voyager xarelto

Create Free Account or

• Acute Coronary Syndromes
• Anticoagulation Management
• Arrhythmias and Clinical EP
• Cardiac Surgery
• Cardio-Oncology
• Cardiovascular Care Team
• Congenital Heart Disease and Pediatric Cardiology
• COVID-19 Hub
• Diabetes and Cardiometabolic Disease
• Dyslipidemia
• Geriatric Cardiology
• Heart Failure and Cardiomyopathies
• Invasive Cardiovascular Angiography and Intervention
• Noninvasive Imaging
• Pericardial Disease
• Pulmonary Hypertension and Venous Thromboembolism
• Sports and Exercise Cardiology
• Stable Ischemic Heart Disease
• Valvular Heart Disease
• Vascular Medicine
• Clinical Updates & Discoveries
• Advocacy & Policy
• Perspectives & Analysis
• Meeting Coverage
• ACC Member Publications
• ACC Podcasts
• View All Cardiology Updates
• Earn Credit
• View the Education Catalog
• ACC Anywhere: The Cardiology Video Library
• CardioSource Plus for Institutions and Practices
• ECG Drill and Practice
• Heart Songs
• Nuclear Cardiology
• Online Courses
• Collaborative Maintenance Pathway (CMP)
• Understanding MOC
• Image and Slide Gallery
• Annual Scientific Session and Related Events
• Chapter Meetings
• Live Meetings
• Live Meetings - International
• Webinars - Live
• Webinars - OnDemand
• Certificates and Certifications
• ACC Accreditation Services
• ACC Quality Improvement for Institutions Program
• CardioSmart
• National Cardiovascular Data Registry (NCDR)
• Advocacy at the ACC
• Cardiology as a Career Path
• Cardiology Careers
• Cardiovascular Buyers Guide
• Clinical Solutions
• Clinician Well-Being Portal
• Diversity and Inclusion
• Infographics
• Innovation Program
• Mobile and Web Apps

VOYAGER-PAD: Rivaroxaban Associated With Reduced Adverse Limb, CV Events in PAD Patients

Acc news story.

Peripheral artery disease (PAD) patients who have undergone lower-extremity revascularization and take rivaroxaban plus aspirin may have a lower incidence of major adverse limb and cardiovascular events than patients who take aspirin alone, according to results of the VOYAGER-PAD trial presented March 28 at ACC.20/WCC during a Late-Breaking Clinical Trial session and simultaneously published in the New England Journal of Medicine .

Marc P. Bonaca, MD, MPH, FACC, et al., randomly assigned 6,564 PAD patients who had undergone lower-extremity revascularization to take rivaroxaban 2.5 mg twice daily plus aspirin or a placebo and aspirin. The international trial involved 534 sites in 34 countries and ran from July 2015 to January 2018.

A total of 3,286 patients were assigned to the rivaroxaban group and 3,278 were assigned to the placebo group. The median age of patients was 67 years, and 26% were women. At baseline, 40% were diabetic, 60% had hyperlipidemia, and about 32% had coronary artery disease.

In terms of their PAD history, 95% had claudication, 35% prior revascularization and 6% amputation. The median ankle brachial index was 0.56. Critical limb ischemia was the indication for revascularization in 23% and claudication in 77%. Surgical revascularization was the approach in 35% and endovascular or a hybrid approach in 77%. 

The primary efficacy outcome – defined as a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction (MI), ischemic stroke or cardiovascular death – occurred in 508 patients in the rivaroxaban group, compared with 584 patients in the placebo group. The Kaplan-Meier estimates of incidence at three years were 17.3% for the rivaroxaban group vs. 19.9% for the placebo group (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76-0.96; p =0.009). The absolute risk reduction was 1.5% at six months, 2.0% at one year and 2.6% at three years.

The principal safety outcome – defined as major bleeding based on the Thrombolysis in Myocardial Infarction (TIMI) classification – occurred in 62 patients in the rivaroxaban group and 44 in the placebo group (HR, 1.43; 95% CI, 0.97-2.10, p=0.07). The secondary safety outcome – defined as International Society on Thrombosis and Haemostasis major bleeding – occurred in 5.9% and 4.1% of the rivaroxaban and placebo groups, respectively (HR, 1.42; 95% CI, 1.10-1.84; p=0.007).

According to the researchers, rivaroxaban significantly reduces the risk of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke or cardiovascular death, compared with aspirin alone in this population and setting. In addition, the researchers note the benefit of rivaroxaban was apparent early in treatment and was consistent over time across major subgroups, including patients with critical limb-threatening ischemia, and reduces the need for unplanned index limb revascularization. Although ISTH major bleeding was increased with rivaroxaban, there was no apparent excess in severe bleeding events.

"We found adding low-dose rivaroxaban after peripheral artery intervention significantly reduced the spectrum of complications that we fear most in PAD, which is acute limb ischemia, major vascular amputation, heart attack and stroke. This benefit was not only seen early on but was also maintained over time," says Bonaca, the study's lead author. "These data provide evidence of an antithrombotic regimen that effectively reduces risk, and although bleeding rates were higher, the overall risk-benefit remains quite favorable and could have a profound impact on patients' lives."

No Benefit in Adding Clopidogrel

Adding clopidogrel to the rivaroxaban and aspirin regime at the time of revascularization did not offer additional clinical benefit, according a VOYAGER-PAD subgroup analysis presented March 29 at ACC.20/WCC during a Late-Breaking Clinical Trial session.

For this prespecified subgroup analysis, William R. Hiatt, MD, et al., randomly assigned half of the patients to receive clopidogrel at the time of revascularization for up to six months. The patients receiving clopidogrel were more likely to undergo endovascular procedures (90.7%) vs. surgery (9.3%).

After a median follow up of 28 months, the addition of clopidogrel had no effect on the 15% reduction in the risk of major limb or cardiovascular complications among patients taking rivaroxaban. TIMI major bleeding was reported in 2.7% of patients who received clopidogrel vs. 2.6% of those who did not. Minor TIMI bleeding events occurred in 1.67% of patients in the clopidogrel group vs. 1.26% who did not take clopidogrel. In addition, ISTH major bleeding occurred in 6.5% of patients taking clopidogrel vs. 5.4% of those not taking the medication. Intracranial bleeds were infrequent and similar among those taking and not taking clopidogrel, respectively.

