Journal of Thrombosis and Haemostasis, 10: 698702

DOI: 10.1111/j.1538-7836.2012.04662.x

OFFICIAL COMMUNICATION OF THE SSC: CLINICAL GUIDELINES

Duration of anticoagulant therapy after a rst episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH
T . B A G L I N , * K . B A U E R , J . D O U K E T I S , H . B U L L E R , A . S R I V A S T A V A and G . J O H N S O N * *
*Department of Haematology, Addenbrookes Hospital, Cambridge, UK; Department of Medicine, Beth Israel Deaconess Medical Center, Roxbury, MA, USA; St. Josephs Hospital, McMaster University, Hamilton, ON, Canada; Vascular Medicine, AMC, Amsterdam, the Netherlands; Department of Haematology, Christian Medical College, Vellore, Tamil Nadu, India; and **Hematology/Oncology Section, VA Medical Center, Minneapolis, MN, USA

To cite this article: Baglin T, Bauer K, Douketis J, Buller H, Srivastava A, Johnson G. Duration of anticoagulant therapy after a rst episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012; 10: 698702.

Scope and methodology This document gives guidance on deciding the duration of anticoagulation after a rst episode of an unprovoked pulmonary embolus (PE) and/or deep vein thrombosis (DVT). Unprovoked PE and DVT are dened as those occurring in the absence of an antecedent (within 3 months) surgical or nonsurgical risk factor [1]. Patients with an unprovoked PE and DVT account for 25% to 50% of all patients with venous thromboembolism. The guidance statements herein do not apply to patients with an unprovoked thrombosis in unusual sites, such as the splanchnic or intracerebral veins, or cancerassociated venous thrombosis. The guidance in this document must be distinguished from a guideline based on a systematic literature review, which it is not. Such guidelines have previously been published [2]. Rather, this guidance outlines factors that may inuence decision-making in individual patients with reference to published evidence-based guidelines. In addition, the guidance recognizes that factors not yet included in clinical guidelines, such as measurement of post-anticoagulation D-dimer or residual vein obstruction (RVO) after a DVT may still be used by some clinicians. The use of these factors in the decisionmaking process is not mandatory but guidance is given on appropriate use should clinicians choose to consider them. The guidance statements included in this document are predicated on the following premises: 1 For each of the clinical situations described herein, our guidance statements are applicable to an average patient with a DVT and/or PE. There may be exceptional circum-

stances for which our guidance statements do not apply and anticoagulant management would be at the treating physicians discretion. 2 The language used to reect the strength of our guidance statements adopts the convention used in the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system [3,4]. 3 The wording we recommend reects a strong guidance statement, whereby the clinician should adopt the practice in most cases. 4 The wording we suggest reects a weak guidance statement, whereby the clinician may adopt the practice in some cases and that an alternative practice also may be acceptable. Denition of terms The denitions of duration of anticoagulation are: 1 Initial anticoagulation: 36 months of treatment; 2 Long-term (indenite) anticoagulation: > 36 months of treatment with no denite stop time which could be either lifelong or until the perceived bleeding risk precludes continuation of anticoagulation. Pulmonary embolism and lower limb DVT A period of adequate vitamin K antagonist (VKA) anticoagulation with a target international normalized ratio (INR) of 2.5 (range 23), as recommended by the American College of Chest Physicians [2], is required to prevent extension of thrombus and prevent early recurrence (within the rst 3 to 6 months). Thereafter, long-term anticoagulation is required to prevent late recurrence. The benet of anticoagulation continues only for as long as therapy is continued [5]. Consequently, long-term anticoagulation may, in effect, equate to lifelong treatment, or for as long as the perceived risk of anticoagulant therapy-related bleeding is not so high as to preclude continued treatment. This is referred to as indenite anticoagulation in the 2008 ACCP guidelines [2]. Therefore, when deciding the
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Correspondence: Trevor Baglin, Department of Haematology, Addenbrookes Hospital, Hills Road, Cambridge, UK. Tel.: +44 1223 217128; fax: +44 1223 256168. E-mail: trevor.baglin@addenbrookes.nhs.uk Received 6 December 2011, accepted 7 February 2012

