Clinical trial NCT02664155: Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants
Official title: Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Renal Insufficiency
Keywords: Renal insufficiency
Direct oral anticoagulants (DOA)
Deep Vein Thrombosis (DVT)
Pulmonary Embolism (PE)
Venous Thromboembolism (VTE)
Heparins
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2016-01-26
Enrollment: 203
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Non inferiority of reduced doses of DOAs
timeFrame: Month 3
Secondary outcomes:
measure: Bleeding events
timeFrame: Month 3
measure: Venous Thromboembolism (VTE) events
timeFrame: Month 3
Other outcomes:
Locations:
city: Arras
country: France
facility: CH ARRAS
state: Boulevard Georges Besnier
city: Tours
country: France
facility: Chu Tours
state: Hôpital Trousseau
city: Agen
country: France
facility: CH d'Agen-Nérac
city: Amiens 1
country: France
facility: Chu Amiens
city: Angers 9
country: France
facility: Chu Angers
city: Besancon
country: France
facility: CH Besançon
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Brest
country: France
facility: CHU La Cavale Blanche Brest
city: Brest
country: France
facility: HIA de Brest
city: Castelnau Le Lez
country: France
facility: CHU Castelnau-le-Lez
city: Chartres
country: France
facility: CH Louis Pasteur - Chartres
city: Clermont-Ferrand
country: France
facility: Chu Clermont-Ferrand
city: Dijon
country: France
facility: CHU Dijon
city: Grenoble 9
country: France
facility: Hôpital La Tronche Grenoble
city: Ivry sur Seine
country: France
facility: Hôpital Charles Foix - APHP Ivry sur Seine
city: Limoges
country: France
facility: Chu Limoges
city: Lyon
country: France
facility: CHU Lyon
city: Lyon
country: France
facility: HCL - Hôpital Edouard Herriot
city: Montpellier 5
country: France
facility: Chu Montpellier
city: Nantes
country: France
facility: CHU de Nantes - Hôpital Bellier
city: Nantes
country: France
facility: CHU de Nantes - Hôpital Hôtel Dieu
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: HEGP - APHP Paris
city: Paris
country: France
facility: Hôpital Louis Mourier- APHP Paris
city: Rouen
country: France
facility: CHU de Rouen
city: Saint Etienne
country: France
facility: Chu Saint Etienne
city: Strasbourg
country: France
facility: Chu Strasbourg
city: Toulon
country: France
facility: CH Toulon
city: Toulon
country: France
facility: HIA de Toulon
city: Toulouse 9
country: France
facility: CHU Toulouse
city: Valenciennes
country: France
facility: CH de Valenciennes
Study officials:
affiliation: CHU SAINT-ETIENNE
name: MISMETTI Patrick, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.