Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Review

Volume 6, Number 3, June 2015, pages 267-277

Unmet Needs in Anticoagulant Therapy: Potential Role of Rivaroxaban

Figure 1. Clinical settings for oral anticoagulation. Clinical questions about the management of the NOACs exist in each of these settings.

Figure 2. Study design of COMPASS. To assess the safety and efficacy of rivaroxaban for the prevention of MI, stroke, and CV death, patients with coronary artery disease (CAD) or peripheral artery disease (PAD), who do not require dual antiplatelet therapy (DAPT), are randomized to rivaroxaban 2.5 mg BID + acetylsalicylic acid (ASA) 100 mg QD; rivaroxaban 5 mg BID; or ASA 100 mg QD. *Patients in each arm are also randomized to pantoprazole 40 mg QD or placebo to investigate if safety can be improved by the addition of a proton pump inhibitor.

Figure 3. Study design of COMMANDER-HF. To determine whether rivaroxaban reduces the risk of MI, stroke or death, patients with a history of coronary artery disease (CAD) or those recently hospitalized for an exacerbation of their heart failure (HF) are randomized to rivaroxaban 2.5 mg BID or placebo in addition to their current standard of care.

**Table 1.** Ongoing Studies With Rivaroxaban Addressing Unresolved Issues in Established Indications
Trial	Clinical question(s) to be addressed	Arms	Targeted enrollment
*P2Y12 inhibitor such as clopidogrel (75 mg QD). ACS: acute coronary syndrome; AF: atrial fibrillation; ASA: acetylsalicylic acid; DAPT: dual antiplatelet therapy; LA: left atrial; PCI: percutaneous coronary intervention; SVT: superficial vein thrombosis; UFH: unfractionated heparin; VKA: vitamin K antagonist; VTE: venous thromboembolic events.
Stroke prevention in patients with AF
VENTURE-AF NCT01729871	Does rivaroxaban need to be stopped prior to catheter ablation in patients with non-valvular AF?	Rivaroxaban 20 mg QD VKA (INR 2.0-3.0)	250
X-TRA NCT01674647	Does treatment with rivaroxaban regress LA thrombi in patients with non-valvular AF or atrial flutter?	Rivaroxaban 20 mg QD	60
VTE treatment
EINSTEIN CHOICE NCT02064439	Can a lower dose (10 mg) of rivaroxaban be used for the long-term prevention of VTE, and is this or 20 mg rivaroxaban superior to ASA?	Rivaroxaban 10 mg QD Rivaroxaban 20 mg QD ASA 100 mg QD	2,850
EINSTEIN Junior NCT01684423	Can rivaroxaban be safely used in children?	Rivaroxaban (age and weight adjusted) Standard of care	50
Superficial vein thrombosis NCT01499953	Can rivaroxaban be used to treat SVT?	Rivaroxaban 20 mg QD	506
Prevention of VTE
MARINER NCT02111564	Can rivaroxaban reduce the risk of post-hospital discharge symptomatic VTE in patients hospitalized for acute medical illness?	Rivaroxaban 10 mg QD or 7.5 mg QD (adjusted for creatine clearance) Placebo	8,000
EPCAT II NCT01720108	Is rivaroxaban more effective than ASA for extended prophylaxis of VTE?	Rivaroxaban 10 mg QD Fondaparinux 2.5 mg QD	3,436
Therapeutic approaches for patients with coronary disease
GEMINI ACS 1 NCT02293395	Can rivaroxaban, in combination with a single antiplatelet agent, be used for secondary prevention in patients with ACS?	Study design not released at the time of publication	3,000
X-PLORER NCT01442792	Can rivaroxaban prevent thrombosis and related adverse ischemic events during elective PCI?	Rivaroxaban 20 mg QD Rivaroxaban 10 mg QD Rivaroxaban 10 mg QD + UFH 50 IU/kg bolus UFH 70-100 IU/kg bolus	106
PIONEER AF-PCI NCT01830543	Should rivaroxaban be used over warfarin in patients who have undergone PCI and are on antiplatelet therapy? If so, what is the optimal rivaroxaban dose and antiplatelet regimen for these patients?	Rivaroxaban 15 mg QD + P2Y12 inhibitor* Rivaroxaban 2.5 mg BID + DAPT VKA + DAPT	2,100

Table 1. Ongoing Studies With Rivaroxaban Addressing Unresolved Issues in Established Indications

Trial

Clinical question(s) to be addressed

Arms

Targeted enrollment

*P2Y12 inhibitor such as clopidogrel (75 mg QD). ACS: acute coronary syndrome; AF: atrial fibrillation; ASA: acetylsalicylic acid; DAPT: dual antiplatelet therapy; LA: left atrial; PCI: percutaneous coronary intervention; SVT: superficial vein thrombosis; UFH: unfractionated heparin; VKA: vitamin K antagonist; VTE: venous thromboembolic events.

Stroke prevention in patients with AF

VENTURE-AF
NCT01729871

Does rivaroxaban need to be stopped prior to catheter ablation in patients with non-valvular AF?

Rivaroxaban 20 mg QD
VKA (INR 2.0-3.0)

250

X-TRA
NCT01674647

Does treatment with rivaroxaban regress LA thrombi in patients with non-valvular AF or atrial flutter?

Rivaroxaban 20 mg QD

VTE treatment

EINSTEIN CHOICE
NCT02064439

Can a lower dose (10 mg) of rivaroxaban be used for the long-term prevention of VTE, and is this or 20 mg rivaroxaban superior to ASA?