Unprovoked VTE: duration of anticoagulation 699

duration of oral anticoagulant therapy in an individual patient with a PE or DVT there are two issues to consider: 1 For how long should initial anticoagulant therapy last? 2 Thereafter, is the risk of recurrence suciently high and the risk of bleeding suciently low to justify continued longterm (indenite) anticoagulant therapy?
Duration of initial anticoagulation

provoking factors). The duration of anticoagulation should be inuenced by the perceived risk in individual patients. However, we suggest long-term anticoagulant therapy generally be reserved for patients with no identiable antecedent risk factor. Patients with DVT conned to the calf have a lower risk of recurrence than patients presenting with a proximal DVT [5] and have a low risk of a recurrent VTE presenting as a PE [7].
Guidance statements

At least 3 months of therapeutic intensity anticoagulant therapy is required to prevent extension of thrombus and prevent early recurrence in patients after a rst PE and/or proximal DVT (i.e. involvement of popliteal or more proximal veins) [5]. However, 6 months of initial anticoagulation of patients with unprovoked PE or proximal DVT appears to offer a lower risk of early recurrence than 3 months of treatment [5]. Patients with unprovoked isolated distal (calf vein) DVT have a risk of recurrence that is about half that of a proximal DVT or PE with anticoagulation for 6 weeks to 3 months, and the recurrence rate after 3 months of anticoagulation appears to be lower than with shorter duration treatment [5].
Guidance statements

1 We suggest that in patients with an unprovoked calf DVT (i.e. not extending into the popliteal vein) anticoagulant therapy for longer than 3 months is not required. 2 We suggest that in patients with an unprovoked PE or proximal DVT anticoagulation should be considered for as long as the perceived risk of anticoagulant-related bleeding (see below) is not so high as to preclude continued treatment. 3 We suggest that in patients with a provoked PE and DVT anticoagulant therapy after 3 months is not required. See also Guidance Statements under Other Factors to Predict Risk of Recurrence. Hormone-associated PE and DVT This can be dened as a PE or DVT occurring in women who are receiving estrogen-containing hormonal therapy (oral contraceptive and estrogen replacement therapy) and do not have additional risk factors. There is a difference of opinion between experts as to whether a VTE in these women should be considered as unprovoked or not. However, in women with a hormone-associated PE or DVT the prognosis is generally good after a 3- to 6-month period of anticoagulant therapy with an approximately 50% lower risk for thrombosis recurrence compared with women with an unprovoked VTE occurring in the absence of hormonal use [8]. Women who develop a hormone-associated PE or DVT are in general advised to stop this preparation. However, continuation of an estrogen-containing preparation may be warranted for selected patients, for example patients with strong gynecological indications or a personal preference for hormonal treatment, combined with continued anticoagulant therapy. Although there are no clinical trials (randomized or not) assessing the safety of continuing hormonal therapy plus anticoagulant therapy after a PE or DVT, continuation is probably safe (without an increase in recurrence) because any prothrombotic effect of hormonal therapy is likely to be suppressed by therapeutic-intensity anticoagulation.
Guidance statements

1 We suggest that patients with an unprovoked calf DVT should be treated for 3 months. 2 We recommend that patients with an unprovoked PE or proximal DVT should be treated for 3 to 6 months.
Continued anticoagulation beyond the initial 3- to 6-month period

It is now clear that the circumstances in which a PE and DVT occur is the strongest predictor of likelihood of recurrence and determining this from the history is the most useful method of stratifying patient risk. Patients with unprovoked venous thrombosis have an annual risk of recurrence > 5% [1]. Given that this risk exceeds the risk of VKA-related bleeding, patients with a rst or recurrent episode of unprovoked PE or proximal DVT should be considered for long-term anticoagulation. The American College of Chest Physicians has recommended that patients with an unprovoked proximal DVT, and/or PE, should be treated initially with 3 months anticoagulant therapy and then considered for long-term (potentially lifelong) anticoagulation depending on their risk of bleeding [2]. Patients with a PE and DVT provoked by surgery are at low risk of recurrence (annual risk < 1%) after completion of 3-months treatment with a VKA [1,6]. Anticoagulant therapy for longer than 3 months is not routinely required. Patients with a PE or DVT associated with non-surgical risk factors have a variable risk of recurrence, which is between that observed in patients with an initial unprovoked venous thromboembolism (VTE) or those provoked by surgery (see Table 2 in reference [1] for a comprehensive denition of
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1 We recommend that anticoagulant therapy for longer than 3 months is not required for women with a hormoneassociated VTE if hormone therapy is stopped at the time of diagnosis.

