ExACT - Extended anticoagulation treatment for VTE: a randomised trial

Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), is a common condition – it affects approximately 1 in 1,000 people every year. VTE causes serious morbidity, including post-thrombotic syndrome, and death.

Currently, patients with a first episode of unprovoked VTE, with no apparent other risk factors for recurrent VTE, are given a course of oral anticoagulation (warfarin) treatment which is then discontinued. Many of these patients will not develop any recurrence of the condition so long-term treatment with warfarin, a drug with potentially life-threatening side effects, is not advised.

However, a substantial proportion of these patients – up to 17% - go on to have a recurrent episode of VTE which can be fatal. If recurrence occurs, the patient is normally managed thereafter with long-term warfarin, provided there are no contraindications. The issue is that the optimum duration of warfarin therapy depends on the individual patient and has not been defined.

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There is an annual recurrence rate following a first VTE of approximately 10% per annum following treatment cessation, irrespective of the duration of warfarin therapy. This suggests that some patients with a first unprovoked VTE should continue warfarin in the long-term - however, we are currently unable to identify this population.

It would be very useful to have an accurate predictor of recurrence of VTE to decide which patients with a first episode of unprovoked proximal DVT or PE would be most likely to benefit from long term oral anticoagulation, and also which patients should only receive short term therapy.

Concern in terms of duration of treatment is due to the risk of bleeding from prolonged warfarin treatment. Several studies have investigated the optimal duration of anticoagulant therapy with the British Committee for Standards in Haematology (BCSH, 1998) recommending between six weeks and six months, depending upon the aetiology.

D-dimer is a fibrin degradation product, present in the blood after a blood clot is degraded by fibrinolysis and levels of D-dimer can be tested using laboratory and POC testing devices. The primary clinical use of D-dimer testing has been in conjunction with probability scores to determine whether further investigation is required for the diagnosis of VTE. More recently interest has been shown in studies which have investigated whether D-dimer can be utilised as a guide for determining who is at risk of recurrent VTE following treatment of the initial acute episode. Studies of extended treatment with low dose warfarin have confirmed that maximal benefit is conferred at standard therapeutic targets rather than fixed low dose regimes.

Previous small studies outside the UK have suggested that D-dimer levels could act as a useful predictor of recurrent thromboembolism in patients whose warfarin is to be discontinued.  Therefore D-dimer levels could be a potentially useful clinical tool to decide which patients, with a first episode of unprovoked proximal DVT or PE, would most likely benefit from long-term warfarin therapy. In addition circulating endothelial cells and microparticles have been shown to be raised in VTE so these may have a predictive value in identifying outcomes in this cohort of patients.

The conclusions of 2 systematic reviews of D-dimer testing after stopping treatment for VTE, (7 studies with a total of 1888 patients) were “additional research is needed to establish the optimal interval between stopping anticoagulation and performing D-dimer testing, to identify the optimum cut-off that predicts recurrence and to develop a clinical prediction rule for recurrent DVT”, and “strategies which incorporate a number of high performing baseline and post-baseline predictors could be more effective in predicting recurrent VTE and should be tested. If oral anticoagulation is continued, there is no evidence on the duration of this extended therapy.”

The only UK data included in these reviews were from a prospective cohort study of 272 patients with a first episode of venous thrombosis that was unprovoked or provoked by a non-surgical trigger. They undertook D-dimer testing 1 month after cessation of warfarin therapy and found a non-significant difference in recurrence (5.5/100 patients years in D-dimer +ve vs 4.1/100 patient years in D-dimer –ve).8 There is limited data on utility of the dimer as a predictor in patients still on therapy, but Rodgers et al have shown that D-dimer can be used to predict recurrence in low risk female patients.

Post thrombotic syndrome (PTS) is a frequent and costly complication of DVT which can lead to chronic venous insufficiency and ulceration. PTS has a cumulative incidence after 2 years of around 25% and it has been postulated that prolonged treatment with oral anticoagulants could prevent the development of PTS.23 The only data available from a randomised trial suggested no association between long-term low dose warfarin treatment and development of PTS. 24 The prevalence of PTS in this study was 37% after 2.2 years, with severe PTS in 4%. There are currently no laboratory factors which appear to predict the development of PTS. .

There are no previous studies which have investigated the utility of D-dimer testing in conjunction with clinical algorithms to prevent recurrence of VTE and there are no data on the incidence of PTS for patients treated with long term therapeutic warfarin.

This is the first UK primary care based study where patients being treated for a first episode of unprovoked proximal DVT or PE will be randomised before treatment end to receive either extended warfarin treatment or no warfarin treatment for the prevention of recurrent VTE and post-thrombotic syndrome. The study will also focus on analysis of costs incurred within the health sector and by patients as well as quality of life measures related to extended treatment and D-dimer testing.

Patients with raised D-dimer levels 1 month after discontinuing oral anticoagulation have been shown to be at high risk of recurrence.


A prospective multi-centre randomised controlled trial.

Aim of study

The aim of the study is to investigate extending treatment with oral anticoagulation beyond 3-6 months, for those patients with first unprovoked proximal DVT or PE prior to discontinuing treatment, in terms of reduction in recurrence of VTE and PTS.


  • To establish the performance characteristics of D-dimer testing whilst still on treatment as a prediction tool for recurrence of VTE in patients with first unprovoked proximal DVT or PE
  • To establish factors which contribute to the recurrence of VTE in patients with a first unprovoked proximal DVT or PE
  • To determine the protective effect of prolonged warfarin therapy against post-thrombotic syndrome in patients with first unprovoked proximal DVT or PE
  • To determine the cost-effectiveness of the measurement of D-dimer and subsequent extended treatment with anticoagulation
  • To determine patient preferences and utilities with regard to extended warfarin treatment


Patients will be identified at anticoagulation clinics from a number of secondary care sites to include University Hospital Birmingham (UHB); Heartlands, Solihull and Good Hope Hospitals (Heart of England NHS Foundation Trust); City and Sandwell Hospitals in Birmingham (Sandwell and West Birmingham Hospitals NHS Trust); Walsgrave Coventry and Rugby St Cross Hospitals (University Hospital Coventry and Warwickshire NHS Foundation Trust); Warwick and Stratford-upon-Avon Hospitals (South Warwickshire NHS Foundation Trust); Leicester General Hospital, Leicester Royal Infirmary and Glenfield Hospital (University Hospitals of Leicester NHS Trust); University Hospital of North Staffordshire; Sir Robert Peel and Samuel Johnson Community Hospitals (Burton Hospitals NHS Foundation Trust); Worcestershire Royal Hospital, Kidderminster Hospital and Alexandra Hospital, Redditch (Worcestershire Acute Hospitals NHS Trust); Russells Hall Hospital, Corbett Hospital and Guest Hospital (The Dudley Group NHS Foundation Trust); George Eliot Hospital (George Eliot Hospital NHS Trust) plus a number of primary care sites running large anticoagulation clinics identified through the National Centre for Anticoagulation Training.

In order to improve recruitment additional secondary care sites may be added to the study following full regulatory approvals.

Participant Identification Centres (PIC) will also be used as a method of identifying patients.

Recruitment will be from primary and secondary care clinics; randomisation, study intervention and data collection will be primarily within primary care.

Target population

The target population will be patients aged 18 years or over with a diagnosis of first unprovoked VTE.