bars the range. Cohort 1: fixed dose, cohort 2: variable dose regimen.
36
Chapter 2
INR
Target INR was achieved in 70 versus 81% of patients in cohort 1 and 2,
respectively (P = 0.37, Table 3). The categorical target INR was reached by
5/7 versus 4/5 for INR <1.5, 3/3 versus 3/4 for INR <1.8 and 13/20 versus
15/18 for INR <2 in cohort 1 and 2, respectively. In cohort 1, median INR
declined from 4.7 at baseline to 1.8 and in cohort 2, from 4.7 to 1.6 (Fig. 2).
In cohort 1, 17 patients had a baseline INR >5 (median INR 7.8, range 5.19.0), which decreased to a median INR 1.7 (1.2-2.8) after PCC treatment.
Of these patients, nine reached their target INR (60%). Another 17 patients
enrolled in this cohort had a baseline <5 (median baseline INR 3.4, range
1.8-4.7), which decreased to a median INR 1.5 (range 1.2-2.7) after PCC
treatment according to the variable dose regimen.
PCC dose
Using the fixed dose regimen in cohort 1 (N = 35), 10 patients were treated
with a fixed dose of 520 IE F IX, and 22 patients with a fixed dose of 1040 IE
F IX, 1 patient received a second dose making a total of 1560 IE F IX and 2
patients were treated with an unplanned dosage of PCC (260 IE and 1820 IE
F IX, respectively). The median dosage used in this cohort was 1040 IU F IX
(range 260 - 1820 IU F IX). Adhering to the variable dosing regimen in cohort
2 (N = 32), the median PCC dosage per patient was 1560 IU F IX (range 260
- 5200 IU F IX), which was significantly higher than the median dosage used
in cohort 1 (P < 0.0001; Fig. 3).
Clinical outcome
Successful clinical outcome was seen in 32/35 (91%) patients in the fixed
dose cohort 1 versus 30/32 (94%) in the variable regimen control cohort
2 (P = 1.0; Table 3). In both cohorts, all patients with a baseline INR <5
(N = 18 in cohort 1 and N = 17 in cohort 2) were judged to have a successful
clinical outcome after PCC treatment. Successful clinical outcome was seen
in 15/17 (88%) patients with a baseline INR >5 in the fixed dose cohort
versus 14/15 (93%) patients with a baseline INR >5 in the variable regimen
cohort. In the fixed dose cohort, three patients remained unstable during
PCC treatment and died: the first was a fatal bleeding due to a ruptured
37
Pilot study
aneurysm in a 91-year-old female. (Initial INR 3.3, INR after a fixed dose
of 1040 IU F IX was not measured because of mortality.) Another patient, a
63-year-old female, died from cardiac complications shortly after admission
to the ICU, after receiving 520 IU F IX instead of the fixed dose of 1040 IU,
for an assumed gastrointestinal (GI) bleeding (initial INR >9, after 520 IU F
IX INR 2.9). Finally, a 93-year-old male died shortly after PCC treatment due
to hypovolaemic shock as a consequence of his major GI bleed (initial INR
>9, after 1040 IU F IX INR 3.9. No additional PCC was administered).
Figure 3: PCC administration.
PCC administered per patient. Graphic conventions as in figure 2. In cohort 1, median
dosage is the same line as upper interquartile range. Cohort 1: fixed dose regimen. In
this cohort 35 patients were included of which 10 were treated with 520 IU F IX, and 22
patients with 1040 IU F IX. One patient received a second dose making a total of 1560 IU
F IX, and two patients were treated with an unplanned dosage of PCC (260 IU and 1820
IU F IX, respectively). Cohort 2: variable dose regimen. In this cohort 32 patients were
included. The PCC dosage per patient ranged from 260 IU to 5200 IU F IX, depending on
the initial INR, target INR, and the body weight.
38
Chapter 2
In the variable dose regimen cohort, bleeding resulted in mortality in two
patients: the first patient was an 88-year-old female, who died due to
hypovolaemic shock during treatment (initial INR >9, INR after 1560 IU F IX
was not measured due to mortality), and the second patient, a 79-year-old
female, died due to multiple organ failure during treatment for GI bleeding
(initial INR >9, INR after 5200 IU F IX 2.84). A direct relation between
mortality and the applied PCC-dosing regimen was judged to be unlikely. In
both cohorts, bleeding complications did not occur in the patients treated
with PCC to counteract VKA therapy for an emergency invasive procedure.
The mortality rate during hospitalization was 6/35 (17%) in cohort 1
versus 10/32 (31%) in cohort 2 (P = 0.25). In the fixed dose group, one
thromboembolic complication during hospitalisation was seen in a patient,
who developed a fatal MI 10 days after PCC treatment. In the variable dose
regimen group, two patients had a fatal suspected PE after respectively 24
h and 5 days after PCC treatment. Neither PE was objectively confirmed.
