Efficacy and Safety of Rivaroxaban Versus Standard Care in Patients with Excessive Supraventricular Ectopy or Short Atrial Runs and High Embolism Risk
- Trial ID
- 2024-516374-29-00
- Protocol
- APHP200002
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and safety of long-term anticoagulation with **rivaroxaban** compared to standard of care in patients with excessive supraventricular ectopies or short atrial runs (ESVEA) and a CHA2DS2VASC score of 3 or higher. The focus is on the incidence of ischemic stroke and peripheral embolism after a 2-year follow-up, as well as the occurrence of major bleeding events. This is clinically relevant as it aims to determine the potential benefits and risks of rivaroxaban in preventing thromboembolic events in a high-risk population.
Secondary objectives include:
- Efficacy-related objectives: Comparing randomized groups on net clinical benefit, major cardiovascular events, overall survival, and cognitive decline. Additionally, comparing individual components of composite primary and secondary efficacy endpoints.
- Exploratory objectives: Describing and comparing the incidence of documented atrial fibrillation diagnosed from patient symptoms or systematic 24-hour ECG Holter at 1-year and 2-year follow-up. Evaluating the incidence of asymptomatic cerebral damage, including silent cerebral ischemia and microbleeds, through cerebral MRI at 2-year follow-up.
- Safety-related objectives: Assessing the occurrence of life-threatening or fatal bleeding, clinically relevant non-major bleeding, intracranial hemorrhage, and minor bleeding.
Participants
The clinical trial involves a study population comprising both **male** and **female** participants aged 65 years and older. The participants are diagnosed with excessive supraventricular ectopy activity (ESVEA), characterized by at least 1% premature atrial contractions (PAC) per 24 hours or any atrial runs of 20 PACs or more, but shorter than 30 seconds, as determined by 24-hour Holter ECG monitoring. Additionally, participants must have a CHA2DS2VASC score of 3 or higher, indicating a high risk of embolism. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Participants are required to be able to attend consultations and undergo cerebral MRI at baseline and after 24 months at the participating center. They must also be affiliated with a social security regime and capable of understanding and complying with the study protocol. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of long-term anticoagulation with **rivaroxaban** compared to standard care in patients with excessive supraventricular ectopies or short atrial runs (ESVEA) and a CHA2DS2VASC score of 3 or higher. This study is a randomized, double-blind, controlled trial with an estimated duration of four years, from April 2023 to September 2027. Participants will be randomly assigned to receive either rivaroxaban or standard care, with the primary objective being the assessment of the incidence of ischemic stroke and peripheral embolism over a two-year follow-up period, as well as the occurrence of major bleeding events.
The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥65 years), diagnosis of ESVEA, and high embolism risk. Participants must provide written consent and demonstrate the ability to comply with the study protocol. Follow-up visits will occur at regular intervals, including assessments at 1 and 2 years, where systematic 24-hour ECG Holter monitoring and cerebral MRI will be conducted to evaluate the primary and secondary endpoints. The end-of-study visit will mark the conclusion of the participant's involvement, with a comprehensive evaluation of all collected data.
Participant involvement is expected to last for a maximum of 24 months, with conditions for early termination including the occurrence of life-threatening or fatal bleeding events, inability to comply with the study protocol, or withdrawal of consent. The primary efficacy endpoint is the first ischemic stroke or peripheral embolism detected clinically and on systematic cerebral MRIs. The primary safety outcome is major bleeding at any site in the body, assessed according to the criteria of the International Society of Thrombosis and Hemostasis (ISTH). Secondary endpoints include a composite of ischemic stroke, peripheral embolism, or major bleeding, as well as exploratory endpoints such as the incidence of documented atrial fibrillation and asymptomatic MRI-detected cerebral damage.
Treatment
The clinical trial involves the administration of **Rivaroxaban**, a chemical compound with the active substance name **Rivaroxaban**. This medication is provided in the form of a film-coated tablet and is intended for **oral use**. The maximum daily dose of Rivaroxaban is 15 mg, with a total maximum dose of 10,944 mg over a treatment period of 24 months. The trial aims to evaluate the efficacy and safety of long-term anticoagulation with Rivaroxaban against standard-of-care therapy in patients with excessive atrial ectopy or short atrial runs and a high embolism risk. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the prescribed regimen.
In addition to Rivaroxaban, the trial also includes the use of **Lactose Monohydrate** as an excipient. Lactose Monohydrate is a chemically derived substance that serves as a stabilizing agent in the formulation of the film-coated tablet. The presence of Lactose Monohydrate does not contribute to the pharmacological action of the medication but is essential for maintaining the integrity and delivery of the active ingredient, Rivaroxaban.