The benefits rivaroxaban and aspirin were consistent regardless of whether patients also took clopidogrel, but clopidogrel increased the risk of bleeding, the researchers conclude. "We found that in this [clinical] setting, where we are treating patients with symptomatic PAD with lower extremity revascularization procedures, the addition of clopidogrel [atop] rivaroxaban and aspirin does not provide any further benefit, but did increase bleeding risks, so there doesn't seem to be a compelling reason to use it," Hiatt says.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure

Keywords: ACC Annual Scientific Session, acc20, Aspirin, Peripheral Arterial Disease, Heart Failure, Primary Prevention, Aneurysm

You must be logged in to save to your library.

Jacc journals on acc.org.

• JACC: Advances
• JACC: Basic to Translational Science
• JACC: CardioOncology
• JACC: Cardiovascular Imaging
• JACC: Cardiovascular Interventions
• JACC: Case Reports
• JACC: Clinical Electrophysiology
• JACC: Heart Failure
• Current Members
• Campaign for the Future
• Become a Member
• Renew Your Membership
• Member Benefits and Resources
• Member Sections
• ACC Member Directory
• ACC Innovation Program
• Our Strategic Direction
• Our History
• Our Bylaws and Code of Ethics
• Leadership and Governance
• Annual Report
• Industry Relations
• Support the ACC
• Jobs at the ACC
• Press Releases
• Social Media
• Book Our Conference Center

Clinical Topics

• Chronic Angina
• Congenital Heart Disease and     Pediatric Cardiology
• Diabetes and Cardiometabolic     Disease
• Hypertriglyceridemia
• Invasive Cardiovascular Angiography    and Intervention
• Pulmonary Hypertension and Venous     Thromboembolism

Latest in Cardiology

Education and meetings.

• Online Learning Catalog
• Products and Resources
• Annual Scientific Session

Tools and Practice Support

• Quality Improvement for Institutions
• Accreditation Services
• Practice Solutions

Heart House

• 2400 N St. NW
• Washington , DC 20037
• Contact Member Care
• Phone: 1-202-375-6000
• Toll Free: 1-800-253-4636
• Fax: 1-202-375-6842
• Media Center
• Advertising & Sponsorship Policy
• Clinical Content Disclaimer
• Editorial Board
• Privacy Policy
• Registered User Agreement
• Terms of Service
• Cookie Policy

© 2024 American College of Cardiology Foundation. All rights reserved.

• Latest News
• Venous News
• Supplements
• Past Issues
• Subscriptions

VOYAGER PAD analyses shed light on use of rivaroxaban in high-risk patient populations

New analyses from the VOYAGER PAD clinical trial in both high-risk and fragile patients and those with and without comorbid coronary artery diseases (CAD) were presented at the American Heart Association (AHA) 2023 Scientific Sessions (11–13 November, Philadelphia, USA).

The randomised, double blind VOYAGER PAD trial enrolled more than 6,500 patients in 34 countries who had peripheral arterial disease (PAD) and had undergone lower extremity revascularisation.

Patients were randomly assigned to receive either rivaroxaban (Xarelto, Janssen) or a placebo in addition to daily aspirin. The research team reported in a late-breaking clinical trial presented at ACC.20/WCC that VOYAGER PAD met its primary endpoint, with a 15% statistically significant reduction in the risk of a first major adverse limb or cardiovascular event (MALE or MACE) seen in patients who received rivaroxaban compared with those who received the placebo.

Fragile patients with PAD can be at a heightened risk for MALE, defined as a composite of acute limb ischemia (ALI) and major amputation. In the first of the two analyses presented by Mario Enrico Canonico (University of Colorado Anschutz Medical Campus, Aurora, USA) fragile patients were defined as being older than 75 years, weighing less than 50kg, or having a baseline estimated glomerular filtration rate (eGFR) less than 50 mL/min/1.73 2 .

Rivaroxaban plus aspirin (2.5mg twice daily plus aspirin 100 mg once daily) was shown to be effective in reducing the occurrence of MALE in both fragile and non-fragile patients, compared to aspirin alone. In fragile patients treated with rivaroxaban plus aspirin, 6.2% of patients experienced a MALE compared to 10.3% of patients treated with placebo. In non-fragile patients, 7.9% of patients treated with rivaroxaban plus aspirin experienced a MALE compared to 9.7% of patients treated with placebo.

The second analysis examined the role of rivaroxaban plus aspirin on myocardial infarction (MI) in patients with PAD with and without concomitant coronary artery disease following lower extremity revascularisation (LER).

Following LER, patients with PAD are four times more likely to experience acute limb ischaemia, or a rapid decrease in lower limb blood flow, which is often associated with long hospitalisations and high incidences of amputation, disability, and death unless appropriate treatment is given.

Patients with PAD are also at a heightened risk of MACE, defined as MI, ischaemic stroke, or cardiovascular death. In this analysis, 14.1% of patients with PAD and coronary artery disease treated with rivaroxaban plus aspirin experienced a MACE versus 17.6% of patients treated with placebo (aspirin alone). In patients with PAD only, 11% of patients treated with rivaroxaban plus aspirin experienced a MACE versus 9.8% of patients treated with placebo. Overall, rivaroxaban plus aspirin showed a consistent benefit in reducing MACE in patients with and without coronary artery disease.

“These analyses reinforce the consistency of the favourable benefit-risk profile of Xarelto plus aspirin for patients with vascular disease, regardless of comorbidity. For example, patients categorised as ‘fragile’ are often undertreated due to concerns about benefit-risk, particularly with antithrombotic treatments,” said Marc Bonaca (University of Colorado Anschutz Medical Campus, Aurora, USA). “We hope the ongoing wealth of data coming from VOYAGER PAD presented at AHA offers clinicians the information they need to support shared decision-making in prescribing Xarelto plus aspirin as the standard of care for their PAD patients, including those who are high-risk or complex.”

