Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia

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

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.

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)