Content uploaded by Faizan Khan
Author content
All content in this area was uploaded by Faizan Khan on Sep 07, 2019
Content may be subject to copyright.
the bmj |
BMJ
2019;366:l4363 | doi: 10.1136/bmj.l4363 1
RESEARCH
Long term risk of symptomatic recurrent venous
thromboembolism after discontinuation of anticoagulant
treatment for first unprovoked venous thromboembolism event:
systematic review and meta-analysis
Faizan Khan,1,2 Alvi Rahman,3 Marc Carrier,1,2,4 Clive Kearon,5 Jerey I Weitz,5 Sam Schulman,5,6
Francis Couturaud,7 Sabine Eichinger,8 Paul A Kyrle,8 Cecilia Becattini,9 Giancarlo Agnelli,9
Timothy A Brighton,10 Anthonie W A Lensing,11 Martin H Prins,12 Elham Sabri,2 Brian Hutton,12
Laurent Pinede,13 Mary Cushman,14 Gualtiero Palareti,15 George A Wells,1,16 Paolo Prandoni,15
Harry R Büller,17 Marc A Rodger,1,2,4 for the MARVELOUS Collaborators
ABSTRACT
OBJECTIVES
To determine the rate of a rst recurrent venous
thromboembolism (VTE) event aer discontinuation
of anticoagulant treatment in patients with a rst
episode of unprovoked VTE, and the cumulative
incidence for recurrent VTE up to 10 years.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES
Medline, Embase, and the Cochrane Central Register
of Controlled Trials (from inception to 15 March 2019).
STUDY SELECTION
Randomised controlled trials and prospective cohort
studies reporting symptomatic recurrent VTE aer
discontinuation of anticoagulant treatment in patients
with a rst unprovoked VTE event who had completed
at least three months of treatment.
DATA EXTRACTION AND SYNTHESIS
Two investigators independently screened studies,
extracted data, and appraised risk of bias. Data
clarications were sought from authors of eligible
studies. Recurrent VTE events and person years of
follow-up aer discontinuation of anticoagulant
treatment were used to calculate rates for individual
studies, and data were pooled using random eects
meta-analysis. Sex and site of initial VTE were
investigated as potential sources of between study
heterogeneity.
RESULTS
18 studies involving 7515 patients were included in
the analysis. The pooled rate of recurrent VTE per 100
person years aer discontinuation of anticoagulant
treatment was 10.3 events (95% condence interval
8.6 to 12.1) in the rst year, 6.3 (5.1 to 7.7) in the
second year, 3.8 events/year (95% condence
interval 3.2 to 4.5) in years 3-5, and 3.1 events/year
(1.7 to 4.9) in years 6-10. The cumulative incidence
for recurrent VTE was 16% (95% condence interval
13% to 19%) at 2 years, 25% (21% to 29%) at 5
years, and 36% (28% to 45%) at 10 years. The
pooled rate of recurrent VTE per 100 person years
in the rst year was 11.9 events (9.6 to 14.4) for
men and 8.9 events (6.8 to 11.3) for women, with a
cumulative incidence for recurrent VTE of 41% (28%
to 56%) and 29% (20% to 38%), respectively, at 10
years. Compared to patients with isolated pulmonary
embolism, the rate of recurrent VTE was higher in
patients with proximal deep vein thrombosis (rate
ratio 1.4, 95% condence interval 1.1 to 1.7) and in
patients with pulmonary embolism plus deep vein
thrombosis (1.5, 1.1 to 1.9). In patients with distal
deep vein thrombosis, the pooled rate of recurrent
VTE per 100 person years was 1.9 events (95%
condence interval 0.5 to 4.3) in the rst year aer
anticoagulation had stopped. The case fatality rate
for recurrent VTE was 4% (95% condence interval
2% to 6%).
CONCLUSIONS
In patients with a rst episode of unprovoked VTE
who completed at least three months of anticoagulant
treatment, the risk of recurrent VTE was 10% in the
rst year aer treatment, 16% at two years, 25% at
ve years, and 36% at 10 years, with 4% of recurrent
VTE events resulting in death. These estimates
should inform clinical practice guidelines, enhance
condence in counselling patients of their prognosis,
and help guide decision making about long term
management of unprovoked VTE.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42017056309.
For numbered aliations see
end of the article.
Correspondence to:
M A Rodger,
Ottawa Blood Disease Centre,
501 Smyth Road, Ottawa,
ON K1H 8L6, Canada
mrodger@ohri.ca
(ORCID 0000-0001-8166-3487)
Additional material is published
online only. To view please visit
the journal online.
Cite this as: BMJ ;:l
http://dx.doi.org/10.1136/bmj.l4363
Accepted: 4 June 2019
WHAT IS ALREADY KNOWN ON THIS TOPIC
Anticoagulant treatment is highly eective at reducing the risk of recurrent
venous thromboembolism (VTE) aer a rst episode of unprovoked VTE, but this
clinical benet is not maintained once anticoagulation is discontinued
Deciding whether patients with a rst unprovoked VTE should stop or continue
anticoagulation indenitely requires balancing the long term risks of recurrent
VTE if anticoagulation is stopped and major bleeding if treatment is continued
The long term risk of recurrent VTE aer discontinuing anticoagulation in patients
with rst unprovoked VTE is uncertain
WHAT THIS STUDY ADDS
In this meta-analysis of 18 studies involving 7515 patients with a rst
unprovoked VTE, the risk of recurrent VTE aer discontinuing anticoagulation was
10% in the rst year, 16% at two years, 25% at ve years, and 36% at 10 years,
with 4% of recurrent events resulting in death
These ndings provide patients, clinicians, and policymakers with reliable
estimates for the long term risks and consequences of recurrent VTE to help
guide decision making about long term management of unprovoked VTE
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
2 doi: 10.1136/bmj.l4363 |
BMJ
2019;366:l4363 | the bmj
Introduction
For patients with unprovoked venous thromboem-
bolism (VTE), comprising deep vein thrombosis
and pulmonary embolism, the optimal duration of
anticoagulant treatment is uncertain. After three
to six months of initial anticoagulation, extended
treatment is highly effective at reducing the risk
of recurrent VTE,1 but this clinical benefit is not
maintained when anticoagulation is stopped.2 After
discontinuation of anticoagulant treatment, patients
with a first unprovoked VTE have a much higher risk of
recurrence compared with patients with VTE provoked
by a major transient risk factor.3-5 Consequently,
anticoagulant treatment is discontinued after three
to six months in patients with VTE due to a major
transient provoking factor, whereas current guidelines
suggest extended (ie, indefinite) anticoagulation
in patients with unprovoked proximal deep vein
thrombosis or pulmonary embolism who have a non-
high bleeding risk.6-8 This is, however, a weak (grade
2B) recommendation, in large part as a result of
uncertainty in estimates of the long term risk of major
bleeding if treatment is continued, and, importantly,
the long term risk of recurrent VTE if anticoagulation
is discontinued. Thus deciding whether patients with
a first episode of unprovoked VTE should receive
indefinite anticoagulation or can stop treatment after
the initial three to six months, remains an important
challenge.
A previous individual patient data meta-analysis5
of 1732 patients with unprovoked VTE from six
randomised trials, reported an overall risk of recurrent
VTE of about 10% per year in the first two years after
discontinuation of anticoagulation. That analysis did
not assess the risk of recurrent VTE in men and women
separately or in patients with isolated pulmonary
embolism, and it only followed patients for 24 months.
Furthermore, trials in that analysis were published
before 2004, whereas since then additional prospective
studies have reported on the risk for recurrent VTE
after discontinuation of anticoagulant treatment in
patients with a first episode of unprovoked VTE, with
several of these studies having followed patients
beyond 24 months and some up to 10 years.9-13 This
offers an opportunity to obtain reliable estimates of
the long term risk of recurrent VTE and to assess how
the risk varies over time—knowledge that is crucial for
deciding the need for indefinite anticoagulation, as
well as defining the burden of illness in this common
patient population.
Methods
We formed the Meta-Analysis of the long term Risk
of recurrent Venous thromboEmboLism after stop-
ping anticOagulation for acute Unprovoked venous
thromboemboliSm (MARVELOUS) collaboration to
undertake a systematic review and meta-analysis to
determine the rate of a first recurrent VTE event in the
first year, in the second year, in years 3-5, and in years
6-10 after discontinuation of anticoagulant treatment
for a first episode of unprovoked VTE, as well as the
cumulative incidence for recurrent VTE at 2, 5, and 10
years.
The study protocol was developed using guidance
from the preferred reporting items for systematic
review and meta-analysis protocols (PRISMA-P)
statement,14 registered in PROSPERO and published.15
This systematic review and meta-analysis is reported
according to the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) guidelines.16
Search strategy and study selection
In conjunction with a medical librarian, we conducted
a comprehensive systematic search (from inception
to 15 March 2019) of Embase, Medline, and the
Cochrane Central Register of Controlled Trials. For
these searches, we combined terms related to VTE
and anticoagulant treatment with those related to
study design, without language restrictions (Appendix
table 1 shows the systematic search strategy used for
Embase). We supplemented the electronic searches
by hand searching reference lists of relevant review
articles, and without consideration of grey literature.
