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Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia (RIVAL-PAD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02260622
Recruitment Status : Completed
First Posted : October 9, 2014
Results First Posted : November 22, 2019
Last Update Posted : December 4, 2019
The Ottawa Hospital
Information provided by (Responsible Party):
Ottawa Hospital Research Institute

Brief Summary:

Background: Up to 10% of patients with peripheral arterial disease (PAD) will develop critical limb ischemia (CLI) which is a decrease of blood flow in the arteries of the limb. CLI results in resting pain, ulcers, gangrene, and limb loss. The outcome for patients with CLI is poor. Within 3 months of onset, 12% of patients will require an amputation (removal of part of the limb) and 9% will die of major cardiovascular events (heart attack or stroke). Percutaneous angioplasty (PTA), a procedure used to open the blockages in blood flow, has become the first-line treatment for CLI given its effectiveness, lower cost, and lower risk of complications. However, 40% of patients will have re-narrowing of the arteries (restenosis) following the PTA procedure. This is thought to happen in part due to build up of blood cells called platelets which can also lead to the formation of blood clots. In order to try to avoid this problem, most patients are prescribed a combination of two blood thinning medications, acetylsalicylic acid (ASA or aspirin) and clopidogrel (the brand name is Plavix).

The purpose of this study is to determine if a new blood thinner called rivaroxaban, given in combination with aspirin, would be more effective in preventing re-narrowing of the arteries than the current standard of care (aspirin and clopidogrel).

Rivaroxaban is a pill and does not require blood test monitoring. It has been approved by Health Canada for use in prevention of blood clots in patients undergoing hip or knee surgery and to treat patients with blood clots in their legs and lungs. Low dose aspirin has been approved for reducing the risk of heart attacks and strokes. These medications have not been tested together in patients for prevention of re-narrowing of their arteries

This is a pilot study conducted at one center, The Ottawa Hospital.

It is a Phase 2 open label randomized controlled trial.

Following the PTA procedure, once all inclusion/exclusion criteria are met, the participant will be randomized into one of two groups:

  1. Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily OR
  2. Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily

Visits will occur at 7 days, 30 days, 90 days, 6 months and 12 months. Participants will be followed for 12 months (± 14 days) in total. All adverse events will be collected for the duration of the study.

Condition or disease Intervention/treatment Phase
Critical Limb Ischemia Drug: rivaroxaban plus aspirin Drug: clopidogrel plus aspirin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase 2, Open Label, Pilot Study to Examine the Use of Rivaroxaban Plus Aspirin vs. Clopidogrel Plus Aspirin for the Prevention of Restenosis After Infrainguinal Percutaneous Transluminal Angioplasty for Critical Limb Ischemia
Study Start Date : October 2014
Actual Primary Completion Date : June 2017
Actual Study Completion Date : March 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angioplasty

Arm Intervention/treatment
Active Comparator: clopidogrel plus aspirin
Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily
Drug: clopidogrel plus aspirin
Clopidogrel 75 mg daily for 90 days (with a loading dose of 300 mg clopidogrel following PTA) and 81 mg of ASA daily for 90 days
Other Names:
  • Plavix plus ASA
  • Standard Care

Experimental: rivaroxaban plus aspirin
Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily
Drug: rivaroxaban plus aspirin
Rivaroxaban 2.5 mg twice daily for 90 days (rivaroxaban will be started 6 to 8 hours after the finalization of the procedure) and 81 mg of ASA daily for 90 days
Other Name: treatment arm

Primary Outcome Measures :
  1. Reintervention, Above Ankle Amputation and Restenosis (RAS) [ Time Frame: 1 year ]
    The primary outcome is a combined endpoint consisting of any Reintervention (surgical procedures to revascularize), Above ankle amputation and restenosis(recurrence of blockage in the vein) (RAS) at one year

Secondary Outcome Measures :
  1. Number of Participants With 2 Class Improvement on the Rutherford Scale [ Time Frame: 1 year ]

    Clinical improvement defined as cumulative improvement of 2 classes of the Rutherford scale without the need for repeated TLR in surviving patients.

    There are seven stages to consider. the lower the score the less severe the disease or condition.

    Rutherford Scale:

    Stage 0 - Asymptomatic Stage 1 - Mild claudication Stage 2 - Moderate claudication - The distance that delineates mild, moderate and severe claudication is not specified in the Rutherford classification, but is mentioned in the Fontaine classification as 200 meters.

    Stage 3 - Severe claudication Stage 4 - Rest pain Stage 5 - Ischemic ulceration not exceeding ulcer of the digits of the foot Stage 6 - Severe ischemic ulcers or frank gangrene

  2. Event-free Survival [ Time Frame: 1 year ]
    Event-free survival How long a patient is alive without the need for any further intervention or vascular events.

