NCT02504216: VOYAGER PAD

Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities

Completed Phase 3 Results posted Last updated 8 December 2020

What this trial tests

Phase 3 trial testing Rivaroxaban (Xarelto, BAY59-7939) in Peripheral Artery Disease in 6,564 participants. Completed in 9 January 2020.

Timeline

18 August 2015

Primary endpoint
27 November 2019

9 January 2020

Quick facts

Lead sponsor	Bayer
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	prevention
Enrollment	6,564
Start date	18 August 2015
Primary completion	27 November 2019
Estimated completion	9 January 2020
Sites	532 locations across Italy, Finland, Japan, Taiwan, Poland, South Korea, Denmark, Netherlands

Drugs / interventions tested

• Rivaroxaban (Xarelto, BAY59-7939) — full drug profile →
• Rivaroxaban-Placebo — full drug profile →

Conditions studied

• Peripheral Artery Disease — all drugs for Peripheral Artery Disease →

Sponsor

Bayer — full company profile →

Who can join

50 and older, any sex, with Peripheral Artery Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Primary Efficacy Outcome: Number of Participants With Composite of Myocardial Infarction (MI), Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia (ALI) and Major Amputation Due to a Vascular Etiology Primary · For each participant, the first occurrence of the composite primary efficacy outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean time in follow-up survival time until ECOD that date was 1109.76 days.

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	508
Rivaroxaban Placebo Bid + Aspirin 100 mg od	584

Primary Safety Outcome: Number of Participants With TIMI (Thrombolysis in Myocardial Infarction) Major Bleeding Primary · For each participant, the first occurrence of the primary safety outcome after randomization up until 2 days after permanent stop of study drug (rivaroxaban or rivaroxaban placebo).

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	62
Rivaroxaban Placebo Bid + Aspirin 100 mg od	44

Number of Participants With Composite of MI, Ischemic Stroke, Coronary Heart Disease (CHD) Death, ALI, and Major Amputation of a Vascular Etiology Secondary · For each participant, the first occurrence of the composite efficacy outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1108.79 days.

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	433
Rivaroxaban Placebo Bid + Aspirin 100 mg od	528

Number of Participants With an Unplanned Index Limb Revascularization for Recurrent Limb Ischemia (Subsequent Index Leg Revascularization That Was Not Planned or Considered as Part of the Initial Treatment Plan at the Time of Randomization) Secondary · For each participant, the first occurrence of the efficacy outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1062.48 days.

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	584
Rivaroxaban Placebo Bid + Aspirin 100 mg od	655

Number of Participants With Hospitalization for a Coronary or Peripheral Cause (Either Lower Limb) of a Thrombotic Nature Secondary · For each participant, the first occurrence of the efficacy outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1154.04 days

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	262
Rivaroxaban Placebo Bid + Aspirin 100 mg od	356

Number of Participants With Composite of MI, Ischemic Stroke, All-cause Mortality (ACM), ALI, and Major Amputation of a Vascular Etiology Secondary · For each participant, the first occurrence of the composite efficacy outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1085.13 days

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	614
Rivaroxaban Placebo Bid + Aspirin 100 mg od	679

Number of Participants With Composite of MI, All-cause Stroke, Cardiovascular (CV) Death, Acute Limb Ischemia (ALI), and Major Amputation of a Vascular Etiology Secondary · For each participant, the first occurrence of the composite efficacy outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1108.29 days

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	514
Rivaroxaban Placebo Bid + Aspirin 100 mg od	588

Number of Mortality (All-cause) Secondary · For each participant, the first occurrence of the outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1188.48 days

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	321
Rivaroxaban Placebo Bid + Aspirin 100 mg od	297

Number of Participants With Venous Thromboembolic (VTE) Events Secondary · For each participant, the first occurrence of the outcome after randomization up until the efficacy cut-off date (08-Sep-2019) was considered. The mean survival time until ECOD was 1187.65 days

Venous thromboembolic events were reported by investigator only.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	25
Rivaroxaban Placebo Bid + Aspirin 100 mg od	41

Secondary Safety Outcome: Number of Participants With ISTH (International Society on Thrombosis and Haemostasis) Major Bleeding Secondary · For each participant, the first occurrence of the major bleeding events according to the ISTH classification after randomization up until 2 days after permanent stop of study drug (rivaroxaban or rivaroxaban placebo).

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered.

