Keywords
atherothrombosis - coronary artery disease - stroke - rivaroxaban
The Rivaroxaban Clinical Research Program
The Rivaroxaban Clinical Research Program
Rivaroxaban is a non-vitamin K antagonist (VKA) oral anticoagulant (NOAC), which acts
as a direct factor Xa inhibitor.[1] The first marketing authorization for rivaroxaban in the European Union (EU) was
for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective
knee or hip replacement surgery.[2] Since 2008, there has been an extensive program of randomized controlled trials
(RCTs) to evaluate the safety and efficacy of rivaroxaban in an increasing range of
patient populations.
Rivaroxaban is approved for a total of seven indications, across five clinical areas
of use:[2]
-
The prevention of VTE in adult patients undergoing elective hip replacement surgery.[3]
[4]
-
The prevention of VTE in adult patients undergoing elective knee replacement surgery.[5]
[6]
-
The prevention of stroke and systemic embolism in adult patients with nonvalvular
atrial fibrillation (NVAF).[7]
-
Treatment of deep vein thrombosis (DVT) in adults.[8]
-
Treatment of pulmonary embolism (PE) in adults.[9]
-
Prevention of recurrent DVT and PE in adults.[8]
[9]
-
The prevention of atherothrombotic events in adult patients following acute coronary
syndrome (ACS) with elevated cardiac biomarkers, co-administered with acetylsalicylic
acid (ASA) alone or with ASA plus clopidogrel or ticlopidine.[10]
More than 275,000 patients will have been included in clinical trials or registries
by the close of the clinical development program for rivaroxaban.[11]
The rivaroxaban research program includes RCTs (both company-sponsored and investigator-initiated
research) with real-world evidence disseminated from non-interventional studies, patient
registries and clinical database studies. One notable area of research is in the setting
of vascular protection, where investigations are ongoing into the most optimal antithrombotic
therapies for reducing long-term residual cardiovascular (CV) risk, while minimizing
bleeding risk.[12]
[13] The aim of this article is to present an overview of the current understanding of
the mechanisms of action of rivaroxaban and to provide an overview of RCTs of rivaroxaban
in stroke prevention, venous protection and vascular protection ([Fig. 1]).
Fig. 1 Areas of focus in the rivaroxaban program: (A) stroke prevention, (B) venous protection and (C) vascular protection. *Data not yet available. Criteria for ESUS contrast with the
original definition proposed by the Cryptogenic Stroke/ESUS International Working
Group in three main ways: intracranial arterial imaging is not required, intracranial
arterial occlusion does not exclude participation if diagnosed as embolic, and exclusion
based on echocardiography is limited to intracardiac thrombus[59]. †Pantoprazole arm still ongoing. Abbreviations: ACS, acute coronary syndrome; AF, atrial
fibrillation; CAD, coronary artery disease; DVT, deep vein thrombosis; ESUS, embolic
stroke of undetermined source; PAD, peripheral arterial disease; PCI, percutaneous
coronary intervention; PE, pulmonary embolism; VTE, venous thromboembolism.
The Coagulation Cascade and Potentiation of Antithrombotic Efficiency with Rivaroxaban
The Coagulation Cascade and Potentiation of Antithrombotic Efficiency with Rivaroxaban
Coagulation involves a complex interaction between platelets, the endothelium, endogenous
procoagulant and anticoagulant proteins, and fibrinolytic factors, to prevent excessive
propagation of thrombus and respond to acute vascular damage.[14]
Factor Xa has a central role in coagulation, as it results from the activation of
factor X by either the intrinsic or extrinsic coagulation pathway.[1]
[14] During the initiation phase of coagulation, the factor Xa produced generates some
thrombin (factor IIa). This initial thrombin activates factor XI, and factors V and
VIII, to factor XIa and the activated cofactors, factor Va and VIIIa, respectively.
Thrombin also activates platelets, which are required for the formation of the intrinsic
tenase (factor VIIIa–factor IXa) and the prothrombinase (factor Va–factor Xa) complexes.