  3. Overall Survival [ Time Frame: 1 year ]
    Overall survival. How long a patient is alive following the intervention.

  4. The Number of Patients Requiring Target Lesions Revascularization Between Day 1 and the Final Visit (TLR) [ Time Frame: 1 year ]
    Target lesion revascularization (TLR) between day 1 and final visit

  5. TVR [ Time Frame: 1 year ]
    Target vessel revascularization (TVR between day 1 and final visit)

  6. Peri-procedure Death [ Time Frame: 30 days ]
    The number of patients that die within 30 days of the revascularization procedure.

  7. MACE [ Time Frame: 1 year ]
    Cumulative rate of major adverse cardiovascular events between day 1 and final visit

  8. Major Bleeding [ Time Frame: 90 days ]
    Cumulative rate of major bleeding between day 1 and day 90

  9. Minor Bleeding [ Time Frame: 90 days ]
    Cumulative clinically relevant or minor bleeding between day 1 and day 90

  10. Biomarkers [ Time Frame: 90 days ]
    Biological plausibility by measuring coagulation changes and SMC proliferation markers within 7 and 90 days based on the following markers: D-dimer, soluble CD40/44 ligands, and ERK 1/2

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Written informed consent.
  2. Infra-inguinal PAD presenting as CLI defined as a Rutherford category of 3, 4, or 5
  3. More than 50% stenosis in the target infrainguinal vessel
  4. Good candidates for PTA using POBA (plain old balloon angioplasty) with or without stenting defined as TASC a and b lesions.

Exclusion Criteria:

  1. Rutherford scale of 0,1,2 or 6
  2. Acute limb-threatening ischemia (e.g. embolic disease)
  3. Previous infrainguinal bypass or PTA procedures of the affected leg
  4. Hybrid procedures
  5. Creatinine clearance <30 mL/min
  6. Platelet count <100x109/L
  7. INR >1.5; Hbg <100 g/L
  8. History of or condition associated with increased bleeding risk including, but not limited to:

    1. Major surgical procedure or trauma within 30 days before the randomization visit
    2. Clinically significant gastrointestinal bleeding within 6 months before the randomization visit
    3. History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding
    4. Chronic hemorrhagic disorder
    5. Known intracranial neoplasm, arteriovenous malformation, or aneurysm
    6. Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg
  9. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit
  10. Aspirin in combination with thienopyridines within 5 days before randomization
  11. Intravenous antiplatelets within 5 days before randomization
  12. Fibrinolytics within 10 days before randomization
  13. Known HIV infection at time of screening
  14. Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis or ALT >3ULN)
  15. Childbearing potential without proper contraceptive measures, pregnancy or breast feeding
  16. Drug addiction or alcohol abuse within 12 months before the randomization visit
  17. Systemic treatment with strong CYP 3A4 and P-glycoprotein inhibitors : such as ketoconazole, itraconazole, posaconazole, or ritonavir
  18. Known allergy or hypersensitivity to any component of rivaroxaban, ASA or clopidogrel
  19. Need for long term anticoagulation or double antiplatelet agents other than PAD such as atrial fibrillation, heart valve replacement, acute coronary syndrome, stroke or venous thromboembolism
  20. Anticipated need for chronic (> 4 weeks) therapy with non-steroidal anti-inflammatory drugs.
  21. Concomitant treatment with any other anticoagulant, including oral anticoagulants, such as warfarin, dabigatran, apixaban, except under circumstances of switching therapy to or from study treatment.
  22. Inability to adhere to protocol.
  23. Severe concomitant condition or disease (e.g. life expectancy <6 months secondary to cancer, advanced liver disease or dementia)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02260622

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Canada, Ontario
The Ottawa Hospital
Ottawa, Ontario, Canada, K1Y4E9
Sponsors and Collaborators
Ottawa Hospital Research Institute
The Ottawa Hospital
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Principal Investigator: Esteban Gandara, MD Ottawa Hospital Research Institute
Principal Investigator: Prasad Jetty, MD Ottawa Hospital Research Institute
  Study Documents (Full-Text)

Documents provided by Ottawa Hospital Research Institute:

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Responsible Party: Ottawa Hospital Research Institute Identifier: NCT02260622    
Other Study ID Numbers: 20130484-01H
First Posted: October 9, 2014    Key Record Dates
Results First Posted: November 22, 2019
Last Update Posted: December 4, 2019
Last Verified: November 2019
Keywords provided by Ottawa Hospital Research Institute:
Critical Limb Ischemia
Infrainguinal Percutaneous Transluminal Angioplasty
Additional relevant MeSH terms:
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Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Pathologic Processes
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Neurotransmitter Agents
Factor Xa Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors