OFFICIAL COMMUNICATION OF THE SSC

Risk of recurrent venous thromboembolism after stoppingtreatment in cohort studies: recommendation for acceptablerates and standardized reporting

C. K EARON,* A . I O R IO� and G . PAL ARET I� ON BEHA LF OF THE SUB COMMI TTEE O N C ONTROL OF

ANT I COAGULA T ION OF THE SSC OF T HE IST H*Department Internal Medicine, McMaster University, Hamilton, ON, Canada; �Department of Internal Medicine, Internal Medicine/Stroke Unit,

University of Perugia; and �Angiology and Coagulation Disorders Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy

To cite this article: Kearon C, Iorio A, Palareti G, on behalf of the Subcommittee on Control of Anticoagulation of the SSC of the ISTH. Risk of

recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J

Thromb Haemost 2010; 8: 2313–5.

Randomized controlled trials are the optimal study design to

compare management strategies, including comparisons of

different durations of anticoagulant therapy for venous

thromboembolism (VTE). The results of randomized trials

suggest that indefinite anticoagulation, rather than just 3 or

6 months of treatment, is of benefit in patients with unpro-

voked proximal deep vein thrombosis (DVT) or pulmonary

embolism (PE) [1]. However, many physicians are reluctant to

treat patients with a first unprovoked proximal DVT or PE

indefinitely. First, there is concern that follow-up in the

randomized controlled trials may not have been long enough to

reliably determine if the benefits of indefinite anticoagulant

therapy outweigh the cumulative risk of bleeding. Second, there

is concern that the findings of randomized controlled trials may

not reflect the risks and benefits of indefinite anticoagulant

therapy in the less controlled setting of usual clinical practice.

Third, even if the findings of randomized trials accurately

reflect a true overall benefit from indefinite anticoagulant

therapy in usual clinical practice, many physicians believe that

the magnitude of this overall benefit is not large enough to

justify the burden and cost of indefinite therapy. Furthermore,

as only about half of patients with a first unprovoked proximal

DVT or PE will have a recurrent episode of venous thrombo-

embolism within 10 years of stopping therapy, there is

reluctance to treat all such patients indefinitely.

Identification of subgroups of patients with unprovoked

proximal DVT and PE who have a low risk of recurrence and

subsequent validation that it is safe to stop anticoagulant

therapy after 3 months of treatment in these subgroups are

high priorities. Once a low-risk group has been identified or

proposed, one way to validate that it is safe to stop therapy in

these patients would be to randomize them to either stop or

remain on indefinite anticoagulant therapy, with a view to

demonstrating that indefinite therapy was not of benefit or that

it was harmful. Such a randomized trial, however, would be

difficult to perform (large and costly), and randomizing

patients to indefinite anticoagulant therapy in order to show

that such therapy is not beneficial, or is harmful, would be hard

to justify. Cohort studies are an alternative andmore appealing

way to test the hypothesis that a predefined subgroup of

patients truly has a low enough risk of recurrent VTE that

stopping anticoagulant therapy is justified.

The primary objective of this ISTH statement is to propose

an absolute risk of recurrent VTE that is at the upper limit of

acceptable, and would justifying stopping anticoagulant ther-

apy, in patients who have completed an initial course of

treatment. Cohort studies could then test the hypothesis that

predefined subgroups of patients with VTE have a rate of

recurrence after stopping anticoagulant therapy that is similar

to, or lower than, this rate of recurrence. Secondary objectives

are to suggest a standardized method for reporting risk of

recurrent VTE after stopping anticoagulant therapy, and to

identify study design elements that are important in cohort

studies that test the validity of prediction rules for recurrent

VTE. In this statement, recurrent VTE during follow-up refers

to all episodes of recurrent VTE, anticipating that most (e.g.

about 90%) of these episodes of recurrent VTE will be

unprovoked or associated with a minor provoking factor and,

therefore, would not be prevented by use of temporary VTE

prophylaxis during high-risk periods (e.g. after surgery).

What is an acceptable risk of recurrence after stopping

anticoagulant therapy for VTE?