Two authors (FK, AR) independently screened titles,
abstracts, and full text publications, and a third author
(MAR) resolved discrepancies.
Randomised controlled trials and prospective
observational cohort studies were included if they were
published in a peer reviewed journal; they enrolled
patients with a first episode of objectively confirmed,
symptomatic VTE that was either unprovoked or
associated with minor transient risk factors, as
defined according to the International Society on
Thrombosis and Haemostasis guidance (see box 1)17;
patients had completed at least three months of initial
anticoagulation before stopping treatment, and the
decision to stop anticoagulation was not influenced
by stratification of the risk of VTE recurrence (eg,
negative D dimer test result, clinical decision rules);
patients were followed-up for at least nine months
after discontinuation of anticoagulant treatment; and
symptomatic recurrent VTE (as defined in individual
studies) events were reported during follow-up after
discontinuation of anticoagulant treatment. When
more than one article included the same population of
patients (ie, duplication), we included the publication
with the longest follow-up.
Data extraction and quality assessment
Using a standardised form, two authors (FK, AR)
independently extracted data, with clarifications
requested from the study’s authors when necessary.
Data were extracted on study design; number of
eligible patients; average age of patients; percentage of
men; number of eligible patients with isolated distal
deep vein thrombosis (ie, in deep veins of the calf),
proximal deep vein thrombosis (ie, in the popliteal,
femoral, or iliac veins), and pulmonary embolism (with
or without deep vein thrombosis); and the definition of
unprovoked VTE. For the calculation of event rates, we
requested the following from the authors: aggregate
data on the number of recurrent VTE events (any
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
the bmj |
BMJ
2019;366:l4363 | doi: 10.1136/bmj.l4363 3
VTE, and subtypes deep vein thrombosis, pulmonary
embolism, pulmonary embolism plus deep vein
thrombosis, and fatal pulmonary embolism), and
the total number of person years of follow-up during
each of the specified intervals (to ensure appropriate
censoring of deaths, patients lost to follow-up and
those withdrawn from study). Patients who did not
satisfy our eligibility criteria (eg, those with cancer or
a second unprovoked VTE event) were not included in
those aggregate data.
The same two authors independently assessed
the risk of bias of studies. Since our objective was to
establish pooled event rates after discontinuation of
anticoagulant treatment, we evaluated all studies,
including each arm of a randomised trial, as an
independent observational cohort. As such, the risk of
bias for each observational cohort was assessed using
a modified version of the Newcastle-Ottawa scale
score18 based on three selection criteria and three
outcome criteria only (criteria assessing comparability
were considered irrelevant in the context of this
systematic review and meta-analysis). Given data
clarifications obtained from the authors of all included
studies, we judged the risk of bias assessment not only
at the published study level but also based on authors’
clarifications. Following quality assessment standards
of a previous meta-analysis,19 we considered studies
in our meta-analysis that met four or more of these
Newcastle-Ottawa scale criteria to be of higher quality.
A third author (MAR) resolved discrepancies.
Data synthesis and analysis
For each study cohort we calculated the rates of recurrent
VTE, expressed as number of events per 100 person
years, from the number of first recurrent VTE events
divided by the person years of follow-up obtained from
the authors of original studies and categorised by four
time intervals after discontinuation of anticoagulant
treatment when a first recurrence of VTE occurred:
year 1 (0-12 months), year 2 (12-24 months), years
3-5, and years 6-10. We used random effects meta-
analyses to pool rates from each study cohort, with
cohorts weighted according to their inverse variance.20
Given that we calculated rates of recurrent VTE in our
analysis based on person time at risk accounting for
deaths and other patient losses to follow-up, obtained
from the authors of the included studies, during each
of the studied intervals, we calculated the cumulative
incidence for recurrent VTE at 2, 5, and 10 years after
discontinuation of anticoagulation. To do this, we first
determined the proportion of patients who did not
experience recurrent VTE based on event rates during
each of the intervals we studied. Then we determined
the proportion of patients who did experience a
recurrent VTE by multiplying the proportion of
patients, in each year under consideration, who did
not experience a recurrent VTE. For example, if the rate
of recurrent VTE (per 100 person years) was 10 events
in year 1, five events in year 2, and four events/year in
years 3-5, then the proportion of patients who did not
experience a recurrent VTE within five years=90.0%
(year 1)×95.0% (year 2)×(96.0%)3 (years 3, 4, and
5)=75.6%, resulting in a cumulative incidence for
recurrent VTE of 24.4% five years after discontinuation
of anticoagulant treatment.
We determined the upper and lower limits of the
95% confidence interval for cumulative incidence by
performing the calculations described on the upper
and lower limits of the 95% confidence interval of
the event rates, respectively. For example, if the rate
of recurrent VTE (per 100 person years) was 10.0
events (95% confidence interval 9.0 to 11.0) in year
1 and 5.0 events (4.0 to 6.0) in year 2, resulting in a
two year cumulative incidence of 14.5%, then the
95% confidence interval of the cumulative incidence
was calculated as follows: using the lower bound 95%
confidence intervals of 9.0 events (year 1) and 4.0
events (year 2), the proportion of patients who did not
experience a recurrent VTE within two years=91.0%
(year 1)×96.0% (year 2)=87.4%, resulting in a lower
bound 95% confidence interval for the cumulative
incidence of 12.6%. Using the upper bound 95%
confidence interval of 11.0 events (year 1) and 6.0
events (year 2), the proportion of patients who did not
experience a recurrent VTE within two years=89.0%
(year 1)×94.0% (year 2)=83.7%, resulting in an upper
bound 95% confidence interval for the cumulative
incidence of 16.3%.
Lastly, to measure the clinical impact of disease
recurrence after discontinuation of anticoagulant
treatment, we determined the case fatality rate of
recurrent VTE from the total number of fatal recurrent
pulmonary embolism events divided by the total
number of recurrent VTE events.
Heterogeneity between studies was assessed using
the I2 statistic, with values of 75% or greater indicating
substantial heterogeneity. All meta-analyses (with
a requirement for at least three cohorts of patients)
Box : International Society on Thrombosis and Haemostasis denition of
unprovoked venous thromboembolism
VTE is defined as unprovoked if the following provoking risk factors are absent:
Persistent
Active cancer, defined as:
• cancer that has not received potentially curative treatment, or
• treatment is ongoing, or
• evidence that treatment has not been curative
Major transient
Surgery with general anaesthesia for more than 30 minutes
Confined to be d (only “bathroom privile ges”) for at least three days with an acute illness
Caesarean section
Minor transient
Surgery with general anaesthesia for less than 30 minutes
Admission to hospital for fewer than three days with an acute illness
Oestrogen treatment
Pregnancy or puerperium
Confined to be d out of hospita l for at least three days with an acu te illness
Leg injury associated with reduced mobility for at least three days
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
4 doi: 10.1136/bmj.l 4363 |
BMJ
2019;366:l4363 | the bmj
were performed using StatsDirect Version 3 (Cheshire,
UK).21
We performed sensitivity and subgroup analyses
to investigate several potential sources of between
study heterogeneity: cohorts with event rates that were
outliers, cohorts randomised to receive aspirin after
completing initial anticoagulant treatment, cohorts
derived from randomised trials versus prospective
observational studies, sex, and site of initial VTE.
Patient and public involvement
Patients were not involved in the design or conduct of
the study. Patient partners in the CanVECTOR network
(www.canvector.ca) will be involved in dissemination
or knowledge translation activities, or both.
Results
Search results
Of the 1034 records identified by the literature
search, 604 remained after removal of duplicates. Of
these, 512 were excluded after screening of titles and
abstracts, leaving 92 articles for full text screening.
A further 68 articles were excluded after full text
screening because they were neither a randomised
controlled trial nor prospective cohort study, did
not include patients with unprovoked VTE, did not
systematically stop anticoagulation, did not have
patient follow-up lasting for a minimum of nine
months after discontinuation of anticoagulation, did
not report on recurrent VTE after anticoagulation,
or included duplicate patients from other included
studies. Thus, 24 studies were identified as eligible
for inclusion in the meta-analysis (fig 1). We requested
data clarifications for person years of follow-up
and recurrent VTE events during follow-up from the
authors of the 24 eligible studies. Data clarifications
were obtained for 18 of the studies. The remaining
six studies22-27 were excluded because the published
manuscript did not provide the data required for our
analysis.
