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Optimal dosing strategy for prothrombin complex concentrateKhorsand, Nakisa

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CHaPter 1Introduction

10

General introduction

HISTOry OF VITAMIN K ANTAGONISTS

The mysterious ability of blood to clot has intrigued people over millennia.

The fascinating story of the discovery of vitamin K antagonists to manipulate

this clotting begins on the Canadian prairies in 1920s. The story ran as

follows:1 Previously healthy cattle in these areas died of internal bleeding

with no obvious cause. Given that livestock was one of the most important

industries in these areas combined with The Great Depression, this was a

disaster for the farmers. As there was an apparent lack of a recognizable

pathological disorder responsible for the haemorrhage, the diet of the

livestock was questioned. The cattle and sheep had grazed on sweet

clover hay (Melilotus alba and Melilotus officinalis) and the incidence of

bleeding occurred most frequently when the climate, and therefore the

hay, in these areas was damp. Damp hay became infected by moulds such as

Penicillium nigricans and Penicillium jensi, which appeared to be integral

in the disease process occurring in the cattle. As Duxbury and Poller point

out in their review article on warfarin,2 such hay would normally have been

discarded if it spoiled in storage, but in the financial hardship of the 1920s

few farmers could afford to buy supplementary fodder for their cattle and

thus the mouldy hay was used for feed. The resultant haemorrhagic disease

was called ‘sweet clover disease’ in 1922.

In 1929, Roderick observed that the affected cattle were deficient in a

clotting factor, prothrombin.3 At the same time, Dam was investigating a

severe bleeding condition with similar depletion of prothrombin in hens that

were maintained on sterol-depleted diets.4 This work led to the discovery

of vitamin K, for which Dam received the Nobel Prize for Medicine in 1943.

Another story is very informative:5 Ten years after the original outbreak of

sweet clover disease, a young Wisconsin farmer, Ed Carlson, angry about

losing his cows from internal bleeding, drove 200 miles with a dead cow in

the back of his truck to the local agricultural experimental station.

11

Chapter 1

As the investigator Karl Link was the only person left working late, Carlson

entered Link’s office handing him a milk can of unclotted blood. Link

experimented with the blood that evening and, as Duxbury and Poller

comment, ‘The can of uncoagulated blood lying on the floor of Link’s

laboratory was to change the course of history, and little did Link know

what the long-term implications would be’.2 Link and colleagues got to

work on finding the active substance from the spoiled hay causing the

internal bleed. In 1940, they published the purification and synthesis of

dicumarol (3,3-methylenebis-9 [4-hydroxycoumarin]), the active component

in the spoiled sweet clover.6 This agent, referred to as “coumarin”, was

promptly made available for clinical studies and already one year later first

experiences on the effectiveness in deep vein thrombosis as well as its

hemorrhagic complications were published.7-9 At that time, the most potent

synthesized coumarin, warfarin, was successfully used to fight rats.10

The first clinical study with administration of coumarins in thromboembolic

conditions is reported in 1948.11 Not much later, president Eisenhower

was treated with warfarin following a heart attack.12 By that time, it was

empirically known that vitamin K reversed the bleeding problem caused

by coumarins as these agents were also called ‘vitamin K antagonists’.

However, it took another 2 decades until in 1974 the vitamin K cycle was

proposed.13, 14 After 30 years the complicating biochemical relation between

vitamin K, vitamin k-epoxide, and the role of vitamin K antagonists was

clarified by identification of VKORC1 in Nature in 2004.15, 16

It is rare for any drug introduced more than 50 years ago to remain

unsurpassed today, yet millions of patients are still being treated with

vitamin K antagonists.17 In 1985, a goal was set to develop new oral

anticoagulants to replace vitamin K antagonists.18 However, due to many

challenges facing the scientists, novel oral anticoagulants did not enter the

market until the 21st century.19-21

12

General introduction

General hemostasis

In case of vessel damage, the body reacts fast to prevent blood loss. This

process, ‘hemostasis’ or ‘coagulation’, involves platelets, coagulation factors

and several other proteins, all working closely together with the vessel wall

in a complicated and precisely balanced process (figure 1).22 Briefly, when the

vessel wall is damaged, tissue factor (TF) is released. This initiates activation

of factor VII in blood with formation of TF-factor VIIa-complex. This complex

enables the conversion of factor X into Xa. After its activation, factor Xa

facilitates the formation of small amounts of thrombin, which is necessary

to activate platelets and cofactor V and VIII. Activated factor X together with

activated factor V configures the prothrombinase complex. This complex

converts prothrombin (factor II) to thrombin (factor IIa). Thrombin initiates

many pathways. For hemostasis, the most important one is the configuration

of fibrinogen into a fibrin and subsequently into fibrinclot.