Rivaroxaban 10 mg QD
Rivaroxaban 20 mg QD
ASA 100 mg QD

2,850

EINSTEIN Junior
NCT01684423

Can rivaroxaban be safely used in children?

Rivaroxaban (age and weight adjusted)
Standard of care

Superficial vein thrombosis
NCT01499953

Can rivaroxaban be used to treat SVT?

Rivaroxaban 20 mg QD

506

Prevention of VTE

MARINER
NCT02111564

Can rivaroxaban reduce the risk of post-hospital discharge symptomatic VTE in patients hospitalized for acute medical illness?

Rivaroxaban 10 mg QD or 7.5 mg QD (adjusted for creatine clearance)
Placebo

8,000

EPCAT II
NCT01720108

Is rivaroxaban more effective than ASA for extended prophylaxis of VTE?

Rivaroxaban 10 mg QD
Fondaparinux 2.5 mg QD

3,436

Therapeutic approaches for patients with coronary disease

GEMINI ACS 1
NCT02293395

Can rivaroxaban, in combination with a single antiplatelet agent, be used for secondary prevention in patients with ACS?

Study design not released at the time of publication

3,000

X-PLORER
NCT01442792

Can rivaroxaban prevent thrombosis and related adverse ischemic events during elective PCI?

Rivaroxaban 20 mg QD
Rivaroxaban 10 mg QD
Rivaroxaban 10 mg QD + UFH 50 IU/kg bolus
UFH 70-100 IU/kg bolus

106

PIONEER AF-PCI
NCT01830543

Should rivaroxaban be used over warfarin in patients who have undergone PCI and are on antiplatelet therapy? If so, what is the optimal rivaroxaban dose and antiplatelet regimen for these patients?

Rivaroxaban 15 mg QD + P2Y12 inhibitor*
Rivaroxaban 2.5 mg BID + DAPT
VKA + DAPT

2,100

**Table 2.** Ongoing Studies With Rivaroxaban in Potential New Indications
Trial	Clinical question(s) to be addressed	Arms	Estimated enrollment
ASA: acetylsalicylic acid; CAD: coronary artery disease; ESUS: embolic stroke of undetermined source; HIT: heparin-induced thrombocytopenia; PAD: peripheral artery disease; TIA: transient ischemic attack.
Secondary prevention of cardiovascular disease
COMPASS NCT01776424	Does rivaroxaban provide additional cardioprotective benefits to high-risk patients? Should rivaroxaban be used alone or in combination with ASA in patients with CAD or PAD?	Rivaroxaban 2.5 mg BID + ASA Rivaroxaban 5.0 mg BID ASA 100 mg QD	19,500
Heart failure
COMMANDER-HF NCT01877915	Does adding low-dose rivaroxaban to optimal medical therapy improve outcomes in heart failure?	Rivaroxaban 2.5 mg BID + single or dual antiplatelet therapy Single or dual antiplatelet therapy	5,000
Confirmed or suspected HIT
Heparin-induced thrombocytopenia NCT01598168	Can rivaroxaban be used to treat HIT?	Rivaroxaban 15 mg BID until HIT excluded, followed by rivaroxaban 20 mg QD	200
Stroke prevention in patients with ESUS
NAVIGATE ESUS NCT02313909	Is rivaroxaban more effective than ASA atreducing the risk of recurrent stroke and systemic embolism in patients with a recent ESUS?	Rivaroxaban 15 mg QD ASA 100 mg QD	7,000
Treatment of high-risk patients with non-disabling cerebrovascular events
TRACE NCT01923818	Should rivaroxaban be used over ASA in patients following TIA or minor ischemic stroke?	ASA 100 mg QD Rivaroxaban 5 mg Rivaroxaban 10 mg	3,700

Table 2. Ongoing Studies With Rivaroxaban in Potential New Indications

Trial

Clinical question(s) to be addressed

Arms

Estimated enrollment

ASA: acetylsalicylic acid; CAD: coronary artery disease; ESUS: embolic stroke of undetermined source; HIT: heparin-induced thrombocytopenia; PAD: peripheral artery disease; TIA: transient ischemic attack.

Secondary prevention of cardiovascular disease

COMPASS
NCT01776424

Does rivaroxaban provide additional cardioprotective benefits to high-risk patients?
Should rivaroxaban be used alone or in combination with ASA in patients with CAD or PAD?

Rivaroxaban 2.5 mg BID + ASA
Rivaroxaban 5.0 mg BID
ASA 100 mg QD

19,500

Heart failure

COMMANDER-HF
NCT01877915

Does adding low-dose rivaroxaban to optimal medical therapy improve outcomes in heart failure?

Rivaroxaban 2.5 mg BID + single or dual antiplatelet therapy
Single or dual antiplatelet therapy

5,000

Confirmed or suspected HIT

Heparin-induced thrombocytopenia
NCT01598168

Can rivaroxaban be used to treat HIT?

Rivaroxaban 15 mg BID until HIT excluded, followed by rivaroxaban 20 mg QD

200

Stroke prevention in patients with ESUS

NAVIGATE ESUS
NCT02313909

Is rivaroxaban more effective than ASA atreducing the risk of recurrent stroke and systemic embolism in patients with a recent ESUS?

Rivaroxaban 15 mg QD
ASA 100 mg QD

7,000

Treatment of high-risk patients with non-disabling cerebrovascular events

TRACE
NCT01923818

Should rivaroxaban be used over ASA in patients following TIA or minor ischemic stroke?

ASA 100 mg QD
Rivaroxaban 5 mg
Rivaroxaban 10 mg

3,700