REVIEW ARTICLE

Rivaroxaban, a New Molecule with Potential to Balance

Bleeding Risk and Ischemic Events in Patients with Chronic
Coronary Syndrome
Lekha Adik-Pathak1*, Salil Shirodkar2, Amit Gupta3
Received: 17 May 2022; Accepted: 25 May 2022

A b s t r ac t at fixed doses; owing to its predictable

pharmacokinetics and pharmacodynamics
Globally, the prevalence of chronic coronary syndrome (CCS) increases with age. In India, there is
a rapidly growing burden of coronary artery disease (CAD), which has become the leading cause properties.9 When the tablet is orally taken, it
of morbidity and mortality. Despite recommended medical therapy, patients with CCS are still at is quickly absorbed, and the maximum plasma
risk of ischemic events. Currently, dual antiplatelet therapy (DAPT) is recommended in the form of concentration is achieved in 2–4 hours.10
aspirin and a P2Y12 inhibitor or low dose rivaroxaban in patients with stable CAD and/or peripheral An increased bioavailability was observed
artery disease (PAD). A low dose of rivaroxaban in combination with aspirin is a promising approach; in case of 10 mg tablets regardless of food
however, for patients who might benefit the most, it still remains a challenge. Clinical trial data consumption; whereas, for 15 and 20 mg
on this new drug was certainly very encouraging, with evidence from the COMPASS trial and tablets, it is higher if consumed with food.11
prespecified subgroups of COMPASS trials suggesting that the addition of rivaroxaban to aspirin Plasma concentration of rivaroxaban
was associated with a significantly lower risk of ischemic events, mortality, and tolerable bleeding was eliminated with a terminal half-life
profile in patients with CCS and high-risk factors. This combination is cost-effective and generally
of 5–9 hours and 11–13 hours in a healthy
well tolerated in patients with CAD and/or PAD, as well as patients with CCS and multimorbidity
or high-risk populations. population of young and older individuals,
resp e c tively. T he pharmaco dy namic
Journal of the Association of Physicians of India (2022): 10.5005/japi-11001-0073 effects of rivaroxaban correlate well with its
plasma concentration. Rivaroxaban is not
associated with the inhibition of cytochrome
B ac kg r o u n d and R at i o n a l e atherosclerotic disease to prevent future CV
P450 enzymes or known drug transporter
events.5 The dual pathway concept is a novel
T he ESC 2019 guidelines have introduced a
new term, CCS, for “stable” angina. CCSs
include patients with suspected CAD and
approach that combines both antiplatelet and
direct oral anticoagulants (DOACs) therapy.
systems. As rivaroxaban is eliminated via
multiple pathways, there are no clinically
DOACs act by inhibiting factor Xa, which relevant drug-drug interactions. Rivaroxaban
‘‘stable’’ anginal symptoms and/or dyspnea, is excreted from the body either through
generates thrombin for platelet activation.
patients with new-onset of heart failure (HF) metabolic degradation or through the renal
Currently, DAPT in the form of aspirin and
or left ventricular dysfunction and suspected pathway. During renal elimination, 36% of the
a P2Y12 inhibitor or low dose rivaroxaban is
CAD, asymptomatic and symptomatic dose is excreted in the form of an unchanged
recommended in patients with stable CAD
patients with stabilized symptoms  <1 year active drug through active renal secretion
and/or PAD, based on evidence-based trials.6,7
after an acute coronary syndrome (ACS), (30%) and glomerular filtration (6%).12
Rivaroxaban, a novel DOAC with the adual-
or patients with recent revascularization, Rivaroxaban showed dose-dependent
pathway mechanism of action, is accepted
asymptomatic, and symptomatic patients  >1 pharmacodynamic properties in healthy
as a promising therapy for the prevention
year after initial diagnosis or revascularization, subje c t s . A similar dos e - dep endent
and treatment of venous thromboembolism
patients with angina and suspec ted relationship was seen among different
(VTE), stroke, and systemic embolism in
vasospastic or microvascular disease, and patient populations, including patients with
patients with atrial fibrillation (AF).8 A low
asymptomatic subjects in whom CAD is AF (stroke prevention), patients with ACS,
dose of rivaroxaban in combination with
detected at screening. All these patients those undergoing deep vein thrombosis
aspirin is a promising approach in terms of
have different risks for future cardiovascular treatment, and those who undergone knee or
reducing the composite of death from CV
(CV) events.1 total hip surgery (VTE prevention).13–15
causes, myocardial infarction (MI), or stroke;
Globally, the prevalence of CCS increases
however, for patients who might benefit the
with age, both in men and women. 2 The
most, it still remains a challenge. The aim of
worldwide prevalence of CAD and PAD was
this review is to discuss the potential role of
reported in the range of 5–8% and 10–20%,
low-dose rivaroxaban in terms of reducing
respectively. 3 In India, there is a rapidly
CV events in patients with CCS based on the 1
Director & Head; 2Honrary Cardiologist,
growing burden of CAD, and it has become
evidence from various clinical trials. Department of Cardiology, Nanavati Max Super
the leading cause of mortality and morbidity Speciality Hospital, Mumbai; 3Physician, Thane,
in the last three decades.4 Maharashtra, India; *Corresponding Author
Rivaroxaban in a Nutshell
Despite recommended medical therapy, How to cite this article: Adik-Pathak L,
including statins, beta-blockers, and calcium Pharmacokinetics and Shirodkar S, Gupta A. Rivaroxaban, a New
channel blockers, patients with CCS are still Pharmacodynamics Profile Molecule with Potential to Balance Bleeding
at risk of significant, and often clinically Rivaroxaban has a low risk of drug-drug Risk and Ischemic Events in Patients with
meaningful, ischemic events.1 Antiplatelet Chronic Coronary Syndrome. J Assoc Physicians
interaction, and it does not require regular
India 2022;70(8):84–88
therapy is suggested in patients with stable monitoring for coagulation if given