The trial also incorporates a comparator treatment, which is the standard-of-care therapy for patients with the specified condition. This comparator serves as a control to evaluate the relative efficacy and safety of Rivaroxaban. The standard-of-care therapy is administered according to established clinical guidelines and is tailored to the individual needs of the participants. Compliance with the comparator treatment is monitored throughout the trial to ensure accurate and reliable results.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary efficacy endpoint is the occurrence of the first **ischemic stroke** or peripheral embolism, which will be detected clinically and through systematic cerebral MRIs, analyzed using a time-to-event approach. Secondary efficacy-related endpoints include a composite of ischemic stroke, peripheral embolism, or major bleeding, as well as a composite of death from cardiovascular causes, stroke, systemic embolism, and myocardial infarction. Additional secondary endpoints involve death from any cause and cognitive decline, assessed by the Mini-Mental State Examination (MMS).
Exploratory endpoints will focus on the incidence of documented atrial fibrillation diagnosed from patient symptoms or systematic 24-hour ECG Holter monitoring at 1- and 2-year follow-ups. The incidence of asymptomatic MRI-detected cerebral damage, including silent cerebral ischemia and microbleeds, will also be evaluated at the 2-year follow-up. Safety-related endpoints will include life-threatening or fatal bleeding events, clinically relevant non-major bleeding, intracranial hemorrhage, and minor bleeding events, with bleeding severity assessed according to the International Society of Thrombosis and Hemostasis (ISTH) classification.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients ≥ 65 years old
- Diagnosis of excessive supraventricular ectopy activity defined as: i) ≥ 1% PAC / 24 h or any atrial runs ≥ 20 PACs (shorter than 30 seconds) on a 24-hour Holter ECG monitoring (the indication for the Holter will be let at the discretion of the doctor according to international guidelines indication) ii) Or any atrial runs ≥ 20 PACs but shorter than 30 seconds on a 15-21 days Holter ECG monitoring
- High risk embolism defined by a CHA2DS2VASC score ≥ 3
- Written consent from patient
- Patients able to attend consultations and Cerebral MRI at baseline and 24 months at the participating centre.
- Ability to understand and comply with the study protocol
- Affiliation of social security regime
Exclusion Criteria
- According to the SmPC, any contraindication to Rivaroxaban (particularly patients with ongoing major bleeding, vascular complication, prior haemorrhagic stroke or over recent stroke) or one of its excipients.
- Inability to perform cerebral MRI
- Life expectancy <24 months
- History of major hemorrhage after taking Rivaroxaban
- Documented atrial fibrillation or any other indication for oral anticoagulation
- Patients with previous documented AF
- Valvular congenital heart disease
- Anticoagulant agents in the month prior to the inclusion visit
- Acute coronary syndrome, coronary revascularization (percutaneous coronary intervention or coronary artery bypass surgery) or in the past 30 days
- Requires long-term antiplatelet therapy other than aspirin (i.e., patient requires any platelet aggregation inhibitor in addition to study treatment, in particular, the combination of two platelet aggregation inhibitors)
- Ongoing need for strong inhibitors of both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir or clarithromycin)
- Ongoing need for strong inducers of both CYP3A4 and P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin)
- Participants considered by the investigator to be unsuitable for the study for any of the following reasons: Patient refuse the treatment with rivaroxaban or anticipated to have poor compliance on study drug treatment Unwilling to attend study follow-up visits
- Cancer or other life threatening conditions
- Severe, disabling stroke within the previous 6 months, or any stroke within the previous 14 days
- Conditions associated with an increased risk of bleeding: a. Major surgery within the previous month b. Planned surgery or intervention within the next 3 months c. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding d. Gastrointestinal hemorrhage within the past year e. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days f. Hemorrhagic disorder or bleeding diathesis g. Need for anticoagulant treatment of disorders other than atrial fibrillation h. Fibrinolytic agents within 48 hours of study entry i. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg) j. Recent malignancy or radiation therapy (within 6 months) and not expected to survive 3 years
- Severe renal impairment (estimated creatinine clearance <30 mL/min or less)
- Active infective endocarditis
- Active liver disease, including but not limited to, associated or not with coagulopathy and a clinically significant risk of bleeding, including cirrhotic patients with a Child Pugh class B or C score.
- Persistent ALT, AST, Alk Phos greater than twice the upper limit of the normal range
- Known active hepatitis C (positive HCV RNA)
- Known active hepatitis B (HBs antigen +, anti HBc IgM +)
- Known active hepatitis A
- Anemia (hemoglobin level less than 110 g/L) or thrombocytopenia (platelet count less than 150 X 109/L)
- Patients who have received an investigational drug in the past 30 days
- Patients considered unreliable by the investigator, or having any condition which, in the opinion of the investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse)
- Patient with cardiac prosthetic devices : Reveal, pace-maker, automatic implantable defibrillator
- Participation in another interventional clinical trial
- Patient on AME (state medical aid)
- Persons under psychiatric care
- Adults subject to a legal protection measure (guardianship, curatorship and safeguard of justice)
- Patients deprived of their liberty by a judicial or administrative decision
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 18 Apr 2023 | 550 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RIVAROXABAN | Test | PHF00082MIG | ORAL USE | 15 | 24 | SCP100377272 |
RIVAROXABAN | Test | — | ORAL USE | 10 | 24 | SUB29263 |
RIVAROXABAN | Test | — | ORAL USE | 15 | 24 | SUB29263 |