The need for oral anticoagulation therapy in adults with isolated subsegmental pulmonary embolism.

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Nov 15, 2013 (3 years and 9 months ago)

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The need for oral anticoagulation therapy in adults with isolated
subsegmental pulmonary embolism.


M.P.Oostveen BSc*,
Y.W.F
.

Roeleveld BSc*



Julius Center for Health Science and Primary Care, Str. 6.131, Heidelberglaan 100, University Medical Center

Utrecht, 3584 CX Utrecht, The Netherlands


* These authors contributed equally to this work

(Word count 1170)



Abstract

Objective:

T
o examine if there is a need for oral anticoagulation therapy
in adults wi
th isolated subsegmental pulmonary embolism

(ISSPE)

to
reduce mortality.

Methods:

A Pubmed, Embase, Cinahl and Cochrane Library search was
performed to i
dentify relevant studie
s. By critical appraisal five

studi
es
were

ranked according to

releva
nce and
validation. Four studie
s were
available to answer the clinical question.

Results:

The four studies did

no
t show any mortality related to

a
pul
m
on
ary embolism (PE)

related
-
cause. There is no difference in
recurrenc
e PE between treated and untreated

groups.

One study
showed 7,2% major h
a
emorrhages in the treated group.

Conclusion:

No conclusiv
e evidence is ava
ila
ble to answer the clinical
question. The best available evidence suggest
s

there is no need for oral
anticoagulation therapy to reduce mortality.

Practice implications:

We do not recommend oral anticoagulation
the
rapy in adults with ISSPE without

fu
r
ther comorbidity.


Key words:

isolated
subsegmental pulmonary embolism; ISSPE; oral anticoagulation therapy;

mortality


Clinical Case

A healthy 24
-
year old man was presented at the first aid after a bicycle
-

car accident. Because of dyspnoea and
pain on the chest, a pulmonary CT was made. An ISSPE was seen without other abnormalities. The question
ra
ised if there was a need to

treat the patient with
oral anticoagulation?


Background

The incidence of
PE

in
t
he Netherlands is approximately 1 per 1000 patients a year.
1

The advent of multi
-
detector row CT (MDCT) improved visualizat
ion up to the levels of the sub
segmental pulmonary
arteries.
Recent clinical studies using MDCT and varied gold standards ha
ve shown improved sensitivity (
90
-
94%) and
specificity (86
-
94%) for the subsegmental vessels.
2
-
4

The

prevalence of
ISSPE
has been reported
6
-
30%

of all PE
.
5

We define ISSPE as a PE
shown on MDCT
,

which

occurs

in a subsegmental b
ranch

and

no
t in a

larger order of
vessels and no

co
-
existing

deep vein thrombosis

(
DVT
)
.

Incidental PE may be found in asymptomatic patients
who undergo CT angiography for reasons other than suspected PE
.

How
ever, the clinical significance of

ISSPE
is
unknown.
Anticoagulation with its associated costs, mortality and
morbidity

can be avoided if small pulmonary
embolisms are not clinically relevant
.
Given the increased incidence of ISSPE and the controversy rega
rding the
risks and benefits of anticoagulation in this patient population, we sought to ascertain the management of
ISSPE.


Clinical Question

Does oral anticoagulation therapy reduce mortality in adults with
isolated subsegmental pulmonary embolism

in three months

after diagnosis
?



What is known about the
subject?

The advent of MDCT
improved diagnosing ISSPE.
The clinical importance and
the need for therapy is
unclear.


What this paper adds:

Best available evidence
suggests ISSPE is a benign
disease thus

there is no
need for oral anti
-
coagulation therapy to
reduce mortality.



Methods

Search strategy and selection

In order to answer the

clinical

question, a search through the Pubmed, Embase, CINAHL and Cochrane Library
databases was performed t
o identify all relevant studies.
In this search a
ll synonyms for subsegmental
pulmonary embolism and anticoag
ulation therapy were combined (t
able 1).

Duplicates were excluded

and
the remaining articles were
screened

by

title and abstract for exclusion criteria
and full text for inclusion criteria (figure 1)
.











