Background and Rationale

What is the problem to be addressed?

Globally, more than 30.5 million people have CKD stage 4 or 5, and another 3 million people are receiving dialysis for ESKD. Compared to the general population, people with CKD have a markedly higher burden of cardiovascular morbidity and mortality. These effects are most obvious in those people with the most severe form of CKD, dialysis-dependent ESKD, who have a 10- to 100-fold greater risk of death than the age-matched general population.

A cardiac cause accounts for nearly 50% and 60% of all deaths in patients with advanced CKD (stages 4-5) and ESKD on dialysis, respectively. This high mortality risk in dialysis patients is further augmented among those with existing coronary artery disease, peripheral artery disease, diabetes or age >65 years.

Despite the unacceptably high burden of cardiovascular disease and associated mortality, trial-data on the management of cardiovascular disease in people with advanced stages of CKD and dialysis-dependent ESKD are sparse.

Since most cardiovascular trials evaluating antithrombotic therapies (antiplatelet or anticoagulant agents) excluded individuals with advanced CKD, including those requiring dialysis, there are no evidence-based guidelines for antithrombotic therapies in this population. Antithrombotic therapy is the least prescribed cardiovascular intervention in dialysis patients. Thus, antithrombotic therapy is as an area of unmet research need in cardiovascular disease in CKD.

Why low-dose rivaroxaban?

The COMPASS trial showed that compared with aspirin alone, the combination of low dose rivaroxaban 2.5 mg twice daily (not intended to cause full systemic anticoagulation) and aspirin reduced the risk of major adverse cardiovascular events in high risk participants, including those with CKD stage 3.

The CKD subgroup analysis of the COMPASS trial showed that the risk of major bleeding with low dose rivaroxaban in participants with CKD (absolute Risk Increase [ARI] 1.2%) was similar to those without CKD (ARI 1.3%). This increased bleeding risk was counterbalanced by a greater absolute reduction in CV events in the CKD subgroup (absolute risk reduction [ARR] 2%) than the non-CKD subgroup (ARR 1%), suggesting a positive net benefit from rivaroxaban.

These results suggest that a dose of rivaroxaban far below that required for full anticoagulation.

Rivaroxaban in ESKD and CKD

The kidneys eliminate one-third of the parent drug and the remaining two-thirds is metabolised into an inactive form in the liver.

Rivaroxaban requires dose reduction with reduced kidney function; and is currently not recommended in people with CrCl <15 mL/min due to absence of data in this population.

However, the influence of kidney function on pharmacokinetics in people with CrCl <30 mL/min is considered to be only moderate. Pharmacokinetic studies have shown that the terminal elimination half-lives of rivaroxaban in dialysis (8.6 h) and CKD stage 4 (9.5 h) patients were similar to those seen in healthy subjects (8.3 h).