Clinical trial NCT02401594: PROphylaxis in NOn Major Orthopaedic Surgery
Official title: A Multicentre, Randomised, Double-blind, Controlled, Phase IIIb Study to Assess the Efficacy and Safety of Rivaroxaban 10mg od Versus Enoxaparin 4000 UI for VTE PROphylaxis in NOn Major Orthopaedic Surgery
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Non-major Orthopaedic Surgery
Keywords: Non-major orthopaedic surgery
deep vein thrombosis
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2015-03-30
Enrollment: 3608
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: PRONOMOS is an international multicentre, interventional, parallel, randomised, double-blind non-inferiority study comparing rivaroxaban 10mg od to an active comparator, enoxaparin 4000 UI od in 4040 valid subjects requiring orthopaedic surgery (except low risk such material removal foot surgery or hallux valgus without patient risk factor \[6\], and major orthopaedic surgeries for femoral neck and trochanteric fractures, THR, TKR)

Pre-randomization treatment with LMWH anticoagulant is allowed for a maximum duration of 24 hours. However, only a single pre-randomization dose of LMWH is allowed. After randomization, patients allocated to the rivaroxaban arm will receive rivaroxaban 10 mg once-daily started 6-10 hours provided haemostasis has been established after surgery or 24h hours after LMWH injection if needed for the intended treatment duration of 2 to 12 weeks based on medical judgment (according to immobilization). Patients allocated to the comparator arm will receive enoxaparin once daily for the same intended treatment duration. All patients will have a 30-day observational period after cessation of treatment.

Detailed description: Major orthopedic surgery (hip, knee replacements and hip fracture) represents only a small part of all orthopaedic surgery procedures. Procedures for trauma patients and orthopaedic lower limb surgery without trauma are much more frequent (tibia osteotomy, arthrodesis, ligament repair....).

The incidence of trauma patients requiring surgery and prolonged immobilisation is rising, mainly because of the increasing popularity of recreational sports. However, the epidemiology and prevention of VTE after such injuries have been poorly studied. The combination of limb surgery with or without trauma in orthopaedic surgery is responsible for an increase in venous thromboembolism (VTE). Usually, surgery of lower limb is considered as moderate or high risk for DVT with different duration related to immobilisation. For instance tibia osteotomy is at very high risk during at least 6 weeks and knee arthroscopy for ligament repair is at moderate risk during 10 days. However LMWH is recommended in both surgeries. Non-major orthopaedic surgery represents a major additional risk factor by itself; therefore such patients undergoing surgery deserve to receive VTE prophylaxis.

Rivaroxaban is a new oral anticoagulant developing a potent anti-Xa activity. In major orthopaedic surgery, it has shown to be more effective and as safe as LMWH (Enoxaparin 4000 IU once daily) in THR and TKR patients (RECORD program). Up to now, pending the limited number of surgical settings in which it has been developed in orthopaedic surgery, it is only approved for the prevention of venous thromboembolism (VTE) in THR and TKR procedures, which represent only 20% of all orthopaedic interventions. Non-major elective lower limb surgery and traumatology population is younger as compared to prosthetic orthopaedic surgery patients. Fewer VTE and cardiovascular events are to be feared. These patients receive quite often injectable thromboprophylaxis for a total duration lying between approximately 6 weeks to 3 months. In the one hand, the risk of major bleeding is low in this younger population. On the other hand, compliance and cost should be in favour of Rivaroxaban, because no injection and no platelets counts are needed.

The results of Xamos descriptive sub-analysis in non-elective (fracture related) orthopaedic surgery are consistent with the overall results of Xamos and are in favour of further investigations in this area. In this small subset of patients (n=790), the incidence of symptomatic thromboembolic events observed was low in patients treated with Xarelto and the overall frequency of treatment emergent major bleedings was low in both groups and serious adverse events occurred less frequently in patients treated with Xarelto. Therefore, collection of clinical data in this population is needed and awaited by many orthopaedic surgeons and anaesthetists in charge of VTE prophylaxis.

The population with femoral neck and trochanteric fracture is a specific one with different characteristics, elderly, frail and with a higher bleeding risk. This population will be excluded.

Eligibility criteria: Inclusion Criteria:

1. Signed and dated informed consent form,
2. Age ≥ 18 years,
3. Hospitalised for non-major orthopaedic surgery and requiring thromboprophylaxis according to the investigator's judgement on VTE risk such Achilles' repair, hip (except femoral neck and trochanteric fracture), knee, tibial plateau, femur (non femoral head), tibial and ankle fractures and tibial osteotomy, tibial transposition, arthrodesis of leg articulation, ligament repair of the knee or the ankle or any elective orthopaedic limb surgery requiring thromboprophylaxis).

