Clinical trial NCT04218656: DUAL Pathway Inhibition to Improve Endothelial Function in Peripheral Artery Disease
Official title: DUAL Pathway Inhibition (Low-dose Rivaroxaban and Aspirin) as Compared to Aspirin Only to Improve Endothelial Function in Peripheral Artery Disease.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Peripheral Artery Disease
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2020-01-06
Enrollment: 159
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two single clinical cohorts will be studied.
Primary purpose: TREATMENT

Brief summary: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis, causing patients to be at high risk of major adverse cardiovascular and limb events. Therefore, single antiplatelet therapy is recommended when patients are symptomatic or have undergone revascularization. Rivaroxaban (2.5 mg twice a day) in addition to Aspirin (100 mg once a day) has shown to be effective in reducing morbidity and mortality from major cardiovascular and limb events in patients with stable peripheral or carotid artery disease compared to Aspirin alone. Although a higher rate of major bleeding was detected, the incidence of fatal or critical organ bleedings was not increased.

Endothelial dysfunction is one of the first signs of atherosclerosis and is related to major cardiovascular events. The level of vascular endothelial dysfunction can be measured using the carotid artery reactivity (CAR) test. The investigators hypothesized that a combination of low-dose rivaroxaban and antiplatelet therapy would improve endothelial function in PAD patients.

The investigators aim to study the effectiveness of this combination therapy in improving vascular endothelial function in patients with stable or symptomatic PAD.

Therefore the investigators will study two clinical cohorts of lower extremity PAD patients (n=159) with intermittent claudication (group A: Fontaine stages 1-2) or critical limb ischemia with pain at rest and/or foot ulcers (group B: Fontaine stages 3-4) who have an indication for single antiplatelet therapy.

Aspirin 100mg once a day + 2.5 mg rivaroxaban twice a day will be given during 3 months, preceded by a run-in period of Aspirin alone (100 mg once a day) as reference.

The change in proportion of patients with CAR-constriction from baseline (Aspirin alone) to 3 months after adding low dose rivaroxaban will be compared for both study groups (A and B).

Detailed description: Rationale: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis, causing patients to be at high risk of major adverse cardiovascular events and major adverse limb events, including amputation. Therefore, clopidogrel or Aspirin depending on national guidelines, is recommended as single antiplatelet therapy when patients are symptomatic or have undergone revascularization. Anticoagulant therapies have not shown to be superior in PAD patients and have high rates of major bleedings. However, rivaroxaban (2.5 mg twice a day), an oral factor Xa inhibitor, in addition to Aspirin (100 mg once a day) has shown to be effective in reducing morbidity and mortality from coronary artery disease and major cardiovascular and limb events in patients with stable peripheral or carotid artery disease compared to Aspirin alone. Although a higher rate of major bleeding was detected, the incidence of fatal or critical organ bleedings was not increased.

Endothelial dysfunction is one of the first signs of atherosclerosis and is present before clinical symptoms appear. Endothelial dysfunction contributes to the progression of atherosclerosis and is related to major cardiovascular events. The level of vascular endothelial dysfunction can be measured using the carotid artery reactivity (CAR) test. This test measures the CAR in response to sympathic stimulation and can also be used to measure endothelial dysfunction in PAD patients and how a combination of rivaroxaban and Aspirin affects it. The investigators hypothesized that a combination of low-dose rivaroxaban and antiplatelet therapy would improve endothelial function in PAD patients.

Objective: To study the effectiveness of low-dose rivaroxaban with Aspirin in improving endothelial function in patients with stable or symptomatic PAD.

Study design: Two clinical cohort studies will be performed. Study population: Lower extremity PAD patients (n=159) with intermittent claudication (group A: Fontaine stages 1-2) or critical limb ischemia with pain at rest and/or foot ulcers (group B: Fontaine stages 3-4) who have an indication for single antiplatelet therapy are eligible for this study.

Intervention (if applicable): Aspirin 100mg once a day + 2.5 mg rivaroxaban twice a day (combination therapy). The use of Aspirin alone (100 mg once a day) during the run-in period is used as reference.

Main study parameters/endpoints: The primary outcome measure is the CAR after 3 months combination treatment. The change in proportion of patients with CAR-constriction from baseline (Aspirin alone) to 3 months after adding low dose rivaroxaban will be compared for both study groups (A and B). Serum endothelin-1 levels will be quantified as a marker for cardiovascular disease at baseline and 3 months after adding low dose rivaroxaban.

Eligibility criteria: Inclusion Criteria:

* Symptomatic or stable lower extremity PAD patients (Fontaine stages 2-4) with an indication for single antiplatelet therapy according to international (ESC) guidelines
* \>16 years old
* Written informed consent

Exclusion Criteria:

* Patients having or at risk of major bleeding:

  * Gastrointestinal ulceration
  * Current malignant neoplasms
  * Brain or spinal injury
  * Brain, spinal or ophthalmic surgery
  * Intracranial hemorrhage
  * Known or suspected esophageal varices
  * Arteriovenous malformations
  * Major intraspinal or intracerebral vascular abnormalities
  * Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C
  * Use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors
* Patients with prosthetic valves
* Patients with a history of asthma attacks caused by salicylates
* Severe renal impairment (creatinine clearance \<30 ml/min)
* Systemic treatment with strong CYP3A4 and/or P-glycoprotein inhibitors (i.e. azole-antimyotics, HIV protease inhibitors)
* Concomitant treatment with other anticoagulants
* Concomitant treatment with methotrexate at a weekly dosage of \>15 mg
* Pregnant or lactating
* Known hypersensitivity to Aspirin or rivaroxaban

Primary outcomes:
measure: Carotid artery reactivity
timeFrame: 3 months
Secondary outcomes:
measure: Plasma endothelin-1 levels
timeFrame: 3 months
Other outcomes:
Locations:
city: Arnhem
country: Netherlands
facility: Rijnstate hospital
city: Nijmegen
country: Netherlands
facility: Radboudumc
Study officials:
affiliation: Radboud University Medical Center
name: Michiel C Warlé, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rijnstate
name: Michel MPJ Reijnen, Professor
role: PRINCIPAL_INVESTIGATOR
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