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Optimal dosing strategy for prothrombin complex concentrateKhorsand, Nakisa

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Chapter 2Fixed 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

28

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.

29

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 1.4-

3.3% 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.

30

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

31

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 23-

26 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 intra-

venously 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

32

Pilot study

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.

2 N. Khorsand et al.

© 2010 The Authors Transfusion Medicine © 2010 British Blood Transfusion Society, Transfusion Medicine, 21, 116 – 123

VKA user presents with bleeding VKA user for invasive procedure (IP)

Major or clinically relevant bleed? Emergency IP (planned within 12 hours)?

yes no

Intracranial? yes no

yes no

Initial PCC dosage is

up to neurologist involved.

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.

33

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

34

Pilot study

tabl

e 1:

PCC

var

iabl

e do

sing

reg

imen

, co

hort

2

Dos

age

of P

CC (

IU o

f fa

ctor

IX p

er p

atie

nt)

Targ

et IN

rBo

dy

wei

ght

(kg)

Init

ial

INr

≥7

•5

Init

ial

INR

5•9

Init

ial

INR

4•8

Init

ial

INR

4•2

Init

ial

INR

3•6

Init

ial

INR

3•3

Init

ial

INR

3•0

Init

ial

INR

2•8

Init

ial

INr

2•6

Init

ial

INR

2•5

Init

ial

INR

2•3

Init

ial

INr

2•2

≤2.1

5010

4010

4010

4078

078

078

052

052

0X

XX

X

6013

0013

0010

4010

4078

078

078

052

0X

XX

X

7015

6013

0013

0013

0010

4010

4078

078

0X

XX

X

8015

6015

6015

6013

0013

0010

4010

4078

0X

XX

X

9015

6015

6015

6015

6013

0013

0010

4078

0X

XX

X

100

1560

1560

1560

1560

1560

1300

1040

1040

XX

XX

≤1.5

5015

6015

6015

6013

0013

0013

0010

4010

4078

078

078

078

0

6020

8018

2018

2015

6015

6015

6013

0013

0010

4010

4010

4078

0

7023

4020

8020

8018

2018

2018

2015

6015

6013

0010

4010

4010

40

8026

0026

0023

4023

4023

4020

8020

8018

2015

6013

0013

0010

40

9026

0026

0026

0023

4023

4023

4020

8020

8018

2015

6013

0010

40

100

2600

2600

2600

2600

2600

2340

2340

2080

1820

1820

1560

1300

The

dosa

ge is

sho

wn

as In

tern

atio

nal U

nits

of

Fact

or IX

, ba

sed

on a

Cof

act®

bat

ch w

ith

26 IU

of

F IX

mL−

1 as

use

d fo

r th

is s

tudy

. Th

is t

able

is

bas

ed o

n m

anuf

actu

rer’

s al

gori

thm

(Sa

nqui

n, A

mst

erda

m,

The

Net

herl

ands

) (v

an A

art

et a

l.,

2006

).

35

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%)

Concomitant antiplatelet agents N (%)

3 (8.6%) 6(18.8%) 0.29

Indication for PCC 0.62

- Major non-cranial bleeding 18 (51%) 19 (59%)

- Invasive procedure 17 (49%) 13 (41%)

Baseline INr median (range) 4.7 (2.0 to >9.0) 4.7 (1.8 to >9.0) 0.54

- Baseline INr >5 N (%) 17 (49%) 15 (47%)

ICU admissions N (%) 4 (11.4%) 7 (21.9%) 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.

36

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.

37

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

38

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.

39

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

40

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, 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

41

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.

42

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.

43

Chapter 2

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