Someone who has had a first episode of venous thromboembolism (VTE) is about 40 times more likely to have an episode in the future than a person who has never experienced such an event.1 Prolonged use of anticoagulation therapy reduces this likelihood of recurrence, but comes with a risk of bleeding. Guidelines cite certain medical conditions that increase the risk of recurrence of VTE (such as cancer and inflammatory bowel disease)2 but, beyond that, there are no reliable tools for stratifying individual patients who are at higher risk of recurrence. Here we review the evidence regarding risk factors for recurrence that might influence the decision to recommend prolonged anticoagulant therapy after a first episode of VTE, and we consider the implications for practice.
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VTE is the collective term for either deep vein thrombosis (DVT) or pulmonary embolism (PE).3 The reported annual incidence of VTE is around 1–2 cases per 1,000 people,4,5 with over 1 million VTE events or deaths occuring per year in the European Union.6
VTE can occur in the absence of an overt predisposing factor (sometimes called ‘idiopathic’ or ‘unprovoked’), or alternatively may be provoked by permanent or transient factors. Established risk factors for VTE include hospitalisation for either surgery or medical illness;7 cancer;8 increased body mass index (BMI);9 current or former smoking;10 use of combined oral contraception (COC);11 pregnancy;12 hormone replacement therapy containing oestrogen;13 hereditary thrombophilias (including the presence of factor V Leiden, prothrombin 20210A mutation);14 antiphospholipid syndrome;15 nephrotic syndrome;16 and long-distance travel.17
Specific guidelines are available on the management of women with VTE who are pregnant or in the puerperium, and of patients with antiphospholipid syndrome;12,15 both these areas are outside the scope of this article.
The Scottish Intercollegiate Guideline Network (SIGN) recommends that, for patients with a clinically suspected VTE, initial treatment until the diagnosis is excluded, should be with either unfractionated or low molecular weight heparin (LMWH), and that if the patient is not pregnant, an oral anticoagulant should also be started.2 The oral therapy is most commonly warfarin, a vitamin K antagonist, which is monitored by measuring a patient's Internationalised Normalised Ratio (INR). Guidelines from the American College of Chest Physicians (ACCP) recommend that patients with cancer should receive LMWH therapy for at least the first 3 months after DVT or PE.18 A recent systematic review has shown that there are improved outcomes in terms of recurrence when LMWH is used in this particular group of patients.19 The ACCP guidelines also advise that patients who have had a proximal DVT wear graduated compression stockings for a minimum of 2 years afterwards (to help prevent post-thrombotic syndrome – see below).18
However, use of anticoagulant therapy is associated with an increased risk of bleeding. A systematic review of eight randomised controlled trials, including a total of 2,994 patients, compared short-term (1–3 months) versus long-term (3–24 months) anticoagulation therapy for the treatment of VTE.5 The risk of major bleeding complications in the longer-duration treatment group was increased in the period that they received anticoagulant therapy compared to the group who had completed therapy (four studies in the analysis, total of 808 patients, odds ratio [OR] 4.87, 95% CI 1.31 to 18.15). The risk of major bleeding appears to be independent of duration of anticoagulant therapy.5,20
RISK FACTORS FOR RECURRENT VTE
What guidelines say
SIGN guidelines recommend that, after at least 3 months of oral anticoagulant therapy following a first episode of DVT or PE, patients should be assessed for continuing risk factors, and the presence of such factors should prompt “consideration of anticoagulation long term, or until such risk factors resolve”.2 Several examples of such risk factors are given (e.g. idiopathic VTE, familial presentation, thrombophilias, malignancy, chronic infection, inflammatory bowel disease, nephrotic syndrome, thromboembolic pulmonary hypertension); however, there is nothing to suggest that the stated list is exhaustive.
Guidelines on oral anticoagulation therapy from the British Society for Haematology do not specifically address the issue of assessment of continuing risk factors for recurrence, but recommend longer therapy (6 months) after an idiopathic VTE, compared to 3 months for a temporary risk factor and low risk of recurrence (not further defined).23
Beyond these guidelines, there are no reliable tools for stratifying who is at higher risk of recurrence. However, there are several possible risk factors that have been evaluated in clinical trials.24–41
In a prospective cohort study of 570 patients with first VTE (which excluded people with malignancy or antiphospholipid syndrome), the cumulative recurrence rate at 2 years from completion of anticoagulant treatment (no duration of treatment specified) was 11%, overall.24 Recurrence was lowest in the subgroup with surgery-related VTE and highest in the sub-group of 193 patients with an ‘unprecipitated’, or idiopathic, VTE (0% vs. 19.4%, respectively, p<0.001).