In August 2021, the US Food and Drug Administration (FDA) approved an expanded PAD indication for Xarelto to include patients following a recent LER due to symptomatic PAD. Xarelto acts on a dual pathway inhibition (DPI) approach to target both clotting mechanisms, thrombin and platelet activation.

LEAVE A REPLY Cancel reply

Save my name, email, and website in this browser for the next time I comment.

Women face increased risk of stroke and readmission after carotid interventions

Fist Assist receives FDA Breakthrough Device designation for wearable vein dilation...

Rates of stroke, death and myocardial infarction post-TCAR do not differ...

Ultrafast contrast-enhanced ultrasound for PAD patients shows promise in early feasibility...

Learning in the workplace: Fostering a culture of reciprocity is key

Who, why and where: Experts address key questions on the future...

Daniel Clair

Peter Schneider

Rachel Bell

Write to us Editor: Jocelyn Hudson [email protected] Advertising: Rav Pankhania [email protected]

Search Results

No matching results, recently viewed.

Listening...

New VOYAGER PAD Analysis Confirms Consistent Benefit of XARELTO ® (rivaroxaban) Plus Aspirin Following Lower Extremity Revascularization (LER)

Findings presented at acc.23 show xarelto ® plus aspirin provides a 33 percent reduction in acute limb ischemia following ler, with consistent benefit demonstrated at 30 days, 90 days and up to three years patients who undergo ler are four times more likely to experience acute limb ischemia, which can lead to amputation or death if left untreated [i] xarelto ® is the first and only anticoagulant approved in combination with aspirin for reducing the risk of major thrombotic vascular events * in patients with peripheral artery disease (pad).

• Copy link Link copied

TITUSVILLE, NJ, March 5, 2023 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced data from a new prespecified analysis from the Phase 3 VOYAGER PAD clinical trial reinforcing the benefits of the XARELTO ® (rivaroxaban) vascular dose (2.5 mg twice daily plus aspirin 100 mg once daily) over standard of care (aspirin alone), demonstrating consistent benefit at 30 days, 90 days and up to three years following LER in patients with PAD. Lower extremity revascularization, also called peripheral revascularization, is a procedure that restores blood flow in blocked arteries or veins. This analysis of the VOYAGER PAD study showed XARELTO ® plus aspirin resulted in a 33 percent reduction in acute limb ischemia and a 15 percent reduction in major adverse limb and cardiovascular events, with or without dual antiplatelet therapy (DAPT). These latest XARELTO ® data were presented at the American College of Cardiology’s 72nd Annual Scientific Session (ACC.23), hosted in New Orleans, Louisiana, March 4-6, 2023.

“These data demonstrate an evolution in the medical therapy of patients undergoing lower extremity revascularization for symptomatic peripheral artery disease, where the addition of low dose rivaroxaban to antiplatelet therapy results in a 33 percent reduction in major adverse limb events both early and late and with a consistently favorable benefit risk,” said Marc P. Bonaca ** , M.D., Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. “We hope these data assist clinicians in understanding how to implement antithrombotic therapy in practice and overall support initiation of rivaroxaban in the first days after revascularization regardless of whether or not DAPT is utilized.”

Following LER, patients with PAD are four times more likely to experience acute limb ischemia, or a rapid decrease in lower limb blood flow, which is often associated with long hospitalizations and high incidences of amputation, disability, and death unless appropriate treatment is given. 1 Those treated with XARELTO ® plus aspirin after LER saw a 33 percent reduction in acute limb ischemia, with a trend toward greater benefit observed early (≤30 days HR=0.45; 95% CI, 0.24–0.85) versus late (>90 days HR=0.75; 95% CI 0.60-0.95). XARELTO ® plus aspirin was more effective than antiplatelet therapy alone in preventing acute limb ischemia after LER (Kaplan-Meier estimate from 0 to 90 days 1.02% vs. 2.10%, respectively, and 4.3% and 5.7% from 91 days to three years). The hazard ratio for the rate of thrombolysis in myocardial infarction (TIMI) major bleeding at 0 to 90 days was HR 2.01 (range 0.9-4.47) and from days 91 up to three years was HR 1.28 (range 0.82-1.99), neither of which were statistically significant.

“These findings provide additional insights on the proven clinical utility of XARELTO ® for people living with PAD, particularly those who have undergone lower extremity revascularization,” said Avery Ince, M.D., Ph.D., Vice President, Medical Affairs, Cardiovascular & Metabolism, Janssen Scientific Affairs, LLC. “At Janssen, we remain steadfast in our commitment to advance science that can transform cardiovascular care for all.”

In August 2021, the U.S. Food and Drug Administration (FDA) approved an expanded PAD indication for the XARELTO ® vascular dose (2.5 mg twice daily plus aspirin 100 mg once daily) to include patients following a recent LER due to symptomatic PAD. The XARELTO ® vascular dose is the first and only approved anticoagulant for PAD. XARELTO ® acts on a dual pathway inhibition (DPI) approach to target both clotting mechanisms, thrombin and platelet activation.

About VOYAGER PAD The Phase 3 VOYAGER PAD study included 6,564 patients from 542 sites across 34 countries worldwide. Patients were randomized in a 1:1 ratio and received either the XARELTO ® vascular dose (2.5 mg twice daily plus aspirin 100 mg once daily) (n=3,286) or aspirin alone (100 mg once daily) (n=3,278). Patients were stratified by revascularization procedure type (endovascular vs. surgical) and use of clopidogrel, which was administered at the treating physician’s discretion. Patients were followed for a median of 28 months.

The VOYAGER PAD study met its primary efficacy and principal safety endpoints, demonstrating the XARELTO ® vascular dose was superior to aspirin alone in reducing the risk of major adverse limb and cardiovascular events (composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or cardiovascular death) by 15 percent in patients with symptomatic PAD after lower-extremity revascularization. The benefit of adding XARELTO ® to aspirin was apparent early, was consistent among major subgroups and continued to accrue over time. There was no significant increase in thrombolysis in myocardial infarction (TIMI) major bleeding observed in patients treated with the XARELTO ® vascular dose compared to aspirin alone (Kaplan-Meier estimate at three years 2.65% vs. 1.87%, respectively).