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	140
Rivaroxaban Placebo Bid + Aspirin 100 mg od	100

Secondary Safety Outcome: Number of Participants With BARC (Bleeding Academic Research Consortium) Type 3b and Above Bleeding Events Secondary · For each participant, the first occurrence of the type 3b and above bleeding events according to the BARC classification after randomization up until 2 days after permanent stop of study drug (rivaroxaban or rivaroxaban placebo)

Only the first occurrence of the outcome event under analysis within the data scope from a participant is considered

Group	Value	95% CI
Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od	93
Rivaroxaban Placebo Bid + Aspirin 100 mg od	73

Adverse events — posted to ClinicalTrials.gov

Time frame: From randomization until 2 days following permanent discontinuation of the study drug. Reporting threshold: 0.1%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Rivaroxaban 2.5 mg Bid + Aspirin 100 mg od

Serious: 948/3256 (29%)

Deaths: 327/3256

Rivaroxaban Placebo Bid + Aspirin 100 mg od

Serious: 927/3248 (29%)

Deaths: 304/3248

Serious adverse events (776 terms)

Reaction	System	Rivaroxaban 2.5 mg Bid + A…	Rivaroxaban Placebo Bid + …
Peripheral arterial occlusive disease	Vascular disorders	—	—
Intermittent claudication	Vascular disorders	—	—
Pneumonia	Infections and infestations	—	—
Peripheral ischaemia	Vascular disorders	—	—
Postoperative wound infection	Infections and infestations	—	—
Peripheral artery stenosis	Vascular disorders	—	—
Carotid artery stenosis	Nervous system disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Gangrene	Infections and infestations	—	—
Cellulitis	Infections and infestations	—	—
Localised infection	Infections and infestations	—	—
Wound infection	Infections and infestations	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Peripheral artery restenosis	Injury, poisoning and procedural complications	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Cardiac failure	Cardiac disorders	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Lung neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Sepsis	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Cholecystitis acute	Hepatobiliary disorders	—	—
Osteomyelitis	Infections and infestations	—	—

Other adverse events (141 terms — click to expand)

Reaction	System	Rivaroxaban 2.5 mg Bid + A…	Rivaroxaban Placebo Bid + …
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Hypertension	Vascular disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Intermittent claudication	Vascular disorders	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Dizziness	Nervous system disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Oedema peripheral	General disorders	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Skin ulcer	Skin and subcutaneous tissue disorders	—	—
Bronchitis	Infections and infestations	—	—
Chest pain	General disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Gastritis	Gastrointestinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Cataract	Eye disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Depression	Psychiatric disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Type 2 diabetes mellitus	Metabolism and nutrition disorders	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—
Sciatica	Nervous system disorders	—	—
Hypertensive crisis	Vascular disorders	—	—
Peripheral artery stenosis	Vascular disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Fatigue	General disorders	—	—
Diabetes mellitus	Metabolism and nutrition disorders	—	—
Peripheral artery occlusion	Vascular disorders	—	—
Vertigo	Ear and labyrinth disorders	—	—

Most-reported serious reactions: Peripheral arterial occlusive disease, Intermittent claudication, Pneumonia, Peripheral ischaemia, Postoperative wound infection, Peripheral artery stenosis, Carotid artery stenosis, Coronary artery disease.

Data from ClinicalTrials.gov NCT02504216 adverse events section.

Sponsor's own description

The purpose of study was to test whether rivaroxaban added to standard of care treatment, when compared to placebo, had the potential to reduce the incidence of the clinical events related to the clots and complications of the heart and brain (CV death, MI, or stroke) or the legs (acute limb ischemia or major amputation) in patients who had undergone recent procedure(s) to improve the blood flow of their legs.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia.
   Conte MS, Bradbury AW, Kolh P, White JV, et al · · 2019 · cited 997× · PMID 31182334 · DOI 10.1016/j.ejvs.2019.05.006
2. Global vascular guidelines on the management of chronic limb-threatening ischemia.
   Conte MS, Bradbury AW, Kolh P, White JV, et al · · 2019 · cited 932× · PMID 31159978 · DOI 10.1016/j.jvs.2019.02.016
3. Rivaroxaban in Peripheral Artery Disease after Revascularization.
   Bonaca MP, Bauersachs RM, Anand SS, Debus ES, et al · · 2020 · cited 646× · PMID 32222135 · DOI 10.1056/nejmoa2000052
4. Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial.
   Kaplovitch E, Eikelboom JW, Dyal L, Aboyans V, et al · · 2021 · cited 91× · PMID 32997098 · DOI 10.1001/jamacardio.2020.4390
5. Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.
   Hiatt WR, Bonaca MP, Patel MR, Nehler MR, et al · · 2020 · cited 67× · PMID 33138628 · DOI 10.1161/circulationaha.120.050465
6. Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial.
   Debus ES, Nehler MR, Govsyeyev N, Bauersachs RM, et al · · 2021 · cited 30× · PMID 34380322 · DOI 10.1161/circulationaha.121.054835
7. Total Ischemic Event Reduction With Rivaroxaban After Peripheral Arterial Revascularization in the VOYAGER PAD Trial.
   Bauersachs RM, Szarek M, Brodmann M, Gudz I, et al · · 2021 · cited 29× · PMID 34010631 · DOI 10.1016/j.jacc.2021.05.003
8. Safety and Effectiveness of Paclitaxel Drug-Coated Devices in Peripheral Artery Revascularization: Insights From VOYAGER PAD.
   Hess CN, Patel MR, Bauersachs RM, Anand SS, et al · · 2021 · cited 22× · PMID 34711335 · DOI 10.1016/j.jacc.2021.08.052