Retinal haemodynamics in individuals with well-controlled type 1 diabetes Aims/hypothesis Abnormalities in retinal haemodynamics have been reported in patients with type 1 diabetes in advance of clinical retinopathy . These abnormalities could therefore be useful as early markers or surrogate endpoints for studying the microangiopathy . Since the DCCT , the increased focus on good glycaemic control is changing the natural history of diabetic retinopathy . Based on this , the aim of this study was to investigate whether patients with type 1 diabetes treated entirely or mostly in the post-DCCT era and tested in the absence of confounding factors show retinal haemodynamic abnormalities . The DCCT proved that good glycaemic control is a powerful means of preventing retinopathy or slowing its course in many patients -LSB- 1 -RSB- . It also proved that today 's means of achieving good control are imperfect , and that some patients may still progress to sight-threatening stages of retinopathy . With the latter finding , the DCCT encouraged continuation of the quest for therapies able to pre-empt the effects of the residual hyperglycaemia ; however , by increasing the prevalence of good glycaemic control it made any trial of such therapies extremely long and expensive . For this reason , there is heightened interest in early markers of retinopathy to be used as surrogates to test adjunct therapies . Retinal haemodynamics have been investigated extensively in the quest for early functional markers of diabetic retinopathy -LSB- 2 -RSB- ; some of the changes detected appear to be a function of the duration of diabetes and the severity of retinopathy -LSB- 2 -- 4 -RSB- . In patients with type 1 diabetes and absent or minimal retinopathy , several investigators using different techniques have observed decreased retinal blood speed -LSB- 3 -- 7 -RSB- . These studies , performed in the early and mid-1990s , were in patients with rather poor glycaemic control by today 's standards , yet the decreased retinal blood speed could not be attributed solely to elevated blood glucose levels at the time of measurement because hyperglycaemia actually increases blood speed -LSB- 2 , 3 , 7 -RSB- . We investigated whether patients with type 1 diabetes treated entirely or mostly in the post-DCCT era and tested in the absence of confounding factors show retinal haemodynamic abnormalities . Methods The institutional review boards of the Schepens Eye Research Institute and Massachusetts General Hospital -LRB- MGH -RRB- approved this study . We recruited , from the MGH Diabetes Center and the greater Boston area , type 1 diabetic patients with the clinical characteristics of patients previously reported -LSB- 3 -- 7 -RSB- to show decreased retinal blood speed : 18 -- 45 years of age , 1 -- 15 years of insulin dependence , and absent or minimal retinopathy . The non-diabetic participants , matched for age and sex , had no history of diabetes and had HbA1c levels lower than 6 % . Exclusion criteria were pregnancy , smoking , systemic diseases other than type 1 diabetes , other retinal diseases , hypertension and renal insufficiency ; also excluded were users of angiotensin-converting enzyme inhibitors , angiotensin receptor antagonists , vitamin E at doses greater than 400 IU/day , aspirin or other antiplatelet drugs , and ibuprofen . After giving informed consent , all participants in the study underwent a complete eye examination . Diabetic individuals were excluded if they had diabetic retinopathy greater than level 20 in the Early Treatment Diabetic Retinopathy Study severity scale -LRB- microaneurysms only -RRB- . HbA1c was measured by the MGH HbA1c laboratory ; a level > 10 % was an exclusion criterion . The retinal haemodynamic parameters were measured when capillary blood glucose levels were between 3.8 and 11.1 mmol/l in order to avoid the confounding effects of acute hypo - or hyperglycaemia on retinal blood flow -LSB- 7 -RSB- . The investigator performing the laser Doppler measurements -LRB- G. T. Feke -RRB- was masked to the diabetes status of the participants . The study eye was chosen on the basis of vascular anatomy . The superior temporal retinal arteries are preferred because temporal arteries are larger than nasal arteries , and the lesions of diabetic retinopathy are more prevalent in the superior temporal than in the other quadrants . The arterial blood column diameter and centreline blood speed were measured using a Canon laser Doppler retinal blood flow instrument -LRB- CLBF 100 ; Canon , Tokyo , Japan -RRB- -LSB- 8 -RSB- . The blood flow rate in units of μl/min is calculated automatically as the product of the cross-sectional area of the artery at the laser Doppler measurement site and the average blood speed , assuming a circular arterial cross-section -LSB- 8 -RSB- . Data are presented as means ± SD . Parameters were compared between diabetic and control participants using the non-paired t test . Results Table 1 summarises the characteristics of the study population . The diabetic and control groups differed only in the levels of HbA1c and blood glucose . The diabetic participants received insulin through multiple daily injections or an external pump . The mean HbA1c level was 7.5 % and the range 5.2 -- 9.3 % , eight patients having HbA1c levels above 8 % . The mean duration of type 1 diabetes was 8.8 years . Only three patients manifested retinopathy , two of them showing one microaneurysm and one several microaneurysms . Of note , no diabetic individual who sought participation in the study was excluded because of advanced retinopathy , and only one diabetic individual was not included because of HbA1c greater than 10 % -LRB- 10.8 % -RRB- . Table 1Characteristics of the study population Diabetic individuals -LRB- n = 33 -RRB- Controls -LRB- n = 31 -RRB- p valueAge -LRB- years -RRB- 30 ± 7.030 ± 5.60.86 Sex -LRB- % female -RRB- 48580.44 HbA1c -LRB- % -RRB- 7.5 ± 1.25.0 ± 0.3 < 0.0001 Diabetes