About XARELTO ® (rivaroxaban) XARELTO ® is a prescription medicine used to:

• reduce the risk of stroke and blood clots in adults who have a medical condition called atrial fibrillation that is not caused by a heart valve problem. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing a stroke, or to other parts of the body
• treat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary embolism or PE)
• reduce the risk of blood clots from happening again in adults who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least 6 months
• help prevent a blood clot in the legs and lungs of adults who have just had hip or knee replacement surgery
• help prevent blood clots in certain adults hospitalized for an acute illness and after discharge, who are at risk of getting blood clots because of the loss of or decreased ability to move around (mobility) and other risks for getting blood clots, and who do not have a high risk of bleeding

XARELTO ® is used with low dose aspirin to:

• reduce the risk of serious heart problems, heart attack and stroke in adults with coronary artery disease (a condition where the blood supply to the heart is reduced or blocked)
• reduce the risk of a sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in adults with peripheral artery disease (a condition where the blood flow to the legs is reduced) and includes adults who have recently had a procedure to improve blood flow to the legs

XARELTO ® is used in children to:

• treat blood clots or reduce the risk of blood clots from happening again in children from birth to less than 18 years, after receiving at least 5 days of treatment with injectable or intravenous medicines used to treat blood clots
• help prevent blood clots in children 2 years and older with congenital heart disease after the Fontan procedure

XARELTO ® was not studied and is not recommended in children less than 6 months of age who:

• were less than 37 weeks of growth (gestation) at birth
• had less than 10 days of oral feeding, or
• had a body weight of less than 5.7 pounds (2.6 kg)

IMPORTANT SAFETY INFORMATION

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO ® ?

XARELTO ® may cause serious side effects, including:

• Increased risk of blood clots if you stop taking XARELTO ® . People with atrial fibrillation (an irregular heart beat ) that is not caused by a heart valve problem (nonvalvular) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO ® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO ® , you may have increased risk of forming a clot in your blood.

Do not stop taking XARELTO ® without talking to the doctor who prescribes it for you. Stopping XARELTO ® increases your risk of having a stroke. If you have to stop taking XARELTO ® , your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

• Increased risk of bleeding. XARELTO ® can cause bleeding which can be serious and may lead to death. This is because XARELTO ® is a blood thinner medicine (anticoagulant) that lowers blood clotting. During treatment with XARELTO ® you are likely to bruise more easily, and it may take longer for bleeding to stop. You may be at higher risk of bleeding if you take XARELTO ® and have certain other medical problems.

You may have a higher risk of bleeding if you take XARELTO ® and take other medicines that increase your risk of bleeding, including:

• Aspirin or aspirin-containing products
• Long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)
• Warfarin sodium (Coumadin ® , Jantoven ® )
• Any medicine that contains heparin
• Clopidogrel (Plavix ® )
• Selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
• Other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you or your child develop any of these signs or symptoms of bleeding:

• Nosebleeds that happen often
• Unusual bleeding from gums
• Menstrual bleeding that is heavier than normal, or vaginal bleeding
• Bleeding that is severe or you cannot control
• Red, pink, or brown urine
• Bright red or black stools (looks like tar)
• Cough up blood or blood clots
• Vomit blood or your vomit looks like “coffee grounds”
• Headaches, feeling dizzy or weak
• Pain, swelling, or new drainage at wound sites
• A thin tube called an epidural catheter is placed in your back to give you certain medicine
• You take NSAIDs or a medicine to prevent blood from clotting
• You have a history of difficult or repeated epidural or spinal punctures
• You have a history of problems with your spine or have had surgery on your spine

If you take XARELTO ® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots.

Tell your doctor right away if you have:

• muscle weakness (especially in your legs and feet
• or loss of control of the bowels or bladder (incontinence)

XARELTO ® is not for use in people with artificial heart valves.

XARELTO ® is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing.

Do not take XARELTO ® if you or your child:

• Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO ® if you currently have unusual bleeding.
• Are allergic to rivaroxaban or any of the ingredients of XARELTO ® .

Before taking XARELTO ® , tell your doctor about all your medical conditions, including if you or your child:

• Have ever had bleeding problems
• Have liver or kidney problems
• Have antiphospholipid syndrome (APS)
• Tell your doctor right away if you become pregnant during treatment with XARELTO ® . Taking XARELTO ® while you are pregnant may increase the risk of bleeding in you or in your unborn baby.
• Females who are able to become pregnant: Talk with your doctor about pregnancy planning during treatment with XARELTO ® . Talk with your doctor about your risk for severe uterine bleeding if you are treated with blood thinner medicines, including XARELTO ® .
• If you take XARELTO ® during pregnancy, tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See “What is the most important information I should know about XARELTO ® ?” for signs and symptoms of bleeding.
• Are breastfeeding or plan to breastfeed. XARELTO ® may pass into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with XARELTO ® .

Tell all of your doctors and dentists that you or your child are taking XARELTO ® . They should talk to the doctor who prescribed XARELTO ® for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some of your other medicines may affect the way XARELTO ® works, causing side effects. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO ® ?”

HOW SHOULD I TAKE XARELTO ® ?

• Take XARELTO ® exactly as prescribed by your doctor.
• Do not change your dose or stop taking XARELTO ® unless your doctor tells you to. Your doctor may change your dose if needed.
• Your doctor will decide how long you should take XARELTO ® .
• XARELTO ® may need to be stopped for one or more days before any surgery or medical or dental procedure. Your doctor will tell you when to stop taking XARELTO ® and when to start taking XARELTO ® again after your surgery or procedure.
• If you need to stop taking XARELTO ® for any reason, talk to the doctor who prescribed XARELTO ® to you to find out when you should stop taking it. Do not stop taking XARELTO ® without first talking to the doctor who prescribes it to you.
• If you have difficulty swallowing XARELTO ® tablets whole, talk to your doctor about other ways to take XARELTO ® .
• Do not run out of XARELTO ® . Refill your prescription of XARELTO ® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO ® available to avoid missing any doses.
• If you take too much XARELTO ® , go to the nearest hospital emergency room or call your doctor right away.