In another prospective follow-up study, a total of 474 consecutive adult patients aged 18–70 years with a first VTE (excluding those with malignancy) were followed up for a mean of 7.3 years, with complete follow-up achieved in 447 (94%).25 Patients whose initial thrombotic event was idiopathic had a higher risk of recurrence than those with a provoked event (hazard ratio [HR] 1.9, 95% CI 1.2 to 2.9).
In a meta-analysis including 15 studies (i.e. prospective cohort studies and randomised trials) involving a total of 5,416 patients, there were 816 episodes of recurrent VTE once anticoagulant treatment was completed (minimum duration of treatment range 1–6 months).26 Of these recurrences, 64% occurred in men and 36% in women, giving an overall relative risk (RR) of recurrence in men of 1.6 (95% CI 1.2 to 2.0, p = 0.0004). However, in a prospective study of 508 patients with one or more previous VTEs, randomised to either low-intensity (e.g target INR of 1.5–2.0 instead of the usual 2.0–3.0) warfarin or placebo for 2.1 years, recurrence rates at 3 years were similar between genders once women with hormone-related index events (e.g. pregnancy, puerperium, oral contraceptives and postmenopausal hormone use) were excluded.27
A multicentre prospective cohort study analysed data from a total of 600 patients with a first VTE with regards to 69 potential predictors of recurrence while they were taking oral anticoagulant therapy.28 They were then followed up for a mean of 18 months after completion of their treatment, during which, there were 91 confirmed episodes of recurrence of VTE. The annual risk of recurrence in men was 13.7% (95% CI 10.8% to 17.0%); no combination of clinical predictors identified a “low risk” sub-group of men. However, in women, the following risk factors helped to distinguish between those at high and low risk of recurrence: hyperpigmentation; oedema or redness of either leg; D-dimer concentration greater than or equal to 250 μg/L while on warfarin; BMI greater than or equal to 30 kg/m2; or aged 65 years or above. Those with none or one of these factors had an annual risk of recurrent VTE of 1.6% (95% CI 0.3% to 4.6%), compared to women with two or more of these factors, who had an annual risk of 14.1% (95% CI 10.9% to 17.3%).
The risk of first VTE increases with age,29 with an exponential increase after the age of 60 years.30 However, we know of no published studies of recurrent VTE in which assessing age as a risk factor was a primary aim.
In a prospective cohort follow-up study, 313 consecutive patients with DVT, who had completed 3 months of anticoagulant therapy without recurrence, had an ultrasound of the affected limb to assess for residual thrombosis at this point, and then every 6–12 months for a total of 3 years.31 They were also monitored for recurrent VTE over a total of 6 years. Although all patients were instructed to stop anticoagulant therapy at 3 months after the index event, 65 patients continued therapy for up to another 6 months. Of the 58 patients with confirmed recurrent VTE, 41 of these patients had a recurrence while a residual thrombus was present (HR for a recurrent event 2.9, 95% CI 1.6 to 5.2, p = 0.001).
Two systematic reviews have assessed the rate of recurrent VTE in patients with or without factor V Leiden and prothrombin mutation, the two most common genetic polymorphisms that predispose to a first VTE episode.32,33
In the first review, results were pooled from 13 cohort studies in patients with a first VTE.32 The risk of recurrent VTE was increased if the patient had factor V Leiden (nine studies, 2,880 patients; OR 1.30, 95% CI 1.03 to 1.63) or prothrombin mutation (nine studies, 2,903 patients; OR 1.72, 95% CI 1.27 to 2.31). Overall, the authors concluded that both “heterozygous [factor V Leiden] and prothrombin [mutation] are each associated with a significantly increased risk of recurrent VTE….the magnitude in risk is modest and by itself unlikely to merit extended-duration anticoagulation”.