The prothrombinase complex, on the platelet surface, is substantially more efficient
than free factor Xa (in plasma) at activating prothrombin to thrombin; the rate of
thrombin formation is increased by approximately 300,000-fold over the rate with factor
Xa alone.[1] Owing to its multiple roles in the coagulation process, thrombin is the principal
enzyme involved in the formation, growth and stabilization of thrombi.[1]
[15]
Reducing thrombin generation by inhibition of factor Xa, together with a reduction
in platelet aggregation using antiplatelet agents, may potentiate the efficacy of
antithrombotic treatment, as previously shown in preclinical studies of rivaroxaban.[16] While anticoagulants and antiplatelets both contribute to this effect, thrombin
is a key target owing to its multifaceted role in platelet activation, fibrin formation
and protein C activation—a concept that has been gaining ground in recent years, with
hypotheses that inhibition of thrombin-induced platelet activation might provide a
larger therapeutic index.[12] The clinical benefits of two rivaroxaban doses (2.5 mg twice daily [bid] and 5 mg
bid) were shown in the ATLAS ACS 2–TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular
Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS
2–Thrombolysis In Myocardial Infarction 51) trial, where both doses significantly
reduced the composite endpoint of death from CV causes, myocardial infarction (MI)
or stroke, when used on background therapy (ASA/clopidogrel) in patients with ACS,
including those presenting with heart failure (HF).[10]
[17] These findings support the rationale for ongoing RCTs investigating rivaroxaban
(2.5 and 5 mg bid) as part of antithrombotic regimen for long-term CV protection.
Two distinct approaches with rivaroxaban have been developed, which differ depending
on the location of the clot and the nature of the thromboembolic event: anticoagulation
for thromboembolic events or antithrombotic therapy for vascular events, comprising
rivaroxaban 2.5 mg bid and an antiplatelet, or rivaroxaban 5 mg bid alone ([Fig. 2]).
Fig. 2 An overview of anticoagulation strategies with rivaroxaban across a spectrum of thromboembolic
and atherothrombotic disorders. Abbreviations: Bid, twice daily; CV, cardiovascular;
DVT, deep vein thrombosis; ESUS, embolic stroke of undetermined source; MI, myocardial
infarction; od, once daily; PAD, peripheral arterial disease; PE, pulmonary embolism;
SPAF, stroke prevention in atrial fibrillation; VTEp, venous thromboembolism prevention.
Vascular Protection with Rivaroxaban: An Update on Ongoing Trials
Vascular Protection with Rivaroxaban: An Update on Ongoing Trials
RCTs in the rivaroxaban vascular protection program include patients with acute and
chronic coronary artery disease (CAD) and/or peripheral arterial disease (PAD). The
trials are based on the hypotheses that targeted inhibition of thrombin generation
with rivaroxaban with or without an antiplatelet in these patients may stabilize multiple
pathophysiological processes and help reduce morbidity and mortality.
The prevention and treatment of atherothrombosis in acute and chronic CAD requires
clinical attention owing to a continued residual risk of atherothrombotic events with
antiplatelet therapy,[18] which is also the case for those with PAD.[19]
[20] CAD may also commonly occur in those with PAD, and patients with both CAD and PAD
may be at increased risk of MI, stroke or death due to CV events, or all-cause mortality.[20]
[21] Moreover, patients with PAD and/or CAD may present with more extensive and calcified
coronary atherosclerosis, constrictive vascular remodelling and accelerated disease
progression.[22]
The phase III ATLAS ACS 2-TIMI 51 and oPen-label, randomized, controlled, multicentre
study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin
K antagonist treatment strategy in patients with Atrial Fibrillation who undergo Percutaneous
Coronary Intervention (PIONEER AF-PCI) trials of rivaroxaban provide further support
for the potential benefit of this agent in CAD and, by extension, in PAD.[10]
[23] In PIONEER AF-PCI, data from patients with an indication for long-term anticoagulation
undergoing PCI showed that using rivaroxaban plus a single antiplatelet agent, rather
than rivaroxaban plus dual antiplatelet therapy (DAPT), reduced bleeding risk without
increasing the risk of ischemic events.[23]
Coronary artery atherothrombosis, resulting in myocardial ischemia is the most common
underlying cause of HF.[24] The pathogenesis of increased thrombosis in patients with HF may be due in part
to hypercoagulability[25]
[26]
[27] and, therefore, anticoagulants may be important in the prevention of CV events in
HF for patients with sinus rhythm.[28] In addition, there are a lack of conclusive data supporting a definitive role of
anticoagulants in patients with HF.[29]
[30]
[31]
In each of these patient groups, it is clear that further research is essential to
ascertain the most appropriate management strategies and minimize thrombotic risk.
