Clinical trial NCT03054727: Long Term Assessment of Post Thrombotic Syndrome : OPTIMEV Study ( SPOT )
Official title: Long Term Natural History of PTS and Other Adverse Outcomes After Venous Thromboembolism in the Optimev Study (SPOT)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Post Thrombotic Syndrome
Venous Thromboembolism
Cardiovascular Diseases
Keywords: Post Thrombotic Syndrome
Venous Thromboembolism
Incidence
Risk factors
Venous ulcer
Lead sponsor: Association des Médecins Vasculaires Hospitaliers
Sponsor class: OTHER
Collaborators: name: Daiichi Sankyo
name: Ministry of Health, France
name: LEO Pharma
name: Sanofi
name: University Hospital, Grenoble
First posted: 2017-02-16
Enrollment: 2475
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: study of exposed and unexposed patients nested in the propsective OPTIMEV cohort

Brief summary: Post-thrombotic syndrome (PTS) is a frequent and burdensome complication of deep-vein thrombosis (DVT). In the absence of curative treatment of established PTS, its management is based on the prevention of its occurrence thanks to anticoagulants and compression stockings.

So far, predictors of disabling PTS are unknown precluding from optimally selecting patients for invasive (early thrombus removal) or innovative/expensive treatments. In addition, little is known on the incidence of PTS in the very long-term.

Objectives: To assess, 12 years after a symptomatic venous thromboembolic (VTE) event, Primary objective: incidence and severity of PTS after a lower limb DVT.

Main Secondary objectives:

1. Incidence and severity of PTS according to VTE initial presentation (isolated distal DVT, isolated proximal DVT, PE + DVT).
2. Incidence and risk factors of disabling PTS Methods: Very long-term follow-up (12 years) of patients recruited in the large, multicentre, prospective, observational OPTIMEV study for a suspicion of VTE confirmed or ruled out with objective tests (Clinical Trials NCT00670540).

All patients with a DVT, an isolated PE and a random selection of controls (VTE - patients without any history of VTE after the 3 years of follow-up) will first benefit from a phone-PTS assessment. Those patients presenting at least a mild venous insufficiency and a selection of controls will undergo a clinical follow-up visit with clinical and Compleat Ultra Sound (CUS) assessment of PTS/venous insufficiency and an assessment of quality of life.

Perspectives: Improving our knowledge of PTS' incidence and predictors and of the impact of usual treatment. Better selecting patients eligible for invasive/innovative/expensive preventative procedures.

Detailed description: Post thrombotic syndrome (PTS) refers to chronic manifestations of venous insufficiency following a deep vein thrombosis (DVT). It is the most frequent complication of DVT, which affects up to 40% of patients after a proximal DVT (popliteal veins and above).

Though not lethal, PTS is burdensome and severly impacts patient's quality of life (QOL). In addition after a DVT, PTS was found to be an important predictor of total and medical costs. Thus PTS is not just a cosmetic problem and constitutes a real public health concern in the field of VTE. However, so far, many epidemiologic and therapeutic issues remain unresolved.

On an epidemiologic point of view, incidence of PTS in the long term (i.e. after 5 years) is largely unknown. In addition, there is no available reliable data on the risk of PTS after isolated distal DVT (i.e. infrapopliteal DVT without pulmonary embolism (PE), \>50% of all lower limb DVT) or isolated PE. At last, risk and independent predictors of the most severe disabling forms of PTS (particularly venous claudication and venous ulcers) need to be assessed (absence or old and outdated data).

On a therapeutic point of view, so far there is no curative treatment of established PTS. The cornerstone of PTS' treatment lies on its prevention via an optimal anticoagulation therapy, the use of compression stockings (the effectiveness of which was recently questioned by the SOX RCT trial) and sometimes thrombolysis for cases of very proximal DVT without bleeding risk. Impact in the very long term of usual DVT treatment on PTS natural history, prescribed in routine clinical practice in a real life setting, has never been assessed. Furthermore, absence of identified independent predictors of disabling PTS constitutes an important break to the use and to assess the full effectiveness of invasive therapies.

In this perspective, the investigators aim performing a very long term follow-up (12 years) of the already constituted OPTIMEV cohort in order to try to answer most of the above-mentioned epidemiologic and therapeutic unresolved issues.

Objectives Primary objective: To assess incidence (from baseline till up to 12 years) and severity of PTS, 12 years after a lower limb DVT, calculated with the clinical Villalta score.

Secondary objectives: To assess in the very long term (12 years)

1. Determine risk factors of disabling PTS (DVT patients).
2. Characterize the incidence and severity of PTS according to VTE initial presentation (isolated distal DVT, isolated proximal DVT, PE + DVT).
3. Determine the rate of venous insufficiency in the unexposed population and also in the exposed population.
4. Estimate the impact of PTS on patient's quality of life.
5. Assess the incidence of cancers in the population, by comparing exposed patients and non exposed patients included in OPTIMEV cohort.
6. Assess the incidence of cardiovascular events in the population, by comparing exposed patients and non exposed patients included in OPTIMEV cohort.
7. Assess the incidence of death in the population, by comparing exposed patients and non exposed patients included in OPTIMEV cohort.
8. Assess the incidence of new DVT in the population, by comparing exposed patients and non exposed patients included in OPTIMEV cohort.
9. Assess the attributable risk of DVT to the signs and symptoms of chronic venous insufficiency in DVT patients
10. Determine whether there is a correlation between CUS findings and PTS clinical severity in 200 patients with PTS (Villalta \> or = 5).
11. Measure the incidence of hemorrhage events in the population, with comparison between exposed and non exposed patients included in OPTIMEV cohort.