duration -LRB- years -RRB- 8.8 ± 4.6 n/an/aBlood glucose level -LRB- mmol/l -RRB- a7 .7 ± 2.85.4 ± 0.8 < 0.0001 Systolic blood pressure -LRB- mmHg -RRB- 106 ± 11109 ± 70.27 Diastolic blood pressure -LRB- mmHg -RRB- 65 ± 866 ± 70.47 Retinopathyb -LRB- % -RRB- 9n/aData are means ± SD or percentagesaMeasured immediately before the retinal haemodynamic studiesbAssessed using the Early Treatment Diabetic Retinopathy Study severity scale . Individuals with a score of greater than 20 were excluded from the studyn/a , not applicable Figure 1 presents the retinal haemodynamic measurements in 27 diabetic and 26 control participants in whom the measurements could be performed at the major superior temporal artery . Arterial diameter and blood speed were not significantly different between the diabetic patients and the controls -LRB- diameter : patients 116 ± 12 μm , controls 112 ± 10 μm , p = 0.18 ; blood speed : patients 32.9 ± 6.0 mm/s , controls 34.6 ± 6.8 mm/s , p = 0.34 -RRB- . Accordingly , retinal blood flow was the same in the two groups -LRB- patients 10.4 ± 2.4 μl/min ; controls 10.4 ± 3.2 μl/min , p = 0.98 -RRB- . In the remaining six diabetic and five control participants there was early bifurcation of the artery , and one of the branches was used for the measurements ; again , no differences were noted between the two groups . The sample size provided 80 % power -LRB- α = 0.05 -RRB- to detect differences as low as 0.75 SD between diabetic and control participants . This translates into differences of 7 , 15 and 24 % for retinal artery diameter , blood speed and blood flow , respectively . Fig. 1Retinal haemodynamic parameters in type 1 diabetic individuals and matched non-diabetic controls . The box plots present the data for the 27 diabetic and 26 control participants in whom the measurements could be performed at the major superior temporal artery . Each box plot shows the 10th , 25th , 50th -LRB- median -RRB- , 75th and 90th percentiles of the indicated parameter . Values above the 90th and below the 10th percentile are plotted as points None of the haemodynamic measurements showed a significant correlation with coincident blood glucose levels , HbA1c , age , diabetes duration , systolic or diastolic blood pressure in either the diabetic or the control participants -LRB- data not shown -RRB- . Discussion The important finding of this study is that in young patients with relatively well-controlled type 1 diabetes and no complications the baseline retinal circulatory parameters are within the normal range , even after several years of diabetes . These results differ from those of studies completed before the publication and widespread application of the DCCT results . In these earlier studies -LSB- 3 -- 7 -RSB- the average HbA1c levels were 8 , 10 or 12 % compared with 7.5 % in our diabetic individuals . Although we did not observe a correlation of HbA1c with retinal blood speed or flow , most likely because of the narrow range of HbA1c values , it was previously shown that retinal blood flow decreased with increasing HbA1c in type 1 diabetic patients without retinopathy -LSB- 4 -RSB- . The relation between HbA1c and retinal circulatory parameters must be interpreted with the knowledge that acute elevations -LSB- 2 , 7 -RSB- or coincident high levels -LSB- 2 , 3 -RSB- of blood glucose increase retinal blood flow , by increasing blood speed . Thus , the decreased blood speed and blood flow found in type 1 patients in previous studies indicated the presence of chronic effects of hyperglycaemia on retinal vessels in advance of clinical retinopathy . Elevated plasma glucose levels at the time of haemodynamic measurements could actually have masked , to some extent , such chronic effects of hyperglycaemia , contributing to the inconsistency with which retinal circulatory abnormalities were detected in diabetic patients without retinopathy -LSB- 2 -RSB- . The design of our study , requiring relatively normal glucose levels prior to the laser Doppler measurements -LRB- Table 1 -RRB- , limited such potential confounding effects , and the normal retinal haemodynamics that we recorded in diabetic participants should be informative of the status of retinal vessels . Our results are empowering for patients with type 1 diabetes and those who care for them , for two reasons . First , it is apparent that good glycaemic control is attainable in a non-clinical trial setting , and is sustainable over time . Second , such good control not only delays or prevents retinopathy , as shown by the DCCT , but also delays or prevents abnormalities in the retinal circulation that may be prodromes to the development of retinopathy . Normal retinal haemodynamics were also reported recently in patients with type 2 diabetes with no retinopathy and mean HbA1c of 7.2 % -LSB- 9 -RSB- or 7.7 % -LSB- 2 -RSB- . From the standpoint of finding early markers of retinopathy , our observations indicate that measurements of retinal circulatory parameters in the unperturbed state may not be sufficiently sensitive in patients with absent or minimal retinopathy and well-controlled diabetes . Insofar as the HbA1c levels in such patients are often still greater than normal , the residual hyperglycaemia is likely to leave signs on the retinal vessels , but these may be uncovered only when a functional challenge is applied to the vessels . In response to hyperoxia , used as a stimulus to test vascular reactivity , patients with well-controlled type 2 diabetes showed normal retinal haemodynamics -LSB- 9 -RSB- , but type 1 patients in another study did not -LSB- 10 -RSB- . Unfortunately , the latter study did not report levels of glycaemic control . The next step will be to compare in the same well-controlled type 1 diabetic individuals the behaviour of retinal haemodynamics at steady state and in response to a challenge . In this way we will begin to reconstruct systematically the history of retinal microangiopathy in the post-DCCT era .