Table 1: Search strategy

Database

Search

Pubmed

((subsegmental OR subsegment OR subsegmentally OR subsegmentary

OR peripheral
OR peripherally) AND (pulmonary OR pulmonal OR lung) AND (embolism OR
embolisms OR thromboembolism OR tromboembolism OR tromboembolisms OR
thromboembolisms OR trombi OR thrombi OR thrombosis OR trombosis OR embolus
OR emboli OR thrombus OR t
rombus))

AND

(anticoagulant OR anticoagulants OR anticoagulation OR antitrombotic OR
antithrombotic OR antitrombotics OR antithrombotics OR antitromboembolic OR
antithromboembolic OR antitromboembolics OR antithromboembolics OR
antitromboembolism OR antith
romboembolism OR trombolitica OR thrombolitica OR
trombolitic OR thrombolytic OR trombolitics OR thrombolitics OR ((anti) AND
(coagulant OR coagulants OR coagulation OR trombotic OR thrombotic OR trombotics
OR thrombotics OR thromboembolic OR thromboemboli
c OR tromboembolics OR
thromboembolics OR thromboembolism OR thromboembolism)) OR
((
vitamin
) AND

(
K
)

AND

(
antagonist OR antagonists
)
)

OR acenocoumarol OR sintrom OR sinthrome OR
phenprocoumon OR marcoumar OR marcumar OR falithrom OR warfarin OR
c
oumadin

OR jantoven OR marevan OR lawarin OR waran OR warfant OR ((coumarin
OR coumarins) AND (derivate OR derivates)))

Embase

CINAHL

Cochrane Library

Cr
itical appraisal

Relevance and validity of the articles were evaluated by multiple ass
essors
using critical appraisal

(table 2).
6,7

The greatest value was attached to relevant domain.

Discordant judgements were resolved by
consensus

discussion.



Results

1812

article
s

were retrieved
. After removal of duplicates and screening residual articles on
title and abstract

(f
igure 1),
five articles

were

quali
fied for
further assessment (t
able 2).
There was no

randomised controlled trial

(RCT)
.

Therefore
cohort studies

were

used

to determ
ine the role of anticoagulation
in adults with
ISSPE.

After critical a
ppraisal four articles were
assessed

as be
st available evidence
. A
summary

of the results
is presented

in t
able 3.
The study of

Stein et al
.
8

was specified to
segmental and

not to
subsegme
ntal PE.

Therefore
this study

is not useful

to answer

the clinical

question.



Table 3: Results

Reference

Sample
size

Loss to
follow
-
up

Death

(non
PE
-
cause)

Treatment with anticoagulation

No treatment

PE
-
related
d
eath

(%)

Recurrent
PE

(%)

Major
h
a
emorrhage

(%)

PE
-
related
death

(%)

Recurrent
PE

(%)

Cha 2010
9

22

0

0

0/15

(0)

0/15

(0)


0/7

(0)

0/7

(0)

Donato
2010
10

93

1

2

0/69
(0)

1/69

(1.4)

5/69

(7.2)

0/21

(0)

0/21

(0)

Eyer
2005
11

77

10

7

0/40

(0)

0/40

(0)


0/20

(0)

0/20

(0)

Schultz
2004
12

17

7

0




0/10

(0)

0/10

(0)


In the s
tudy of Cha et al
.
9
, the data for 334
patient
s

who were diagnosed with a PE
by

CT

pulmonary
angiography and indirect CT venography

was reviewed
. Of all patients
, 22
(6.
6%)

were diagnosed with a
subsegmental PE.
Nine
of these

patients had a co
-
existing DVT.
Fifteen
patients (
68.
2%
)

with a subse
gmental PE
received anticoagulation therapy. The most common cause of non
-
anticoagulation was missed diagnosis.
During the follow
-
up
period
there were no recurrent PE and no PE
-
related deaths

in both groups
.

Donato et al
.
10

reviewed 10
.
453 CT pulmonary
angiography radiology reports over

a

74
-
month period
.
They diagnosed 93 pa
tients with ISSPE. The follow
-
up
period

was three months. Individual physicians made
decisions about treatment based on their judgment.

71 patients (
76%
)

received treatment (58
w
arfa
rin, 10
warfarin and a IVC filter, 1 low molecular weight heparin and
2

IVC filter only).
No patients died

of a PE
-
related
cause. There was one recurrent PE in the treatment group, none in the control group.
Haemorrhages

occurred
in eight

patients in the treatment group
;

three

minor and five

major
.

