Marc Righini1, Jean-Philippe Galanaud2, Hervé Guenneguez3, Dominique Brisot2, Antoine Diard4, Pascale Faisse5, Marie-Thérèse Barrellier6, Claudine Hamel-Desnos7, Christine Jurus8, Olivier Pichot9, Myriam Martin10, Lucia Mazzolai11, Clarisse Choquenet12, Sandrine Accassat13, Helia Robert-Ebadi14, Marc Carrier15, Grégoire Le Gal15, Bernadette Mermilllod14, Jean-Pierre Laroche2, Henri Bounameaux16, Arnaud Perrier17, Susan R Kahn18, Isabelle Quere2. 1. Division of Angiology and Hemostasis, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland. Electronic address: marc.righini@hcuge.ch. 2. Clinical Investigation Centre and Department of Internal and Vascular Medicine, Montpellier University Hospital, Montpellier, France. 3. Vascular Medicine Unit, Clinique Mégival, St Aubin sur Scié, France. 4. Vascular Medicine Unit, Langoiran, France. 5. Vascular Medicine, Alès, France. 6. Vascular Medicine Unit, Caen University Hospital, Caen, France. 7. Vascular Medicine Unit, Centre Hospitalier Privé Saint-Martin, Caen, France. 8. Vascular Medicine Unit, Clinique du Tonkin, Villeurbanne, France. 9. Vascular Medicine, Grenoble University Hospital, Grenoble, France. 10. Vascular Medicine, Annecy, France. 11. Lausanne University Hospital, Lausanne, Switzerland. 12. Vascular Medicine, Le Robert, France. 13. Clinical Investigation Centre, Saint Etienne University Hospital, Saint Etienne, France. 14. Division of Angiology and Hemostasis, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland. 15. Ottawa Health Research Institute, Ottawa, ON, Canada. 16. Division of Angiology and Hemostasis, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland; Clinical Investigation Centre and Department of Internal and Vascular Medicine, Montpellier University Hospital, Montpellier, France. 17. General Internal Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland. 18. Department of Medicine and Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
Abstract
BACKGROUND: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538. FINDINGS: Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2. INTERPRETATION:Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective. FUNDING: Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research. Copyright Â
RCT Entities:
BACKGROUND: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparinnadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538. FINDINGS: Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2. INTERPRETATION:Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective. FUNDING: Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research. Copyright Â
Authors: Behnood Bikdeli; César Caraballo; Javier Trujillo-Santos; Jean Philippe Galanaud; Pierpaolo di Micco; Vladimir Rosa; Gemma Vidal Cusidó; Sebastian Schellong; Meritxell Mellado; María Del Valle Morales; Olga Gavín-Sebastián; Lucia Mazzolai; Harlan M Krumholz; Manuel Monreal Journal: JAMA Cardiol Date: 2022-08-01 Impact factor: 30.154
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