Figure 1: Coagulation pathway adopted from Borissoff et al, NEJM 2011.22

13

Chapter 1

Vitamin K antagonists

Most coagulation factors are synthesized in the liver. Some of these factors

need vitamin K as a co-enzyme for their formation.23 These factors are

coagulation factors II (prothrombin), VII, IX, X, and coagulation inhibiting

factors Protein C and S.

For this process, vitamin K is oxidized into vitamin K epoxide. As vitamin K

is very limitedly available in tissues, the epoxide must rapidly be reduced

again to vitamin K. An enzyme called ‘vitamin K epoxide reductase complex’

(VKOr) is needed to facilitate this step.16

Vitamin K antagonists (earlier referred to as coumarins) block the VKOr

enzyme and prevent the regeneration of reduced vitamin K.23 Therefore, the

synthesis of coagulation factors cannot be completed; subsequently these

factors cannot take part in the coagulation cascade. As this blockage only

affects the new formation of the clotting factors, the effect of vitamin K

antagonists is delayed for 72 to 96 hours after the start of treatment.

To date, different vitamin K antagonist agents are known of which warfarin,

acenocoumarol, and phenprocoumon are the most widely used. In the

United States of America and the United Kingdom only warfarin is used,

whereas in the Netherlands only acenocoumarol and phenprocoumon are

available. The most important differences of these drugs are summarized

in table 1.

The effectiveness of vitamin K antagonists has been established by well-

designed clinical trials.17, 29 They are applied for the primary and secondary

prevention of venous thromboembolism, for the prevention of systemic

embolism in patients with prosthetic heart valves or atrial fibrillation and for

the prevention of stroke, recurrent infarction or death after acute coronary

syndrome. For the prevention of stroke in patients with atrial fibrillation,

vitamin K antagonists showed a 64% reduction of stroke risk compared to

placebo and 37% risk reduction compared to antiplatelet therapy.30

14

General introduction

table 1: Differences in VKA drugs

Onset period Half-life time Wash out period

Metabolism27-29

Warfarin 36-72 hours 40 hours 4-5 days CyP2C9 mainly, also CyP1A2 and CyP3A4

acenocoumarol 36-48 hours 11 hours 48 hours CyP2C9 mainly, also CyP2C19

Phenprocoumon 48-72 hours 160 hours 1-2 weeks CyP2C9 (less than acenocoumarol), also

CyP3A4 and urinary

and gut excretion

Vitamin K antagonists all have a narrow therapeutic range as the effective

dose is close to the minimum and maximum safe dose. Deviating from the

effective dose to under-treatment increases the risk of thrombosis and to

over-treatment the risk of bleeding.24 However, finding the right dose is

difficult because of the large inter- and intra-individual differences in dosage

requirement for optimal efficacy. The inter- and intra-individual variability

thereby the range in required dosages can, at least in part, be explained by

factors such as age, gender, co-morbidity, vitamin K intake, co-medication,

and genetic variation in its main metabolizing enzyme, cytochrome P450

isoform CyP2C9.25, 26 This means that the anticoagulant effect in patients on

vitamin K antagonists needs to be measured regularly and that doses need

to be adjusted accordingly.

The level of anticoagulation is historically monitored by a coagulation test

that measures the prothrombin time (PT). However, because laboratories

used different reagents for this test, PT results between different

laboratories were not comparable. Therefore, a standardized expression of

the level of anticoagulation, the International Normalized ratio (INr) has

been adopted.31-33 For this, the International Sensitivity Index (ISI) is used,

which indicates the level of tissue factor in the PT-reagent. When the ISI

and PT are known, INr is calculated using a formula:

15

Chapter 1

The INr, being a ratio, has no units. The normal INr is 1. When using VKA,

elevated INrs from 2 to 3,5 are desired. Higher INr intensities are associated

with higher incidences of bleeding complications, whereas lower intensities

are associated with more thromboembolic events.24, 34

Complications of vitamin K antagonists

As its toxicity was discovered before the active therapeutic component

itself, it is of no surprise that vitamin K antagonists are among the most

toxic drugs in current medicine. In fact, these drugs are one of the main

reason for drug-related hospital admissions.35, 36

Despite many thrombosis services and anticoagulation clinics world-wide

and rapid INr controls for individual vitamin K antagonist dosage regimens,

major bleeding complications are still common practice. Intracranial bleeds

are the most feared complication as these bleeds are most often fatal. Other

frequently seen major bleeds include gastrointestinal, intra-peritoneal,

intraocular and muscle bleeds.