Methods Cohort study of exposed and unexposed patients nested in the OPTIMEV multicentre observational study (Clinical Trials NCT00670540) Constitution of the OPTIMEV cohort: From November 2004 to January 2006, 8256 patients with a suspicion of symptomatic VTE (lower and upper extremity DVT, PE) were enrolled and benefited from objective tests to confirm or rule out the suspicion of VTE. This included a bilateral whole leg compression CUS for all cases of suspicion of DVT; Baseline characteristics including patient's demographics, signs, symptoms \& risk factors for VTE, venous status, results of objective tests and treatments were prospectively collected in an electronic case report form.

Patients with a confirmed VTE and a random selection of controls (patients for whom VTE was ruled out at baseline) were initially followed up by phone by clinical research assistants during 3 years using standardized questionnaires to obtain information on health-related events (death, VTE recurrence, bleeding, arterial cardiovascular events, diagnosis of cancer or of lower limb ulcer, hospitalization and treatments). The general practitioner or the vascular medicine physician was contacted whenever a possible event was reported or when the patient's history seemed potentially unreliable. Medical records were reviewed in case of hospitalization or a new visit to the vascular physician during the follow- up period. All suspected adverse events were adjudicated by the study's expert committee.

At 3 years our rate of lost to follow-up or of patients who declined to continue the study was low (\<3%) For this very long-term follow-up (12 years), patients with VTE and a random selection of patients free from any VTE will be considered.

As per previous follow-up visits, clinical research assistants will contact all eligible patients using the same standardized questionnaires and will assess PTS/venous insufficiency using a validated phone-questionnaire (Villalta score of Utne and Sandset). Patients with a suspicion of disabling PTS/venous insufficiency and a random selection of controls will be referred to a participating vascular medicine physician for a clinical follow-up visit with realization of a PTS assessment (Villalta score and CEAP) and a whole limb CUS exploration of the venous system + Ankle Brachial Index (ABI) measurement). QOL questionnaires will also be filled.

Statistical considerations Statistical analyses will be performed by the Themas team in Grenoble. Based on the results of a pilot-feasibility study (random selection of 100 VTE patients, 15% lost to Follow-Up (FU) and 5% of death), 1000 patients with lower limb DVT or PE at baseline ("exposed" patients) should attend the clinical follow-up visit. This will allow us to estimate, with a precision of plus or menus 3% an incidence of PTS at 12 years of 45% and with a precision of plus or menus 2.5% an incidence of disabling PTS of 20%.

Perspectives This study should improve our knowledge on the long term incidence of PTS according to various presentations of VTE disease, on the impact of routine clinical practice therapeutic management (particularly compression therapies and anticoagulation) on the risk of PTS, and should allow determining independent predictors of disabling PTS. On a clinical practice point of view, this study should assess the benefit of PTS preventative treatment after an isolated DVT or an isolated PE and to better selecting patients eligible for invasive procedures.

Eligibility criteria: Inclusion Criteria:

* Exposed patients: Patients with a lower limb DVT and/or a PE
* Unexposed patients: Random selection of controls (1:1) free from any VTE event at the 3 years follow-up visit

Exclusion Criteria:

* Severe venous insufficiency at baseline (CEAP C5-C6)
* Severe lower limb peripheral arterial disease (critical limb ischemia)
* Altered mental status
* Decline to participate