If you take XARELTO ® for:

• Take XARELTO ® 1 time a day with your evening meal.
• If you miss a dose of XARELTO ® , take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
• Take XARELTO ® 1 or 2 times a day as prescribed by your doctor.
• For the 10-mg dose , XARELTO ® may be taken with or without food.
• For the 15-mg and 20-mg doses , take XARELTO ® with food at the same time each day.
• If you take the 15-mg dose of XARELTO ® 2 times a day (a total of 30 mg of XARELTO ® in 1 day): Take XARELTO ® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.
• If you take XARELTO ® 1 time a day: Take XARELTO ® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
• Take XARELTO ® 1 time a day with or without food.
• Take XARELTO ® 1 time a day, with or without food, while you are in the hospital and after you are discharged as prescribed by your doctor.
• Take XARELTO ® 2.5 mg 2 times a day with or without food.
• If you miss a dose of XARELTO ® , take your next dose at your regularly scheduled time.
• Take aspirin 75 to 100 mg once daily as instructed by your doctor.

Reducing the risk of a sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in people with peripheral artery disease, including those who have recently had a procedure to improve blood flow to the legs:

For children who take XARELTO ® :

• The dose of XARELTO ® depends on your child’s body weight and will be calculated by your child’s doctor. Your child’s doctor will tell you if XARELTO ® can be given to your child with or without food.
• The adult caregiver should give the dose.
• If your child is taking the tablet, the tablet should be taken whole and should not be split in an attempt to provide a lower dose of XARELTO ® .
• If your child is taking the oral suspension, use the syringes provided in the original carton. The suspension will be prepared by the pharmacy. See the Instructions for Use included in the carton on how to properly give a dose of XARELTO ® oral suspension to your child.
• Do not switch between the XARELTO ® oral suspension or tablet without first talking to your doctor.
• right after or within 30 minutes of taking the oral suspension, give a new full dose.
• more than 30 minutes after taking the oral suspension, do not give the dose again. Give the next dose at the regularly scheduled time.

if vomiting or spitting up persists, contact your child’s doctor right away.

If your child misses a dose:

• If your child is taking XARELTO ® 1 time a day, give the dose as soon as you remember on the same day. If this is not possible, skip this dose and give the next dose at the regularly scheduled time.
• If your child is taking XARELTO ® 2 times a day, give the missed morning dose as soon as you remember. You may give the missed morning dose together with the evening dose. However, a missed evening dose can only be taken in the same evening.
• If your child is taking XARELTO ® 3 times a day, skip the missed dose and give the next dose at the regularly scheduled time.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO ® ?

XARELTO ® may cause serious side effects:

• See “What is the most important information I should know about XARELTO ® ?”

The most common side effect of XARELTO ® in adults was bleeding.

The most common side effects of XARELTO ® in children include:

• inflamed stomach and gut

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).

Please read full Prescribing Information , including Boxed Warnings, and Medication Guide for XARELTO ® .

Trademarks are those of their respective owners. Janssen and Bayer together are developing rivaroxaban.

About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension.

Learn more at www.janssen.com . Follow us at www.twitter.com/JanssenUS and https://twitter.com/JanssenGlobal . Janssen Scientific Affairs, LLC, is part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking Statements This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of rivaroxaban. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Scientific Affairs, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 1, 2023, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov , www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

* Reduction of a composite of myocardial infarction, ischemic stroke, acute limb ischemia and major amputation of a vascular etiology.

** Dr. Marc Bonaca is the lead study author of the VOYAGER PAD analysis entitled “Consistent Benefit of Rivaroxaban Early and Late after Lower Extremity Revascularization” and was provided payment for his participation in the study; he has not been compensated for contributing to this press release.

Media Contacts: Joy-Lee Pasqualoni Phone: (917) 547-8078 [email protected]

Kaitlin Meiser Phone: (908) 938-3209 [email protected]

Investor Relations: Raychel Kruper Phone: (732) 524-6164

Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD

Affiliations.

• 1 Division of Cardiology, Department of Medicine (C.N.H., M.S., J.H., S.D.B., M.P.B.), University of Colorado School of Medicine, Aurora.
• 2 Colorado Prevention Center Clinical Research, Aurora (C.N.H., M.R.N., M.S., W.H.C., J.H., S.D.B., M.P.B.).
• 3 Department of Vascular Medicine, Vascular Surgery-Angiology-Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany (E.S.D.).
• 4 Department of Surgery (M.R.N.), University of Colorado School of Medicine, Aurora.
• 5 Population Health Research Institute, Hamilton Health Sciences, McMaster University, Canada (S.S.A.).
• 6 Duke Clinical Research Institute, Division of Cardiology, Duke University Medical Center, Durham, NC (M.R.P.).
• 7 State University of New York Downstate Health Sciences University, Brooklyn (M.S.).
• 8 Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora (W.H.C.).
• 9 Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN (J.A.B.).
• 10 Division of Angiology, Medical University Graz, Austria (M.B.).
• 11 Instituto Cardiovascular de Rosario, Argentina (R.D.).
• 12 Vascular Surgery, Konventhospital Barmherzige, Brüder Linz, Austria (P.H.).
• 13 Division of Vascular Surgery, Department of Surgery, Stanford University, CA (N.J.L.).
• 14 Section of Vascular Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.P.).
• 15 Department of Vascular Surgery, Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Denmark (H.S.).
• 16 Bayer AG, Research & Development, Wuppertal, Germany (E.M.).
• 17 Janssen Research and Development, Raritan, NJ (L.P.H.).
• 18 Cardiovascular Center Bethanien, CCB, Frankfurt, and Center for Thrombosis and Hemostasis, University of Mainz, Germany (R.M.B.).
• PMID: 34637332
• DOI: 10.1161/CIRCULATIONAHA.121.055146

Background: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Previous lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking.

Methods: The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; r NCT02504216 ) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan-Meier estimates, and Cox proportional hazards models were used to generate hazard ratios and associated CIs. Analyses were performed as intention-to-treat.

Results: Among 6564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, previous LER, baseline ankle-brachial index <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (hazard ratio [HR], 2.59 [95% CI, 1.98-3.39]) and major amputation (HR, 24.87 [95% CI, 18.68-33.12]). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction, 2.6% at 3 years; HR, 0.67 [95% CI, 0.55-0.82]; P =0.0001), with benefit starting early (HR, 0.45 [95% CI, 0.24-0.85]; P =0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and intensive care unit stay, HR, 0.58 [95% CI, 0.40-0.83]; P =0.003) and regardless of LER type (surgical versus endovascular revascularization, P interaction=0.42) or clopidogrel use ( P interaction=0.59).

