Clinical trial NCT00954395: DULCIS (D-dimer and ULtrasonography in Combination Italian Study)
Official title: Optimizing the Duration of Anticoagulation in Venous Thromboembolism: the DULCIS Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Venous Thromboembolism
Keywords: vitamin K antagonists, D-dimer,
deep vein thrombosis, pulmonary embolism,
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
Collaborators: name: University of Bologna
First posted: 2009-08-07
Enrollment: 1100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with a first episode of venous thromboembolism attending anticoagulation clinics or general practitioners

Brief summary: The purpose of this study is to evaluate the efficacy and safety of a standardized procedure to establish the optimal duration of anticoagulation in patients with venous thromboembolism.

Detailed description: Venous thromboembolism (VTE- the deposition of thrombi in the deep veins of the lower limbs-deep vein thrombosis- and/or pulmonary embolism) has an incidence of 1.0 - 1.6 events per year per 1000 persons. While the prevention and treatment of the acute phase of VTE is well established, the secondary prevention of the disease, that is its long-term management, is not well standardized. Venous thromboembolism tends to recur regardless of the duration of treatment , with an incidence of 30% over 5-10 years. Both the duration and the quality of treatment after the acute event are not well established nor consistently applied in clinical practice. Recently, the 7th Consensus Conference on Anti-thrombotic therapy of the American College of Chest Physicians recommended that patients with unprovoked VTE receive at least 3 months of anticoagulant therapy. Afterwards the risk-benefit ratio of long-term therapy should be evaluated. Long term treatment is recommended in patients at low risk of bleeding and for whom good anticoagulant monitoring is achievable. However, the risk of recurrence is greatest in the first 6 to 12 months after the initial episode while it gradually decreases thereafter. As a result, the benefits of extending anticoagulation are offset over time by the risk of clinically important bleeding associated with anticoagulation. Moreover, vitamin K antagonists (VKAs) are currently the drugs of choice, and their require a strict laboratory monitoring, but in the near future newer oral anticoagulants not requiring monitoring will be available.

Several individual characteristics such as post-anticoagulation D-dimer and residual venous obstruction have been shown to be associated with an increased risk of recurrent events. We have shown in a multicentre randomized study PROLONG (N Engl J Med 2006; 355: 1780-1789) showed that D-dimer could play a role in establishing the duration of anticoagulation after a first episode of idiopathic VTE. Patients were treated with VKA for a minimum of 3 months and D-d was tested at one month after anticoagulation withdrawal . If D-dimer was normal patients did not resume treatment, whereas those with elevated D-dimer were randomized to either stop or resume anticoagulation. Patients with an abnormal D-dimer had a statistically significant higher risk for recurrence when compared with those with normal D-d. Continued anticoagulation in patients with elevated D-d significantly reduced the risk of recurrent VTE over a follow-up of 18 months.

The purpose of this study is to evaluate the efficacy and safety of a procedure employing the evaluation of residual vein obstruction and D-dimer to establish the individual risk of recurrence and thus the necessity to prolong or stop anticoagulation ( with VKAs but also with newer anticoagulants) after venous thromboembolism.

The pre-defined objectives of the study are the following:

i) to obtain a recurrence rate \< 5% per year in the first and second year after anticoagulation is suspended according to the procedure ii) to allow that after treatment for the first episode of venous thromboembolism, anticoagulation suspension in feasible in at least 40% of all subjects included in the study.

Eligibility criteria: Inclusion Criteria:

Age \> 18 years first episode of objectively documented symptomatic idiopathic VTE, either proximal lower extremity deep vein thrombosis (DVT) and/or pulmonary embolism (PE).

Unprovoked or idiopathic , or associated with one or more of the following favouring factors

· - minor general surgery, arthroscopy or laparoscopy

* pregnancy or puerperium
* hormonal treatment (contraceptive or replacement therapy)
* travel
* minor traumas
* hospitalization in a medical ward
* reduced mobility (non complete immobilization) at least six months of VKA therapy ( or other type) for at least 3 months and not longer than 12 months ability to provide informed consent

Exclusion criteria:

* Two or more episodes of objectively documented proximal DVT and or PE ( previous distal of superficial vein thrombosis are not exclusion criteria)
* Index event was isolate distal ( calf) vein thrombosis
* Index event was PE associated with shock or prolonged hypotension at high risk
* Index event was DVT in sites different from the lower limbs
* Pregnancy or puerperium ( first 6 weeks after delivery) at the time of the visit
* Solid or haematological malignancy in the active phase or undergoing chemotherapy or radiotherapy
* Antiphospholipid antibody syndrome, diagnosed according to the Sydney criteria
* Hereditary antithrombin deficiency
* Necessity to prolong anticoagulation for any reason (due to the thrombotic event or other clinical indications
* Severe respiratory or heart failure (NYHA classes: III or IV)
* Presence of criteria indicating a short anticoagulant treatment:

Venous thromboembolism secondary to one of the following triggering factors:

* Major surgery \[orthopedic, general, oncological (only if radical)\]
* Bed rest (\>4 dd)
* Severe trauma
* Plaster cast of the lower limbs
* high bleeding risk
* limited life expectancy,
* geographical inaccessibility
* Inability or refusal to provide informed consent

Primary outcomes:
measure: Recurrent venous thromboembolism (VTE) and major and minor but clinically relevant bleeding
timeFrame: two years after enrollment
Secondary outcomes:
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: U.O. Angiologia e Malattie della Coagulazione "Marino Golinelli"; Dipartimento Cardio-Toraco-Vascolare Azienda Ospedaliero-Universitaria di Bologna
Study officials:
affiliation: St.Orsola Malpighi University Hospital
name: Gualtiero Palareti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, Pengo V, Ghirarduzzi A, Pattacini C, Testa S, Lensing AW, Tripodi A; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006 Oct 26;355(17):1780-9. doi: 10.1056/NEJMoa054444.
citation: Legnani C, Palareti G, Cosmi B, Cini M, Tosetto A, Tripodi A; PROLONG Investigators (FCSA and Italian Federation of Thrombosis Centers). Different cut-off values of quantitative D-dimer methods to predict the risk of venous thromboembolism recurrence: a post-hoc analysis of the PROLONG study. Haematologica. 2008 Jun;93(6):900-7. doi: 10.3324/haematol.12320. Epub 2008 Apr 28.
citation: Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S-545S. doi: 10.1378/chest.08-0658.
citation: Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P, Frulla M, Mosena L, Tormene D, Piccioli A, Simioni P, Girolami A. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002 Dec 17;137(12):955-60. doi: 10.7326/0003-4819-137-12-200212170-00008.
citation: Pengo V, Prandoni P. From acute pulmonary embolism to chronic thromboembolic pulmonary hypertension. Ital Heart J. 2005 Oct;6(10):830-3.
citation: Palareti G, Cosmi B, Antonucci E, Legnani C, Erba N, Ghirarduzzi A, Poli D, Testa S, Tosetto A, Pengo V, Prandoni P; DULCIS investigators. Duration of anticoagulation after isolated pulmonary embolism. Eur Respir J. 2016 May;47(5):1429-35. doi: 10.1183/13993003.01126-2015. Epub 2016 Feb 25.
citation: Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, Poli D, Testa S, Tosetto A, Pengo V, Prandoni P; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014 Jul 10;124(2):196-203. doi: 10.1182/blood-2014-01-548065. Epub 2014 May 30.