Eyer et al
.
11

researched the clinician
response

and patient outcome
associated with the radiologist
s


report
s

of ISSPE on MDCT. 1
.
435 patient
s

with a clinical suspicion of pulmonary embolism wer
e scanned.
Of the
77 patients

with
ISSPE,

32 (42%) did not re
ceive anticoagulation therapy. Five

of
the 25 patients with a
completed 3
-
months follow
-
up,
died of a non
-
PE
related
cause.
42 of 45 patients with ISSPE

who received
anticoagulation therapy, completed
the
follow
-
up.

Two

of the 4
2
treated patients died of a non
-
PE

related

cause.
Four

patients, two

in each group
,

returned with
symptoms suggesting a recurrent PE
, b
ut all had
negative findings on
repeated
MDC
T. None of the patients in both groups died of a PE
-
related
cause.


The study of Schultz et al
.
12

is a prospective cohort study to determine the incidence of asymptomatic
pulmonary embolism in trauma patients. 90 trauma patients with an injury severity sco
re >9 and no suggestive
symptoms for PE were studied with contrast
-
enhanced
helical CT images of the chest.
Seventeen

patients were
diagnosed with minor clot burden, 75% of them had

ISSPE
. Ten

of
this seventeen

patients

completed

the

3
-
month follow
-
up period. No patients were treated. None of the patients had PE
-
related symptoms during the
follow
-
up period. There were no deaths.


Discussion

The evidence suggesting that patients with ISSPE could do without treatment comes from four small cohort
studies.

I
n none of the studies

the patients were randomised.

T
his will lead to differences between the
treatme
nt and the control group. S
trictly
speaking

hereby

the groups are

not

comparable
.

In none of the
studies, a protocol
for

the

management of ISSPE

was used
.
Thus

the decisions for treatme
nt or no treatment
were made by
doctors

at their discretion at the ti
me of a positive scan for ISSPE,

with

selection bias as a result.

T
hree of the four included studies are retrospective studies. This study design may be limited

by
reporting
b
ias

and ascertainment bias
. Outcome events may be omitted by medical records o
r

ignored
by the
patients
, for instance
recurrent PE symptoms

(reporting bias)
. Thereby patients treated with oral
anticoagulation therapy require more monitoring as patients without therapy.
Thus

it

is

easier to report
outcome events.

Furthermore it is possible

that outcome events may be over
-
i
nterpreted by the study
examiners (ascertainment bias).


To make a decision about the treatment of ISSPE, the

clinical

importance
of ISSPE must be balanced
against the risk of anticoagulation. The risk on major bleeding is 7% per

treatment

year a
nd fatal b
leeding
occurred in 1.
3% per
treatment
year
5
. Possibly these risks may be
even
higher outside of controlled studies
.
10

Based on these data, we suggest

there is no need for

oral anticoagulation therapy

for patients with
ISSPE.

T
he severity of ISSPE should
not only depend on the anatomical burden of PE. Also the comorbidity, like
the adequate cardiopulmonary reserve, evidence of DV
T, major risk factors for PE

such as major surgery,
cancer

and a genetic increased risk of PE, should be assessed.

A prospective
trial

is indicate
d

to

determine the
most suited patients for observation.


Conclusion and
clinical

recommendation

There is no

c
onclusive evidence to answer the

clinical
question.

The best available evidence suggests there is no
need for oral anticoagulatio
n therapy to reduce mortality

in adults with ISSPE without further comorbidity. For
our patient, without

comorbidity, we recommend no oral anticoagulation therapy.





References

1.

CBO richtlijn
.

Diagnostiek, preventie en behandeling van veneuze trombo
-
embolie en secundaire
preventie van arteriële trombose.
2008.

ISBN: 978
-
90
-
8523
-
193
-
6.

2.

Qanadli SK, Hajjam ME, Mesurolle B et al. Pulmonary embolism detection: prospective evaluation of
dual
-
section h
elical CT versus selective pulmonary arteriography in 157 patients. (commentary)
Radiology 2000; 217:447
-
455.

3.

Coche E,
V
erschuren F, Keyeux A, et al.
Diagnosis of acute pulmonary embolism in outpatients:
comparison of thin
-
collimation multi
-
detector row sp
iral CT and planar ventilation
-
perfusion
scintigraphy. Radiology 2003; 229: 757
-
765.