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2 We recommend that women diagnosed with a hormoneassociated VTE discontinue hormonal therapy (oral contraceptive and estrogen replacement) before stopping anticoagulant therapy; however, in premenopausal women an eective alternative contraception must be utilized to avoid the potential toxicity of early fetal warfarin exposure. 3 We suggest that hormonal therapy can be continued in selected patients if there is a strong clinical indication for such treatment but anticoagulant therapy should be continued for the duration of hormonal therapy.
Risk of bleeding and quality of anticoagulant therapy

bleeding. Thus, in patients who are receiving VKA therapy, the case fatality of VKA-associated bleeding (both during the initial 3 months and subsequent period) is 9% [10]. On the other hand, in patients who stop VKA therapy, the casefatality of recurrent VTE is 5% [12,13].
Other factors to predict risk of recurrence

Major determinants of bleeding as a result of VKA therapy include: (i) advanced age; (ii) previous bleeding; (iii) increased (or variable) intensity of anticoagulation; (iv) comorbidities such as renal or hepatic impairment; (v) concomitant use of drugs that affect hemostasis, such as aspirin or clopidogrel; and (vi) duration of therapy [9]. The risk of oral anticoagulantassociated bleeding is likely to be low in: 1 patients with a target INR of 2.5 (range 2.03.0) compared with a higher target; 2 younger patients, particularly under 70 years of age; 3 patients who do not require long-term treatment with drugs that aect hemostasis (e.g. ASA, clopidogrel and NSAIDs); 4 patients who have not had episodes of overanticoagulation or suered bleeding during the initial 3 to 6 months of therapy; 5 patients who understand anticoagulant treatment e.g. those who follow dose instructions, have regular INR monitoring, are aware of food and drug interactions, comply with more frequent monitoring during periods of intercurrent illness or initiation of other medications. In a meta-analysis of VKA-associated bleeding among patients with VTE, the rate of major hemorrhage was 2.06% (equivalent to about 9% per year) during the initial 3 months of therapy; after the rst 3 months the rate was 2.7 per 100 patient-years (2.7% per year). The rate of intracranial hemorrhage was 1.48 per 100 patient-years during the initial 3 months of therapy but decreased to 0.65 per 100 patientyears thereafter [10]. The likelihood of a hemorrhage (and recurrent venous thrombosis) was related to the INR time in range in a retrospective study of 2300 patients [11]. In that study, the risk of haemorrhage was lowest in patients spending at least 45% of time in range. As the time in range during the initial 30 days was predictive of future INR control, one approach to assessing patients risk of VKA-related bleeding associated with continued treatment may involve reviewing the quality of anticoagulation during the initial treatment period, either by formally calculating the time in range (we suggest a time in range of less than 50% is inadequate) or alternatively identifying patients with INRs greater than 5.0, after completion of the VKA initiation period. This approach, although sensible, requires validation in future studies. The safety of anticoagulation should also take into account the case-fatality rate of recurrent thrombosis and major

D-dimer While the overall risk for thrombosis recurrence in patients with a previous unprovoked PE or DVT is about 10% in the rst year after a minimum of 3 months of anticoagulant therapy, individual risk is heterogeneous. This is illustrated by a lower annual risk in patients with a low D-dimer result after completion of initial VKA therapy compared with those with a high D-dimer (4% vs. 9%) [1416]. If D-dimer is done, it is reasonable to do so 34 weeks after stopping anticoagulation to ensure no residual effect of anticoagulation on the D-dimer level and to minimize the time patients are off treatment. Overall, exactly how D-dimer measurement should be used is still under investigation. D-dimer assays have different performance characteristics and only D-dimer methods validated by clinical management studies should be used to strongly inuence clinical decisions. Residual vein occlusion Residual vein occlusion, as detected by venous ultrasound, does not predict a likelihood of a recurrent DVT to a degree that is clinically useful [17,18]. Post-thrombotic Syndrome In a prospective cohort study, post-thrombotic syndrome (PTS) was associated with a 2.6fold increased risk of recurrence after unprovoked DVT [19]. This risk is similar to that observed in patients with a high Ddimer. PTS is associated with a high D-dimer [20] and it is as yet unknown if the presence of PTS has a predictive value independent of D-dimer measurement. Thrombophilia Testing for heritable thrombophilic defects does not usefully predict likelihood of thrombosis recurrence after a rst episode of VTE and for this reason testing for heritable thrombophilia is not routinely required [21]. Testing for heritable thrombophilias in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may inuence decisions regarding duration of anticoagulation. However, it is not possible to give a validated guidance statement as to how such patients should be selected as a family history is a poor predictor of likelihood of identifying a heritable thrombophilic defect [22]. Male gender Males appear to be at 1.8-fold higher risk of recurrence after an episode of an unprovoked VTE although a mechanism to explain this observation has not been elucidated [8]. Mode of clinical presentation Although patients presenting with symptoms of a DVT are as likely to develop thrombosis recurrence as patients presenting with symptoms of PE, the
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Unprovoked VTE: duration of anticoagulation 701

