PROphylaxis in NOn Major Orthopaedic Surgery

NCT ID: NCT02401594

Last Updated: 2018-12-07

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 3608 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-08
• Study Completion Date: 2018-04-16

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.

Conditions

Non-major Orthopaedic Surgery

Keywords

Non-major orthopaedic surgery; deep vein thrombosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Group 1: Rivaroxaban treatment

Rivaroxaban active substance plus a placebo of enoxaparin

Group Type: EXPERIMENTAL

Rivaroxaban

Intervention Type: DRUG

10 mg once daily of Rivaroxaban active substance (10 mg tablet) plus a placebo syringe of enoxaparin 4000 UI once daily

Grouyp 2: Enoxaparine treatment

Enoxaparin active substance plus a placebo tablet of Rivaroxaban

Group Type: ACTIVE_COMPARATOR

Enoxaparin

Intervention Type: DRUG

A syringe of enoxaparin active substance 4000 UI once daily plus a placebo tablet of Rivaroxaban 10 mg.

Interventions

Rivaroxaban

10 mg once daily of Rivaroxaban active substance (10 mg tablet) plus a placebo syringe of enoxaparin 4000 UI once daily

Intervention Type: DRUG

Enoxaparin

A syringe of enoxaparin active substance 4000 UI once daily plus a placebo tablet of Rivaroxaban 10 mg.

Intervention Type: DRUG

Other Intervention Names

Group 1: Group 2:

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marc SAMAMA, PhD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Nadia ROSENCHER, MD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Patrick MISMETTI, PhD

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire de Saint Etienne

Locations

CHU AMIENS Picardie

Amiens, , France

CHU Angers

Angers, , France

Clinique Générale d'ANNECY

Annecy, , France

CHU BESANCON- Hôpital Jean Minjoz

Besançon, , France

Hopital Ambroise Pare

Boulogne-Billancourt, , France

Médipôle de Savoie

Challes-les-Eaux, , France

Clinique Léonard de Vinci

Chambray-lès-Tours, , France

CHU de Dijon- Bocage

Dijon, , France

Hôpitaux Universitaires de Strasbourg C.C.O.M

Illkirch-Graffenstaden, , France

CHU de Grenoble 6 Hôpital Michallon

La Tronche, , France

Chu Kremlin Bicetre

Le Kremlin-Bicêtre, , France

CHRU Lille -Hôpital Roger Sallengro

Lille, , France

CHU Dupuytren

Limoges, , France

Ch Lyon Sud Pierre Benite

Lyon, , France

Chu Marseille La Timone

Marseille, , France

Ch Les Chanaux

Mâcon, , France

CHU de MONTPELLIER - Lapeyronnie

Montpellier, , France

CHRU NANTES - Hôtel Dieu

Nantes, , France

CHU Carémeau

Nîmes, , France

Clinique ARAGO

Paris, , France

GH Paris Saint-Joseph

Paris, , France

Hopital Cochin

Paris, , France

Hopital Europeen Georges POMPIDOU

Paris, , France

Ch Paris Pitie Salpetriere

Paris, , France

Ch Saint Louis-Lariboisiere

Paris, , France

CHU Bordeaux

Pessac, , France

Polyclynique de Poitiers

Poitiers, , France

CHU de Reims - Hôpital MAsion Blanche

Reims, , France

Hôpital Robert Debré

Reims, , France

CHU de Rennes - Hôpital Pontchaillou

Rennes, , France

CHU de Rouen

Rouen, , France

CHU de SAINT-ETIENNE

Saint-Etienne, , France

Clinique de la Mutualiste

Saint-Etienne, , France

Chp Saint Gregoire

Saint-Grégoire, , France

Polyclinique Du Parc

Saint-Saulve, , France

CHRU de Strasbourg- Hôpital Hautepierre

Strasbourg, , France

Clinique Médipôle

Toulouse, , France

CHU Toulouse - Hôpital Pierre-Paul Riquet

Toulouse, , France

Countries

France

References

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.

Reference Type: DERIVED

PMID: 32223113 (View on PubMed)

Other Identifiers

2015-000981-70

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1408143

Identifier Type: -

Identifier Source: org_study_id