4.

Blachere H, Latrabe V, Montaudon M, et al. Pulmonary embolism revealed on helical CT angiography:
comparison with ventilation
-
perfusion radionuclide lung scanning. AJR 200
; 174: 1041
-
1047.

5.

Stein PD, Goodman, LR, Hull RD et al.
Diagnosis and Management of Isolated Subsegmental Pulmonary
Embolism: Review and Assessment of the Options. Clin

A
ppl

Thromb

H
emost
.

2011; 18(1):20
-
6
.

6.

Heneghan C, Badenoch

D. Evidence
-
based medicine toolkit, 2e ed. Oxfor
d
: BMJ Publishing Group.
2008
.

7.

Perera R, Heneghan C, Badenoch C. Statistics toolkit. 1e ed. Oxford: Blackwell Publishing & BMJ Books.
2008
.

8.

Stein PD, Henry JW, Relyea B, Untreated patients with
pulmonary emb
olism: outcome, clinical and
laboratory assessment. Chest. 1995;107(4):931
-
935
.

9.

Cha SI, Shin KM, Lee JW et al.
Clinical characteristics of patients
with

peripheral pulmonary embolism.
Respiration. 2010

;80(6)

:500
-
508
.

10.

Donato AA, Khoche S, Santora J, Wagne
r B. Clinical outcomes in patients with isolated subsegmental
pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res.
2010

;126(4)

:e266
-
e270.

11.

Eyer BA, Goodman LR, Washin
gton L. Clinicians’ response to

radiologists’ reports of iso
lated
subsegmental pulmonary embolism or inconclusive interpretation of pulmonary embolism using
MDCT. AJR Am J Roentgenol. 2005
;

184(2)
:

623
-
628.

12.

Schultz DJ, Brasel KJ, Washington L, et al.
Incidence of asymptomatic pulmonary
embolism in
moderately to severely injured trauma patients. J Trauma. 2004;

56(4)
:

727
-
731.
Table 2: Critical appraisal


Study

Relevance

Validity

Reference

Sample
size (N)

Study design

Domain

Deter
-

minant

Outcome

Rando
-
misation

Conceal
-

ment

Power
analysis

Loss to
follow
up

Missing
data

Blinding

Standardi
-
s
ation of
treatment

Intention
to treat
analysis

Mortality

Follow
-

up
(m
on
ths)

Cha 2010
9

22

Retrospective
cohort study

+

+

+

8

-

n.a.

n.a.

?

?

n.a.

?

n.a.

Donato
2010
10

93

Retrospective
cohort study

+

+/
-

+

3

-

n.a.

n.a.

+

+

n.a.

-

n.a.

Eyer
2005
11

77

Retrospective
cohort study

+

+

+

3

-

n.a.

n.a.

-

?

n.a.

?

n.a.

Stein
1995
8

16

Retrospective
cohort study

-

+/
-

+

3

-

n.a.

n.a.

?

?

n.a.

-

n.a.

Schultz
2004
12

17

Prospective
cohort study

+

+/
-

+

3

-

n.a.

n.a.

-

?

n.a.

n.a.

n.a.

Relevance Validity

Domain

Randomisation

Loss to follow up

Standardisation of treatment

+: Isolated subsegmental pulmonary embolism

+: P
resent

+: < 20% loss to follow up (if random)


+
: Treatment according to standard

-
: N
o
t specified to isolated subsegmental pulmonary embolism

-
: A
bsent

-
: >20% loss to follow up


-
: T
reatment not according to standard


Determinant Concealment

Missing data


Intention to treat analysis

+: Oral anticoagulation therapy

+: A
dequate

+: < 10% missing data (if not selective)

+: I
ntention to treat analysis

+/
-
: Oral anticoagulation therapy combi
ned with other therapy
-
: I
nadequate



-
: > 10% missing data



-
: N
o intention to treat analysis

-
: O
ther than oral anticoagulation therapy



Outcome Power analyse


Blinding

+: C
orresponding to outcome
+: A
nalysis performed, power achieved

+:

B
linding physician and patient

-
: C
orresponding not to outcome +/
-
:

A
nalysis performed, < 90% power achieved

+/
-
:

B
linding physician



-
: N
o analysis performed

-
:

N
o blinding



?: Unclear

n.a.:

N
ot applicable