In the rivaroxaban vascular protection program, the following key trials are ongoing
or have recently completed.
Cardiovascular OutcoMes for People using Anticoagulation StrategieS: COMPASS
Cardiovascular OutcoMes for People using Anticoagulation StrategieS: COMPASS
COMPASS is a landmark phase III trial designed to determine the efficacy and safety
of rivaroxaban, rivaroxaban plus ASA, or ASA alone for reducing the risk of MI, stroke
and CV death in patients with stable atherosclerotic disease.[32]
[33]
[34] COMPASS included 27,395 patients with CAD or PAD receiving a 1:1:1 ratio of rivaroxaban
2.5 mg bid + ASA 100 mg once daily (od); rivaroxaban 5 mg bid; or ASA 100 mg od. Another
randomized comparison is still ongoing and is comparing pantoprazole with placebo
in those patients not receiving a proton-pump inhibitor (the main outcome is upper
gastrointestinal complications).
The primary efficacy endpoint of the trial was the composite of MI, stroke or CV death.[34] The primary safety outcome was based on a modification of the International Society
on Thrombosis and Haemostasis (ISTH) criteria and included fatal bleeding, symptomatic
bleeding in a critical organ, or bleeding into a surgical site requiring reoperation,
and bleeding leading to hospitalization (includes presentation to an acute care facility
without overnight stay). All bleeding that led to presentation at an acute care facility
or hospitalization was regarded as major. Recruitment for the COMPASS trial began
in February 2013, with an original completion date scheduled for 2018. However, after
a mean follow-up period of 23 months and observed superiority of the rivaroxaban and
ASA arm, the study ceased in February 2017, a year ahead of schedule.[35] A total of 602 centres across 33 countries were included in the trial. A total of
9,152; 9,117 and 9,126 patients were included in the rivaroxaban + ASA arm, rivaroxaban
arm and ASA arm, respectively. The primary outcome occurred in 4.1% of patients in
the rivaroxaban + ASA group, 4.9% in the rivaroxaban group and 5.4% in the ASA group
(hazard ratio [HR] for rivaroxaban + ASA vs. ASA: 0.76; 95% confidence interval [CI]:
0.66–0.86; p < 0.001; HR for rivaroxaban vs. ASA: 0.90; 95% CI: 0.79–1.03; p = 0.12). The incidence of major bleeding was 3.1% in the rivaroxaban + ASA group,
2.8% in the rivaroxaban group and 1.9% in the ASA group (HR for rivaroxaban + ASA
vs. ASA: 1.70; 95% CI: 1.40–2.05; p < 0.001; HR for rivaroxaban vs. ASA: 1.51; 95% CI: 1.25–1.84; p < 0.001). The incidence of intracranial bleeding and fatal bleeding was comparable
between the rivaroxaban + ASA and ASA groups (0.4 vs. 0.3%; p = 0.40) and between the rivaroxaban and ASA groups (0.5 vs. 0.3%; p = 0.05). There were 313 deaths (3.4%) in the rivaroxaban + ASA group, 366 deaths
(4%) in the rivaroxaban group and 378 deaths (4.1%) in the ASA group (HR for rivaroxaban + ASA
vs. ASA: 0.82; 95% CI: 0.71–0.96; p = 0.01; HR for rivaroxaban vs. ASA: 0.97; 95% CI: 0.84–1.12; p = 0.67). While significant benefits were observed following use of rivaroxaban 2.5 mg