The risk of recurrent VTE is highest shortly after stopping

anticoagulant therapy, and then decreases over time. Through-

outthecurrentstatement,basedonthepatternofrecurrencethat

has been reported in previous prospective studies, we have

Correspondence: Clive Kearon, Hamilton Health Sciences, Henderson

Division, 711 Concession Street, Hamilton, Ontario, L8V 1C3, Canada.

Tel.:+1 905 383 2252; fax:+1 905 574 7625.

E-mail: kearonc@mcmaster.ca

Journal of Thrombosis and Haemostasis, 8: 2313–2315 DOI: 10.1111/j.1538-7836.2010.03991.x

� 2010 International Society on Thrombosis and Haemostasis

assumed that the risk of recurrence after stopping anticoagulant

therapyconformstoanegatively-acceleratingcurve,andthatthe

cumulative risk of recurrence after 5 years of follow-up is about

three times the riskafter thefirst year.The riskof recurrence that

we suggest is low enough to justify stopping anticoagulant

therapy is based on the following observations. First, the risk of

recurrence after three ormoremonths of anticoagulant therapy

in unselected patients with a first episode of proximal DVT or

PE,which is estimatedat10%at1 yearand30%at5 yearsafter

stopping therapy, is judged to be unacceptably high by many

physicians [1]. Second, the risk of recurrence after 3 months of

anticoagulant therapy in patientswithVTEprovokedby a non-

surgical transient provoking factor, which is estimated at about

5%at1 yearand15%at5 years [2], is judgedtobeanacceptable

risk by most physicians [1]. Third, we suggest that a risk of

recurrence appreciably higher than 5% at 1 year and 15% at

5 years would not be acceptable to many physicians and

patients, and would usually discourage stopping anticoagulant

therapy. Cohort studies that prospectively test that the rate of

recurrent VTE is about 5% at 1 year and 15% at 5 years (or

lower), need to be large enough for their findings to be able to

exclude a rate of recurrence that is appreciably higher than these

values. We suggest that, whereas a recurrence rate of 5% at

1 year and 15%at 5 years would justify stopping anticoagulant

therapy, this recurrence rate is too stringent (too low) to serve as

anupperboundaryrateforsamplesizecalculation.Forexample,

if a study was designed to exclude the possibility that observed

rates of recurrence could include a rate of recurrence of 5% at

1 year (and15%at5 years), the true rateof recurrencewouldbe

less than 5% at 1 year 97.5% of the time (assuming a one-sided

alpha error of P = 0.025). We suggest that cohort studies

should be powered (e.g. 90% power) to be able to exclude (e.g.

withaone-sidedalphaerrorofP = 0.025)arecurrencerate that

corresponds to 8% at 1 year and 24% at 5 years.

How should the frequency of recurrent VTE be reported?

We recommend that the cumulative risk (i.e. cumulative

proportion) of recurrent VTE after stopping anticoagulant

therapy is displayed using theKaplan–Meiermethod, including

presentation of the number of subjects who are being followed

at each increment of follow-up. In addition, the (i) number of

recurrent events, (ii) number of patients studied, (iii) total

number of patient-years of follow-up and (iv) average duration

of follow-up, should be reported in the study population and in

subgroups.

Additional recommendations for design and reporting of

cohort studies that establish recurrence rates after stopping

anticoagulant therapy include:

1 Definition of the study population (i.e. inception cohort) in

terms of explicit inclusion (e.g. clear definition of �unpro-voked VTE�) and exclusion criteria (e.g. clear definition of

�high risk of bleeding�).

2 Description of measurements used to determine study

eligibilityandtoidentifysubjectswhowill stopanticoagulant

therapy (e.g. clinical, laboratory and diagnostic imaging),

who performed these measurements, and which measure-

mentsweredonebeforeorafterenrollment.Measurementof

variables that will determine which subjects stop, andwhich

subjects will continue, anticoagulant therapy is preferred

after enrollment, as this reduces the possibility that knowl-

edgeof theresultsofsuchtestingwould influenceenrollment.

3 Prospective enrollment of consecutive (i.e. without addi-

tional selection) eligible patients, with reasons why patients

who met the inclusion criteria were not eligible (i.e. relevant

exclusion criteria), the number of eligible patients who

declined toparticipateand the reasonswhyanyother eligible

patients were not enrolled (e.g. physician preference).

