Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia
Condition: Critical Limb Ischemia
MeSH terms: Chronic Limb-Threatening Ischemia; Ischemia
Intervention: rivaroxaban plus aspirin; clopidogrel plus aspirin
Intervention description: 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; 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
Intervention MeSH terms: Aspirin; Rivaroxaban; Clopidogrel
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Restenosis; Critical Limb Ischemia; Infrainguinal Percutaneous Transluminal Angioplasty; Rivaroxaban; Clopidogrel

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.
    

Eligibility criteria:

        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)