Randomized Controlled Trial of Anticoagulation vs. Placebo for a First Symptomatic Isolated Distal Deep-vein Thrombosis (IDDVT) (CACTUS-PTS)

Contention Alone Versus Anticoagulation for Symptomatic Calf Vein Thrombosis Diagnosed by Ultrasonography

CACTUS-PTS is a randomized, placebo-controlled, double-blind study which aims primarily to determine the effectiveness of a 6 week course of therapeutic-dose LMWH (nadroparine) injections vs. placebo in patients with a first symptomatic isolated distal (calf) deep-vein thrombosis (IDDVT), as measured by rate of proximal DVT and symptomatic PE at 6 weeks. Additionally, the study aims to determine if the 6 week course of treatment with therapeutic-dose LMWH (nadroparine) injections, compared to placebo, decreases the frequency of post-thrombotic syndrome (PTS) at 1 year.

Study Overview

• Status: Completed
• Conditions: Distal (Calf) Deep-vein Thrombosis
• Intervention / Treatment: Drug: nadroparine calcium; Drug: Placebo

Detailed Description

The CACTUS-PTS study will compare anticoagulant treatment for 6 weeks versus placebo in acute, symptomatic distal DVT. Patients will be randomized to receive either a six-week period of LMWH at therapeutic dosage or a six-week period of placebo. All patients will be treated with elastic compression stockings and followed-up with a standardized ultrasonography protocol. Strict ultrasonographic diagnostic criteria for distal DVT have been defined. Control compression ultrasonography will be performed between days 3 and 7 and at six weeks after inclusion. The primary outcome will be a composite of the proportion of patients with extension of the thrombus to the proximal veins (detected by the programmed ultrasound examinations or by an ultrasound performed because of recurrent symptoms) or symptomatic PE in both arms of the study during the 6-weeks study period. Patients with such an outcome will be anticoagulated as currently admitted in presence of a proximal DVT. Secondary outcomes will be the individual components of the composite endpoint (distal DVT extension to proximal veins; symptomatic PE), major bleeding, serious adverse events and death reported at 6 weeks and 90 days. To answer the research question of the PTS add-on study, patients will self-assess and be assessed for PTS by a clinician using the Villalta scale, 1 year following their enrolment into the trial. In addition, patients will complete a Quality of Life (QOL) questionnaire. The QOL questionnaire will be comprised of both the VEINES-QOL and SF-36. The primary outcome is the rate of PTS, with secondary outcomes of QOL scores and PTS severity.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital
    • Ottawa, Ontario, Canada
      • Ottawa General Hospital
  • Quebec
    • Montreal, Quebec, Canada
      • Jewish General Hospital
    • Montreal, Quebec, Canada
      • Hôpital Maisonneuve-Rosemont
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Royal University Hospital
• France
  • Languedoc
    • Montpellier, Languedoc, France, 34295
      • Montpellier University Hospital
• Switzerland
  • Geneva, Switzerland
    • University Hospital of Geneva

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All outpatients with an acute, symptomatic, distal DVT will be included in the study, provided they correspond to the following diagnostic and exclusion criteria, and they have signed an informed consent form.

Exclusion Criteria:

• Age less than 18 years
• Previously objectively diagnosed DVT or PE
• Distal DVT involving the tibioperoneal trunk (i.e. calf trifurcation)
• Clinically suspected pulmonary embolism
• Active cancer, receiving cancer treatment or cancer considered cured for <6 months
• Ipsilateral or contralateral proximal DVT
• Indication for long-term anticoagulation (e.g. atrial fibrillation, mechanical heart valve...)
• Pregnancy
• Thrombocytopenia (platelet count < 100 g/l)
• Impaired renal function (serum creatinine > 180 micromol/l or clearance to creatinine less than 30 ml/min)
• Known hypersensitivity to heparin
• Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (gastric ulcer, cerebral malignant disease...)
• Treatment with daily NSAIDs (aspirin ≤160 mg/day permitted)
• Body weight >115 kg or <40 kg
• Treatment with therapeutic doses of anticoagulants for >2 days, corresponding to: 2 injections of LMWH if once daily therapeutic LMWH used; 3 injections of LMWH if twice-daily therapeutic LMWH used; 1 dose of oral vitamin K antagonist (e.g. warfarin)
• Ongoing requirement for prophylactic dose thromboprophylaxis (e.g. acute post-op patient receiving thromboprophylaxis)
• Enrolled in another clinical trial within previous 30 days
• Inability or refusal to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: LMWH; Therapeutic dose of Nadroparin	Drug: nadroparine calcium; Once-daily injection of 171 U/Kg/day of nadroparine calcium for 6 weeks.
Placebo Comparator: Placebo; Injectable placebo	Drug: Placebo; Once-daily injectable placebo (sterilized NaCL 0.9%) for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of rate of extension of distal DVT to proximal deep veins (includes ipsilateral extension or new contralateral proximal DVT) or symptomatic PE at 6 weeks		6 weeks
Rate of post-thrombotic syndrome (PTS)	Rate of post-thrombotic syndrome (PTS) diagnosed using the Villalta scale.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Individual components of the composite endpoint: distal DVT extension to proximal veins at 6 weeks and 90 days; PE at 6 weeks and 90 days		6 weeks and 3 months
Major bleeding at 6 weeks and 90 days		6 weeks and 3 months
Death at 6 weeks and 90 days		6 weeks and 3 months
Serious adverse events at 6 weeks and 90 days		6 weeks and 3 months
Generic and venous disease-specific Quality of Life scores		1 year
PTS severity category	Can either be mild, intermediate, severe	1 year

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Collaborators: Canadian Institutes of Health Research (CIHR); Ministry of Health, France; Swiss National Science Foundation; Lady Davis Institute
• Investigators: Principal Investigator: Isabelle Quéré, MD, Montpellier University Hospital; Principal Investigator: Susan Kahn, MD, Jewish General Hospital; Principal Investigator: Marc Carrier, MD, Ottawa Hospital

Publications and helpful links

General Publications

• Righini M, Robert-Ebadi H, Glauser F, Blondon M, Ouvry P, Diamand JM, Tissot A, Frappe P, Quere I, Kahn SR, Galanaud JP, Le Gal G. Effect of anticoagulant treatment on pain in distal deep vein thrombosis: an ancillary analysis from the cactus trial. J Thromb Haemost. 2019 Mar;17(3):507-510. doi: 10.1111/jth.14387. Epub 2019 Feb 3.
• Righini M, Galanaud JP, Guenneguez H, Brisot D, Diard A, Faisse P, Barrellier MT, Hamel-Desnos C, Jurus C, Pichot O, Martin M, Mazzolai L, Choquenet C, Accassat S, Robert-Ebadi H, Carrier M, Le Gal G, Mermilllod B, Laroche JP, Bounameaux H, Perrier A, Kahn SR, Quere I. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol. 2016 Dec;3(12):e556-e562. doi: 10.1016/S2352-3026(16)30131-4. Epub 2016 Nov 8.
• Guanella R, Righini M. Serial limited versus single complete compression ultrasonography for the diagnosis of lower extremity deep vein thrombosis. Semin Respir Crit Care Med. 2012 Apr;33(2):144-50. doi: 10.1055/s-0032-1311793. Epub 2012 May 30.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2008
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: January 11, 2007
• First Submitted That Met QC Criteria: January 11, 2007
• First Posted (Estimate): January 12, 2007

Study Record Updates

• Last Update Posted (Actual): May 4, 2018
• Last Update Submitted That Met QC Criteria: May 3, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Placebo; Deep vein Thrombosis; Calf vein thrombosis; Low-molecular weight heparin; Elastic contention; Compression Ultrasonography
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Calcium-Regulating Hormones and Agents; Anticoagulants; Calcium; Nadroparin
• Other Study ID Numbers: 3200B0-105991; CACTUS-PTS Trial