O O O O O O B I I O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

diabetic retinopathy
retinal blood flow
retinal circulation
type 1 diabetes


Coumarin

anticoagulants

and

co-trimoxazole

avoid

the

combination

rather

than

manage

the

interaction

Objective

The

objective

of

our

study

was

to

examine

the

management

of

the

interaction

between

acenocoumarol

or

phenprocoumon

and

several

antibiotics

by

anticoagulation

clinics

and

to

compare

the

consequences

of

this

interaction

on

users

of

co-trimoxazole

with

those

for

users

of

other

antibiotics

Introduction

Coumarin-type

anticoagulants

have

a

narrow

therapeutic

range

One

important

aspect

of

their

safety

is

their

sensitivity

to

drug

interactions

many

of

which

have

been

described

-LSB-

-RSB-

There

are

several

reasons

why

antibiotic

use

can

be

considered

to

be

indicative

of

a

change

in

anticoagulation

status

in

users

of

coumarin-type

anticoagulants

When

the

antibiotic

is

used

for

febrile

illness

it

may

be

associated

with

overanticoagulation

-LSB-

-RSB-

In

two

studies

on

the

interaction

between

coumarin

anticoagulants

and

antibiotics

the

risk

of

severe

overanticoagulation

defined

as

an

International

Normalised

Ratio

-LRB-

INR

-RRB-

was

increased

more

in

users

of

sulfamethoxazole-trimethoprim

-LRB-

co-trimoxazole

-RRB-

than

in

users

of

other

antibiotics

-LSB-

-RSB-

Sulfamethoxazole

is

a

strong

inhibitor

of

-LSB-

-RSB-

the

main

liver

enzyme

involved

in

the

metabolism

of

warfarin

-LSB-

-RSB-

acenocoumarol

-LSB-

-RSB-

and

probably

phenprocoumon

-LSB-

-RSB-

which

could

explain

this

stronger

association

with

overanticoagulation

Current

clinical

guidelines

in

The

Netherlands

for

the

management

of

coumarin

drug

interactions

advise

healthcare

givers

to

avoid

prescribing

the

concurrent

use

of

co-trimoxazole

and

coumarins

-LSB-

-RSB-

Nevertheless

in

daily

practice

co-trimoxazole

is

frequently

prescribed

to

users

of

coumarins

since

physicians

in

anticoagulation

clinics

assume

that

an

interaction

with

co-trimoxazole

can

be

managed

in

a

manner

similar

to

those

used

to

manage

interactions

that

arise

with

the

concurrent

use

of

coumarins

with

other

antibiotics

An

anticoagulation

clinic

will

initiate

one

of

the

following

procedures

once

it

has

been

notified

of

the

initiation

of

the

use

of

an

antibiotic

-LRB-

-RRB-

measurement

of

the

INR

during

the

antibiotic

course

and

adjustment

of

the

coumarin

dose

depending

on

the

INR

value

-LRB-

a

reactive

dose-adjustment

-RRB-

-LRB-

-RRB-

a

preventive

-LRB-

coumarin

-RRB-

dose

reduction

-LRB-

PDR

-RRB-

preceding

an

INR

measurement

during

or

after

the

antibiotic

course

assuming

that

use

of

an

antibiotic

or

the

intercurrent

infection

itself

increases

the

risk

of

overanticoagulation

The

PDR

approach

seems

even

more

relevant

to

co-trimoxazole

than

to

other

antibiotics

because

the

effect

of

the

former

might

increase

the

risk

of

overanticoagulation

more

than

the

infectious

state

alone

However

PDR

could

also

lead

to

temporary

undertreatment

and

evidence

for

the

effectiveness

of

this

approach

is

currently

lacking

There

are

no

official

guidelines

for

such

dose

adjustments

and

the

application

of

PDR

strongly

depends

on

the

personal

view

of

the

responsible

physician

The

aim

of

the

present

study

was

to

examine

the

management

of

the

interaction

between

coumarin

anticoagulants

and

antibiotics

by

anticoagulation

clinics

and

its

consequences

for

users

of

co-trimoxazole

and

other

antibiotics

To

this

end

we

conducted

a

prospective

follow-up

study

at

four

anticoagulation

clinics

in

The

Netherlands

Materials

and

methods

Study

design

This

was

a

follow-up

study

conducted

at

four

anticoagulation

clinics

in

The

Netherlands

We

included

patients

who

were

stabilised

on

one

of

the

coumarin

anticoagulants

acenocoumarol

or

phenprocoumon

and

who

had

started

using

one

of

the

following

antibiotics

between

January

and

October

co-trimoxazole

amoxicillin

amoxicillin-clavulanic

acid

clarithromycin

doxycyclin

nitrofurantoin

norfloxacin

or

trimethoprim

In

addition

to

co-trimoxazole

we

chose

the

other

antibiotics

based

on

their

use

for

the

same

kind

of

infections

mainly

those

of

the

urinary

and

respiratory

tract

The

subjects

included

in

our

study

were

prospectively

followed

during

the

antibiotic

course

until

the

last

INR

measurement

which

occurred

within

weeks

following

the

starting

date

of

the

antibiotic

-LRB-

follow-up

time

-RRB-

We

did

not

intervene

in

the

daily

routine

of

the

participating

anticoagulation

clinics

and

in

particular

we

made

no

agreements

on

checking

the

INR

of

patients

during

the

antibiotic

course

on

making

additional

INR

measurements

on

the

time

intervals

between

INR

measurements

after

the

antibiotic

courses

or

on

dose

adjustments

when

antibiotics

were

prescribed

To

assess

the

consequences

of

interaction

management

reliably

and

to

avoid

confounding

by

an

unstable

anticoagulation

status

preceding

the

antibiotic

course

we

only

included

stabilised

patients

in

our

study

Criteria

for

the

assessment

of

stability

were

-LRB-

-RRB-

use

of

the

coumarin

anticoagulant

for

at

least

days

before

initiation

of

the

antibiotic

-LRB-

-RRB-

availability

of

at

least

four

INR

measurements

before

the

initiation

of

the

antibiotic

-LRB-

-RRB-

the

last

two

INR

measurements

before

initiation

of

the

antibiotic

were

within

the

therapeutic

range

-LRB-

-RRB-

a

maxim

of

one

out

of

the

last

four

INR

measurements

or

a

maxim

of

of

the

INR

measurements

during

the

days

immediately

preceding

initiation

of

the

antibiotic

were

outside

of

the

therapeutic

range

with

no

INR

being

above

Similar

criteria

for

stability

have

been

used

in

other

studies

-LSB-

-RSB-

We

excluded

subjects

from

our

analyses

in

whom

the

