Long Term Assessment of Post Thrombotic Syndrome : OPTIMEV Study ( SPOT )

Cardiovascular Diseases Clinical Trial

— SPOT  

Official title:

Long Term Natural History of PTS and Other Adverse Outcomes After Venous Thromboembolism in the Optimev Study (SPOT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03054727
• Other study ID #: OPTIMEV SPOT
• Status: Completed
• Start date: July 11, 2017
• Est. completion date: December 31, 2022

Study information

• Verified date: January 2023
• Source: Association des Médecins Vasculaires Hospitaliers
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2475
• Est. completion date: December 31, 2022
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Post Thrombotic Syndrome
• Postphlebitic Syndrome
• Postthrombotic Syndrome
• Syndrome
• Thromboembolism
• Venous Thromboembolism

Intervention

Other:
• Villalta phone score > or = to 5
Follow up call. At the end of the follow-up, the patients who received an Utne and Sandset Villalta phone score > or = 5 will have a visit with clinical and CUS assessments of PTS/ venous insufficiency. All patients will have self administered-questionnaires. For Grenoble Center, the 200 first patients with clinical follow-up will have an Echo-Doppler examination.
• Villalta phone score < 5
Follow up call. At the end of the follow-up, the patients who received an Utne and Sandset Villalta phone score < 5, will don't have a clinical follow up. All patients will have self administered-questionnaires.

Locations

Country	Name	City	State
France	CHU Grenoble Alpes	Grenoble

Sponsors (6)

Lead Sponsor	Collaborator
Association des Médecins Vasculaires Hospitaliers	Daiichi Sankyo, Inc., LEO Pharma, Ministry of Health, France, Sanofi, University Hospital, Grenoble

Country where clinical trial is conducted

France, 

References & Publications (17)

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. — View 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. — View 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. — View 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. — View Citation

Galanaud JP, Genty C, Sevestre MA, Brisot D, Lausecker M, Gillet JL, Rolland C, Righini M, Leftheriotis G, Bosson JL, Quere I; OPTIMEV SFMV investigators. Predictive factors for concurrent deep-vein thrombosis and symptomatic venous thromboembolic recurrence in case of superficial venous thrombosis. The OPTIMEV study. Thromb Haemost. 2011 Jan;105(1):31-9. doi: 10.1160/TH10-06-0406. Epub 2010 Sep 30. — View 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. — View 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. — View 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. — View Citation

Galanaud JP, Sevestre-Pietri MA, Bosson JL, Laroche JP, Righini M, Brisot D, Boge G, van Kien AK, Gattolliat O, Bettarel-Binon C, Gris JC, Genty C, Quere I; OPTIMEV-SFMV Investigators. Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost. 2009 Sep;102(3):493-500. doi: 10.1160/TH09-01-0053. — View 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. — View 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. — View 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. — View Citation

Sevestre MA, Labarere J, Brin S, Carpentier P, Constans J, Degeilh M, Deslandes B, Elgrishi I, Lanoye P, Laroche JP, Le Roux P, Pichot O, Quere I, Bosson JL; OPTIMEV study. [Optimizing history taking for evaluating the risk of venous thromboembolism: the OPTIMEV study]. J Mal Vasc. 2005 Sep;30(4 Pt 1):217-27. doi: 10.1016/s0398-0499(05)88206-x. French. — View 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. — View 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. — View 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. — View Citation

Utne KK, Ghanima W, Foyn S, Kahn S, Sandset PM, Wik HS. Development and validation of a tool for patient reporting of symptoms and signs of the post-thrombotic syndrome. Thromb Haemost. 2016 Jan;115(2):361-367. doi: 10.1160/th15-04-0318. Epub 2015 Sep 17. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	disabling PTS	Clinical Villalta score > or = 10 (moderate or severe PTS) and/or venous claudication (Villalta score assessed during the clinical Follow-Up visit by a vascular medicine physician (signs) and by the patient (symptoms)	12 years
Secondary	Risk factors of disabling PTS	Risk factors could be evaluated by the data base and the 3 years follow-up of the OPTIMEV cohort and with the follow-up call on medical history of the patient.	at inclusion
Secondary	PTS severity	PTS severity will be assessed with the Villalta scale : 0-4 : no PTS ; 5-9 : mild PTS 10-14 : moderate PTS; > or = to 15 or presence of ulcer: severe PTS	at inclusion
Secondary	Incidence of venous insufficiency	incidence of venous insufficiency will be evaluated with the CEAP classification and the analyse of collected signs and symptoms by the Utne and Sandset Villalta phone score.	at inclusion
Secondary	Global Quality of life	EUROQUOL questionnaire (generic questionnaire)	at inclusion
Secondary	Specific Quality of life	chronic venous disease quality-of-life (CIVIQ) questionnaire	at inclusion
Secondary	Incidence of cancers	number of cancers in the population. Information on cancer occurence will be collected during the phone follow-up	at inclusion
Secondary	Incidence of cardio-vascular events (stroke, myocardial infarction, peripheral arterial disease)	Description with the same definition of the 3-year-follow-up of OPTIMEV. The events will be adjudicated by the study expert committee composed of at the last two doctors, on the basis of medical reports	at inclusion
Secondary	Incidence of deaths	number of deaths in the population. Deaths data will be collected during the phone follow-up visit	at inclusion
Secondary	Incidence of new thromboembolic disease	The event will be adjudicated by the study expert committee composed of at the last two doctors, on the basis of medical reports	at inclusion
Secondary	Attributable risk of DVT in PTS severity	Assessed via the Villalta score by comparing exposed patients and non-exposed patients.	at inclusion
Secondary	Doppler Ultrasound and PTS severity	correlation between Doppler Ultrasound results (deep and/or superficial reflux , lack of recanalization or partial recanalization, parietal sequelae) and different levels of severity of PTS (mild , moderate and severe +/- venous claudication)	at inclusion
Secondary	Incidence of hemorrhage events	The event will be adjudicated by the study expert committee composed of at the last two doctors, on the basis of medical reports	at inclusion