Numerous studies have shown that the incidence of vitamin K antagonist-

associated major bleeding is 0.4-7.2% per year.37-39 This wide range is

considered to be the result of the many patient-related factors that can

alter the pharmacokinetics and pharmacodynamics of vitamin K antagonists.

In addition, earlier studies often had different definitions of major

bleed. More recent studies have been more consistent and usually define

major bleed as proposed by the International Society of Thrombosis and

Haemostasis.40 According to this, a major bleed is defined as a fatal bleed,

and/or a symptomatic bleed in a critical area or organ, such as intracranial,

intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or

intramuscular with compartment syndrome, and/or bleeding that causes

a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more, or leading to

transfusion of two or more units of whole blood or red blood cells.

In recent years, several well-designed studies have been conducted due to

the discovery of novel oral anticoagulants and their effectiveness compared

16

General introduction

to the well-established vitamin K antagonists. Throughout these studies,

knowledge has increased about incidences of major, intracranial and fatal

bleeds in the studied populations. In table 2 these incidences are shown.

table 2: incidences of different VKA-associated bleeds obtained from novel oral anticoagulant studies

Gastrointestinal Major Intracranial Fatal

reLY19 1.02%/year 3.36%/year 0.74%/year -

rocket-aF20 2.2%/year 3.4%/year 0.7%/year 0.5%/year

aristotle21 0.86%/year 3.09%/year 0.80%/year -

re-Cover41 2.8% 1.9% 0.24% 0.08%

einstein42 - 1.2%* 0.3%* -

* per treatment period resulting in lower percentages than other studies

treatment of vitamin K antagonist-associated bleeds

Management of vitamin K antagonist-associated bleeds depends mainly on

the severity of the bleed and is still a common clinical challenge.

In addition to hemodynamic stabilization, and possible surgical, endoscopic

or other interventional control, the anticoagulant effect of vitamin K

antagonist must be reversed.17 This can be accomplished by withholding

vitamin K antagonist therapy. In this case, it takes 3 to 5 days, depending on

the vitamin K antagonist (table 1), before the vitamin K cycle is restored and

the vitamin K antagonist effect is diminished. In case a more rapid reversal

is needed, vitamin K can be replaced by its administration. This allows

the liver to directly start producing normally carboxylized clotting factors.

By administering vitamin K, the vitamin K antagonist effect is diminished

within 24 hours. However, for a longer-term correction of the coagulopathy,

daily administration of vitamin K is necessary.

For an urgent, direct reversal of vitamin K antagonists, the depleted vitamin

K dependent clotting factors as described above, should be administered.

This could either be done by infusion of fresh frozen plasma in which clotting

factors are present or by transfusion of prothrombin complex concentrates,

which contain clotting factors II, IX and X and a variable amount of factor

17

Chapter 1

VII (see below). Prothrombin complex concentrates usage is associated with

several benefits when compared to fresh frozen plasma, of which the lower

volume of prothrombin complex concentrate43 and the rapid correction

of the INr resulting to better clinical outcome44 are the most important

ones. Currently, the American College of Chest Physicians (ACCP) guidelines

recommend the use of prothrombin complex concentrates rather than

plasma for reversal of VKA-induced coagulopathy in patients with a vitamin

K antagonist-associated major bleeding.45

Prothrombin Complex Concentrate

Prothrombin Complex Concentrates are human plasma-derived products

containing clotting factors II, IX, X, and VII. In addition to these so-called

4 factor concentrates, 3 factor concentrates are available that contain

far less factor VII. Furthermore, all prothrombin complex concentrates

contain variable amounts of natural anticoagulant proteins C and S, and

anti-thrombin. Different prothrombin complex concentrates are available

worldwide. These agents and their content, related to 100 units of factor IX

are summarized in table 3. In the Netherlands only 4 factor PCCs are used.