4 Description of enrolled patients in terms of demographics,

extent and location of VTE, anticoagulant therapy before

enrollment, history of previous VTE (if such patients are

eligible) and other potentially relevant prognostic factors.

5 Description of whether subjects who did not satisfy criteria

for stopping anticoagulant therapy were enrolled and

followed and, even if they were not enrolled, if they received

standardized anticoagulant management (e.g. did they all

remain on anticoagulants?).

6 Descriptions of patients who were scheduled to, but did

not, stop anticoagulant therapy, and those who restarted

anticoagulant therapy during follow-up.

7 Accounting for all enrolled patients during follow-up,

including description of patients who were lost to follow-up

(with reasons for this) or who withdrew from the study.

8 Standardization of other post-enrollment treatment that

might influence risk of recurrence (e.g. use of graduated

compression stockings; use of antiplatelet therapy or a

statin).

9 Standardization of diagnostic testing for recurrent VTE,

and the criteria used to interpret such testing.

10 Central adjudication of outcomes, with adjudicators

blinded to important baseline (e.g. gender and D-dimer

results) or post-enrollment (e.g. anticoagulant therapy)

prognostic variables.

11 Description of recurrent episodes of VTE (i.e. isolated distal

DVT, proximal DVT and fatal or non-fatal PE), including

if these episodes were provoked or unprovoked.

12 Follow-up that is long enough to be able to describe the

temporal pattern of recurrence (e.g. mean of 2 years or

longer after stopping therapy). Longer follow-up has the

added advantage of yielding more episodes of recurrence,

and a more precise estimate of the rate of recurrence.

13 Description, in a study protocol and in the final report, of

primary and secondary hypotheses, the basis for the study�ssample size and statistical analyzes.

14 Registration of the study protocol with a clinical studies

registry.

Additional desirable features for the design and reporting of

observational studies are described in the STROBE statement

[3].

2314 C. Kearon et al

� 2010 International Society on Thrombosis and Haemostasis

A number of issues are worth emphasizing. First, the

upper limit for an acceptable rate of recurrence after

stopping anticoagulant therapy that we have suggested is

considered appropriate for patients with an average risk of

bleeding while on vitamin K antagonist therapy. It may be

reasonable for investigators to select a different pre-defined

acceptable rate of recurrence for a study that enrolled a

markedly different study population, or was considering

whether or not to stop a different anticoagulant therapy. For

example, a lower rate of recurrence might be required in

order to justify stopping anticoagulant therapy if this decision

applies: (i) only to patients without risk factors for bleeding;

or (ii) to whether or not to stop an anticoagulant therapy

that was less burdensome than (e.g. oral and did not require

laboratory monitoring), or was associated with a lower risk

of bleeding than, vitamin K antagonist therapy. Conversely,

a higher rate of recurrence might be acceptable if the decision

was to stop a more burdensome (e.g. parenterally adminis-

tered) or costly therapy. Second, these recommendations are

proposed for subgroups of patients with VTE rather than for

individual patients; the risk of recurrence that individual

patients will accept after stopping anticoagulant therapy is

expected to differ markedly. Third, although this statement is

intended for cohort studies, many of these recommendations

are equally relevant for randomized trials. For example, in

studies that randomize patients to different durations of

anticoagulation, we encourage investigators to report recur-

rence rates in each study group after stopping anticoagulant

therapy (preferably after a similar duration of follow-up), in

addition to reporting recurrence rates during the total period

of follow-up after randomization (which often includes a

period of anticoagulation in one study group). Fourth, the

rates of recurrence that we have proposed as acceptable are

considered appropriate for well-resourced settings and may

be too low for setting where long-term anticoagulant therapy

is more difficult to provide (e.g. infrastructure not available,

cost is considered excessive).

Acknowledgements

C.Kearon is supported by theHeart and Stroke Foundation of

Canada and a Canadian Institutes of Health Research Team

Grant in Venous Thromboembolism (FRN 79846).

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.

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� 2010 International Society on Thrombosis and Haemostasis