Rivaroxaban is a novel oral anticoagulant that acts by inhibiting factor Xa. The document discusses the potential role of low-dose rivaroxaban in reducing cardiovascular events in patients with chronic coronary syndrome based on evidence from clinical trials. The COMPASS and VOYAGER trials found that combining low-dose rivaroxaban with aspirin significantly reduced the risk of cardiovascular death, myocardial infarction, and stroke compared to aspirin alone, with a moderate increase in major bleeding risk. While this combination increases ischemic event prevention, its cost-effectiveness was not fully established and it is not currently approved in India.

1. Rivaroxaban, a New Molecule with Potential
to Balance
Bleeding Risk and Ischemic Events in
Patients with Chronic
Coronary Syndrome
Presented by:- Dr. Abhishek Shinde
Moderator:-Dr. Mayank Goyal

2. INTRODUCTION
The ESC 2019 guidelines have introduced a new term, chronic coronary
syndrome(CCS), for “stable” angina.
CCSs include patients with
• suspected CAD and ‘‘stable’’ anginal symptoms and/or dyspnea,
• patients with new-onset of heart failure (HF) or left ventricular dysfunction and
suspected CAD,
• asymptomatic and symptomatic patients with stabilized symptoms <1 year after
an acute coronary syndrome (ACS),
• patients with recent revascularization,
• asymptomatic, and symptomatic patients >1 year after initial diagnosis or
revascularization,
• patients with angina and suspected vasospastic or microvascular disease,
• asymptomatic subjects in whom CAD is detected at screening.

3. • Globally, the prevalence of CCS increases with age, both in men
and women
• In India, there is a rapidly growing burden of CAD, and it has
become the leading cause of mortality and morbidity in the last
three decade.
• Despite recommended medical therapy, including statins, beta-
blockers, and calcium channel blockers, patients with CCS are
still at risk of significant, and often clinically meaningful, ischemic
events. Antiplatelet therapy is suggested in patients with stable
atherosclerotic disease to prevent future CV events.

4. • The dual pathway concept is a novel approach that combines
both antiplatelet and direct oral anticoagulants (DOACs)
therapy.
• DOACs act by inhibiting factor Xa, which generates thrombin for
platelet activation.
• Currently, DAPT in the form of aspirin and a P2Y12 inhibitor or
low dose rivaroxaban is recommended in patients with stable
CAD and/or PAD, based on evidence-based trials.

5. RIVAROXABAN
• Rivaroxaban, a novel DOAC with the a dual pathway
mechanism of action, is accepted as a promising therapy for the
prevention and treatment of venous thromboembolism (VTE),
stroke, and systemic embolism in patients with atrial fibrillation
(AF).
• A low dose of rivaroxaban in combination with aspirin is a
promising approach in terms of reducing the composite of death
from CV causes, myocardial infarction (MI), or stroke; however,
for patients who might benefit the most, it still remains a
challenge.

6. • The aim of this review is to discuss the potential role of low-
dose rivaroxaban in terms of reducing CV events in patients
with CCS based on the evidence from various clinical trials.
• Rivaroxaban has a low risk of drug-drug interaction, and it does
not require regular monitoring for coagulation if given at fixed
doses; owing to its predictable pharmacokinetics and
pharmacodynamics properties

7. • When the tablet is orally taken, it is quickly absorbed, and the
maximum plasma concentration is achieved in 2–4 hours. An
increased bioavailability was observed in case of 10 mg tablets
regardless of food consumption; for 15 and 20 mg tablets, it is
higher if consumed with food.
• Plasma concentration of rivaroxabanwas eliminated with a
terminal half-life of 5–9 hours and 11–13 hours in a healthy
population of young and older individuals, respectively. The
pharmacodynamic effects of rivaroxaban correlate well with its
plasma concentration.