INR

was

not

measured

during

the

course

of

the

antibiotic

and

who

used

the

antibiotic

for

a

period

shorter

than

days

and

longer

than

days

If

the

INR

was

not

measured

during

the

course

an

interaction

effect

of

the

antibiotic

could

be

missed

Antibiotics

used

for

less

than

days

or

more

than

days

are

usually

prescribed

for

prophylaxis

not

for

acute

infections

All

patients

were

informed

of

the

aims

of

the

study

and

were

asked

for

their

written

consent

to

participate

in

the

study

Setting

and

attitudes

of

anticoagulation

clinics

on

antibiotic

use

All

anticoagulation

clinics

in

The

Netherlands

monitor

the

INR

in

outpatients

at

a

frequency

varying

from

a

few

days

to

maximally

weeks

The

two

target

therapeutic

ranges

are

the

normal

therapeutic

range

-LRB-

INR

-RRB-

and

the

high

therapeutic

range

-LRB-

INR

-RRB-

The

initiation

of

the

use

of

an

antibiotic

is

usually

reported

to

the

anticoagulation

clinics

by

the

patients

their

pharmacists

and/or

the

prescribing

physicians

The

four

anticoagulation

clinics

participating

in

this

study

had

different

attitudes

on

the

management

of

the

interaction

between

coumarins

and

antibiotics

The

approach

of

three

of

the

anticoagulation

clinics

was

to

decrease

the

coumarin

dose

preventively

if

co-trimoxazole

was

prescribed

one

of

the

anticoagulation

clinics

applied

a

PDR

of

in

the

case

of

co-trimoxazole

use

If

one

of

the

other

antibiotics

examined

in

this

study

was

prescribed

the

application

of

a

PDR

would

depend

on

the

seriousness

of

the

disease

and

on

the

occurrence

of

fever

The

fourth

anticoagulation

clinic

had

no

established

protocols

for

dose

reduction

but

indicated

that

it

would

monitor

the

INR

of

every

user

of

co-trimoxazole

within

days

after

initiation

of

the

course

Data

collection

We

collected

relevant

data

on

the

participating

patients

and

recorded

these

in

a

database

sex

and

age

of

patient

dosage

and

indication

of

the

coumarin

prescribed

antibiotics

-LRB-

indication

dosage

and

duration

of

use

-RRB-

results

of

INR

measurements

before

during

and

after

the

antibiotic

course

co-medication

relevant

co-morbidities

-LRB-

malignancies

thyroid

diseases

heart

failure

-RRB-

These

data

were

retrieved

from

the

medical

files

of

the

anticoagulation

clinics

Patients

were

asked

to

indicate

on

a

questionnaire

for

which

infection

the

antibiotic

was

prescribed

and

whether

they

had

suffered

from

fever

during

the

antibiotic

course

We

recorded

this

as

fever

yes/no

in

our

database

If

the

coumarin-dose

was

reduced

as

soon

as

the

antibiotic

was

started

in

the

absence

of

an

actual

INR

we

recorded

this

as

a

preventive

dose-reduction

and

calculated

the

percentage

of

the

dose

reduction

from

the

data

on

dosage

in

the

file

of

the

anticoagulation

clinic

In

order

to

assess

the

anticoagulation

status

shortly

after

the

antibiotic

course

we

recorded

the

time

spent

within

above

and

under

the

therapeutic

range

from

the

starting

date

of

the

antibiotic

until

the

last

INR

measurement

within

weeks

following

the

starting

date

of

the

antibiotic

Six

weeks

is

the

maximal

period

between

two

INR

measurements

if

a

patient

is

well

stabilised

Furthermore

after

a

longer

follow-up

period

differences

between

patients

could

be

more

attributable

to

other

factors

than

to

the

infection

or

antibiotic

use

If

after

the

first

INR

during

the

antibiotic

course

no

second

INR

measurement

was

available

within

the

period

after

the

starting

date

of

the

antibiotic

we

recorded

no

follow-up

time

and

no

time

spent

within

above

or

under

the

therapeutic

range

Outcomes

The

end

points

of

our

study

were

chosen

to

assess

the

effectiveness

of

the

management

of

the

interaction

between

coumarin

anticoagulants

and

co-trimoxazole

and

other

antibiotics

We

examined

the

following

parameters

in

users

of

co-trimoxazole

with

and

without

PDR

as

well

as

in

users

of

other

antibiotics

with

and

without

PDR

occurrence

of

moderate

overanticoagulation

-LRB-

INR

-RRB-

and

severe

overanticoagulation

-LRB-

INR

-RRB-

time

spent

within

above

and

under

the

therapeutic

INR

range

from

the

starting

date

of

the

antibiotic

until

the

last

INR

measurement

within

weeks

following

the

starting

date

of

the

antibiotic

Calculations

and

statistical

analysis

We

assessed

the

effects

of

the

PDR

within

the

group

of

users

of

co-trimoxazole

and

within

the

group

of

users

of

other

antibiotics

by

comparing

the

occurrence

of

overanticoagulation

in

patients

for

whom

a

PDR

had

been

applied

with

the

occurrence

of

overanticoagulation

in

patients

for

whom

PDR

had

not

been

applied

-LRB-

logistic

regression

models

-RRB-

We

also

compared

the

occurrence

of

overanticoagulation

and

time

spent

within

under

and

above

the

therapeutic

range

of

co-trimoxazole

users

with

users

of

other

antibiotics

-LRB-

reference

group

-RRB-

These

comparisons

were

made

for

patients

with

PDR

and

for

patients

without

PDR

Finally

we

compared

the

time

spent

within

under

and

above

the

therapeutic

range

in

patients

for

whom

a

PDR

had

been

applied

with

those

for

whom

a

PDR

had

not

been

applied

-LRB-

reference

-RRB-

within

the

groups

of

co-trimoxazole

users

and

users

of

other

antibiotics

-LRB-

linear

regression

models

-RRB-

In

all

models

we

adjusted

for

the

potential

confounding

covariates

sex

age

target

therapeutic

range

and

fever

as

indicated

by

the

patient

Covariates

were

added

to

the

statistical

models

one

at

a

time

We

adjusted

for

a

covariate

if

it

changed

the

point

estimation

of

the

outcome

of

interest

by

or

more

upon

inclusion

in

the

model

Time

spent

within

above

and

under

the

therapeutic

INR

range

was

calculated

by

the

step-up

method

described

by

Rosendaal

et

al.