The safety of prothrombin complex concentrates has been subject to

research for several decades as well. A recent meta-analysis reported the

incidence of thromboembolic events to be +1,8% in patients after receiving

four-factor prothrombin complex concentrates.47 It is also believed that

the thrombogeneity of prothrombin complex concentrates increases with

higher doses.48

18

General introduction

tabl

e 3:

Pro

thro

mbi

n co

mpl

ex c

once

ntra

tes

and

thei

r co

nten

t re

late

d to

100

IU o

f fa

ctor

IX a

dopt

ed f

rom

Wor

ld F

eder

atio

n of

Hem

o-ph

ilia

regi

ster

of

clot

ting

fac

tor

conc

entr

ates

46 a

nd t

he a

vaila

ble

Sum

mar

y of

Pro

duct

Cha

ract

eris

tics

(SP

C)

Bran

d na

me

Man

ufac

ture

r3

or 4

fac

tor

Fact

or II

Fa

ctor

VII

Fact

or IX

Fa

ctor

XO

ther

Beri

plex

CSL

Behr

ing,

Ger

man

y

4F12

868

100

152

Prot

ein

C, h

epar

in,

anti

thro

mbi

n an

d

albu

min

Cofa

ctSa

nqui

n,

Net

herl

ands

4F56

-140

28-8

010

056

-140

Prot

ein

S an

d C

and

anti

thro

mbi

n

Kask

adil

LFB,

Fra

nce

4F14

840

100

160

Hep

arin

Oct

aple

xO

ctap

harm

a,

Aust

ria

& F

ranc

e

4F44

-152

36-9

610

050

Prot

ein

C &

S an

d

hepa

rin,

low

acti

vate

d fa

ctor

VII

PPSB

-Ht

Nic

hiya

kuN

ichi

yaku

, Ja

pan

4F10

010

010

010

0Pr

otei

n C

Profi

linG

rifo

ls,

USA

3F14

8Lo

w10

064

-

PtX-

VFCS

L Bi

opla

sma,

Aust

ralia

3F10

0-

100

100

-

Um

anKe

drio

n, It

aly

3F10

0-

100

80An

tith

rom

bin

and

hepa

rin

19

Chapter 1

The efficacy of prothrombin complex concentrate is well-established. Also,

its safety has been subject to many trials. However, its safety and efficacy

have never been investigated in relation to the optimal dose. Ideally, optimal

dose of prothrombin complex concentrate is the minimum effective dose as

its thrombogeneity is supposed to increase with the dosage. Furthermore,

the optimal, minimum effective dose is cost-effective as this low dosage

should not lead to any other additional interventions.

In this thesis we aimed to find the optimal prothrombin complex concentrate

dose while addressing its effectiveness, safety and costs.

SCOPE OF THE THESIS

In this thesis, we address the use of prothrombin complex concentrates in

emergency reversal of vitamin K antagonists. In this, we focus on finding

the optimal cost-effective and safe prothrombin complex concentrate dose

strategy in vitamin K antagonist taking population who need prothrombin

complex concentrate for acute reversal of vitamin K antagonists.

In chapter 2, by means of a pilot, we explored the feasibility of a simple,

low fixed dose prothrombin complex concentrate treatment strategy.

In chapter 3, we prospectively enrolled consecutive patients with a major

vitamin K antagonist associated bleed who were either treated by the

earlier mentioned low fixed dose or a more widely used variable, INR and

weight dependent, prothrombin complex concentrate dosing strategy.

Subsequently, as we found the fixed dose to be non-inferior to the variable

dosing strategy in terms of clinical outcome, an important question from

both a clinical and costing point of view rose about whether additional

interventions were needed in the fixed dose cohort to reach the non-

inferior outcome. We studied this by performing a cost-study which is

reported in chapter 4.

20

General introduction

A review of the literature is performed in chapter 5 to assess the currently

used prothrombin complex concentrate strategies for emergency vitamin

K antagonist reversal and to present their efficacy in terms of target INR

achievement and clinical outcome.

Finally, in chapter 6, patients, who survived the vitamin K antagonist

related major bleed in the study described in chapter 3, were followed

to determine their long term outcome in terms of incidences of (fatal)

thromboembolism, recurrent (fatal) bleed and mortality. In addition, we

characterized patients who either continued or discontinued the vitamin K

antagonist therapy.

21

Chapter 1

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