bid + ASA versus ASA alone, the use of rivaroxaban 5 mg bid alone did not lead to
a significant reduction in the primary outcome compared with ASA alone and the incidence
of major bleeding was again observed to be significantly higher compared with ASA
alone.[34]
Vascular Outcomes studY of ASA alonG with Rivaroxaban in Endovascular or Surgical
Limb Revascularization for PAD: VOYAGER PAD
Vascular Outcomes studY of ASA alonG with Rivaroxaban in Endovascular or Surgical
Limb Revascularization for PAD: VOYAGER PAD
VOYAGER PAD is a phase III, randomized, double-blind, placebo-controlled trial, to
determine the efficacy and safety of a dual-pathway treatment approach versus standard
care with ASA alone, for the reduction of thrombotic vascular events.[36] Approximately 6,500 patients with symptomatic and hemodynamic PAD who have undergone
technically successful peripheral infrainguinal revascularization within 10 days prior
to randomization will be randomized 1:1 to receive rivaroxaban 2.5 mg bid plus ASA
100 mg od, or ASA 100 mg od alone. The primary efficacy outcome is the composite of
MI, ischemic stroke, CV death, acute limb ischemia (ALI) and major amputation due
to PAD. The primary safety endpoint is major bleeding, as assessed by the Thrombolysis
in Myocardial Infarction (TIMI) score.[36] VOYAGER PAD began enrolling in late 2015 and results are expected in 2019. VOYAGER
PAD complements the COMPASS trial, which is exploring new ways to reduce complications
of atherothrombosis in CAD or PAD.
Cardiovascular Outcome Modification, Measurement AND Evaluation of Rivaroxaban in
patients with Heart Failure: COMMANDER HF
Cardiovascular Outcome Modification, Measurement AND Evaluation of Rivaroxaban in
patients with Heart Failure: COMMANDER HF
COMMANDER HF is an international, phase III, prospective, randomized, double-blind,
placebo-controlled, event-driven, parallel-group comparison of the efficacy and safety
of rivaroxaban with placebo and standard of care in patients with HF and significant
CAD who have experienced a recent exacerbation of HF.[28] Approximately 5,000 patients will be randomized to receive rivaroxaban 2.5 mg bid
plus standard of care versus placebo plus standard of care. Patients will have follow-up
visits at week 4, week 12, and every 12 weeks for the assessment of outcome events
and safety. When it is estimated that 984 primary outcome events have occurred, the
investigator sites will be notified of the global treatment end date. It is anticipated
that patients will be followed up for 7 to 30 months. The primary efficacy outcome
event is a composite of all-cause mortality, MI or stroke. The primary safety outcome
is the composite of fatal bleeding or bleeding into a critical space with a potential
for permanent disability.[28]
[37] COMMANDER HF began enrolling patients in Q3 2013, with results expected in 2019.[37]
Each of these ongoing trials is described in further detail in the accompanying article
‘Rivaroxaban: A New Treatment Paradigm in the Setting of Vascular Protection?’ by Bauersachs et al.