Primary outcomes:
measure: disabling PTS
timeFrame: 12 years
Secondary outcomes:
measure: Risk factors of disabling PTS
timeFrame: at inclusion
measure: PTS severity
timeFrame: at inclusion
measure: Incidence of venous insufficiency
timeFrame: at inclusion
measure: Global Quality of life
timeFrame: at inclusion
measure: Specific Quality of life
timeFrame: at inclusion
measure: Incidence of cancers
timeFrame: at inclusion
measure: Incidence of cardio-vascular events (stroke, myocardial infarction, peripheral arterial disease)
timeFrame: at inclusion
measure: Incidence of deaths
timeFrame: at inclusion
measure: Incidence of new thromboembolic disease
timeFrame: at inclusion
measure: Attributable risk of DVT in PTS severity
timeFrame: at inclusion
measure: Doppler Ultrasound and PTS severity
timeFrame: at inclusion
measure: Incidence of hemorrhage events
timeFrame: at inclusion
Other outcomes:
Locations:
city: Grenoble
country: France
facility: CHU Grenoble Alpes
Study officials:
affiliation: University Hospital, Grenoble
name: Jean-Luc JB Bosson, MD, PhD
role: STUDY_CHAIR
affiliation: Montpellier University Hospital
name: Jean-Philippe JP Galanaud, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Grenoble
name: Gilles GP Pernod, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amiens University Hospital
name: Marie-Antoinette MS Sevestre, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Galanaud JP, Sevestre MA, Genty C, Pernod G, Quere I, Bosson JL. Is it useful to also image the asymptomatic leg in patients with suspected deep vein thrombosis?: comment. J Thromb Haemost. 2015 Nov;13(11):2127-30. doi: 10.1111/jth.13123. Epub 2015 Sep 30. No abstract available.
citation: Galanaud JP, Arnoult AC, Sevestre MA, Genty C, Bonaldi M, Guyard A, Giordana P, Pichot O, Colonna M, Quere I, Bosson JL; OPTIMEV-SFMV Investigators. Impact of anatomical location of lower limb venous thrombus on the risk of subsequent cancer. Thromb Haemost. 2014 Dec;112(6):1129-36. doi: 10.1160/TH14-04-0351. Epub 2014 Aug 7.
citation: Le Moigne E, Genty C, Meunier J, Arnoult AC, Righini M, Bressollette L, Bosson JL, Le Gal G; OPTIMEV Investigators. Validation of the LEFt score, a newly proposed diagnostic tool for deep vein thrombosis in pregnant women. Thromb Res. 2014 Sep;134(3):664-7. doi: 10.1016/j.thromres.2014.07.009. Epub 2014 Jul 17.
citation: Galanaud JP, Sevestre MA, Genty C, Kahn SR, Pernod G, Rolland C, Diard A, Dupas S, Jurus C, Diamand JM, Quere I, Bosson JL; OPTIMEV-SFMV investigators. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost. 2014 Apr;12(4):436-43. doi: 10.1111/jth.12512.
citation: Galanaud JP, Bosson JL, Genty C, Presles E, Cucherat M, Sevestre MA, Quere I, Decousus H, Leizorovicz A. Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies. J Thromb Haemost. 2012 Jun;10(6):1004-11. doi: 10.1111/j.1538-7836.2012.04704.x.
citation: Maufus M, Bosson JL, Genty C, Delluc A, Imbert P, Gagne P, Rolland C, Bressollette L, Le Gal G. [Validation of a deep vein thrombosis prediction rule in primary care]. J Mal Vasc. 2012 Feb;37(1):9-14. doi: 10.1016/j.jmv.2011.10.005. Epub 2011 Dec 12. French.
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citation: Johnson SA, Stevens SM, Woller SC, Lake E, Donadini M, Cheng J, Labarere J, Douketis JD. Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis. JAMA. 2010 Feb 3;303(5):438-45. doi: 10.1001/jama.2010.43.
citation: Galanaud JP, Sevestre MA, Genty C, Laroche JP, Zizka V, Quere I, Bosson JL; OPTIMEV SFMV investigators. Comparison of the clinical history of symptomatic isolated muscular calf vein thrombosis versus deep calf vein thrombosis. J Vasc Surg. 2010 Oct;52(4):932-8, 938.e1-2. doi: 10.1016/j.jvs.2010.05.019. Epub 2010 Jul 13.
citation: Sevestre MA, Quashie C, Genty C, Rolland C, Quere I, Bosson JL; Optimev study investigators. Clinical presentation and mortality in pulmonary embolism: the Optimev study. J Mal Vasc. 2010 Jul;35(4):242-9. doi: 10.1016/j.jmv.2010.05.004. Epub 2010 Jul 2.
citation: Sevestre MA, Labarere J, Casez P, Bressollette L, Haddouche M, Pernod G, Quere I, Bosson JL. Outcomes for inpatients with normal findings on whole-leg ultrasonography: a prospective study. Am J Med. 2010 Feb;123(2):158-65. doi: 10.1016/j.amjmed.2009.05.034.
citation: Casez P, Labarere J, Sevestre MA, Haddouche M, Courtois X, Mercier S, Lewandowski E, Fauconnier J, Francois P, Bosson JL. ICD-10 hospital discharge diagnosis codes were sensitive for identifying pulmonary embolism but not deep vein thrombosis. J Clin Epidemiol. 2010 Jul;63(7):790-7. doi: 10.1016/j.jclinepi.2009.09.002. Epub 2009 Dec 2.
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citation: Sevestre MA, Labarere J, Casez P, Bressollette L, Taiar M, Pernod G, Quere I, Bosson JL. Accuracy of complete compression ultrasound in ruling out suspected deep venous thrombosis in the ambulatory setting. A prospective cohort study. Thromb Haemost. 2009 Jul;102(1):166-72. doi: 10.1160/TH09-01-0048.
citation: Constans J, Salmi LR, Sevestre-Pietri MA, Perusat S, Nguon M, Degeilh M, Labarere J, Gattolliat O, Boulon C, Laroche JP, Le Roux P, Pichot O, Quere I, Conri C, Bosson JL. A clinical prediction score for upper extremity deep venous thrombosis. Thromb Haemost. 2008 Jan;99(1):202-7. doi: 10.1160/TH07-08-0485.
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