mode of initial presentation appears to predict the mode of thrombosis recurrence. Patients with an initial unprovoked PE are three to four times more likely to suffer recurrence as a PE rather than DVT [7,23,24] and the risk of a fatal PE is two to four times more likely in patients with a symptomatic PE as compared with patients with a symptomatic DVT alone [13,25,26]. Consequently, continued anticoagulation is an appropriate consideration in selected patients who initially present with a PE, particularly patients with a limited cardiorespiratory reserve in whom a recurrent PE may be life threatening. Ideally, these and other putative predictors of thrombosis recurrence should be incorporated into a clinical decision guide to stratify patients according to the risk for recurrent VTE. Several guides have been proposed but require independent validation before they can be considered for use in everyday clinical practice [2729].
Guidance statements

necessitate the removal of a central venous catheter, especially when it remains functional and can be used to administer medically necessary treatment. There is evidence from observational studies that this approach may be safe and efcacious [30]. Long-term VKA therapy is not routinely required even if a DVT is unprovoked as the recurrence rate appears to be low (< 5%) in rst year after anticoagulation is discontinued [31,32]. Risk factors that may indicate consideration of continued anticoagulation include a persistent thoracic outlet syndrome, severe post-thrombotic syndrome or the continued use of an indwelling central venous catheter. As thoracic outlet syndrome isariskfactorforanupperlimbDVT,imagingstudies,suchasCT or MR venography of the affected vasculature, can be useful to dene the site of obstruction. Vascular surgical intervention can be undertaken for severe thoracic outlet syndrome to obviate consideration of continued anticoagulation.
Guidance statements

1 It is not possible to give a denitive guidance statement as to which patients should or should not receive long-term anticoagulant therapy after an episode of an unprovoked PE or DVT. Patients should be assessed on an individual basis, taking into consideration factors contributing to thrombosis recurrence risk and bleeding risk, and should be oered information outlining the risks and benets of long-term anticoagulation. Moreover, patients values and preferences should be considered, relating to the impact of thrombosis recurrence (if anticoagulation is stopped) and bleeding (if anticoagulation is continued). 2 We suggest that the following factors may favor long-term anticoagulation in patients with a rst unprovoked PE or DVT: a male gender; b moderate-to-severe post-thrombotic syndrome; c ongoing dyspnoea (possibly related to unresolved or recurrent PE); d satisfactory initial anticoagulant control; e elevated D-dimer result based on individual D-dimer assay performance characteristics using a study-validated assay. 3 We suggest that the following factors may favor stopping anticoagulation in patients with a rst unprovoked VTE: a female gender; b absent or mild post-thrombotic syndrome; c unsatisfactory initial anticoagulant control; d low D-dimer result based on individual D-dimer assay performance characteristics using a study-validated assay. Upper limb DVT Initial anticoagulant therapy for venous thrombosis of the upper limb is the same as for the lower limb. Randomized trials of different durations of anticoagulation have not been performed. Most cases of an upper limb DVT are provoked by central venous catheters. The development of a DVT should not
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1 We suggest that patients with an unprovoked upper limb DVT should be treated for 3 months initially. 2 We suggest that long-term anticoagulant therapy is not routinely used in patients with an upper limb DVT in the absence of continuing risk factors. 3 We suggest that continued anticoagulation should be considered in patients with an indwelling central venous catheter, persistent thoracic outlet syndrome or severe postthrombotic syndrome. Disclosure of Conict of Interests The authors state that they have no conict of interest. References
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