-LSB-

-RSB-

Although

all

patients

were

stable

when

they

were

included

in

our

study

we

re-analysed

our

statistically

significant

outcomes

after

excluding

patients

in

whom

destabilisation

could

be

due

to

factors

other

than

those

of

infection

and/or

fever

-LRB-

presence

of

thyroid

disease

malignancy

or

use

of

other

enzyme-inhibiting

or-inducing

drugs

-RRB-

All

statistical

analyses

were

performed

with

the

statistical

software

package

SPSS

ver

-LRB-

SPSS

Chicago

Ill.

-RRB-

Results

A

total

of

patients

who

met

the

inclusion

criteria

gave

their

informed

consent

to

participate

in

our

study

Of

these

patients

did

not

have

assesment

of

the

INR

during

the

antibiotic

course

used

the

antibiotic

for

less

than

days

and

used

the

antibiotic

for

more

than

days

A

PDR

was

applied

more

frequently

for

users

of

co-trimoxazole

-LRB-

-RRB-

than

for

users

of

other

antibiotics

-LRB-

-RRB-

-LRB-

Table

-RRB-

Table

of

patients

-LRB-

n

-RRB-

using

antibiotics

treated

by

four

anticoagulation

clinicsCharacteristicCo-trimoxazole

-LRB-

n

-RRB-

Other

antibioticsa

-LRB-

n

-RRB-

PDR

b

-LRB-

n

-RRB-

PDR-c

-LRB-

n

-RRB-

PDR

b

-LRB-

n

-RRB-

PDR-c

-LRB-

n

-RRB-

Men

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

in

years

mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Users

of

acenocoumarol

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Follow-up

time

mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Fever

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Normal

target

therapeutic

range

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Respiratory

infections

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Urinary

tract

infections

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Malignancies

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Thyroid

diseases

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Users

of

inhibiting

drugs

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Users

of

inducing

drugs

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

INR

measurements

mean

no

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Acenocoumarol

mean

dose

mg/day

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Percentage

PDR

applied

mean

-LRB-

SD

-RRB-

in

acenocoumarol

-LRB-

-RRB-

-LRB-

-RRB-

Phenprocoumon

mean

dose

mg/day

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Percentage

PDR

applied

mean

-LRB-

SD

-RRB-

in

phenprocoumon

-LRB-

-RRB-

-LRB-

-RRB-

Percentage

PDR

applied

all

coumarins

mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aOther

antibiotics

Trimethoprim

-LRB-

n

-RRB-

doxycyclin

-LRB-

n

-RRB-

amoxicillin

-LRB-

n

-RRB-

amoxicillin-clavulanic

acid

-LRB-

n

-RRB-

clarithromycin

-LRB-

n

-RRB-

norfloxacin

-LRB-

n

-RRB-

nitrofurantoin

-LRB-

n

-RRB-

bPDR

Preventive

dose

reduction

appliedcPDR

Preventive

dose

reduction

not

applieddNormal

target

therapeutic

range

INR

The

PDR

applied

was

significantly

greater

in

users

of

co-trimoxazole

than

in

users

of

other

antibiotics

-LRB-

and

respectively

P

value

for

difference

two-sided

t-test

-RRB-

The

number

of

INR

measurements

during

follow-up

was

significantly

higher

in

both

users

of

co-trimoxazole

-LRB-

PDR

applied

and

PDR

not

applied

-RRB-

and

users

of

other

antibiotics

-LRB-

PDR

applied

-RRB-

than

in

users

of

other

antibiotics

in

whom

a

PDR

was

not

applied

-LRB-

P

values

of

and

respectively

two-sided

t-test

-RRB-

Mean

daily

dosages

for

acenocoumarol

were

lower

in

users

of

co-trimoxazole

than

in

users

of

other

antibiotics

but

this

difference

was

not

statistically

significant

and

even

smaller

-LRB-

mg

-RRB-

after

adjustment

for

differences

in

age

-LRB-

Table

-RRB-

In

co-trimoxazole

users

the

PDR

protected

strongly

against

both

moderate

and

severe

overanticoagulation

-LSB-

adjusted

odds

ratio

-LRB-

OR

-RRB-

confidence

interval

-LRB-

CI

-RRB-

for

INR

adjusted

OR

CI

for

INR

-RSB-

For

other

antibiotics

the

effect

of

the

PDR

on

overanticoagulation

was

not

as

strong

and

not

statistically

significant

-LRB-

Tables

and

-RRB-

Table

of

overanticoagulation

and

time

spent

within

above

and

under

the

therapeutic

range

by

patients

using

co-trimoxazole

and

other

antibioticsaOutcomeCo-trimoxazoleOther

antibioticsPDR

b

-LRB-

n

-RRB-

PDR-b

-LRB-

n

-RRB-

PDR

b

-LRB-

n

-RRB-

PDR-b

-LRB-

n

-RRB-

INR

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

dINR

no

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

eTime

within

therapeutic

range

mean

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

fTime

above

therapeutic

range

mean

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

gTime

under

therapeutic

range

mean

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

ha

Calculated

for

the

time

from

the

date

the

antibiotic

was

first

taken

until

the

last

INR

measurement

within

weeks

following

the

starting

date

of

the

antibiotic

Time

within

above

and

under

therapeutic

range