Stroke Prevention with Rivaroxaban: An Update on Ongoing Trials
Stroke Prevention with Rivaroxaban: An Update on Ongoing Trials
There is a recognized clinical need for effective primary and secondary stroke prevention
in several groups. Meta-analysis data have shown that 3.3% of patients who have undergone
transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS) experience
a stroke or transient ischemic attack (TIA) within 30 days following TAVR, and patients
also have an increased long-term risk of cerebrovascular events due to AF.[38] There are no clear clinical guidelines recommending any specific antithrombotic
regimen for stroke prevention following TAVR.[39]
[40]
[41]
Evidence suggests that 20 to 45% of patients with AF and CAD require coronary revascularization
by PCI or coronary artery bypass grafting (CABG),[42]
[43] and poorer outcomes may be likely in those with both conditions.[42]
[43]
[44] In patients with AF who have undergone PCI, triple combination therapy with an oral
anticoagulant and DAPT is often recommended,[45]
[46]
[47] despite an associated three- to fourfold increased risk of fatal and nonfatal bleeding.[48]
[49]
[50]
[51]
[52]
The recorded prevalence of embolic stroke of undetermined source (ESUS; embolic stroke
for which the etiology of embolism remains undetermined) varies in the literature
due to variations in the definition and degree of investigation, but it is estimated
that approximately one in six ischemic strokes is ESUS.[53]
[54] Experts propose that diagnosis of ESUS should be based on visualized non-lacunar
infarct in the absence of proximal occlusive atherosclerosis or major risk cardioembolic
source of embolism.[55] The risk of recurrent stroke in patients with ESUS has been reported to be as high
as 29.0% over 5 years.[56] Again, clinical guidelines for the management of ESUS are unclear. A selection of
completed and ongoing clinical trials elucidating the role of rivaroxaban in these
areas in the rivaroxaban stroke prevention program is covered below.
PIONEER AF-PCI
PIONEER AF-PCI was an open-label, randomized, controlled, multicenter trial that evaluated
the safety of two different regimens of rivaroxaban compared with VKA in patients
with NVAF who underwent PCI with stent placement.[23]
[57] PIONEER AF-PCI included 2,124 stented subjects with NVAF, who were randomized 1:1:1
to treatment with a reduced dose of rivaroxaban at 15 mg od with a P2Y12 inhibitor for 12 months (Group 1); rivaroxaban 2.5 mg bid with patient stratification
to a prespecified duration of DAPT of 1, 6 or 12 months (Group 2); or the reference
arm of dose-adjusted VKA daily with a similar DAPT stratification (Group 3). The primary
safety endpoint was the occurrence of clinically significant bleeding (TIMI major
or minor bleeding, or bleeding requiring medical attention) during the 12-month treatment
period. Efficacy endpoints were secondary and included the occurrence of major adverse
CV events (CV death, MI or stroke).[23]
[57]
PIONEER AF-PCI completed in late 2016. Findings showed that the rates of clinically
significant bleeding were lower in the two groups receiving rivaroxaban than in the
group receiving standard therapy (Group 1: 16.8%; Group 2: 18.0% and Group 3: 26.7%;
HR for Group 1 vs. Group 3: 0.59; 95% CI: 0.47–0.76; p < 0.001; HR for Group 2 vs. Group 3: 0.63; 95% CI: 0.50–0.80; p < 0.001). The incidence of major adverse CV events (death from CV causes, MI or stroke)
was similar in the three groups (Group 1: 6.5%; Group 2: 5.6% and Group 3: 6.0%).
While the investigational arms had similar efficacy rates, the broad confidence intervals
suggest that no solid conclusions can be drawn regarding efficacy.[23]
[57] Following completion of PIONEER AF-PCI, the European Medicines Agency (EMA) has
since approved the use of rivaroxaban 15 mg od (or 10 mg od for patients with moderate
renal impairment [creatinine clearance: 30–49 mL/min]) in combination with a P2Y12 inhibitor for a maximum of 12 months' duration for the treatment of patients with
NVAF who require oral anticoagulation and undergo PCI with stent placement.[2]
New Approach riVaroxaban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT
Embolism in Embolic Stroke of Undetermined Source: NAVIGATE ESUS
New Approach riVaroxaban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT
Embolism in Embolic Stroke of Undetermined Source: NAVIGATE ESUS
NAVIGATE ESUS was a phase III, double-blind, randomized, controlled study to assess
the efficacy and safety of rivaroxaban versus ASA for the prevention of recurrent
stroke and systemic embolism in patients with recent ESUS.[58]
[59] Patients were randomized 1:1 to rivaroxaban 15 mg od or ASA 100 mg od between 7
days and 6 months after the qualifying ESUS. The primary efficacy outcome was time
to recurrent stroke (ischemic, hemorrhagic and undefined stroke, including TIAs with
positive neuroimaging) or systemic embolism. The primary safety measure was the first
occurrence of a major bleeding event. Between December 2014 and September 2017, a
total of 7,214 patients were enrolled from 459 centres across 31 countries.[60] Mean patient follow-up was expected to be about 2 years, with the trial continuing
until at least 450 participants had experienced a primary efficacy outcome event—initially
expected to be February 2018.[58]
[59] However, in October 2017, the decision was taken to stop the trial early, based
on a recommendation by the Independent Data Monitoring Committee.[60] Comparable efficacy was noted between the rivaroxaban and ASA arms. Minimal overall
benefit was anticipated in the rivaroxaban arm if the study was taken to completion.