Characteristics of included studies
Eighteen studies2 9-13 28-39 with a total of 7515 patients
were included in the analysis (fig 1). Four of the
18 studies were prospective observational cohort
studies11-13 31 and 14 were randomised controlled
trials2 9 28-30 32-39 (table 1). Fifteen studies2 10-13 28-34 36 38 39
met the criteria for the International Society on
Thrombosis and Haemostasis definition of unprovoked
VTE or VTE associated with minor transient risk
factors (table 1). All 18 studies with 24 independent
observational cohorts followed patients for one year
after discontinuation of anticoagulant treatment.
Thirteen studies2 9 10-13 28 31-33 35 36 39 (18 cohorts and
5078 patients) followed patients for two years, four
studies10 11 12 13 (four cohorts and 2638 patients)
followed patients for five years, three studies10 11 13
(three cohorts and 1975 patients) followed patients
for 10 years after discontinuation of anticoagulation
(table 1). All studies were of high quality according to
the Newcastle-Ottawa scale (table 1). Appendix table
2 presents the components of the Newcastle-Ottawa
scale score for all studies.
Recurrent VTE aer anticoagulation
Table 2 presents the pooled person years of follow-
up, number of events for recurrent VTE, deep vein
thrombosis, pulmonary embolism, pulmonary embo-
lism plus deep vein thrombosis, and fatal pulmonary
embolism, as well as the corresponding rates and
cumulative incidence for these outcomes. Appendix
tables 3, 6, and 7 provide the results from individual
study cohorts.
In the first year after discontinuation of anti-
coagulation, the pooled rate of recurrent VTE per 100
person years was 10.3 events (95% confidence interval
8.6 to 12.1; I2=81%). The rate of recurrent VTE events
per 100 person years for deep vein thrombosis was
6.2 (95% confidence interval 4.8 to 7.7; I2=79%), for
pulmonary embolism was 3.3 (2.4 to 4.2; I2=68%), and
for pulmonary embolism plus deep vein thrombosis
was 0.3 (0.1 to 0.5; I2=44%) (table 2).
In the second year after discontinuation of treatment,
the pooled rate of recurrent VTE events per 100 person
years was 6.3 (95% confidence interval 5.1 to 7.7;
I2=56%). The rate of recurrent VTE events per 100
person years for deep vein thrombosis was 3.7 (2.8 to
4.7; I2=55%), for pulmonary embolism was 2.0 (1.4 to
2.6; I2=36%), and for pulmonary embolism plus deep
vein thrombosis was 0.2 (0.1 to 0.4; I2=0%) (table 2).
In years 3-5 after discontinuation of treatment, the
pooled rate of recurrent VTE per 100 person years was
3.8 events/year (95% confidence interval 3.2 to 4.5;
I2=24%). The recurrent VTE events annually per 100
person years for deep vein thrombosis was 2.5 (95%
confidence interval 2.0 to 2.9; I2=0%), for pulmonary
embolism was 1.0 (0.4 to 1.8; I2=83%), and for
pulmonary embolism plus deep vein thrombosis was
0.1 (0.0 to 0.3; I2=71%) (table 2).
During years 6-10 after discontinuation of treatment,
the pooled rate of recurrent VTE per 100 person years
was 3.1 events/year (95% confidence interval 1.7
to 4.9; I2=84%). The recurrent VTE events annually
per 100 person years for deep vein thrombosis was
2.2 (95% confidence interval 1.0 to 3.8; I2=86%), for
pulmonary embolism was 0.7 (0.2 to 1.6; I2=79%),
and 0.0 for pulmonary embolism plus deep vein
thrombosis was 0.0 (0.0 to 0.1; I2=0%) (table 2).
The cumulative incidence for recurrent VTE was
16.0% (95% confidence interval 13.3% to 18.8%) at 2
years, 25.2% (21.3% to 29.3%) at 5 years, and 36.1%
(27.8% to 45.0%) at 10 years after discontinuation of
anticoagulant treatment. The corresponding values
for recurrent deep vein thrombosis were 9.7% (95%
confidence interval 7.5% to 12.0%), 16.3% (12.9% to
19.5%), and 25.1% (17.2% to 33.7%), for recurrent
pulmonary embolism were 5.2% (3.7% to 6.7%),
8.0% (4.0% to 11.6%), and 11.2% (5.9% to 18.4%),
and for recurrent pulmonary embolism plus deep vein
thrombosis were 0.5% (0.2% to 0.9%), 0.8% (0.2% to
1.8%), and 0.8% (0.2% to 2.3%) after discontinuation
of anticoagulation (table 2).
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
the bmj |
BMJ
2019;366:l4363 | doi: 10.1136/bmj.l4363 5
Fatal recurrent pulmonary embolism and case
fatality rate of recurrent VTE
After discontinuation of anticoagulation, the pooled
rate of fatal recurrent pulmonary embolism events per
100 person years was 0.4 (95% confidence interval
0.2 to 0.7; I2=57%) in the first year, 0.3 (0.2 to 0.6;
I2=10%) in the second year, and 0.1 (95% confidence
interval 0.0 to 0.3) in both years 3-5 (I2=53%) and
years 6-10 (I2=0%) (table 2). The cumulative incidence
for fatal recurrent pulmonary embolism was 0.7%
(95% confidence interval 0.4% to 1.3%) at 2 years,
1.0% (0.4% to 2.2%) at 5 years, and 1.5% (0.4% to
3.6%) at 10 years (table 2).
Based on 17 studies involving 6864 patients
with information available on both fatal recurrent
pulmonary embolism (n=49) and recurrent VTE
(n=1145), the pooled case fatality rate of recurrent
VTE after discontinuation of anticoagulation was 3.8%
(95% confidence interval 2.0% to 6.1%; I2=59%) (fig
2), which remained constant over time (Appendix
table 5).
Recurrent VTE according to sex
Among men with a first unprovoked VTE, the pooled
rate of recurrent VTE per 100 person years after
discontinuation of anticoagulation was 11.9 events
(95% confidence interval 9.6 to 14.4; I2=76%) in the
first year, 7.3 events (5.3 to 9.5; I2=63%) in the second
year, 4.4 events/year (95% confidence interval 3.2 to
5.7; I2=60%) in years 3-5, and 3.8 events/year (1.6 to
6.9; I2=89%) in years 6-10 (table 3). The cumulative
incidence for recurrent VTE in men was 18.3% (95%
confidence interval 14.4% to 22.5%) at 2 years, 28.6%
(22.3% to 35.0%) at 5 years, and 41.2% (28.4% to
55.6%) at 10 years (table 3).
Among women with a first unprovoked VTE, the
pooled rate of recurrent VTE per 100 person years after
discontinuation of anticoagulation was 8.9 events
(95% confidence interval 6.8 to 11.3; I2=72%) in the
first year, 5.2 events (3.6 to 7.0; I2=57%) in the second
year, 3.0 events/year (95% confidence interval 1.6 to
4.7; I2=74%) in years 3-5, and 2.0 events/year (1.3
to 2.9; I2=0%) in years 6-10 (table 3). The cumulative
incidence for recurrent VTE in women was 13.6% (95%
confidence interval 10.1% to17.5%) at 2 years, 21.2%
(14.4% to 28.6%) at 5 years, and 28.8% (19.8% to
38.4%) at 10 years (table 3).
Overall, men had 1.4 times the rate of recurrent VTE
compared with women (rate ratio 1.4, 95% confidence
interval 1.3 to 1.6, P<0.001) (see table 5).
Recurrent VTE according to site of initial VTE
In patients with a first unprovoked distal deep vein
thrombosis, the pooled rate of recurrent VTE in the first
year after discontinuation of anticoagulation was 1.9
events per 100 person years (95% confidence interval
0.5 to 4.3; I2=0%) (table 4).
Among patients with a first unprovoked proximal
deep vein thrombosis, the pooled rate of recurrent VTE
in the first year after discontinuation of anticoagulation
was10.6 events per 100 person years (8.1 to 13.3;
I2=73%). In the second year after treatment had
stopped, the rate was 6.5 events per 100 person years
(5.2 to 7.8; I2=0%) (table 4). The cumulative two
year incidence for recurrent VTE was 16.4% (95%
confidence interval 12.9% to 20.1%) (table 4).
In patients with a first unprovoked isolated
pulmonary embolism, the pooled rate of recurrent VTE
in the first year after discontinuation of anticoagulation
was 7.7 events per 100 person years (95% confidence
interval 5.6 to 10.2; I2=49%). In the second year after
treatment had stopped, the rate was 4.5 events per
100 person years (2.6 to 6.8; I2=45%) (table 4). The
cumulative two year incidence for recurrent VTE was
11.9% (8.1% to 16.3%) (table 4).
Among those with pulmonary embolism plus deep
vein thrombosis as the initial unprovoked VTE, the
pooled rate of recurrent VTE in the first year after
discontinuation of anticoagulation was 10.2 events
per 100 person years (6.7 to 14.2; I2=59%). In the
second year after treatment had stopped, the rate
was 7.6 events per 100 person years (4.7 to 11.2;
I2=23%) (table 4). The cumulative two year incidence
for recurrent VTE was 17.0% (95% confidence interval
11.1% to 23.8%) (table 4).
Overall, patients with distal deep vein thrombosis
had a lower rate of recurrent VTE compared to patients
Records screened aer duplicates removed
Full text articles excluded
Inadequate length of follow-up
Wrong patient population
Wrong study design
Duplicate cohort
Wrong intervention
Primary outcome not reported
22
21
11
8
4
2
Articles excluded
Additional records identified
through other sources
Records identified through
database searching
1030
Full text articles assessed for eligibility
Studies eligible for inclusion in meta-analysis
24
Studies included in meta-analysis
18
4
604
Titles or abstracts screened on relevance
604
512
Studies excluded because
published manuscript did not
provide data required for analysis
92
68
6
Fig | Flow diagram of study identication and selection
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
6 doi: 10.1136/bmj.l4363 |
BMJ
2019;366:l4363 | the bmj
Table | Characteristics of studies included in meta-analysis
Source (year)
Study
design
No of
patients
(n=) Men (%)
Age (range
or SD)
(years)
No and site of
initial VTE
Denition of unprovoked
VTE (minor transient risk
factors included)
Follow-up
(years)*
Independent
adjudication
of outcomes
Overall
Newcastle-Ottawa
scale score (out of )
LAFIT: Kearon
et al28
RCT 83 53.058
(16)
61 proximal DVT; 22 PE
with or without DVT
International Society
on Thrombosis and
Haemostasis
2Yes 6
WODIT-DVT:
Agnelli et al29
RCT 133 61.2 67.7
(7.3)
133 proximal DVT International Society
on Thrombosis and
Haemostasis
1Yes 6
DOTAVK:
Pinede et al30:
RCT 308 53 distal DVT; 145
proximal DVT; 18 PE; 92
PE plus DVT
International Society
on Thrombosis and
Haemostasis
Yes 6
Arm 1 161 47.6 58.2
(1.0)
30 distal DVT; 79
proximal DVT; 8 PE; 44
PE plus DVT
1
Arm 2 147 47.0 58.9
(0.9)
23 distal DVT; 66 prox-
imal DVT; 10 PE; 48 PE
plus DVT
1
Palareti et al31 Cohort 166 50.067
(12-91)
4 distal DVT; 137
proximal DVT; 25 PE
plus DVT
International Society
on Thrombosis and
Haemostasis
2Yes 6
WODIT-PE:
Agnelli et al32
RCT 181 72 PE; 109 PE plus DVT International Society
on Thrombosis and
Haemostasis
Yes 6
Arm 1 91 41.6 61.0
(15.5)
37 PE; 54 PE plus DVT 2
Arm 2 90 39.4 62.9
(16.3)
35 PE; 55 PE plus DVT 2
PREVENT:
Ridker et al9
RCT 160 52.9 67.7
(7.3)
20 distal DVT with or
without PE; 100 proxi-
mal DVT with or without
PE; 40 unspecied VTE
Unprovoked VTE events
were dened as those
that did not occur within
90 days aer surgery or
trauma
2Yes 6
DURAC I:
Schulman et al10
RCT 272 61.4 60.6
(15.4)
234 DVT with or without
PE; 38 PE
International Society on
Thrombosis and
Haemostasis
10 Yes 6
Prandoni et al11 Cohort 864 45.2 66.0
(16-96)
735 DVT with or without
PE; 129 PE
International Society on
Thrombosis and
Haemostasis
10 Yes 6
AESOPUS:
Prandoni et al33
RCT 151 57.6 69.0
(21-89)
151 proximal DVT International Society on
Thrombosis and
Haemostasis
2Yes 6
EINSTEIN-Extension:
Bauersachs et al34
RCT 465 58.5 57.6
(16.2)
267 DVT; 144 PE; 46 PE
plus DVT
International Society
on Thrombosis and
Haemostasis (oestrogen
treatment; pregnancy and
puerperium; leg trauma
with transient impairment
of mobility)
1Yes 6
WARFASA:
Becattini et al35
RCT 402 252 proximal DVT; 55
PE; 95 PE plus DVT
Yes 6
Arm 1 197 61.9 62.1
(15.1)
130 proximal DVT; 18
PE; 49 PE plus DVT
Unprovoked VTE events
were dened as those that
occurred in the absence
of any known persistent
or temporary risk factors
for VTE
2
Arm 2 205 65.8 61.9
(15.3)
122 proximal DVT; 37
PE; 46 PE plus DVT
2
ASPIRE:
Brighton et al36
RCT 822 468 proximal DVT; 231
PE; 114 PE plus DVT
International Society on
Thrombosis and
Haemostasis
Yes 6
Arm 1 411 54 54
(15.8)
232 proximal DVT; 119
PE; 59 PE plus DVT
2
Arm 2 411 55 55
(16)
236 proximal DVT; 112
PE; 56 PE plus DVT
2
RE-SONATE:
Schulman et al37†
RCT 651 42.4 56.1
(15.5)
Not available Patients were initially
treated for more than 10
months
1Yes 6
PADIS-PE:
Couturaud et al2
RCT 371 259 PE; 112 PE plus
DVT
International Society
on Thrombosis and
Haemostasis (oestrogen
treatment)
Yes 6
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
the bmj |
BMJ
2019;366:l4363 | doi: 10.1136/bmj.l4363 7
with proximal deep vein thrombosis (rate ratio 0.2,
95% confidence interval 0.04 to 0.5, P<0.001), isolated
pulmonary embolism (0.2, 0.05 to 0.7, P=0.009),
as well as pulmonary embolism plus deep vein
thrombosis (0.2, 0.03 to 0.5, P<0.001). Patients with
proximal deep vein thrombosis had 1.4 times the rate
of recurrent VTE of patients with isolated pulmonary
embolism (1.4, 1.1 to 1.7, P=0.004), and 0.9 times
the rate of recurrent VTE of patients with pulmonary
embolism plus deep vein thrombosis (0.9, 0.7 to 1.2,
P=0.47). Patients with pulmonary embolism plus deep
vein thrombosis had 1.5 times the rate of recurrent VTE
of patients with isolated pulmonary embolism (1.5,
1.1 to 1.9, P=0.005) (table 5).
Sensitivity analyses
Estimates of the rate of recurrent VTE events were
not different in the overall and subgroup analyses
excluding outliers or cohorts among included trials
with participants randomised to receive aspirin after
completing initial antaicoagulant treatment, as well
as in cohorts derived from either randomised trials or
prospective observational studies (Appendix tables 3,
4, 6, and 7).
Discussion
In this meta-analysis of 7515 patients with a first
unprovoked venous thromboembolism (VTE) event
who had completed at least three months of
Table | Risk of recurrent venous thromboembolism (VTE) aer discontinuation of anticoagulation in patients with a rst unprovoked VTE event
Interval aer
anticoagulation
Person
years of
follow-up
Recurrent events Event rate per person years*
VTE DVT PE PE+DVT Fatal PE VTE DVT PE PE+DVT Fatal PE
1st year 6678.0 644 350 194 20 28 10.3 (8.6 to 12.1);
81, <0.001
6.2 (4.8 to 7.7);
79, <0.001
3.3 (2.4 to 4.2);
68, <0.001
0.3 (0.1 to 0.5);
44, 0.008
0.4 (0.2 to 0.7);
57, <0.001
2nd year 3906.0 262 151 82 712 6.3 (5.1 to 7.7);
56, 0.002
3.7 (2.8 to 4.7);
55, 0.003
2.0 (1.4 to 2.6);
36, 0.07
0.2 (0.1 to 0.4);
0, 0.63
0.3 (0.2 to 0.6);
10, 0.34
2 year cumulative
incidence, % (95% CI)
16.0
(13.3 to 18.8)
9.7
(7.5 to 12.0)
5.2
(3.7 to 6.7)
0.5
(0.2 to 0.9)
0.7
(0.4 to 1.3)
Years 3-54772.0 182 116 54 56 3.8 (3.2 to 4.5);
24, 0.27
2.5 (2.0 to 2.9);
0, 0.59
1.0 (0.4 to 1.8);
83, <0.001
0.1 (0.0 to 0.3);
71, 0.02
0.1 (0.0 to 0.3);
53, 0.09
5 year cumulative
incidence, % (95% CI)
25.2
(21.3 to 29.3)
16.3
(12.9 to 19.5)
8.0
(4.0 to 11.6)
0.8
(0.2 to 1.8)
1.0
(0.4 to 2.2)
Years 6-10 3023.4 99 67 27 03 3.1 (1.7 to 4.9);
84, <0.001
2.2 (1.0 to 3.8);
86, <0.001
0.7 (0.2 to 1.6);
79, 0.009
0.0 (0.0 to
0.1); 0, 1.00
0.1 (0.0 to 0.3);
0, 0.37
10 year cumulative
incidence, % (95% CI)
36.1
(27.8 to 45.0)
25.1
(17.2 to 33.7)
11.2
(5.9 to 18.4)
0.8
(0.2 to 2.3)
1.5
(0.4 to 3.6)
DVT=deep vein thrombosis; PE=pulmonary embolism.