8. • Rivaroxaban is eliminated via multiple pathways, there are no
clinically relevant drug-drug interactions. Rivaroxaban is
excreted from the body either through metabolic degradation or
through the renal pathway. During renal elimination, 36% of the
dose is excreted in the form of an unchanged active drug
through active renal secretion (30%) and glomerular filtration
(6%).
• Rivaroxaban showed dose-dependent pharmacodynamic
properties in healthy subjects. A similar dose-dependent
relationship was seen among different patient populations,
including patients with AF (stroke prevention), patients with ACS
, those undergoing deep vein thrombosis treatment, and those
who undergone knee or total hip surgery (VTE prevention).

9. • The COMPASS trial was done in which 3 groups were made
• ASA with rivaroxaban 2.5 mg BD,Asa alone,Rivaroxaban 5 mg BD
alone.
• Patients treated with rivaroxaban in combination with ASA
experienced significant benefits compared with ASA alone.
• After a mean follow-up of 23 months, low-dose rivaroxaban in
combination withASA was significantly associated with lower
rates of a composite of CV death, stroke, or MI than ASA alone.

10. • Even though the bleeding risk was increased in the combination
arm without a significant increase in fatal or critical organ
bleeding, combination therapy resulted in lower mortality and
ischemic events compared to ASA monotherapy.
• A VOYAGER trial also showed same results.

11. • Rivaroxaban increased the risk of major bleeding and
intracranial hemorrhage but not the risk of fatal bleeding.
• Moreover, mortality benefits were observed with rivaroxaban
and aspirin combination in patients with CCS. There is an
increased risk of CV morbidity and mortality in patients with
PAD.

12. • However, a significant reduction in overall and cause-specific
CV mortality was observed with the rivaroxaban plus aspirin
combination therapy compared with aspirin alone in patients
with chronic CAD or PAD.
• Although absolute mortality rates were improved in high-risk
patients, death due to HF remains unchanged.

13. • A meta-analysis of the COMPASS and VOYAGER trials
reported the beneficial use of low-dose rivaroxaban plus aspirin
in terms of decreasing the number of events such as acute limb
ischemia and major vascular amputation in patients with PAD
compared to aspirin alone.
• In spite of the significant reductions seen in efficacy endpoints,
the relative increase in major bleeding events raises concern
about the tolerability of the above-mentioned combination;
however, fatal or critical organ bleeding was low and
nonsignificant

14. • The cost-effectiveness of low-dose rivaroxaban in combination
with aspirin was assessed in the entire COMPASS population
including CAD, PAD, CAD and PAD, CAD with HF, and CAD
with CKD, based on the specific health event risk and relative
treatment impact.
• Current approval-Rivaroxaban 2.5 mg orally twice daily is
recommended in chronic CAD or PAD in combination with
aspirin (75–100 mg) once daily with or without food for
prevention of risk of major CV events (CV death, MI, and
stroke).

16. • Diabetes mellitus is a common risk factor associated in patients
with atherosclerotic disease. Despite advances in the treatment
of atherosclerotic disease, diabetes mellitus is considered as
the main cause of the development of a prothrombotic state and
residual CV risk.
• Antiplatelet therapy, especially DAPT, has been reported as an
effective treatment strategy across the world for stable
atherosclerotic patients, and more benefits were observed in
those with diabetes mellitus as a comorbid condition.

17. • The results indicate that the addition of low-dose rivaroxaban to
aspirin should be warranted in patients with atherosclerosis and
diabetes mellitus who are at an acceptable risk of bleeding.

18. LIMITATIONS
• Cost effectiveness of the combination was not identified.
• It is not approved in INDIA at present.

19. TAKE HOME MESSAGE
• The addition of rivaroxaban to aspirin was associated with a
significantly lower risk of ischemic events, mortality, and
tolerable bleeding profile in patients with CCS and high-risk
factors.
• This combination is cost effective and generally well tolerated in
patients with CAD and/or PAD as well as patients with CCS and
multimorbidity or high-risk populations.