The second systematic review involved 10 studies (i.e. prospective cohort and randomised controlled trials) and a total of 3,203 patients with a first VTE and tested for factor V Leiden.33 The relative risk of VTE recurrence in patients heterozygous for factor V Leiden was 1.39 (95% CI 1.15 to 1.67) compared to those without the factor, and the relative risk of VTE recurrence in patients heterozygous for prothrombin mutation was 1.20 (95% CI 0.89 to 1.61). The authors concluded that heterozygous carriage of factor V Leiden is “clearly associated” with an increased risk of recurrent thromboembolism. They also concluded that the risk is lower in patients with prothrombin mutation, but the risk is “difficult to interpret since it varies according to the assessment method used”.
Long-term sequelae of VTE include post-thrombotic syndrome, which is characterised by pain, heaviness, swelling and skin changes in the affected limb and an associated reduction in quality of life; it occurs in up to 50% of patients with DVT.34
A prospective study of 406 patients with a first DVT, followed for at least 18 months after the index event, and assessed at a mean of 44 months, found that at 4 years, the cumulative risk of a recurrent symptomatic DVT was 7.4% among patients with post-thrombotic syndrome compared to 1.6% among patients without the condition (RR 2.6, 95% CI 1.2 to 5.9).35
Five prospective studies, including a total of 2,383 patients with VTE who had been on anticoagulant therapy for at least 3 months, found increased rates of elevated D-dimer concentrations (defined as >500 ng/mL in five of the six studies) at 1–3 months after cessation of warfarin therapy in patients who went on to have a recurrent VTE.
IMPLICATIONS FOR PRACTICE
Once patients with a first VTE reach the end of the planned duration of initial anticoagulant therapy (usually at least 3 months), they need to be reviewed to gauge whether they are at a higher risk of recurrence. Medical conditions, such as malignancy, inflammatory bowel disease or nephrotic syndrome, put patients at increased risk of recurrence,2 as does an initial VTE with no identifiable cause.24,25 Also, men are more likely than women to experience recurrence.26–28 A residual thrombus, which can be detected by ultrasonography if the initial thrombus was a DVT, suggests an increased risk of recurrence,31 as does a raised D-dimer concentration (above 500 ng/mL) at cessation of therapy.37–41 Although increased age, especially if over 60 years, is recognised as a risk factor for VTE,29,30 it can also be argued that patients of a younger age have more time for a recurrent VTE and are therefore at higher cumulative risk of recurrence; this suggests that the decision to continue anticoagulant therapy should be independent of the patient's age.
If one or more of the risk factors are present, the risk of recurrence should be discussed with the patient, as should the possibility of continuing anticoagulant therapy. However, the risk of recurrence needs to be balanced with the increased risk of bleeding with anticoagulant therapy, and with how the patient feels about the implications of being on long-term treatment (i.e. in terms of regular monitoring and potential interactions with other drugs). For patients who receive long-term anticoagulation, it is advisable to reassess the risk-benefit ratio of continued treatment at regular intervals (e.g. annually), or following an episode of severe over-anticoagulation or bleeding. Assessment at the end of planned initial anticoagulant therapy is a good opportunity to check that the patient is wearing the appropriate graduated compression stockings (if he or she presented initially with a DVT), to help prevent post-thrombotic syndrome.18
In the UK, care of patients on anticoagulant therapy is commonly ‘shared’ (e.g. hospital clinic monitoring of INR levels, the general practitioner prescribing of warfarin). Such arrangements have implications as to who is responsible for assessing continued anticoagulant therapy after initial treatment has been completed.
Once initial treatment for venous thromboembolism (VTE) is completed, patients need to be assessed as to whether they are at higher risk of recurrence. In patients without underlying medical conditions predisposing to VTE, risk factors for recurrence include an unprovoked first event, male gender, residual thrombus, presence of post-thrombotic syndrome and a high D-dimer level on completion of initial anticoagulant therapy. Increasing age, particularly over 60 years, has been identified as a risk factor for VTE. Evidence for heritable thrombophilias, suggests that being heterozygous for factor V Leiden modestly increases risk of recurrence. Further studies are required to obtain reliable estimates of risk of recurrence associated with individual and combinations of these risk factors.
If one or more of these risk factors are present, this, and the possibility of continuing anticoagulant therapy, should be discussed with the patient. The increased risk of bleeding while on anticoagulant therapy needs to balanced with the risk of recurrent VTE. For patients who receive long-term anticoagulation the risk-benefit ratio of continued treatment should be reassessed at regular intervals (e.g. annually), and following any episode of severe over-anticoagulation or bleeding.