*Data are event rate (95% CI); I2 (%), P value unless stated otherwise. P value is for heterogeneity.
Table | Characteristics of studies included in meta-analysis
Source (year)
Study
design
No of
patients
(n=) Men (%)
Age (range
or SD)
(years)
No and site of
initial VTE
Denition of unprovoked
VTE (minor transient risk
factors included)
Follow-up
(years)*
Independent
adjudication
of outcomes
Overall
Newcastle-Ottawa
scale score (out of )
Arm 1 187 55.1 57.3
(17.4)
131 PE; 56 PE plus DVT 2
Arm 2 184 42.5 58.7
(16)
128 PE; 56 PE plus DVT 2
REVERSE I:
Rodger et al11
Cohort 663 51.4 53.2
(18-95)
346 proximal DVT; 194
PE; 123 PE plus DVT
International Society
on Thrombosis and
Haemostasis (oestrogen
treatment)
5Yes 6
AUREC:
Kyrle et al12
Cohort 839 66.053
(14)
154 distal DVT; 349
proximal DVT; 336 PE
with or without DVT
International Society on
Thrombosis and
Haemostasis
10 Yes 6
EINSTEIN-Choice:
Weitz et al38
RCT 880 56.7 58.4
(15.0)
442 proximal DVT; 295
PE; 139 PE plus DVT
International Society
on Thrombosis and
Haemostasis (oestrogen
treatment; pregnancy and
puerperium; lower limb
trauma with transient
impairment of mobility)
1Yes 6
PADIS-DVT:
Couturaud
et al39
RCT 104 104 proximal DVT International Society
on Thrombosis and
Haemostasis (oestrogen
treatment)
Yes 6
Arm 1 54 72.2 61.5
(14.5)
2
Arm 2 50 62.0 59.0
(17.2)
2
DVT=deep vein thrombosis; PE=pulmonary embolism; RCT=randomised controlled trial.
*Duration of follow-up as applicable to intervals of 1, 2, 5, and 10 years aer discontinuation of anticoagulation used in analysis.
†Data corresponds to post-treatment follow-up in dabigatran arm. Data during 12 months of follow-up in placebo arm of trial were not accessible.
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
8 doi: 10.1136/bmj.l4 363 |
BMJ
2019;366:l4363 | the bmj
anticoagulant treatment, we found that the long
term risk for recurrent VTE was substantial. The risk
reached 10.3% in the first year after discontinuation
of treatment, with a cumulative incidence of 16% at 2
years, 25% at 5 years, and 36% at 10 years.
Our observed rate of recurrent VTE in the year
after discontinuation of anticoagulation is consistent
with that of 9.8 events per 100 person years (95%
confidence interval 8.7 to 11.2) reported in a previous
individual patient data meta-analysis,5 but our study
provides precise estimates for the risk of symptomatic
recurrent VTE up to 10 years. Thus our findings extend
the knowledge for the prognosis of unprovoked VTE.
Our results indicate that after diagnosis of a first
unprovoked VTE, 36% of patients will experience a
recurrent VTE within 10 years after discontinuation
of anticoagulant treatment, underscoring that
unprovoked VTE is a chronic disease imposing a
substantial long term burden.
To measure the clinical impact of VTE recurrence
in this patient population, we determined the case
fatality rate of recurrent VTE after discontinuation of
anticoagulant treatment. Our analysis showed that
after treatment for a first unprovoked VTE, 3.8% (95%
confidence interval 2.0% to 6.1%) of recurrent VTE
events are fatal. This case fatality rate is similar to the
reported 3.6% (1.9% to 5.7%) in a previous study of
patients with VTE.40
Clinicians, patients, and policymakers currently
lack clear guidance on decision making about duration
of anticoagulation for unprovoked VTE. To date, no
randomised trial has compared the risk after 3-6
months of initial treatment with that of continuing
treatment indefinitely. Furthermore, no trial that has
compared durations of anticoagulant treatment for VTE
has been powered to detect differences in mortality.
Consequently, we must rely on indirect evidence to
project absolute long term rates of recurrent VTE and
major bleeding, and combine these rates with surrogate
measure of mortality (ie, case fatality rate) to balance
the risks and benefits of anticoagulant treatment.
Our results provide clinicians, patients, and
policymakers with rigorous benchmarks as well as
a management framework in which to consider the
long term risks and consequences of recurrent VTE
if anticoagulation is stopped. When weighed against
current best estimates for risks and consequences of
major bleeding if anticoagulation is continued, our
results could be used to decide whether to consider
indefinite anticoagulation for unprovoked VTE. For
example, in a typical patient with a first episode of
unprovoked VTE with a risk for recurrent VTE of 36%
at 10 years, combined with a case fatality rate for
recurrent VTE of 4% as determined by our analysis,
the risk of death from a first recurrent VTE after
discontinuation of anticoagulant treatment would be
about 1.44% by 10 years. Indeed, our pooled results
showed a cumulative risk of recurrent fatal VTE of
1.5% at 10 years after discontinuation of treatment.
For the same patient, the annual risk for major
bleeding if treatment is continued is estimated at
1.2%,1 translating to a 10 year risk for major bleeding
of 12%. When combined with the case fatality rate
for major bleeding of 11%,40 the risk of death from
major bleeding if anticoagulation is continued would
Table | Risk of recurrent venous thromboembolism (VTE) aer discontinuation of anticoagulation in patients with rst unprovoked VTE event
according to sex
Interval aer anticoagulation
Person years of follow-up Recurrent VTE Event rate per person years*
Men Women Men Women Men Women
1st year 3273.8 2528.1 377 205 11.9 (9.6 to 14.4); 76, <0.001 8.9 (6.8 to 11.3); 72, <0.001
2nd year 2026.8 1738.1 160 97 7.3 (5.3 to 9.5); 63, <0.001 5.2 (3.6 to 7.0); 57, 0.003
2 year cumulative incidence, % (95% CI) 18.3 (14.4 to 22.5)13.6 (10.1 to 17.5)
Years 3-52880.6 1891.7 125 57 4.4 (3.2 to 5.7); 60, 0.06 3.0 (1.6 to 4.7); 74, 0.01
5 year cumulative incidence, % (95% CI) 28.6 (22.3 to 35.0)21.2 (14.4 to 28.6)
Years 6-10 1820.6 1202.4 76 23 3.8 (1.6 to 6.9); 89, <0.001 2.0 (1.3 to 2.9); 0, 1.02
10 year cumulative incidence, % (95% CI) 41.2 (28.4 to 55.6)28.8 (19.8 to 38.4)
*Data are event rate (95% CI); I2 (%), P value unless stated otherwise. P value is for heterogeneity.
LAFIT28
WODIT-DVT29
DOTAVK30: arm 1
DOTAVK30: arm 2
Palareti et al31
WODIT-PE32: arm 1
WODIT-PE32: arm 2
PREVENT9
DURAC I10
Prandoni et al11
AESOPUS33
EINSTEIN-Extension34
WARFASA35: arm 1
WARFASA35: arm 2
ASPIRE36: arm 1
ASPIRE36: arm 2
PADIS-PE2: arm 1
PADIS-PE2: arm 2
REVERSE I11
AUREC12
EINSTEIN-Choice38
PADIS-DVT39: arm 1
PADIS-DVT39: arm 2
Pooled
P<0.001; I2=59%
5.9 (0.1 to 28.7)
0.0 (0.0 to 28.5)
0.0 (0.0 to 28.5)
0.0 (0.0 to 28.5)
6.3 (0.2 to 30.2)
0.0 (0.0 to 33.6)
10.0 (0.3 to 44.5)
0.0 (0.0 to 25.0)
4.8 (1.3 to 11.7)
10.1 (6.7 to 14.3)
10.7 (2.3 to 28.3)
0.0 (0.0 to 9.0)
3.1 (0.1 to 16.2)
5.6 (0.1 to 27.3)
1.9 (0.0 to 10.9)
0.0 (0.0 to 9.0)
0.0 (0.0 to 12.8)
14.3 (4.0 to 32.7)
0.0 (0.0 to 2.7)
1.7 (0.5 to 4.2)
1.0 (0.0 to 10.9)
6.3 (0.2 to 30.2)
0.0 (0.0 to 26.5)
3.8 (2.0 to 6.1)
08
16 32 4024 48
Source Case fatality
rate (95% CI)
Case fatality
rate (95% CI)
1
0
0
0
1
0
1
0
4
27
3
0
1
1
1
0
0
4
0
4
0
1
0
49
Recurrent
fatal PE
17
11
11
11
16
9
10
13
84
268
28
37
32
18
53
39
27
28
135
238
32
16
12
1145
Recurrent
VTE
Fig | Case fatality rate of recurrent venous thromboembolism (VTE) aer
discontinuation of anticoagulant treatment in patients with a rst unprovoked VTE
event. P value is for heterogeneity
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
the bmj |
BMJ
2019;366:l4363 | doi: 10.1136/bmj.l4363 9
be about 1.32% at 10 years. Hence, over a 10 year
horizon, patients with a first unprovoked VTE might
be expected to derive a small net long term mortality
benefit from continuing anticoagulation, consistent
with current guidelines that suggest considering
indefinite anticoagulation in patients with unprovoked
proximal deep vein thrombosis or pulmonary embolism
who are not at high risk for bleeding.6-8 Nevertheless,
our estimation of the net mortality benefit is limited
owing to the uncertainty in estimates of the long term
risk of major bleeding and case fatality rate of major
bleeding during extended anticoagulation in patients
with a first unprovoked VTE event, which should be
the focus of future research.