Conclusions: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.

Keywords: lower extremity; peripheral arterial disease; rivaroxaban; thrombosis.

Publication types

• Multicenter Study
• Randomized Controlled Trial
• Research Support, Non-U.S. Gov't
• Acute Disease
• Aspirin / administration & dosage
• Ischemia / therapy*
• Lower Extremity / blood supply*
• Middle Aged
• Numbers Needed To Treat
• Rivaroxaban / administration & dosage*
• Rivaroxaban

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• JAMA Network

Rivaroxaban and Risk of Venous Thromboembolism in Patients With Symptomatic Peripheral Artery Disease After Lower Extremity Revascularization

Connie n. hess.

1 Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora

2 CPC Clinical Research, Aurora, Colorado

Michael Szarek

3 The State University of New York Downstate Health Sciences University, Brooklyn

Sonia S. Anand

4 Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Canada

Rupert M. Bauersachs

5 Department of Vascular Medicine, Klinikum Darmstadt, Darmstadt, and Center for Thrombosis and Hemostasis, University of Mainz, Mainz, Germany

Manesh R. Patel

6 Duke Clinical Research Institute, Division of Cardiology, Duke University Medical Center, Durham, North Carolina

E. Sebastian Debus

7 Department of Vascular Medicine, Vascular Surgery–Angiology–Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany

Mark R. Nehler

8 University of Colorado School of Medicine, Department of Surgery, Aurora

Warren H. Capell

9 Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

Joshua A. Beckman

10 Cardiovascular Division, Vanderbilt University Medical Center, Nashville, Tennessee

Gregory Piazza

11 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Stanislav Henkin

12 Heart and Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

Alessandra Bura-Rivière

13 Toulouse University Hospital, Toulouse, France

Holger Lawall

14 Praxis für Herzkreislaufkrankheiten und Akademie für Gefäßkrankheiten, Ettlingen, Germany

Karel Roztocil

15 Department of Transplantational Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic

Judith Hsia

Eva muehlhofer.

16 Bayer, Research & Development, Wuppertal, Germany

Scott D. Berkowitz

17 Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora

Lloyd P. Haskell

18 Janssen Research and Development, Raritan, New Jersey

Marc P. Bonaca

Accepted for Publication: April 15, 2022.

Published: June 22, 2022. doi:10.1001/jamanetworkopen.2022.15580

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License . © 2022 Hess CN et al. JAMA Network Open .

Author Contributions: Drs Hess and Szarek had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Hess, Anand, Bauersachs, Patel, Nehler, Bura-Riviere, Haskell, Bonaca.

Acquisition, analysis, or interpretation of data: Hess, Szarek, Anand, Patel, Debus, Nehler, Capell, Beckman, Piazza, Henkin, Bura-Riviere, Lawall, Roztocil, Hsia, Muehlhofer, Berkowitz, Haskell, Bonaca.

Drafting of the manuscript: Hess, Bauersachs, Bonaca.

Critical revision of the manuscript for important intellectual content: Hess, Szarek, Anand, Patel, Debus, Nehler, Capell, Beckman, Piazza, Henkin, Bura-Riviere, Lawall, Roztocil, Hsia, Muehlhofer, Berkowitz, Haskell, Bonaca.

Statistical analysis: Szarek.

Obtained funding: Patel, Bura-Riviere, Berkowitz.

Administrative, technical, or material support: Hess, Bura-Riviere, Roztocil, Berkowitz, Haskell.

Supervision: Anand, Bauersachs, Patel, Debus, Piazza, Bura-Riviere, Lawall, Hsia, Muehlhofer, Berkowitz, Haskell, Bonaca.

Conflict of Interest Disclosures: Dr Szarek reported receiving grants from Baxter and Resverlogix; personal fees from CiVi and Esperion; grants, personal fees, and nonfinancial support from Sanofi; and grants and nonfinancial support from Regeneron outside the submitted work. Dr Anand reported receiving personal fees from Bayer and Janssen outside the submitted work. Dr Bauersachs reported receiving personal fees from Bayer during the conduct of this study and personal fees from Bristol Myers Squibb, Daiichi Sankyo, Leo Pharma, and Pfizer outside the submitted work. Dr Patel reported receiving personal fees from Bayer and Heartflow during the conduct of the study and grants and personal fees from AstraZeneca and Heartflow and grants from Heartflow, Janssen, Medtronic, Novartis, and Philips Healthcare outside the submitted work. Dr Debus reported receiving grants from Cook and Terumo Aortic outside the submitted work. Dr Beckman reported receiving personal fees from Amgen, Bayer, JanOne, Janssen, Novartis, and VIVA and grants from Bristol Myers Squibb outside the submitted work. Dr Piazza reported receiving grants from Alexion, Amgen, Bayer, Boston Scientific, Bristol Myers Squibb/Pfizer Alliance, and Janssen (paid to his institution), and personal fees from Amgen, Boston Scientific, Brazilian Clinical Research Institute, Bristol Myers Squibb, Janssen, Pfizer, Prairie Education and Research Cooperative, and Syntactx outside the submitted work. Dr Henkin reported receiving personal fees from Pfizer outside the submitted work. Dr. Bura-Rivière reported serving as a paid consultant for Bayer. Dr Lawall reported receiving personal fees from Bayer Vital during the conduct of the study. Dr Roztocil reported serving as a national coordinator for Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial. Dr Hsia reported receiving personal fees from the University of Pittsburgh and owning stock in AstraZeneca. Dr Muehlhofer reported being employed by Bayer during the conduct of this study. Dr Berkowitz reported being employed by Bayer during the conduct and operationalization of VOYAGER PAD. Dr Haskell reported being employed by Janssen Pharmaceuticals and owning stock in Johnson & Johnson outside the submitted work. Drs Hess, Szarek, Nehler, Capell, Hsia, Berkowitz, and Bonaca reported receiving salary support from CPC Clinical research, a nonprofit academic research organization affiliated with the University of Colorado, that receives grants and consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading, Esperion Therapeutics, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group. No other disclosures were reported.

