Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants

NCT ID: NCT02664155

Last Updated: 2022-10-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 203 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-19
• Study Completion Date: 2022-05-30

Brief Summary

In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented and patients with severe renal insufficiency not at all. So no dose reduction was considered.

Surprisingly, DOAs have been approved for VTE treatment in moderate and severe renally impaired patients. There is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency.

We plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.

Detailed Description

In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. These patients represent more than 20% of the VTE population in clinical practice. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented (<10%) and patients with severe renal insufficiency not at all. So no dose reduction was considered.

The new DOAs have also been developed for stroke prevention in atrial fibrillation (SPAF). Patients including in AF trials are generally older and more prone to present renal impairment (>20%) than in VTE trials. So a reduced dose of DOAs was evaluated and shown to be at least as effective as, and safer than VKA in the subgroup of patients with moderate renal insufficiency (creatinine clearance between 30 to 50 ml/min).

Surprisingly, DOAs have been approved for VTE treatment and SPAF in moderate and severe renally impaired patients (creatinine clearance between 15 to 30 mL/min). Moreover, patients have to receive a reduced dose of DOAs for SPAF but a full dose of DOAs for VTE that could be associated with an increased bleeding risk, as suggested by some subgroup analyses. So, there, there is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency (creatinine clearance between 15 to 50 mL/min).

Apixaban and rivaroxaban appear to be the best candidates since:

• both are approved in France in VTE patients
• they have mixed pathway of elimination (hepatic and renal)
• they have several other pharmacological similarities and they respective clinical trials have shown similar efficacy and safety profiles when compared with SOC for VTE treatment.
• they do not need to be preceded by initial parenteral heparins on the contrary to dabigatran and edoxaban. This allows evaluating the impact of DOAs in renally impaired patients independently from the initial heparins effect
• a reduced dose regimen is available and approved in AF
• the evaluation of 2 DAOs allows evaluating the concept of this new class in renally impaired VTE patients independently from the pharmaceutical companies.

Finally we plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.

Conditions

Renal Insufficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DOA : Direct Oral Anticoagulants

The experimental group receiving DOA regimens: patients will be secondarily randomly assigned within DOAs group between:

• Apixaban (Eliquis® tablet) 10 mg bid for 7 days then 2.5 mg bid for 3 months
• Rivaroxaban (Xarelto® tablet) 15 mg bid for 21 days then 15 mg od for 3 months.

Group Type: EXPERIMENTAL

Apixaban

Intervention Type: DRUG

Direct Oral Anticoagulant

Rivaroxaban

Intervention Type: DRUG

Direct Oral Anticoagulant

SOC : Standard Of Care

The control group receiving the standard of care (SOC), i.e. heparins/VKA regimen. Patients will receive the current recommended therapy: subcutaneous or intravenous UFH/VKA in case of severe renal insufficiency and subcutaneous LMWH/VKA in case of moderate renal insufficiency for at least 5 days. VKA will begin concomitantly and continue for 3 months.

Group Type: ACTIVE_COMPARATOR

Heparin

Intervention Type: DRUG

Standard Of Care

VKA

Intervention Type: DRUG

Standard Of Care

Interventions

Apixaban

Direct Oral Anticoagulant

Intervention Type: DRUG

Rivaroxaban

Direct Oral Anticoagulant

Intervention Type: DRUG

Heparin

Standard Of Care

Intervention Type: DRUG

VKA

Standard Of Care

Intervention Type: DRUG

Other Intervention Names

Eliquis®; Xarelto®; vitamin K antagonists

Eligibility Criteria

Inclusion Criteria

• Patients with a moderate renal insufficiency defined by a creatinine clearance between 30 to 50 ml/min (Cockcroft and Gault formulae) or a severe renal insufficiency (between 15 to 29 ml/min)
• Patients with acute objectively confirmed symptomatic proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (with or without deep-vein thrombosis), planned to be treated for at least 3 months
• Patients >18 years
• Life expectancy more than 3 months
• Social security affiliation
• Signed informed consent

Exclusion Criteria

• Indication for anticoagulants other than VTE
• Active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; a systolic blood pressure of more than 180 mm Hg or a diastolic blood pressure of more than 110 mm Hg
• Anticoagulation for more than 72 hours prior to randomization
• Chronic liver disease or chronic hepatitis
• Patient at high risk of bleeding
• Creatinine clearance <15 ml/min or end stage renal disease or indication for extra-renal dialysis
• Need for concomitant anti-platelet therapy other than aspirin 75-325 mg per day. However concomitant treatment with aspirin is discouraged in this population at bleeding risk.
• Concomitant use of a strong inhibitor of cytochrome P-450 3A4 (CYP3A4) (e.g., a protease inhibitor for human immunodeficiency virus infection or azole-antimycotics agents ketoconazole, itraconazole, voriconazole, posaconazole) or a CYP3A4 inducer (e.g., rifampin, carbamazepine, or phenytoin),
• Active pregnancy or expected pregnancy or no effective contraception
• Any contraindication listed in the local labeling of UFH, LMWH or VKA or oral anticoagulant.
• Cancer-associated VTE requiring long-term treatment with LMWH
• Life expectancy of less than 3 months.

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

Sponsors

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MISMETTI Patrick, MD

Role: PRINCIPAL_INVESTIGATOR

CHU SAINT-ETIENNE

Locations

CH ARRAS

Arras, Boulevard Georges Besnier, France

Chu Tours

Tours, Hôpital Trousseau, France

CH d'Agen-Nérac

Agen, , France

Chu Amiens

Amiens, , France

Chu Angers

Angers, , France

CH Besançon

Besançon, , France

CHU de Bordeaux

Bordeaux, , France

CHU La Cavale Blanche Brest

Brest, , France

HIA de Brest

Brest, , France

CHU Castelnau-le-Lez

Castelnau-le-Lez, , France

CH Louis Pasteur - Chartres

Chartres, , France

Chu Clermont-Ferrand

Clermont-Ferrand, , France

CHU Dijon

Dijon, , France

Hôpital La Tronche Grenoble

Grenoble, , France

Hôpital Charles Foix - APHP Ivry sur Seine

Ivry-sur-Seine, , France

Chu Limoges

Limoges, , France

CHU Lyon

Lyon, , France

HCL - Hôpital Edouard Herriot

Lyon, , France

Chu Montpellier

Montpellier, , France

CHU de Nantes - Hôpital Bellier

Nantes, , France

CHU de Nantes - Hôpital Hôtel Dieu

Nantes, , France

CHU Nice

Nice, , France

HEGP - APHP Paris

Paris, , France

Hôpital Louis Mourier- APHP Paris

Paris, , France

CHU de Rouen

Rouen, , France

Chu Saint Etienne

Saint-Etienne, , France

Chu Strasbourg

Strasbourg, , France

CH Toulon

Toulon, , France

HIA de Toulon

Toulon, , France

CHU Toulouse

Toulouse, , France

CH de Valenciennes

Valenciennes, , France

Countries

France

References

Wetmore JB, Herzog CA, Yan H, Reyes JL, Weinhandl ED, Roetker NS. Apixaban versus Warfarin for Treatment of Venous Thromboembolism in Patients Receiving Long-Term Dialysis. Clin J Am Soc Nephrol. 2022 May;17(5):693-702. doi: 10.2215/CJN.14021021. Epub 2022 Apr 25.

Reference Type: DERIVED

PMID: 35470214 (View on PubMed)

Other Identifiers

2016-000858-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1508189

Identifier Type: -

Identifier Source: org_study_id