was

calculated

for

antibiotic

users

in

whom

at

least

one

INR

measurement

had

been

performed

within

weeks

after

the

INR

measurement

during

the

antibiotic

course

This

resulted

in

the

exclusion

from

the

analysis

of

the

following

number

of

subjects

co-trimoxazole

-LRB-

-RRB-

other

antibiotics

-LRB-

-RRB-

The

numbers

in

parenthesis

indicate

the

number

of

subjects

with

a

PDR

and

those

without

a

PDR

respectively.bPDR

Preventive

dose

reduction

applied

PDR

preventive

dose

reduction

not

CI

Confidence

interval

for

the

reported

mean

valuedRange

for

nitrofurantoin

to

for

norfloxacineRange

for

nitrofurantoin

and

trimethoprim

to

for

doxycyclinfRange

for

amoxicillin

to

for

norfloxacingRange

for

norfloxacin

to

for

amoxicillinhRange

for

norfloxacin

to

for

clarithromycinTable

ratios

for

effect

of

preventive

dose

reduction

-LRB-

PDR

-RRB-

and

for

-LRB-

severe

-RRB-

overanticoagulation

in

users

of

co-trimoxazole

compared

with

users

of

other

antibiotics

Odds

ratios

-LRB-

CI

-RRB-

PAdjusted

Odds

ratios

-LRB-

CI

-RRB-

aPEffect

of

PDR

on

overanticoagulationb

Co-trimoxazole

PDR

applied

INR

-LRB-

-RRB-

-LRB-

-RRB-

PDR

applied

INR

-LRB-

-RRB-

-LRB-

-RRB-

PDR

not

appliedReferenceReference

Other

antibiotics

PDR

applied

INR

-LRB-

-RRB-

N.A.d

PDR

applied

INR

-LRB-

-RRB-

N.A

PDR

not

appliedReferenceRisk

of

overanticoagulation

PDR

not

applied

Co-trimoxazole

INR

-LRB-

-RRB-

-LRB-

-RRB-

Co-trimoxazole

INR

-LRB-

-RRB-

-LRB-

-RRB-

Other

antibioticsReferenceReference

PDR

applied

Co-trimoxazole

INR

-LRB-

-RRB-

N.A.

Co-trimoxazole

INR

-LRB-

-RRB-

-LRB-

-RRB-

Other

antibioticsReferenceReference

Statistically

significant

difference

at

P

aAdjusted

for

differences

in

fever

as

indicated

by

patient

age

sex

target

therapeutic

range

unless

otherwise

indicatedbPDR

Preventive

dose

reductioncAdjusted

for

differences

in

age

and

sexdN.A.

Adjustment

not

applied

because

the

inclusion

of

covariates

in

our

model

did

not

result

in

a

change

of

at

least

in

the

odds

ratios

-LRB-

see

text

-RRB-

eAdjusted

for

differences

in

age

sex

and

fever

as

indicated

by

patient

If

PDR

was

applied

the

risk

of

overanticoagulation

was

not

increased

in

users

of

co-trimoxazole

compared

with

users

of

other

antibiotics

However

if

PDR

was

not

applied

there

was

a

strongly

increased

risk

of

moderate

as

well

as

severe

overanticoagulation

in

co-trimoxazole

users

compared

with

users

of

other

antibiotics

-LRB-

adjusted

OR

CI

for

INR

adjusted

OR

CI

for

INR

-RRB-

-LRB-

Tables

and

-RRB-

During

the

follow-up

co-trimoxazole

users

with

a

PDR

spent

more

time

within

and

less

time

under

the

therapeutic

range

than

co-trimoxazole

users

without

a

PDR

but

these

differences

were

not

statistically

significant

Users

of

co-trimoxazole

without

a

PDR

spent

significantly

less

time

within

the

therapeutic

range

than

users

of

other

antibiotics

with

a

PDR

whereas

significantly

more

time

was

spent

under

the

therapeutic

range

Moreover

co-trimixazole

users

with

a

PDR

also

spent

significantly

more

time

under

the

therapeutic

range

than

did

all

users

of

other

antibiotics

-LRB-

adjusted

mean

difference

CI

-RRB-

-LRB-

Tables

and

-RRB-

Table

of

time

spent

within

under

and

above

the

therapeutic

range

by

users

of

co-trimoxazole

and

other

antibioticsaMean

differencePAdjusted

mean

differencebPPDR

applied

Co-trimoxazole

time

within

TRc

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Co-trimoxazole

time

above

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Co-trimoxazole

time

under

-LRB-

to

-RRB-

N.A.d

Other

antibioticsReferenceReferencePDR

not

applied

Co-trimoxazole

time

within

TR

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Co-trimoxazole

time

above

-LRB-

to

-RRB-

N.A.

Co-trimoxazole

time

under

-LRB-

to

-RRB-

-LRB-

to

-RRB-

f

Other

antibioticsReferenceReferenceCo-trimoxazole

PDR

applied

time

within

-LRB-

to

-RRB-

-LRB-

to

-RRB-

PDR

applied

time

above

TR

-LRB-

to

-RRB-

-LRB-

to

-RRB-

PDR

applied

time

under

TR

-LRB-

to

-RRB-

-LRB-

to

-RRB-

PDR

not

appliedReferenceReferenceOther

antibiotics

PDR

applied

time

within

-LRB-

to

-RRB-

-LRB-

to

-RRB-

PDR

applied

time

above

TR

-LRB-

to

-RRB-

N.A.

PDR

applied

time

under

-LRB-

to

-RRB-

N.A.

PDR

not

appliedReferenceReferenceCo-trimoxazole

PDR

applied

time

within

TR

-LRB-

to

-RRB-

-LRB-

to

-RRB-

time

above

TR

-LRB-

to

-RRB-

-LRB-

to

-RRB-

time

under

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Other

antibiotics

PDR

applied

PDR

not

appliedReferenceReference

Statistically

significant

difference

at

P

aCalculated

for

the

time

from

the

starting

date

of

the

antibiotic

until

the

last

INR

measurement

within

weeks

following

the

starting

date

of

the

antibiotic.bAdjusted

for

differences

in

fever

as

indicated

by

patient

age

sex

target

therapeutic

range

unless

otherwise

indicated.cTR

Therapeutic

range

dN.A.