DISCUSSION
The present pilot study demonstrates that target INR after a single PCC
infusion is reached in 70% of patients with a fixed PCC dose regimen, while
81% of patients in the historical cohort reached target INR with a PCC
dose regimen based on initial INR, target INR and body weight. Although
statistically not significant (P = 0.37), the numerically lower proportion
of patients achieving the target INR in the fixed dose cohort could be of
clinical importance. However, we did not observe less successful clinical
outcome in this cohort. The attending physician judged 91% of the patients
in the fixed dose cohort to have a successful clinical outcome and only one
patient needed an additional PCC infusion. In the variable dose cohort, 94%
of patients were judged to have a successful clinical outcome (P = 1.0).
The comparable successful clinical outcome was achieved with significantly
lower PCC doses in the fixed dose cohort (median dosage of 1040 IU F IX in
cohort 1 versus 1560 IU F IX in cohort 2). When only patients are analysed
39
Pilot study
with a baseline INR >5, the results resemble those for the whole study
population: a numerically higher achieved INR (median 2.0) and fewer
patients reaching their target INR (41%) after a fixed PCC dose compared
to the variable PCC dose (median achieved INR 1.7 and 60% reaching target
INR), while observing comparable successful clinical outcome. Interestingly,
for patients with a baseline INR <5, no difference was observed in the
achieved INR between both dosing regimens. Further studies should address
whether a higher fixed PCC dose than the one investigated in our study for
patients with a baseline INR >5, will lead to a lower achieved median INR
and more patients reaching target INR in this subgroup. Successful clinical
outcome was comparable between the two dosing groups. This finding
suggests that in VKA reversal the primary goal should not be to restore INR to
normal level, but to minimise the acute effect of heamorrhage by a prompt
decision on the dose and infusion of PCC. An initial PCC administration in
terms of a fixed dose seems to lead to a clinical outcome rate comparable
with the variable dosing regimen, despite fewer patients reaching the
target INR. This may possibly be the result of the speed of initiating
the treatment compared to a variable dose regimen for which patients’
weight and INR need to be collected before PCC treatment can be started.
Because of the observational character of our pilot study in which
all treated VKA patients are included, our patient population is a
good representation of clinical practice. The majority of the patients
included in our study were both elderly and ill when admitted to
our hospital. This is reflected by the high mortality rate during
hospitalization in both cohorts (17% in cohort 1 and 31% in cohort 2).
Although complications occur rarely, recognition of risk factors and
avoidance of overdosing are recommended to avert adverse thrombotic
events (Ehrlich et al., 2002, Ansell et al., 2008). In our study population one
MI 10 days after fixed PCC dose treatment and two fatal suspected PEs 24 h
and 5 days, respectively, after treatment with a variable PCC dose regimen
were seen. Because of the time lag between PCC administration and the
MI and one of the two suspected PE developments, these thromboembolic
events are unlikely to be related to PCC treatment. Considering the second
40
Chapter 2
suspected PE, which developed 24 h after PCC treatment, a correlation with
PCC infusion cannot be excluded. Therefore, our data advocate treatment
with the lowest possible effective dose of PCC. There are a number of
limitations to our study. Firstly, the sample size is small and our study is
neither clearly powered nor designed to give a definite comparison between
the two strategies. It does, however, provide data of clinical relevance for
further studies. Secondly, part of the data was collected retrospectively
(cohort 2, variable dose regimen). Those data were objective and readily
available, but we cannot exclude the possibility of bias. Furthermore,
generalizability needs to be discussed. In this study, we used the PCC
Cofact® and (in the majority of patients) the VKA phenprocoumon. Although
Cofact® is commonly used in Dutch hospitals, other commercially available
PCCs, e.g. Beriplex® (CSL Behring GmbH, Marburg, Germany) and Octaplex®
(Octapharma Pharmazeutika Produktionsges.m.b.H, Vienna, Austria),
are more often used elsewhere. No comparative studies on dosing are
performed. It is assumable that the difference between products will
probably influence the absolute required dose as expressed by units of
factor IX. Regarding the type of VKA, the main difference between the VKAs
is their elimination half-life time (acenocoumarol t 1/2 = 11 h, warfarin t
1/2 = 40 h and phenprocoumon t 1/2 = 140 h) (Gadisseur et al., 2002). One
study, in which all these VKA’s were well represented, showed no differences
among recipients of PCC for successful VKA reversal (Pabinger et al., 2008).
This suggests that the PCC dosage is not influenced by the VKA used. Lastly,
a number of studies on effectiveness are available in which higher PCC
dosages are applied to reach a lower target INR compared to our target INR
(Lubetsky et al., 2004; Lankiewics et al., 2006; Riess et al., 2007; Pabinger
et al., 2008). However, there is a lack of evidence that these high doses
and low target INRs improve clinical outcome, and that dose finding studies
should be performed to find the lowest effective PCC dose. The present
study provides a basis for such future studies.
41
Pilot study
In conclusion, the present pilot study suggests positive results for a relatively
low fixed dose regimen in terms of successful clinical outcome despite the
trend that target INR is reached in fewer patients than with the variable
dose regimen. Further ongoing studies would have to definitely prove this
while addressing the optimal dose regimen.
42
Chapter 2
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