© The Author(s). 2022 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/
by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.
org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
 Rivaroxaban in CCS

Efficacy and Safety Profile (Evidence From or 5 mg twice daily dose of rivaroxaban or death, stroke, or MI, acute limb ischemia, and
Clinical Trials) placebo. In this trial, rivaroxaban was found major amputation for vascular causes.
In clinical practice, it is challenging to developto be associated with a reduced risk of the There is limited data on the cost-
strategies that will lower the risk of ischemic composite endpoint of death from CV causes, effectiveness of rivaroxaban plus aspirin
events without increasing bleeding events in MI, or stroke. Rivaroxaban increased the risk of antiplatelet therapy. An economic analysis
patients with CCS. Recently more attention major bleeding and intracranial hemorrhage conducted in Netherland and Italy showed
has focused on the use of rivaroxaban in such but not the risk of fatal bleeding. b e n e f i cia l e f f e c t s o f r i v arox ab an in
populations to improve clinical outcomes. A combination of aspirin with a P2Y12 combination with ASA in patients with
The COMPASS is a large trial that included inhibitor is the standard DAPT for ACS. When stable CAD or PAD compared with ASA
more than 27,000 patients with stable CAD rivaroxaban is added to this DAPT, it reduces monotherapy.8,21
or PAD. Participants were randomly assigned both mortality and ischemic events but Compared with aspirin alone, rivaroxaban
to receive rivaroxaban (2.5 mg twice daily) increases bleeding risk. However, observations plus aspirin is cost-effective in preventing
plus acetylsalicylic acid (ASA) (once daily), of the GEMINI-ACS-1 trial indicate that a recurrent CV events in all patients with CAD
rivaroxaban (5 mg twice daily) alone, or low-dose rivaroxaban in combination with or PAD, from the Italian perspective. 8 The
ASA (once daily) alone. Patients treated either ticagrelor or clopidogrel was established cost-effectiveness of low-dose rivaroxaban
with rivaroxaban in combination with ASA as a safe treatment approach for ACS without in combination with aspirin was assessed in
experienced significant benefits compared increasing major bleeding events.18 the entire COMPASS population and in all five
with ASA alone. After a mean follow-up Moreover, mortality benefits were observed subpopulations, including CAD, PAD, CAD and
of 23 months, low-dose rivaroxaban in with rivaroxaban and aspirin combination in PAD, CAD with HF, and CAD with CKD, based
combination with ASA was significantly patients with CCS.19 There is an increased risk on the specific health event risk and relative
associated with lower rates of a composite of of CV morbidity and mortality in patients with treatment impact.
CV death, stroke, or MI than ASA alone [hazard PAD. However, a significant reduction in overall
ratio (HR): 0.76; 95% confidence interval and cause-specific CV mortality was observed Current Approval Status: Global and
(CI): 0.66–0.86; p < 0.001). Even though the with the rivaroxaban plus aspirin combination Indian
bleeding risk was increased in the combination therapy compared with aspirin alone in patients Rivaroxaban can be prescribed according to
arm (HR: 1.70; 95% CI: 1.40–2.05; p < 0.001) with chronic CAD or PAD. Although absolute country-specific drug approval. Rivaroxaban
mortality rates were improved in high-risk
without a significant increase in fatal or critical was approved in the USA and Europe for
organ bleeding, combination therapy resulted patients, death due to HF remains unchanged. various indications (Table 1). Though Food and
in lower mortality and ischemic events A meta-analysis of the COMPASS and Drug Administration approved rivaroxaban
compared to ASA monotherapy.6 VOYAGER trials reported the beneficial use for patients with atherosclerosis, approval in
A VOYAGER trial was conducted in patients of low-dose rivaroxaban plus aspirin in terms India is expected in the near future.
with PAD who underwent lower-extremity of decreasing the number of events such Rivaroxaban 2.5 mg orally twice daily
revascularization.16 A significant reduction in as acute limb ischemia and major vascular is recommended in chronic CAD or PAD in
terms of a composite of acute limb ischemia, amputation in patients with PAD compared combination with aspirin (75–100 mg) once
major amputation for vascular causes, MI, to aspirin alone.20 In spite of the significant daily with or without food for prevention of risk
ischemic stroke, or death from CV causes reductions seen in efficacy endpoints, the of major CV events (CV death, MI, and stroke).22
was observed with a combination therapy relative increase in major bleeding events
of rivaroxaban at a dose of 2.5 mg twice raises concern about the tolerability of the Use in Different Patient Populations
daily plus aspirin compared to aspirin alone above-mentioned combination; however, In recent clinical trials, rivaroxaban has
(HR: 0.85; 95% CI: 0.76–0.96; p = 0.009). fatal or critical organ bleeding was low and been evaluated in CAD or PAD patients with
According to the International Society on nonsignificant. other risk factors. However, it is too early
Thrombosis and Haemostasis major bleeding The uniform results seen in these trials to recommend a rivaroxaban plus aspirin
definition, bleeding was significantly higher indicate the benefits of using this combination regimen in patients with stable CAD and/or
in patients treated with rivaroxaban and therapy across a wide range of patient PAD for secondary CV prevention. A global
aspirin (HR: 1.42; 95% CI, 1.10–1.84; p = 0.007); populations with stable CAD or PAD. This COMPASS trial showed that rivaroxaban plus
however, bleeding was comparable between combination provides significant benefits aspirin combination has greater benefits in
both groups according toThrombolysis in in terms of lower rates of a composite of CV terms of prevention of secondary CV events
Myocardial Infarction (TIMI) major bleeding
definition (HR: 1.43; 95% CI, 0.97–2.10; p = Table 1:  Indications and approval of rivaroxaban
0.070). Therefore, while interpreting, it is
Indication Year of approval Country
important to look for which definition is
followed. Consistent benefits of rivaroxaban DVT/PE prophylaxis in acute medical illness 2019 USA
added to aspirin therapy were reported in PAD 2018 USA and Europe
patients with PAD undergoing lower-extremity Stable CAD 2018 USA and Europe
revascularization.7,17 A total of 15,526 patients To reduce risk of VTE after 6 months of treatment of DVT/PE 2017 USA and Europe
with a recent ACS were included in anti-Xa ACS 2013 Europe
therapy to lower CV events in addition to DVT/PE treatment 2012 USA and Europe
standard therapy in subjects with Acute
Atrial fibrillation 2011 USA and Europe
Coronar y Syndrome –Thrombolysis in
Myocardial Infarction 51 (ATLAS ACS 2–TIMI 51) DVT/PE prophylaxis in hip and knee surgery 2011 USA
2008 Europe
trial and administered with either 2.5 mg