Because the overall reduction in mortality with
indefinite anticoagulation is small, other factors that
affect the risk of recurrence (eg, sex, site of initial VTE)
and the risk of bleeding, as well as patient preferences,
could influence decisions about whether to continue
or stop treatment. We found that the cumulative risk
of recurrent VTE at 10 years after discontinuation of
anticoagulation was 41% in men and 29% in women
with a first unprovoked VTE event. Estimating the
long term mortality risks over a 10 year horizon shows
that a net long term mortality benefit from continuing
anticoagulation might be expected in men (1.64%
risk of fatal recurrent VTE versus 1.32% risk of fatal
major bleeding) but not in women (1.16% risk of fatal
recurrent VTE versus 1.32% risk of fatal major bleeding).
Consequently, our findings affirm the importance of
considering a patient’s sex in deciding the optimal
duration of treatment, suggesting that there might
be a stronger argument for indefinite anticoagulation
in men with a first unprovoked VTE than in women.
However, given the closely balanced risks of mortality
from recurrent VTE and major bleeding, as well as the
lack of precise sex specific estimates of the risks for
major bleeding during extended anticoagulation in
this patient population, the need for an individualised,
patient centred approach in the long term management
of unprovoked VTE is emphasised.
Certainly, risk stratification approaches enable
individualised management of unprovoked VTE.
Although there appears to be no clear subgroup
of men who can be identified as having low risk
of recurrent VTE41 42 the prospectively validated
HERDOO2 (Hyperpigmentation, Edema, or Redness
in either leg; D-dimer level ≥250 μg/L; Obesity with
body mass index ≥30; or Older age, ≥65 years) clinical
decision rule43 allows about 50% of women with a first
unprovoked VTE to be classified as having a low risk
of recurrent VTE (3% in the year after discontinuing
treatment), with a long term risk of recurrent VTE
of less than 10% at eight years after discontinuing
anticoagulation.11 On the other hand, as suggested by
current guidelines,6 7 it is unlikely that patients with
a major bleeding risk that exceeds 3% a year would
ever experience a net long term mortality benefit from
indefinite anticoagulation. Currently, however, there
are no validated prediction tools to identify subgroups
of patients with VTE at high risk of major bleeding.
Additional findings from our study are noteworthy.
Firstly, our results show that it is unlikely that patients
with a first unprovoked distal deep vein thrombosis
will benefit from indefinite anticoagulation given the
low rate of recurrent VTE (1.9%, 95% confidence
interval 0.5% to 4.3%) in the year after discontinuation
of treatment. Secondly, a cohort study44 suggested
that patients with a first unprovoked pulmonary
embolism have a higher rate of recurrent VTE after
discontinuation of anticoagulation is discontinued
than patients with a first unprovoked proximal deep
vein thrombosis, whereas another cohort study
suggested the opposite.45 Our meta-analysis shows
that the rate of recurrent VTE after discontinuation
Table | Risk of recurrent venous thromboembolism (VTE) aer discontinuation of anticoagulation in patients with a
rst unprovoked VTE event according to site of initial event
Interval aer anticoagulation
Site of initial VTE
Distal DVT Proximal DVT Isolated PE PE+DVT
1st year
Total person years of follow-up 198.0 2387.4 1200.5 638.9
Total recurrent VTE events 3233 86 66
Event rate per 100 person years (95% CI);
I2 (%), P value*
1.9 (0.5 to 4.3);
0, 0.56
10.6 (8.1 to 13.3);
73, <0.001
7.7 (5.6 to 10.2);
49, 0.02
10.2 (6.7 to 14.2);
59, 0.005
2nd year
Total person years of follow-up NA 1417.1 763.5 347.9
Total recurrent VTE events NA 89 36 25
Event rate per 100 person years (95% CI);
I2 (%), P value*
NA 6.5 (5.2 to 7.8);
0, 0.55
4.5 (2.6 to 6.8);
45, 0.07
7.6 (4.7 to 11.2);
23, 0.24
2 year cumulative incidence, % (95% CI) NA 16.4 (12.9 to 20.1)11.9 (8.1 to 16.3)17.0 (11.1 to 23.8)
DVT=deep vein thrombosis; PE=pulmonary embolism; NA=not available.
*P is for heterogeneity.
Table | Comparison of rate of recurrent venous thromboembolism (VTE) aer
discontinuation of anticoagulation in subgroups of patients with a rst unprovoked VTE
event
Patient subgroups Recurrent VTE rate ratio (% CI) P value
Men versus women 1.4 (1.3 to 1.6)<0.001
Distal DVT versus proximal DVT 0.2 (0.04 to 0.5)<0.001
Distal DVT versus isolated PE 0.2 (0.05 to 0.7)0.009
Distal DVT versus PE+DVT 0.2 (0.03 to 0.5)<0.001
Proximal DVT versus isolated PE 1.4 (1.1 to 1.7)0.004
Proximal DVT versus PE+DVT 0.9 (0.7 to 1.2)0.47
PE+DVT versus isolated PE 1.5 (1.1 to 1.9)0.005
DVT=deep vein thrombosis; PE=pulmonary embolism.
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
10 doi: 10.1136/bmj.l4 363 |
BMJ
2019;366:l4363 | the bmj
of anticoagulation in patients with a first unprovoked
proximal deep vein thrombosis is 1.4-fold higher than
in patients with a first unprovoked isolated pulmonary
embolism and is comparable to the rate of recurrent
VTE in patients with pulmonary embolism plus deep
vein thrombosis. Thirdly, our study establishes that the
absolute risk of recurrent VTE in patients with a first
unprovoked VTE varies considerably over time—it is
highest in the first year after treatment, reaching 10.3%
(95% confidence interval 8.6% to 12.1%), declines
in the second year after treatment to 6.3% (5.1% to
7.7%), and then significantly drops to an average of
3.1% to 3.8% (95% confidence interval 1.7% to 4.9%)
per year in the subsequent eight years. Given current
guideline recommendations on treatment duration for
unprovoked VTE, this finding might help clinicians
counsel patients who have already stopped treatment
and want advice about resuming anticoagulation. Our
results suggest that patients who have not experienced
a recurrence within two years of discontinuing
anticoagulant treatment are unlikely to experience
a net long term mortality benefit from restarting
anticoagulation.
Strengths and limitations of this study
This study has several strengths. Firstly, despite a
heterogeneous population of patients with VTE in
studies included in our analysis, we were able to
obtain and pool data from a large number of patients
specifically with a first episode of unprovoked VTE
who were prospectively followed for recurrent VTE
after stopping anticoagulant treatment. Secondly, with
the help of data clarifications from authors of included
studies, we were able to capture accurately the time
varying risk for recurrent VTE by standardising the
varying durations of follow-up across patient cohorts,
as well as compare the rates of recurrent VTE in six
relevant subgroups of patients with unprovoked VTE.
Limitations of our study include the finding of
moderate to high statistical heterogeneity in the
primary analyses. However, the extent of heterogeneity
as measured by the I2 statistic tends to be larger for
meta-analyses of proportions.46 We were unable to
fully explain between study heterogeneity through
subgroup and sensitivity analyses, which could
potentially be explored better with a meta-analysis of
individual patient data. Secondly, owing to the lack
of individual patient data, we could not account for
death from causes other than pulmonary embolism as
a competing event for recurrent VTE, adjust for other
potentially confounding variables such as patient’s
age, and explore the potential effect of an age-sex
interaction on the differences in the risk of recurrent
VTE observed between men and women. Lastly,
we did not assess the risk of major bleeding during
extended anticoagulant treatment, as well as other
long term consequences of recurrent VTE that should
also be considered in weighing the long term risk
and benefits of anticoagulation, including the risk for
post-thrombotic syndrome, chronic thromboembolic
pulmonary hypertension, and quality of life.
