Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants

Renal Insufficiency Clinical Trial

— VERDICT  

Official title:

Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02664155
• Other study ID #: 1508189
• Secondary ID: 2016-000858-35
• Status: Terminated
• Phase: Phase 3
• Start date: October 19, 2016
• Est. completion date: May 30, 2022

Study information

• Verified date: October 2022
• Source: Centre Hospitalier Universitaire de Saint Etienne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 203
• Est. completion date: May 30, 2022
• Est. primary completion date: November 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Renal Insufficiency
• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• Apixaban
Direct Oral Anticoagulant
• Rivaroxaban
Direct Oral Anticoagulant
• Heparin
Standard Of Care
• VKA
Standard Of Care

Locations

Country	Name	City	State
France	CH d'Agen-Nérac	Agen
France	Chu Amiens	Amiens 1
France	Chu Angers	Angers 9
France	CH ARRAS	Arras	Boulevard Georges Besnier
France	CH Besançon	Besancon
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 9
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 5
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 9
France	Chu Tours	Tours	Hôpital Trousseau
France	CH de Valenciennes	Valenciennes

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Saint Etienne	Ministry of Health, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Non inferiority of reduced doses of DOAs	To demonstrate that reduced doses of DOAs (rivaroxaban or apixaban) are non-inferior to standard of care (heparins/VKA) on the net clinical benefit (recurrent VTE and major bleeding) in renally impaired patients suffering from an acute VTE.	Month 3
Secondary	Bleeding events	To demonstrate the non--inferiority of reduced dose of DOAs on the risk of major bleedings.	Month 3
Secondary	Venous Thromboembolism (VTE) events	To demonstrate the non--inferiority of reduced dose of DOAs on the risk of recurrent VTE.	Month 3