Exclusion Criteria:

1. Major orthopaedic surgery Hip and Knee replacement, femoral neck and trochanteric fractures, spine surgery,
2. Low risk surgery without patient VTE risk: foot surgery (Hallux Valgus), material removal,
3. Delay between hospitalisation and randomisation greater than two days,
4. Women of childbearing potential not using a reliable contraceptive method throughout the study period (a list of reliable contraceptive methods is provided in the accompanying SPM),
5. Women pregnant or breast-feeding during the study period,
6. Body weight less than 50 kg (to avoid bleeding over risk) or over 120 kg,
7. Long term treatment with VKA therapy or NOAC,
8. Concomitant treatment with clopidogrel, prasugrel and ticagrelor,
9. Platelet count \< 100 Giga/L,
10. Documented history of acquired or inherited bleeding disorder (e.g., von Willebrand's disease),
11. Severe renal failure with calculated creatinine clearance (Cockcroft Formula) \< 30 mL/min,
12. Severe hepatic insufficiency with prothrombin time \< 60% or liver impairment associated with coagulation disorders,
13. History of thrombocytopenia,
14. Any other current significant medical condition that might interfere with treatment evaluation according to the investigator's judgement,
15. Known hypersensitivity or other severe reaction to any component of the investigational medicinal product(s),
16. Participation in another clinical study involving an investigational medicinal product within 30 days prior to inclusion or concomitantly with this study,
17. Active bleeding or contraindication to anticoagulant therapy
18. Chronic alcoholic intoxication,
19. Anticipated poor compliance of subject with study procedures

Primary outcomes:
measure: Major VTE
timeFrame: From date of randomization until the date of the end of the treatment period (up to 3 months maximum).
Secondary outcomes:
measure: Major bleeding
timeFrame: From date of randomization until the date of the end of the treatment period (up to 3 months maximum).
measure: Clinically relevant non-major bleeding
timeFrame: From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..
measure: Overt thrombocytopenia
timeFrame: From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..
measure: Mortality
timeFrame: From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU AMIENS Picardie
city: Angers
country: France
facility: CHU Angers
city: Annecy
country: France
facility: Clinique Générale d'ANNECY
city: Besancon
country: France
facility: CHU BESANCON- Hôpital Jean Minjoz
city: Boulogne Billancourt
country: France
facility: Hopital Ambroise Pare
city: Challes Les Eaux
country: France
facility: Médipôle de Savoie
city: Chambray Les Tours
country: France
facility: Clinique Léonard de Vinci
city: Dijon
country: France
facility: CHU de Dijon- Bocage
city: Illkirch-Graffenstaden
country: France
facility: Hôpitaux Universitaires de Strasbourg C.C.O.M
city: La Tronche
country: France
facility: CHU de Grenoble 6 Hôpital Michallon
city: Le Kremlin Bicetre
country: France
facility: Chu Kremlin Bicetre
city: Lille
country: France
facility: CHRU Lille -Hôpital Roger Sallengro
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Ch Lyon Sud Pierre Benite
city: Macon
country: France
facility: Ch Les Chanaux
city: Marseille
country: France
facility: Chu Marseille La Timone
city: Montpellier
country: France
facility: CHU de MONTPELLIER - Lapeyronnie
city: Nantes
country: France
facility: CHRU NANTES - Hôtel Dieu
city: Nîmes
country: France
facility: CHU Carémeau
city: Paris
country: France
facility: Clinique ARAGO
city: Paris
country: France
facility: GH Paris Saint-Joseph
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Europeen Georges POMPIDOU
city: Paris
country: France
facility: Ch Paris Pitie Salpetriere
city: Paris
country: France
facility: Ch Saint Louis-Lariboisiere
city: Pessac
country: France
facility: CHU Bordeaux
city: Poitiers
country: France
facility: Polyclynique de Poitiers
city: Reims
country: France
facility: CHU de Reims - Hôpital MAsion Blanche
city: Reims
country: France
facility: Hôpital Robert Debré
city: Rennes
country: France
facility: CHU de Rennes - Hôpital Pontchaillou
city: Rouen
country: France
facility: CHU de Rouen
city: Saint Gregoire
country: France
facility: Chp Saint Gregoire
city: Saint-etienne
country: France
facility: CHU de SAINT-ETIENNE
city: Saint-etienne
country: France
facility: Clinique de la Mutualiste
city: Saint-saulve
country: France
facility: Polyclinique Du Parc
city: Strasbourg
country: France
facility: CHRU de Strasbourg- Hôpital Hautepierre
city: Toulouse
country: France
facility: Clinique Médipôle
city: Toulouse
country: France
facility: CHU Toulouse - Hôpital Pierre-Paul Riquet
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Marc SAMAMA, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Nadia ROSENCHER, MD
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier Universitaire de Saint Etienne
name: Patrick MISMETTI, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Samama CM, Laporte S, Rosencher N, Girard P, Llau J, Mouret P, Fisher W, Martinez-Martin J, Duverger D, Deygas B, Presles E, Cucherat M, Mismetti P; PRONOMOS Investigators. Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery. N Engl J Med. 2020 May 14;382(20):1916-1925. doi: 10.1056/NEJMoa1913808. Epub 2020 Mar 29.