Funding/Support: The VOYAGER PAD trial was funded by Bayer and Janssen Pharmaceuticals. Dr Bonaca was supported by the American Heart Association Strategically Focused Research Network in Vascular Disease under award No. 18SFRN3390085 (Brigham and Women’s Hospital [BWH]–Dartmouth-Hitchcock [DH] Medical Center Strategically Focused Research Networks Center) and 18SFRN33960262 (BWH-DH Clinical Project). The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association.

Role of the Funder/Sponsor: CPC Clinical Research held the database and performed all analyses, and the decision to submit this manuscript for publication was made by the VOYAGER PAD Publications Committee. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Associated Data

What are the risks of venous thromboembolism (VTE) after lower extremity revascularization (LER) for peripheral artery disease (PAD), and is use of low-dose rivaroxaban plus aspirin associated with risk of VTE after LER?

In this cohort study of 6564 patients undergoing LER for PAD, the 3-year rate of VTE in patients receiving placebo was 1.66%, and low-dose rivaroxaban plus aspirin was associated with reduced risk for VTE.

These findings suggest that patients who underwent LER for PAD were at risk for VTE in addition to arterial thrombotic events, and low-dose rivaroxaban plus aspirin should be considered for reduction of the full spectrum of thrombotic risk.

This cohort study assesses the risk factors and outcomes associated with venous thromboembolism after lower extremity revascularization among patients with peripheral artery disease.

Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER).

To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER.

Design, Setting, and Participants

This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021.

Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician.

Main Outcomes and Measures

Symptomatic VTE was a prespecified secondary outcome and prospectively collected.

Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P  = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67).

Conclusions and Relevance

In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.

Introduction

Peripheral artery disease (PAD) is associated with risk of arterial thrombotic complications and a broad range of manifestations of atherosclerosis-associated arterial thrombosis. 1 Studies have demonstrated elevated risk of severe cardiovascular and limb ischemic events, including myocardial infarction (MI), stroke, acute limb ischemia, and major amputation, among patients with chronic PAD. 2 , 3 , 4 , 5 After lower extremity revascularization (LER) for symptomatic PAD, the risk of arterial thrombotic complications is even greater, both early and in the long term after the procedure. 1 , 5 , 6 , 7 The contribution of arterial thrombosis to ischemic risk in PAD has thus formed the basis for antithrombotic treatment.

Beyond risk for arterial thrombosis, data support an association between atherosclerosis and venous thromboembolism (VTE). 8 Patients with VTE have been observed to have increased risk of concomitant atherosclerosis, as well as increased risk of subsequent atherosclerotic ischemic events. 8 , 9 , 10 More recently, in a combined analysis 11 of 2 antiplatelet therapy trials, Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50 (TRA°2P-TIMI 50) 12 and Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–TIMI 54 (PEGASUS-TIMI 54), 13 patients with stable atherosclerotic cardiovascular disease, including PAD, were at risk for not only arterial thrombosis but also VTE, with higher VTE risk associated with greater burden of atherosclerosis. In the combined study by Cavallari et al, 11 more intensive antiplatelet therapy was associated with lower risk of VTE. Similarly, the addition of a low-dose anticoagulant, rivaroxaban 2.5 mg twice daily, to aspirin vs aspirin alone was also associated with a 39% lower rate of VTE (hazard ratio [HR], 0.61; 95% CI, 0.37-1.00) in patients with stable atherosclerotic cardiovascular disease in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial. 14

These observations raise the question as to the pattern and magnitude of VTE risk in patients with symptomatic PAD in the acute postrevascularization setting and whether the potential benefits of more potent antithrombotic therapy with low-dose rivaroxaban observed in stable, chronic PAD might extend to the postprocedural setting, where use of dual antiplatelet therapy is common. Therefore, VTE was a prespecified outcome of the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial. 15 This study describes the risk of, factors associated with, and outcomes after VTE, as well as the association between rivaroxaban plus antiplatelet therapy and VTE in the VOYAGER PAD trial.

This cohort study, a prespecified secondary analysis of the VOYAGER PAD study, was approved by institutional review boards at VOYAGER PAD participating institutions. All patients provided written, informed consent. This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

Data Source

Data for this cohort were from VOYAGER PAD ( {"type":"clinical-trial","attrs":{"text":"NCT02504216","term_id":"NCT02504216"}} NCT02504216 ), the design and results of which have been previously published. 15 , 16 VOYAGER PAD was a double-blind randomized clinical trial conducted at 542 sites in 34 countries, randomizing patients undergoing LER for symptomatic PAD to rivaroxaban 2.5 mg twice daily or placebo with a background of aspirin 100 mg daily. Concomitant clopidogrel use for no more than 6 months was allowed. The trial was designed and overseen by Colorado Prevention Center (CPC) Clinical Research (an academic research organization affiliated with the University of Colorado), the academic executive committee, and the sponsors, Bayer and Janssen Pharmaceuticals. CPC Clinical Research holds the clinical database and independently performed all analyses for this study.

Study Population

From 2015 to 2018, VOYAGER PAD enrolled patients with symptomatic PAD aged 50 years and older who underwent successful LER for claudication or critical limb ischemia via an endovascular (including hybrid) or surgical approach within the previous 10 days. Key exclusion criteria included planned dual antiplatelet therapy for more than 6 months, need for systemic anticoagulation (including acute treatment or long-term secondary prevention of VTE), recent acute limb ischemia or acute coronary syndrome, increased risk of bleeding, significantly impaired baseline kidney function, and prior intracranial hemorrhage, stroke, or transient ischemic attack. In VOYAGER PAD, race was self-reported as American Indian or Alaska Native, Asian, Black, Native Hawaiian or other Pacific Islander, multiple races, and White. These data were collected as part of an international clinical trial, as they can provide information about the study population.