Journal of the Association of Physicians of India, Volume 70 Issue 8 (August 2022) 85

 Rivaroxaban in CCS

in patients with stable CAD and/or PAD along
with comorbidities when compared to aspirin
alone. 23 As reported in the COMPASS trial,
rivaroxaban plus aspirin combination therapy
was significantly associated with decreased
risk of primary composite major adverse CV
event outcome and composite major adverse
limb event outcome in adult patients with
stable CAD and/or PAD irrespective of the
presence or absence of risk factors including
age, gender, geographical region, eGFR status,
and history of CV risk factors.6
Patients with HF having sinus rhythm
were at high risk of stroke in the range of
1–2% year, and none of the guidelines have
recommended anticoagulation or antiplatelet
therapy due to lacking evidence of lower risk of
stroke and considerable risk of gastrointestinal
bleeding, especially in elderly patients. 24 In
the COMPASS trial, rivaroxaban use has shown
clinically meaningful benefits in patients
with HF and sinus rhythm; however, the
COMMANDER-HF trial showed neutral benefits
on ischemic risk but a substantial increase in
mortality rate, which was not influenced by
anticoagulation. Further subgroup analysis
of the COMMANDER-HF trial demonstrated
the possible benefit of rivaroxaban in stroke
prevention among different conditions such
as CAD, HF, and sinus rhythm. 25 According
to a subgroup analysis of COMPASS trials,
the ef fect of low- dose rivaroxaban is
consistent in patients with polypharmacy
and multimorbidity and in patients with
vascular disease, irrespective of comorbidities
and BMI, respectively. 26,27 Patients with
LE-PAD with high-risk limb features (prior
amputation, Fontaine III or IV symptoms,
or prior peripheral artery revascularization)
or high-risk comorbidities (diabetes, kidney
dysfunction, HF, or polyvascular disease)
included in the COMPASS trial suggested that
the rivaroxaban plus aspirin combination is
favorable in terms of absolute risk reduction
for major vascular events compared to
aspirin monotherapy.28 Moreover, a network
meta-analysis suggested that compared
with aspirin monotherapy, rivaroxaban
plus aspirin combination therapy is the
favored choice of long-term antithrombotic
therapy, which showed an effective reduction
in ischemic and bleeding events and all-
cause mortality in patients with CCS and
high-risk factors.29
In patients with chronic vascular disease, net
clinical benefit (NCB) was assessed between low-
dose rivaroxaban plus aspirin and aspirin alone,
suggesting patients treated with combination
therapy had fewer NCB events in terms of
reduction in stroke and CV mortality and risk
of major bleeding was not frequent. On the
other hand, high-risk subgroups and patients
with multiple comorbidities had more NCB
as compared to the overall study population.
Overall data indicate the use of rivaroxaban
plus aspirin remains favorable in terms of