Conclusion
In patients with a first episode of unprovoked VTE who
have completed at least three months of anticoagulant
treatment, the risk of recurrent VTE after discontinuing
anticoagulation reached 10% in the first year, 16% at 2
years, 25% at 5 years, and 36% at 10 years, with 4% of
recurrent VTE events resulting in death. These findings
provide rigorous benchmarks of the long term risks
and consequences of recurrent VTE that should inform
clinical practice guidelines, enhance confidence in
counselling patients of their prognosis, and help guide
decision making about long term management of
unprovoked VTE.
AUTHOR AFFILIATIONS
1School of Epidemiology and Public Health, University of Ottawa,
Ottawa, ON, Canada
2Clinical Epidemiology Program, Ottawa Hospital Research Institute,
Ottawa, ON, Canada
3Department of Epidemiology, Biostatistics and Occupational
Health, McGill University, Montreal, QC, Canada
4Ottawa Blood Disease Centre, Department of Medicine, The Ottawa
Hospital, Ottawa, ON, Canada
5Department of Medicine, McMaster University, and the Thrombosis
and Atherosclerosis Research Institute, Hamilton, ON, Canada
6Department of Obstetrics and Gynaecology, The First I.M. Sechenov
Moscow State Medical University, Moscow, Russia
7Department of Internal Medicine and Chest Diseases, Brest
University Hospital, Brest, France
8Department of Medicine I, Medical University of Vienna, Vienna,
Austria
9Internal and Cardiovascular Medicine, Stroke Unit, University of
Perugia, Perugia, Italy
10Department of Haematology, Prince of Wales Hospital, Sydney,
Australia
11Bayer, Leverkusen, Germany
12Department of Epidemiology and Technology Assessment,
University of Maastricht, Maastricht, Netherlands
13Department of Internal Medicine, Inrmerie Protestante, Caluire-
Lyon, France
14Department of Medicine, Larner College of Medicine at the
University of Vermont, Burlington, VT, USA
15Arianna Foundation on Anticoagulation, Bologna, Italy
16Cardiovascular Research Methods Centre, University of Ottawa
Heart Institute, Ottawa, ON, Canada
17Department of Vascular Medicine, Academic Medical Center,
Amsterdam, Netherlands
Contributors: FK and MAR conceived the study. FK, AR, BH, GAW, and
MAR developed the design and methodology of the study. All authors
were involved in the acquisition, analysis, or interpretation of data. FK
and MAR draed the manuscript and all authors critically revised the
manuscript for important intellectual cont ent. All authors gave nal
approval of the version to be published. FK and MAR are guarantors.
The corresponding author attests that all listed authors meet authorship
criteria and that no others meeting th e criteria have been omi tted.
Funding: MC, CK, SS, JIW, and MAR are investigators of the
CanVECTOR Network; the Network receives grant funding from
the Canadian Institutes of Health Research (CDT-142654). FK was
supported by the Canada Graduate Scholarship from the Canadian
Institutes of Health Research (CIHR), the CIHR Drug Safety and
Eectiveness Cross-Disciplinary Training award, the Queen Elizabeth II
Graduate Scholarship in Science and Technology, and is supported by
the CIHR Fredrick Banting and Charles Best Doctoral Research Award.
CK is supported by the Jack Hirsh Fellowship in Thromboembolism,
McMaster University. MAR is supported by a Heart and Stroke
Foundation Career Investigator Award and a University of Ottawa,
Faculty of Medicine Tier 1 Clinical Research Chair. The funding
organisations did not have any role in the design and conduct of the
study; collection, management, analysis, and interpretation of the
data; and preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
the bmj |
BMJ
2019;366:l4363 | doi: 10.1136/bmj.l4363 11
Competing interests: All authors have completed the ICMJE uniform
disclosure form at http://www.icmje.org/coi_disclosure.pdf and
declare: MC has received grants from Leo Pharma, Bristol-Myers
Squibb, Bayer, Octapharma, personal fees from Sano Aventis, Pzer,
Boehringer Ingelheim, Leo Pharma, Bayer Pzer, Servier, and been
on the advisory board for Leo Pharma and Sano Aventis, outside
the submitted work; CK has received grants from Bayer, outside
the submitted work. JIW has received personal fees from Bayer,
Boehringer Ingelheim, Bristol Myers Squibb Daiichi-Sankyo, Ionis
Pharmaceuticals, Janssen, Merck, Pzer, and Portola, outside the
submitted work; SS has received grants from Boehringer Ingelheim
and Octapharma, personal fees from Boehringer Ingelheim, Bayer,
Daiichi Sankyo, Octapharma, Sano, Alnylam, and Bristol-Myers-
Squibb, outside the submitted work; FC has received grants from
Pzer, and personal fees from Bayer, BMS, Aztra Zeneca, leopharma,
outside the submitted work; CB has received personal fees from Bayer
HealthCare, Daiichi Sankyo, Bristol Myers Squibb, and Servier, outside
the submitted work; GA has received personal fees from Bristol-Myers-
Squibb, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo,
outside the submitted work; AWAL reports being an employee of
Bayer HealthCare; MHP has received personal fees from Pzer and
Daiichi Sankyo, outside the submitted work; BH reports past research
from Cornerstone Research Group for methodologic advice related
to the conduct of systematic reviews and meta-analysis, outside the
submitted work; GP has received personal fees from Alfasigma, Pzer,
BMS, Roche, and Werfen, outside the submitted work. There are no
other relationships or activities that could appear to have influenced
the submitted work.
Ethical approval: Not required.
Data sharing: No additional data available.
Transparency: The lead author (FK) and senior author (MAR) arm
that the manuscript is an honest, accurate, and transparent account of
the study being reported; that no important aspects of the study have
been omitted; and that any discrepancies from the study as planned
have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
1 Castellucci LA, Cameron C, Le Gal G, et al. Ecacy and safety
outcomes of oral anticoagulants and antiplatelet drugs in the
secondary prevention of venous thromboembolism: systematic
review and network meta-analysis. BMJ2013;347:f5133.
doi:10.1136/bmj.f5133
2 Couturaud F, Sanchez O, Pernod G, et al, PADIS-PE Investigators.
Six months vs extended oral anticoagulation aer a rst episode
of pulmonary embolism: The PADIS-PE randomized clinical trial.
JAMA2015;314:31-40. doi:10.1001/jama.2015.7046
3 Ost D, Tepper J, Mihara H, Lander O, Heinzer R, Fein A. Duration of
anticoagulation following venous thromboembolism: a meta-
analysis. JAMA2005;294:706-15. doi:10.1001/jama.294.6.706
4 Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence aer a rst
episode of symptomatic venous thromboembolism provoked
by a transient risk factor: a systematic review. Arch Intern
Med2010;170:1710-6. doi:10.1001/archinternmed.2010.367
5 Boutitie F, Pinede L, Schulman S, et al. Influence of preceding
length of anticoagulant treatment and initial presentation of
venous thromboembolism on risk of recurrence aer stopping
treatment: analysis of individual participants’ data from seven trials.
BMJ2011;342:d3036. doi:10.1136/bmj.d3036
6 Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy
for VTE disease: CHEST guideline and expert panel report.
Chest2016;149:315-52. doi:10.1016/j.chest.2015.11.026
7 Konstantinides SV, Torbicki A, Agnelli G, et al, Task Force for the
Diagnosis and Management of Acute Pulmonary Embolism of the
European Society of Cardiology (ESC). 2014 ESC guidelines on the
diagnosis and management of acute pulmonary embolism. Eur Heart
J2014;35:3033-69, 3069a-3069k. doi:10.1093/eurheartj/ehu283
8 Mazzolai L, Aboyans V, Ageno W, et al. Diagnosis and management
of acute deep vein thrombosis: a joint consensus document from
the European society of cardiology working groups of aorta and
peripheral circulation and pulmonary circulation and right ventricular
function. Eur Heart J2018;39:4208-18. doi:10.1093/eurheartj/
ehx003.
9 Ridker PM, Goldhaber SZ, Danielson E, et al, PREVENT Investigators.
Long-term, low-intensity warfarin therapy for the prevention of
recurrent venous thromboembolism. N Engl J Med2003;348:1425-
34. doi:10.1056/NEJMoa035029
10 Schulman S, Lindmarker P, Holmström M, et al. Post-thrombotic
syndrome, recurrence, and death 10 years aer the rst episode of
venous thromboembolism treated with warfarin for 6 weeks or 6
months. J Thromb Haemost2006;4:734-42. doi:10.1111/j.1538-
7836.2006.01795.x
11 Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent
venous thromboembolism aer discontinuing anticoagulation in
patients with acute proximal deep vein thrombosis or pulmonary
embolism. A prospective cohort study in 1,626 patients.