Adjustment

not

applied

because

including

covariates

in

our

model

did

not

result

in

a

change

of

at

least

of

mean

difference

-LRB-

see

text

-RRB-

eAdjusted

for

differences

in

sex.fAdjusted

for

differences

in

sex

and

target

therapeutic

range.gAdjusted

for

differences

in

age

sex

and

target

therapeutic

range.hAdjusted

for

differences

in

sex

target

therapeutic

range

and

fever

as

indicated

by

patients

Co-trimoxazole

users

with

more

than

a

PDR

spent

significantly

more

time

under

the

therapeutic

range

than

users

of

other

antibiotics

-LRB-

adjusted

mean

difference

mg

CI

P

-RRB-

If

less

than

a

PDR

was

applied

the

difference

between

the

users

of

co-trimoxazole

and

those

of

other

antibiotics

shrunk

and

was

no

longer

significant

The

application

of

a

PDR

differed

between

anticoagulation

clinics

Three

of

the

four

anticoagulation

clinics

participating

in

this

study

applied

PDR

as

a

rule

in

co-trimoxazole

users

-LRB-

-RRB-

In

terms

of

users

of

other

antibiotics

the

application

of

a

PDR

was

more

varied

in

three

of

the

anticoagulation

clinics

PDR

was

sometimes

applied

-LRB-

in

of

all

cases

-RRB-

whereas

one

anticoagulation

clinic

did

not

apply

the

PDR

approach

at

all

The

overall

percentage

of

time

spent

within

the

therapeutic

range

during

the

first

weeks

after

initiation

of

an

antibiotic

ranged

from

to

at

all

four

anticoagulation

clinics

In

the

anticoagulation

clinic

that

did

not

apply

a

PDR

overanticoagulation

-LRB-

INR

-RRB-

occurred

most

frequently

for

the

all

antibiotics

class

-LRB-

vs.

in

the

other

clinics

-RRB-

with

the

difference

being

most

marked

for

co-trimoxazole

-LRB-

vs.

in

the

other

clinics

-RRB-

We

also

analysed

our

data

separately

for

users

of

acenocoumarol

and

phenprocoumon

There

were

no

differences

in

the

point

estimates

of

most

of

our

main

outcomes

between

users

of

either

of

these

coumarins

with

the

exception

of

percentage

of

time

spent

under

the

therapeutic

range

in

phenprocoumon

users

for

whom

PDR

was

applied

However

most

of

the

results

that

were

statistically

significant

for

all

coumarin

users

were

also

significant

for

users

of

acenocoumarol

-LRB-

n

-RRB-

whereas

they

were

in

most

cases

not

significant

for

the

smaller

group

of

users

of

phenprocoumon

-LRB-

n

-RRB-

-LRB-

Table

-RRB-

Table

outcomes

stratified

for

users

of

acenocoumarol

and

phenprocoumonOutcomeAcenocoumarol

-LRB-

n

-RRB-

Phenprocoumon

-LRB-

n

-RRB-

Protective

effect

of

PDRAdjusted

OR

-LRB-

CI

-RRB-

aPAdjusted

OR

-LRB-

CI

-RRB-

aPCo-trimoxazole

PDR

applied

INR

-LRB-

-RRB-

-LRB-

-RRB-

b

PDR

not

appliedReferenceReferenceRisk

of

overanticoagulation

PDR

not

applied

Co-trimoxazole

INR

-LRB-

-RRB-

-LRB-

-RRB-

Other

antibioticsReferenceReference

Time

within

or

under

TRMean

difference

-LRB-

CI

-RRB-

Mean

difference

-LRB-

CI

-RRB-

Co-trimoxazole

time

within

TR

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Co-trimoxazole

time

under

-LRB-

-RRB-

-LRB-

-RRB-

Other

antibioticsReferenceReference

Co-trimoxazole

PDR

applied

time

under

-LRB-

-RRB-

-LRB-

to

-RRB-

Other

antibiotics

PDR

applied

PDR

not

appliedReferenceReference

Statistically

significant

difference

at

P

aAdjusted

for

differences

in

fever

as

indicated

by

patient

age

sex

and

target

therapeutic

rangebAdjustment

not

applied

because

the

number

of

patients

with

INR

was

zero

OR

was

calculated

by

increasing

the

values

of

each

of

the

cells

of

the

crosstable

by

Re-analysis

of

our

results

after

excluding

patients

with

thyroid

diseases

and

malignancy

or

those

using

enzyme-inhibiting

or

inducing

drugs

gave

similar

point

estimates

or

trends

significance

for

severe

overanticoagulation

in

users

of

co-trimoxazole

compared

to

other

antibiotics

and

for

time

spent

within

the

therapeutic

range

for

users

of

co-trimoxazole

in

whom

PDR

was

not

applied

-LRB-

data

not

shown

-RRB-

Discussion

The

results

of

the

present

study

in

which

we

evaluated

the

management

of

the

interaction

between

antibiotics

and

coumarin

anticoagulants

by

anticoagulation

clinics

demonstrated

that

a

PDR

reduces

the

risk

of

overanticoagulation

in

co-trimoxazole

users

to

the

level

of

other

antibiotic

users

but

also

that

management

of

the

interaction

between

coumarins

and

co-trimoxazole

results

in

a

significantly

longer

period

of

undertreatment

during

the

first

weeks

after

initiation

of

the

antibiotic

In

three

of

the

four

anticoagulation

clinics

PDR

was

applied

more

frequently

and

was

significantly

higher

in

users

of

co-trimoxazole

than

in

users

of

other

antibiotics

indicating

that

anticoagulation

clinics

are

aware

of

the

seriousness

of

the

interaction

between

coumarins

and

co-trimoxazole

In

the

cases

and

case

series

that

have

reported

on

overanticoagulation

and

bleeding

with

the

concurrent

use

of

antibiotics

and

co-trimoxazole

-LSB-

-RSB-

an

effect

of

the

intercurrent

infection

on

the

anticoagulation

status

could

not

be

ruled

out

However

Penning-van

Beest

et

al.