Overall bleeding rates were low; however, an increase in bleeding was observed in
the rivaroxaban arm compared with the low-dose ASA arm. Therefore, the hypothesis
that anticoagulation is better than antiplatelet therapy in patients with ESUS could
not be confirmed by the NAVIGATE ESUS trial. A complete data analysis is expected
in 2018.[60]
Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based
strategy after transcatheter aortIc vaLve rE-placement to Optimise clinical outcomes:
GALILEO
Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based
strategy after transcatheter aortIc vaLve rE-placement to Optimise clinical outcomes:
GALILEO
GALILEO is a phase III, multicentre, open-label, international, randomized, event-driven
trial that includes more than 1,520 patients who are without an indication for oral
anticoagulation and who have undergone successful TAVR.[61]
[62] The trial design includes randomization in a 1:1 ratio, at between 1 and 7 days
following a successful TAVR, to either a rivaroxaban-based treatment strategy or an
antiplatelet-based strategy. In the experimental arm, patients will receive rivaroxaban,
at a dose of 10 mg od, plus ASA 75 to 100 mg od for 90 days, followed by rivaroxaban
alone. In the control arm, patients will receive clopidogrel 75 mg od plus ASA 75
to 100 mg od for 90 days, followed by ASA alone. If new onset AF (NOAF) develops,
the rivaroxaban dose will be raised from 10 to 20 mg od, or from 10 to 15 mg od for
subjects with moderate renal impairment (estimated glomerular filtration rate <50
and ≥30 mL/min per 1.73 m2). If NOAF occurs within the first 90 days in subjects randomized to the rivaroxaban
strategy, ASA will be discontinued at 90 days, and rivaroxaban will be continued as
monotherapy. If NOAF occurs under the clopidogrel-based strategy, clopidogrel (≤90
days) or ASA monotherapy (>90 days) will be replaced by a VKA to target an international
normalized ratio of 2 to 3. If NOAF occurs within the first 90 days in this group,
ASA will be discontinued at 90 days, and VKA continued as a monotherapy. The primary
efficacy endpoint of GALILEO will be the composite of stroke, MI, symptomatic valve
thrombosis, PE, DVT, systemic embolism and all-cause death. The primary safety endpoint
will be the composite of disabling, life-threatening and major bleeding events, according
to Valve Academic Research Consortium-2 (VARC-2) definitions.[61]
[62] Recruitment began in December 2015, from approximately 140 centres across 15 countries,
with an anticipated completion date of 2018.
Each of these trials is described in further detail in the accompanying article ‘Beyond Stroke Prevention in Atrial Fibrillation: Exploring Further Unmet Needs with
Rivaroxaban’ by Gibson et al.
Venous Protection with Rivaroxaban: An Update on Ongoing Trials
Venous Protection with Rivaroxaban: An Update on Ongoing Trials
There are specific patients with VTE for whom optimal anticoagulant therapy remains
challenging. Patients with VTE are known to be at high risk of recurrent thromboembolic
events,[63] which can be further exacerbated by ceasing anticoagulation prematurely owing to
potential bleeding risks. Cancer-associated thrombosis (CAT) is also a common cause
of morbidity and mortality in patients with malignancy.[64]
[65]
[66]
[67] Recent evidence from the United States suggests that adherence to traditional anticoagulants
in the setting of CAT is poor.[68] Low-molecular-weight heparin (LMWH) continues to be widely recommended for the prevention
of CAT in hospitalized patients with cancer and for the treatment of CAT.[67]
[69]
[70]
[71] Data supporting the use of NOACs for the prevention and treatment of CAT are lacking,
particularly head-to-head trials with LMWH. The following trials and programs were
designed to investigate rivaroxaban for extended VTE treatment (EINSTEIN CHOICE) and
the prevention and treatment of CAT (Cancer Associated thrombosis—expLoring soLutions
for patIentS through Treatment and prevention with rivarOxaban [CALLISTO]).