Table 2:  Ongoing clinical trials of rivaroxaban for CCS

Study Phase Intervention Location Patient Estimated Duration Primary endpoints Secondary endpoints
identifier population sample of study
[ref.] size
NCT IV Aspirin 75 mg UK CCS 48 14 days Difference in bleeding Bleeding time predose
049,90791 Aspirin 20 mg time, measured at Fibrin clot lag time by fibrin
Rivaroxaban 2 hours postdose clot turbidimetry
2.5 mg Fibrin clot lysis time by fibrin
clot turbidimetry
NCT IV Clopidogrel UK ACS 150 30 days The change in LT in the Frequency of further
037,75746 75 mg three treatment groups angioplasty
Rivaroxaban assessed using the Frequency of further heart
2.5 mg GTT from admission to attack, stroke or death
Ticagrelor follow-up at 30 days
90 mg
NCT IV Rivaroxaban Pakistan ACS 320 12 weeks Presence or absence Stroke or systemic embolism
049,70576 Warfarin Left ventricular of LV thrombus Major bleeding
thrombus on transthoracic
echocardiographic
NCT – Rivaroxaban Netherland CAD 1000 12 months Major Adverse Occurrence stroke,
047,53372 2.5 mg PAD Cardiovascular Events myocardial infarction,
ASA 100 mg Clinically driven cardiovascular death, coronary
coronary, peripheral or revascularization procedures
carotid revascularization (PCI, CABG), peripheral
Stent thrombosis revascularization procedures,
carotid revascularization
procedures, minor bleeding
complications (according to
ISTH)
NCT – Dabigatran, France Atrial fibrillation 156 12 months Incidence of at least Occurrence of stent
050,68414 Rivaroxaban ACS one event from the thrombosis (at 1, 6, 12 months)
and/or Thrombosis composite clinical Occurrence of stroke (at 1, 6,
Apixaban Hemorrhage benefit endpoints: 12 months)
death, non-fatal Occurrence of myocardial
myocardial infarction, infarction (at 1, 6, 12 months)
ischemic stroke, or Occurrence of death from any
major bleeding defined cause (at 1, 6, 12 months)
by a Bleeding Academic
Research Consortium
(BARC) score ≥2
ACS, acute coronary syndrome; CAD, coronary artery disease; CCS, chronic coronary syndrome; PAD, peripheral arterial disease

86 Journal of the Association of Physicians of India, Volume 70 Issue 8 (August 2022)

 Rivaroxaban in CCS
reducing the absolute risk of severe bleeding from the COMPASS trial and pre-specified
and improving NCB. This evidence suggests that subgroups of the COMPASS trials suggesting
there is a significant impact of rivaroxaban in that the addition of rivaroxaban to aspirin
high-risk patients who usually remain untreated was associated with a significantly lower risk
owing to the high bleeding risk.30 of ischemic events, mortality, and tolerable
bleeding profile in patients with CCS and
Use of Antiplatelet in Combination with high-risk factors. This combination is cost-
Anticoagulation Agents among Diabetes effective and generally well tolerated in
Population with Cardiovascular Disease: patients with CAD and/or PAD as well as
COMPASS Trial patients with CCS and multimorbidity or
Diabetes mellitus is a common risk factor high-risk populations. Therefore, on the
associated in patients with atherosclerotic basis of comorbidities and other risk factors,
disease. 31, 32 D espite advances in the patients should be individually evaluated
treatment of atherosclerotic disease, for polypharmacy approach and cost while
diabetes mellitus is considered as the main considering the addition of rivaroxaban to the
cause of the development of a prothrombotic ongoing therapy.
state and residual CV risk. 33 Antiplatelet
therapy, especially DAPT, has been reported R e f e r e n c e s
as an effective treatment strategy across 1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines
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