-LRB-

case

control

study

-RRB-

and

Visser

et

al.

-LRB-

follow-up

study

-RRB-

both

demonstrated

that

an

increased

risk

of

severe

overanticoagulation

-LRB-

INR

-RRB-

was

particularly

associated

with

co-trimoxazole

-LSB-

-RSB-

A

plausible

explanation

is

the

strong

inhibition

of

the

main

metabolising

enzyme

of

the

coumarins

by

sulfamethoxazole

the

sulphonamide

component

of

co-trimoxazole

-LSB-

-RSB-

Although

PDRs

as

applied

in

clinical

practice

are

effective

in

reducing

the

overanticoagulation

risk

in

co-trimoxazole

users

the

price

that

has

to

be

paid

for

the

concurrent

use

of

co-trimoxazole

is

a

significantly

prolonged

period

of

underanticoagulation

compared

with

the

use

of

other

antibiotics

during

the

first

weeks

after

the

antibiotic

course

This

difference

was

more

marked

in

the

subgroup

of

subjects

in

whom

PDR

was

not

applied

Possible

explanations

for

this

result

are

-LRB-

-RRB-

the

usually

shorter

time

span

between

PDR

and

the

first

INR

measurement

-LRB-

always

within

the

course

-RRB-

compared

to

the

time

span

between

a

reactive

dose

reduction

following

supratherapeutic

INR

and

subsequent

INR

measurement

-LRB-

usually

after

the

course

-RRB-

and

-LRB-

-RRB-

the

higher

reactive

dose

reduction

which

is

applied

in

the

case

of

severe

overanticoagulation

-LRB-

INR

-RRB-

However

even

co-trimoxazole

users

for

whom

the

PDR

had

been

applied

had

a

significantly

prolonged

period

of

underanticoagulation

compared

with

all

of

the

users

of

other

antibiotics

-LRB-

PDR

applied

and

PDR

not

applied

taken

together

-RRB-

This

last

comparison

is

totally

logical

because

our

results

strongly

suggest

that

a

PDR

should

always

be

applied

in

co-trimoxazole

users

whereas

this

is

as

a

rule

not

required

in

users

of

other

antibiotics

The

adjusted

difference

in

time

spent

under

the

therapeutic

range

ranging

from

-LRB-

PDR

applied

-RRB-

to

-LRB-

PDR

not

applied

-RRB-

corresponds

to

about

days

of

the

mean

follow-up

time

of

days

in

otherwise

stabilised

patients

this

time

interval

is

clinically

relevant

and

can

be

avoided

by

substituting

co-trimoxazole

It

is

not

difficult

to

explain

the

prolonged

period

of

underanticoagulation

in

co-trimoxazole

users

The

application

of

a

PDR

which

was

in

this

study

higher

in

co-trimoxazole

users

might

overcompensate

for

overanticoagulation

whereas

the

reactive

dose

reduction

following

overanticoagulation

carries

the

same

risk

of

overcompensation

and

undertreatment

as

PDR

Consequently

the

inhibition

of

by

co-trimoxazole

superimposes

an

additional

problem

upon

the

already

potentially

destabilising

effects

of

the

infection

and

fever

Because

our

results

for

acenocoumarol

in

the

separate

analyses

were

predominantly

in

agreement

with

the

overall

results

our

findings

primarily

apply

to

acenocoumarol

users

It

is

possible

that

users

of

phenprocoumon

are

less

sensitive

to

interactions

with

inhibitors

such

as

co-trimoxazole

-LSB-

-RSB-

We

do

expect

that

our

results

also

apply

to

users

of

warfarin

which

seems

to

be

even

more

sensitive

than

acenocoumarol

-LSB-

-RSB-

Our

study

has

several

limitations

Because

we

retrieved

medical

data

from

anticoagulation

clinics

it

is

possible

that

not

all

of

the

relevant

data

on

potentially

destabilising

factors

such

as

malignancies

thyroid

diseases

and

the

use

of

other

inhibitors

of

coumarin

metabolism

were

available

However

by

only

including

patients

who

were

obviously

stable

at

the

moment

of

initiation

of

the

antibiotic

we

decreased

the

chance

that

such

factors

changed

the

anticoagulant

status

during

the

antibiotic

course

A

second

limitation

is

the

absence

of

data

on

the

presence

of

polymorphisms

of

the

genes

encoding

the

coumarin-metabolising

enzyme

or

the

pharmacodynamic

target

of

coumarins

The

genotypes

of

both

-LSB-

-RSB-

and

are

strongly

associated

with

interindividual

variability

in

coumarin

dose

requirements

-LSB-

-RSB-

Further

studies

would

be

needed

to

assess

whether

the

risk

of

overanticoagulation

in

co-trimoxazole

users

differs

between

carriers

of

a

or

polymorphism

and

wild-type

patients

It

should

be

clear

that

our

results

only

apply

to

patients

with

a

stabilised

anticoagulation

state

at

the

initiation

of

the

antibiotic

course

In

conclusion

if

co-trimoxazole

is

prescribed

to

users

of

coumarin

anticoagulants

the

interaction

can

be

managed

by

applying

PDR

which

adequately

decreases

the

risk

of

overanticoagulation

but

this

successful

management

comes

at

the

cost

of

a

prolonged

period

of

underanticoagulation

after

the

course

Consequently

rather

than

managing

the

interaction

it

is

better

to

avoid

prescribing

co-trimoxazole

as

a

therapeutically

equivalent

alternative

is

always

available

O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O 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O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

acenocoumarol
antibiotics
anticoagulation clinic
coumarins
phenprocoumon