• Composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke. [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of a composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke.
• Composite outcome of all-cause death, non-fatal myocardial infarction, stroke, or PAD events. [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of a composite of all-cause death, non-fatal myocardial infarction, stroke, or PAD events.
• Composite outcome of all-cause death, non-fatal myocardial infarction, or stroke. [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of a composite of all-cause death, non-fatal myocardial infarction, or stroke.
• Incidence of Cardiovascular Death [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of Cardiovascular Death
• Incidence of Non-Fatal Myocardial Infarction [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of Non-Fatal Myocardial Infarction
• Incidence of Stroke [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of Stroke
• Incidence of PAD Events [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of PAD events
• Net Clinical Benefit - incidence of MACE & Bleeding [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of a composite outcome of cardiovascular death, non-fatal myocardial infarction, stroke, PAD events, fatal bleeding, or symptomatic bleeding into a critical organ.
• Incidence of Venous Thromboembolism [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of Venous Thromboembolism

• Cost Effectiveness of Intervention - Cost of intervention, & Net benefit in time to MACE event in intervention, when compared to placebo. [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, is cost effective. Where the primary outcome is positive, the cost of providing the intervention will be assessed against the MACE benefit achieved to determine if the treatment meets regulatory guidelines for cost effectiveness. E.g of the Australian Pharmaceutical Benefits Scheme (PBS).
• Incidence of Thrombosis of dialysis vascular access [ Time Frame: 5 years or trial closure ]
  To determine whether the intervention, compared to placebo, changes the risk of thrombosis of dialysis vascular access among participants with an arteriovenous fistula/graft.

The TRACK trial is an investigator-initiated, multicentre, prospective, randomised, double-blind, placebo-controlled trial. TRACK is a global trial and will be conducted in renal units that provide comprehensive CKD care. Approximately 2000 participants will be recruited.

The TRACK trial will assess a strategy of administering low dose rivaroxaban to reduce the risk of major adverse cardiac event (MACE) in people with Chronic Kidney Disease (CKD) stages 4 or 5 or dialysis-dependent End Stage Kidney Disease (ESKD), and elevated cardiovascular (CV) risk, whilst maintaining an acceptable bleeding risk.

Background and Rationale Chronic Kidney Disease (CKD) is a major international health burden. Despite the unacceptably high burden of cardiovascular disease (CVD) and associated mortality, trial-data on the management of CVD in people with advanced stages of CKD and dialysis-dependant End Stage Kidney Disease (ESKD) are sparse. Risk of bleeding in CKD and ESKD is increased when compared to the general population. Anticoagulant agents, such as rivaroxaban, are a core intervention in the prevention of CVD in the general population, although 90% of the trials evaluating these, exclude patients with CKD and ESKD, to mitigate trial risks.

The TRACK trial will evaluate the effect of low dose rivaroxaban in patients with CKD and ESKD. Other trials have demonstrated that rivaroxaban reduces the risk of major cardio-vascular outcomes in high risk patients, and the limited data showed that CKD status did not significantly affect this result.

Hypothesis Compared to placebo, low dose rivaroxaban reduces the risk of major adverse cardiac event (MACE) in people with CKD stages 4 or 5 or dialysis-dependent ESKD, and elevated cardiovascular (CV) risk, with an acceptable bleeding risk.

Objectives The primary objective is to determine whether low dose rivaroxaban, compared to placebo, significantly reduces the risk of a composite outcome of;

• CV death,
• non-fatal myocardial infarction,
• stroke, or
• peripheral artery disease (PAD) events in people with CKD stages 4 or 5 or dialysis-dependent ESKD, and an elevated CV risk.

A full list of secondary objectives are detailed in the protocol, and include identifying risk reduction in the treatment group, and whether this treatment is cost effective.

Methodology The TRACK trial is an investigator-initiated, multicentre, prospective, randomised, double-blind, placebo-controlled trial. The trial will test for the superiority of the trial intervention using a 1:1 allocation to parallel trial groups, on the basis of a pre-specified number of primary outcomes events.

This is a global trial and will be conducted in renal units that provide comprehensive CKD care. Approximately 2,000 participants will be recruited.

• Chronic Kidney Diseases
• End-Stage Kidney Disease
• Cardiovascular Disease

• Drug: Rivaroxaban 2.5 Mg Oral Tablet
  Rivaroxaban is an orally administered selective direct factor Xa inhibitor.
  Other Name: Xarelto
• Other: Placebo
  Rivaroxaban matched placebo

• Experimental: Rivaroxaban
  Rivaroxaban 2.5mg, twice daily.
  Intervention: Drug: Rivaroxaban 2.5 Mg Oral Tablet
• Placebo Comparator: Placebo
  Matched placebo, twice daily.
  Intervention: Other: Placebo

Inclusion Criteria:

• People able to provide informed consent who meet all of the following inclusion criteria:

  1. Age ≥18 years,
  2. ESKD on haemodialysis or peritoneal dialysis, or CKD stage 4 or 5 (eGFR ≤29 mL/min/1.73 m2) not receiving renal replacement therapy,

  3. Elevated cardiovascular risk, defined by at least one of the following:

     1. History of Coronary Artery Disease (CAD) or PAD or non-haemorrhagic non-lacunar stroke, or
     2. Diabetes mellitus, or
     3. Age ≥65 years.

Exclusion Criteria:

• Potential participants must have none of the following exclusion criteria at the time of study enrolment:

  1. Mechanical/prosthetic heart valve,
  2. Indication for, or contraindication to, anticoagulant therapy,
  3. High bleeding risk including any coagulopathy,
  4. Lesion or condition considered to be a significant risk of major bleeding,
  5. Major bleeding episode in the 30 days prior to study enrolment, or any active and clinically significant bleeding,
  6. Current treatment with P2Y12 inhibitors/adenosine diphosphate (ADP) receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) or phosphodiesterase inhibitors (dipyridamole), where the treating physician or patient does not wish to stop these medications,
  7. Concurrent treatment with strong inhibitors of combined CYP3A4 and P-glycoprotein; or strong inducers of CYP3A4,
  8. Any stroke within 1 month prior to enrolment,
  9. Any previous history of a haemorrhagic or lacunar stroke,
  10. Severe heart failure with known ejection fraction <30% or New York Heart Association class III or IV symptoms,
  11. History of hypersensitivity or known contraindication to rivaroxaban,
  12. Uncontrolled hypertension (systolic BP ≥180 mm Hg or diastolic BP ≥110 mm Hg),
  13. Haemoglobin <90 g/L, or platelet count <100 x 109/L,
  14. Significant liver disease or Alanine Aminotransferase (ALT) >3 times upper normal limit,
  15. Kidney transplant recipients with a functioning allograft, or scheduled for living-donor kidney transplant surgery,
  16. Pregnancy or intention to become pregnant or breast-feeding,
  17. Inability to understand or comply with the requirements of the study.

• George Clinical Pty Ltd
• Bayer