Reduced-Dosed Rivaroxaban in the Extended Prevention of Recurrent Symptomatic Venous
Thromboembolism: EINSTEIN CHOICE
Reduced-Dosed Rivaroxaban in the Extended Prevention of Recurrent Symptomatic Venous
Thromboembolism: EINSTEIN CHOICE
EINSTEIN CHOICE was a phase III, randomized, double-blind trial that compared the
safety and efficacy of two doses of rivaroxaban with ASA for the prevention of recurrent
VTE.[72]
[73] The EINSTEIN CHOICE study assigned 3,396 patients with VTE to receive either rivaroxaban
at doses of 10 or 20 mg od or ASA 100 mg od. The patients who were included in the
EINSTEIN CHOICE study had previously completed 6 to 12 months of anticoagulation therapy;
study drugs were administered for up to 12 months, with a one-month follow-up period.
The findings from EINSTEIN CHOICE were that the risk of a recurrent VTE event was
significantly reduced with rivaroxaban at a dose of either 20 or 10 mg od than with
ASA, without a significant increase in the rate of bleeding.[72]
[73]
EINSTEIN CHOICE is the only trial to date that has investigated a NOAC in the setting
of extended VTE treatment versus ASA, and complements EINSTEIN EXT by further demonstrating
the benefit of rivaroxaban at a lower dose of 10 mg od.[73] Based on EINSTEIN CHOICE results, rivaroxaban 10 mg od is approved for extended
prevention of recurrent VTE following ≥6 months of standard anticoagulation, by both
the European Medicines Agency and the U.S. Food and Drugs Administration.[74]
[75]
The CALLISTO Program
CALLISTO is an umbrella program that addresses multiple clinically relevant questions
in CAT via multiple studies, expert recommendations and a survey, the combination
of which will result in improved quality of care in oncology. CALLISTO initiatives
have been designed in collaboration with oncologists as an overarching international
research program to identify and prioritize unmet needs and unanswered questions and
to explore the potential role of rivaroxaban in the prevention and treatment of CAT.
[Table 1] provides an overview of the CALLISTO initiatives.
Table 1
The CALLISTO program: Summary of ongoing initiatives
|
Trial
|
Design
|
Dose
|
Duration
|
Population
|
|
VTE Prevention
|
|
CASSINI[79]
|
Prospective, randomized, double-blind superiority (∼700 patients)
|
Rivaroxaban 10 mg od vs. placebo
|
6 mo
|
Ambulatory cancer patients at high VTE risk planned to initiate chemotherapy
|
|
PRO-LAPS II[80]
|
Randomized, double-blind (∼650 patients)
|
Rivaroxaban 10 mg od vs. placebo
|
Extended antithrombotic prophylaxis
|
Colorectal cancer patients after laparoscopic surgery
|
|
VTE Treatment
|
|
Select-d[81]
[82]
|
Randomized, open-label, multicenter pilot (∼530 patients)
|
Rivaroxaban vs. dalteparin[a]; rivaroxaban vs. placebo
|
6 mo[b]
|
Cancer patients with symptomatic VTE; PE and RVT patients
|
|
CASTA-DIVA[83]
|
Randomized, open-label (∼200 patients)
|
Rivaroxaban vs. dalteparin[c]
|
3 mo
|
Patients with active cancer at high risk of VTE recurrence
|
|
Conko-011[84]
|
Prospective, randomized, open-label, multicenter (∼450 patients)
|
Rivaroxaban vs. LMWH[d]
|
3 mo
|
Patients with active cancer and newly diagnosed VTE event
|
|
QAI[85]
|
Following up CAT patients with VTE whose full anticoagulation course was with rivaroxaban
for 6 mo (200 patients)
|
|
COSIMO[86]
|
Patient-reported outcomes, follow-up of 6 mo (∼500 patients)
|
|
Frontline-2[87]
|
Second CAT survey of up to 5,000 oncologists/haematologists to identify current practice
|
Abbreviations: bid, twice daily; CAT, cancer-associated thrombosis; d, days, DVT,
deep vein thrombosis; LMWH, low-molecular-weight heparin; mo, month; od, once daily;
PE, pulmonary embolism; QAI, Quality Assessment Initiative; RVT, residual vein thrombosis;
VTE, venous thromboembolism; wk, week.