Haematologica2007;92:199-205. doi:10.3324/haematol.10516
12 Rodger MA, Scarvelis D, Kahn SR, et al. Long-term risk of venous
thrombosis aer stopping anticoagulants for a rst unprovoked
event: A multi-national cohort. Thromb Res2016;143:152-8.
doi:10.1016/j.thromres.2016.03.028
13 Kyrle PA, Kammer M, Eischer L, et al. The long-term recurrence
risk of patients with unprovoked venous thromboembolism: an
observational cohort study. J Thromb Haemost2016;14:2402-9.
doi:10.1111/jth.13524
14 Shamseer L, Moher D, Clarke M, et al, PRISMA-P Group. Preferred
reporting items for systematic review and meta-analysis
protocols (PRISMA-P) 2015: elaboration and explanation.
BMJ2015;350:g7647. doi:10.1136/bmj.g7647
15 Khan F, Rahman A, Carrier M, et al, MARVELOUS Collaborators. Long-
term risk of recurrence aer discontinuing anticoagulants for a rst
unprovoked venous thromboembolism: protocol for a systematic
review and meta-analysis. BMJ Open2017;7:16950. doi:10.1136/
bmjopen-2017-016950
16 Moher D, Liberati A, Tetzla J, Altman DGPRISMA Group. Preferred
reporting items for systematic reviews and meta-analyses: the
PRISMA statement. Ann Intern Med2009;151:264-9, W64.
doi:10.7326/0003-4819-151-4-200908180-00135
17 Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle
PASubcommittees on Control of Anticoagulation, and Predictive
and Diagnostic Variables in Thrombotic Disease. Categorization
of patients as having provoked or unprovoked venous
thromboembolism: guidance from the SSC of ISTH. J Thromb
Haemost2016;14:1480-3. doi:10.1111/jth.13336
18 Wells GA, Shea B, O’Connnell D, et al. The Newcastle-Ottawa Scale
(NOS) for assessing the quality of nonrandomised studies in meta-
analyses. www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf.
Accessed December, 2017.
19 Douketis J, Tosetto A, Marcucci M, et al. Risk of recurrence aer
venous thromboembolism in men and women: patient level meta-
analysis. BMJ2011;342:d813. doi:10.1136/bmj.d813
20 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials1986;7:177-88. doi:10.1016/0197-2456(86)90046-2
21 StatsDirect. Cheshire, UK. www.statsdirect.com
22 Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent
venous thromboembolism in relation to clinical and thrombophilic
risk factors: prospective cohort study. Lancet2003;362:523-6.
doi:10.1016/S0140-6736(03)14111-6
23 Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson HTHRIVE
III Investigators. Secondary prevention of venous thromboembolism
with the oral direct thrombin inhibitor ximelagatran. N Engl J
Med2003;349:1713-21. doi:10.1056/NEJMoa030104
24 Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG,
Williamson IJ. Anticoagulation for three versus six months in
patients with deep vein thrombosis or pulmonary embolism, or
both: randomised trial. BMJ2007;334:674-7. doi:10.1136/
bmj.39098.583356.55
25 Andresen MS, Sandven I, Brunborg C, et al. Mortality and recurrence
aer treatment of VTE: long term follow-up of patients with good
life-expectancy. Thromb Res2011;127:540-6. doi:10.1016/j.
thromres.2011.02.017
26 Agnelli G, Buller HR, Cohen A, et al, AMPLIFY-EXT Investigators.
Apixaban for extended treatment of venous thromboembolism. N
Engl J Med2013;368:699-708. doi:10.1056/NEJMoa1207541
27 Franco Moreno AI, García Navarro MJ, Ortiz Sánchez J, et al. A risk
score for prediction of recurrence in patients with unprovoked venous
thromboembolism (DAMOVES). Eur J Intern Med2016;29:59-64.
doi:10.1016/j.ejim.2015.12.010
28 Kearon C, Gent M, Hirsh J, et al. A comparison of three months of
anticoagulation with extended anticoagulation for a rst episode of
idiopathic venous thromboembolism. N Engl J Med1999;340:901-7.
doi:10.1056/NEJM199903253401201
29 Agnelli G, Prandoni P, Santamaria MG, et al, Warfarin Optimal
Duration Italian Trial Investigators. Three months versus one
year of oral anticoagulant therapy for idiopathic deep venous
thrombosis. N Engl J Med2001;345:165-9. doi:10.1056/
NEJM200107193450302
30 Pinede L, Ninet J, Duhaut P, et al, Investigators of the “Durée Optimale
du Traitement AntiVitamines K” (DOTAVK) Study. Comparison of 3
and 6 months of oral anticoagulant therapy aer a rst episode
of proximal deep vein thrombosis or pulmonary embolism and
comparison of 6 and 12 weeks of therapy aer isolated calf deep
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
RESEARCH
No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe
vein thrombosis. Circulation2001;103:2453-60. doi:10.1161/01.
CIR.103.20.2453
31 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C,
Coccheri S. Risk of venous thromboembolism recurrence:
high negative predictive value of D-dimer performed aer oral
anticoagulation is stopped. Thromb Haemost2002;87:7-12.
doi:10.1055/s-0037-1612936
32 Agnelli G, Prandoni P, Becattini C, et al, Warfarin Optimal Duration
Italian Trial Investigators. Extended oral anticoagulant therapy aer a
rst episode of pulmonary embolism. Ann Intern Med2003;139:19-
25. doi:10.7326/0003-4819-139-1-200307010-00008
33 Prandoni P, Prins MH, Lensing AW, et al, AESOPUS Investigators.
Residual thrombosis on ultrasonography to guide the duration
of anticoagulation in patients with deep venous thrombosis:
a randomized trial. Ann Intern Med2009;150:577-85.
doi:10.7326/0003-4819-150-9-200905050-00003
34 Bauersachs R, Berkowitz SD, Brenner B, et al, EINSTEIN Investigators.
Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J
Med2010;363:2499-510. doi:10.1056/NEJMoa1007903
35 Becattini C, Agnelli G, Schenone A, et al, WARFASA Investigators.
Aspirin for preventing the recurrence of venous thromboembolism. N
Engl J Med2012;366:1959-67. doi:10.1056/NEJMoa1114238
36 Brighton TA, Eikelboom JW, Mann K, et al, ASPIRE Investigators. Low-
dose aspirin for preventing recurrent venous thromboembolism. N
Engl J Med2012;367:1979-87. doi:10.1056/NEJMoa1210384
37 Schulman S, Kearon C, Kakkar AK, et al, RE-MEDY Trial Investigators,
RE-SONATE Trial Investigators. Extended use of dabigatran,
warfarin, or placebo in venous thromboembolism. N Engl J
Med2013;368:709-18. doi:10.1056/NEJMoa1113697
38 Weitz JI, Lensing AWA, Prins MH, et al, EINSTEIN CHOICE Investigators.
Rivaroxaban or aspirin for extended treatment of venous
thromboembolism. N Engl J Med2017;376:1211-22. doi:10.1056/
NEJMoa1700518
39 Couturaud F, Pernod G, Presles E, et al. Six months versus
two years of oral anticoagulation aer a rst episode of
unprovoked deep-vein thrombosis. The PADIS-DVT randomized
clinical trial. Haematologica2019;314:31-40. doi:10.3324/
haematol.2018.210971
40 Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review:
case-fatality rates of recurrent venous thromboembolism and
major bleeding events among patients treated for venous
thromboembolism. Ann Intern Med2010;152:578-89.
doi:10.7326/0003-4819-152-9-201005040-00008
41 Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked
thromboembolism patients at low risk for recurrence who can
discontinue anticoagulant therapy. CMAJ2008;179:417-26.
42 Kearon C, Spencer FA, O’Keee D, et al, D-dimer Optimal Duration
Study Investigators. D-dimer testing to select patients with a rst
unprovoked venous thromboembolism who can stop anticoagulant
therapy: a cohort study. Ann Intern Med2015;162:27-34.
doi:10.7326/M14-1275
43 Rodger MA, Le Gal G, Anderson DR, et al, REVERSE II Study
Investigators. Validating the HERDOO2 rule to guide treatment
duration for women with unprovoked venous thrombosis:
multinational prospective cohort management study.
BMJ2017;356:j1065. doi:10.1136/bmj.j1065
44 Eichinger S, Weltermann A, Minar E, et al. Symptomatic pulmonary
embolism and the risk of recurrent venous thromboembolism. Arch
Intern Med2004;164:92-6. doi:10.1001/archinte.164.1.92
45 Kovacs MJ, Kahn SR, Wells PS, et al. Patients with a rst symptomatic
unprovoked deep vein thrombosis are at higher risk of recurrent
venous thromboembolism than patients with a rst unprovoked
pulmonary embolism. J Thromb Haemost2010;8:1926-32.
doi:10.1111/j.1538-7836.2010.03958.x
46 Mills EJ, Jansen JP, Kanters S. Heterogeneity in meta-analysis of
FDG-PET studies to diagnose lung cancer. JAMA2015;313:419.
doi:10.1001/jama.2014.16482
Supplementary information: additional tables 1-7
on 24 July 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l4363 on 24 July 2019. Downloaded from