a Dalteparin (200 IU/kg daily subcutaneously for 1 mo and 150 IU/kg for 2–6 mo); and
rivaroxaban (15 mg bid for 21 d and 20 mg od for 6 mo in total).
b A second placebo-controlled randomization (rivaroxaban vs. placebo) is comparing
the duration of therapy (6 vs. 12 mo) in all patients with PE and those with a DVT
who are RVT positive.
c Dalteparin 200 IU/kg od for 4 wk followed by 150 IU/kg od for 8 wk or rivaroxaban
15 mg bid for 21 d followed by 20 mg od for 9 wk.
d Therapeutic licensed dose of LMWH according to standards of the individual study
centre or rivaroxaban 15 mg bid for 21 d, followed by 20 mg od over a period of 3
mo.
EINSTEIN CHOICE and a selection of studies from CALLISTO are described in further
detail in the accompanying article ‘Treatment Challenges in Venous Thromboembolism: An Appraisal of Rivaroxaban Studies’ by Khorana et al.
Conclusion
Since receiving its first marketing authorization in 2008, rivaroxaban has been approved
across several indications for the prevention and treatment of thromboembolic disease.
The concept that rivaroxaban impacts not only fibrin formation but also platelet activation
forms the basis for new therapeutic approaches in vascular protection. CAT is also
an extensive area of investigation within the CALLISTO program. Key findings to date
from the new wave of trials in stroke prevention have shown that rivaroxaban is the
first NOAC (vs. VKA) to provide data from a dedicated RCT—PIONEER AF-PCI—for patients
with AF undergoing PCI. The additional benefits of prophylactic dose rivaroxaban (10 mg
od) in extended VTE treatment, as shown in EINSTEIN CHOICE, may mean that physicians
can tailor treatments to meet patients' needs and minimize thrombotic risk in the
future. A range of hypotheses are currently being tested in new areas of research
(see completed and ongoing studies in [Fig. 1]). Further studies of note, which are investigating rivaroxaban in under-represented
populations, include INVestIgation of rheumatiC aTrial Fibrillation Treatment Using
Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Superiority (INVICTUS-VKA),
a program comprising an RCT and a registry in rheumatic AF, which is an extension
of the Global Rheumatic Heart Disease Registry, REMEDY.[76]
[77] The RCT (INVICTUS-VKA) commenced in July 2016 and will ascertain whether rivaroxaban
20 mg od is noninferior to VKAs for the prevention of stroke or systemic embolism,
rheumatic AF and either CHA2DS2VASc ≥2 or moderate to severe mitral stenosis in approximately 4,500 patients. Completion
is expected in October 2020.[76] The RIvaroxaban for Valvular Heart diseasE and atRial Fibrillation Trial (RIVER)
is a Phase II, randomized, open-label, noninferiority clinical trial to explore the
safety and efficacy of rivaroxaban 20 mg od versus warfarin in patients with persistent
or paroxysmal AF or flutter with bioprosthetic mitral valves.[78] RIVER commenced in August 2015, enrolling approximately 1,000 patients, and is expected
to complete in August 2018.[78] These and other trials from the rivaroxaban clinical development program are addressing
major areas of unmet medical needs in thrombosis, and are likely to contribute toward
considerable clinical change for practitioners in the future.