In VOYAGER PAD, the primary efficacy end point was a composite of acute limb ischemia, major amputation of vascular etiology, MI, ischemic stroke, or cardiovascular death; symptomatic VTE, defined as pulmonary embolism or deep vein thrombosis, was prospectively ascertained by investigator report and was a prespecified secondary end point. For this analysis, symptomatic VTE was the primary end point. VTE severity was classified according to hospitalization or death within 30 days of the VTE event. An independent clinical events committee blinded to treatment assignment adjudicated all deaths and potential ischemic cardiovascular and limb events.

Statistical Analysis

Examining the association between rivaroxaban and risk of VTE was a prespecified secondary analysis of VOYAGER PAD. Categorical variables are reported as count (percentage), and continuous variables as median (IQR). Baseline characteristics grouped by incident VTE status during follow-up were compared using Wilcoxon rank-sum tests for continuous variables and χ 2 or Fisher exact tests (where possible) for categorical variables.

A multivariable Cox regression model with stepwise selection was used to identify baseline demographic and clinical variables associated with VTE. Given the small number of VTE events, P  = .10 was used for model entry or exit. Candidate variables are listed in the eTable in the Supplement . A model to estimate the association between all-cause death and incident VTE as a time-varying covariate was determined, with adjustment for treatment assignment and other baseline factors significantly related to VTE during follow-up, and stratification according to the type of procedure and according to whether clopidogrel was intended to be used. The risk of these events before vs after VTE was also summarized by the number of events per 100 patient-years of follow-up and associated 95% CIs. The association between rivaroxaban and time to first VTE was assessed by a Cox proportional hazards models, stratified by type of revascularization procedure and intended use of baseline clopidogrel. The treatment effect was summarized by an HR with associated Wald 95% CI and log-rank P value. A sensitivity analysis for the outcome accounted for death from any cause as a competing terminal event. Event probabilities were determined by Kaplan-Meier estimates of cumulative incidence. Potential heterogeneity of the association of rivaroxaban with VTE for subgroups defined by baseline demographic and clinical characteristics was assessed by the significance of interaction terms in proportional hazards models. Analyses of clinical outcomes were performed according to the intention-to-treat principle, including all patients and events from randomization to the study efficacy cutoff date. Two-tailed P  < .05 was considered statistically significant, with no adjustment for multiple testing. Analyses were performed in SAS version 9.4 (SAS Institute) and S-Plus version 8.2 (MS Miami International Software). Data were analyzed from September 2020 to September 2021.

Baseline Characteristics

Among 6564 patients randomized in VOYAGER PAD and followed for a median (IQR) of 28 (22-34) months, 66 patients (1.0%) had at least 1 VTE event, and the incidence of VTE was 0.42 per 100 patient-years. Baseline characteristics according to incident VTE status are shown in the Table . Patients with VTE, compared with patients without VTE, were older (median [IQR] age, 68 [64-75] years vs 67 [61-73] years), had greater body weight (7.6% vs 16.6% with weight ≤60 kg), and more frequently had hypertension (90.9% vs 81.3%). Patients with VTE vs those without also had more severe PAD, as indicated by more frequent history of LER (43.9% vs 35.5%) and amputation (10.6% vs 5.9%).

Abbreviations: ABI, ankle-brachial index; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.

Factors Associated With VTE

After multivariable modeling ( Figure 1 ), baseline factors independently associated with VTE risk included older age (HR, 1.81; 95% CI, 1.06-3.11), weight (HR, 3.04; 95% CI, 1.09-8.43), and hypertension (HR, 2.11; 95% CI, 0.91-4.89). Prior amputation (HR, 2.07; 95% CI, 0.95-4.53), an indicator of PAD severity, was also associated with VTE risk. Clopidogrel use at randomization was not associated with VTE risk (HR, 0.66; 95% CI, 0.41-1.08), but rivaroxaban use was (HR, 0.60; 95% CI, 0.37-0.998; P  = .047). Clopidogrel was used for a median (IQR) of 29 (26-50) days in the overall study population.

Associated variables (candidate variables are listed in the eTable in the Supplement ) were identified by stepwise selection with a P  = .10 for model entry or exit. HR indicates hazard ratio.

Outcomes After VTE

Of the first VTE events occurring during follow-up, 27 (40.9%) were nonfatal and did not lead to hospitalization, 29 (43.9%) led to hospitalization, and 10 (15.2%) were associated with death within 30 days of the VTE event ( Figure 2 ). Overall, of 66 patients who experienced a VTE event, 23 (34.8%) subsequently died over a median (IQR) of 1.2 (0.2-1.8) years. Across treatment groups, incident VTE was associated with a greater risk of subsequent death compared with no VTE, with a marked increase in events per 100 patient-years after a VTE event (all-cause mortality: 3.7 [95% CI, 3.4-4.0] deaths per 100 patient-years before VTE vs 28.8 [95% CI, 18.2-43.1] deaths per 100 patient-years after VTE). After adjusting for the factors significantly associated with VTE, VTE was associated with significantly increased risk of all-cause death during follow-up (HR, 7.22; 95% CI, 4.66-11.19).

Shown are the distributions of venous thromboembolism event severity in patients randomized to placebo or rivaroxaban.

Rivaroxaban vs Placebo and VTE

In patients randomized in VOYAGER PAD, rivaroxaban was associated with a 39% lower risk of VTE (HR, 0.61; 95% CI, 0.37-0.998; P  = .047) ( Figure 3 ), with event rates at 3 years of 1.7% in those receiving antiplatelet therapy alone, with a linear pattern of risk (year 1: 0.5%; year 2: 1.1%), and 0.8% in those receiving rivaroxaban in addition to antiplatelet therapy. Among 41 patients in the placebo group with VTE, 25 events were deep vein thrombosis and 16 events were pulmonary embolism; among 25 patients in the rivaroxaban group with VTE, 19 events were deep vein thrombosis and 6 events were pulmonary embolism. Furthermore, the association between rivaroxaban and decreased risk of VTE was unchanged when death from any cause was treated as a competing terminal event (HR, 0.61; 95% CI, 0.37-0.995; P  = .048). The association between rivaroxaban and VTE was consistent among multiple subgroups and irrespective of use of clopidogrel and statin at randomization ( Figure 4 ). There were no statistically significant differences in the number of events in each category of VTE severity ( Figure 2 ).

Shown are the cumulative incidence curves for venous thromboembolism in patients assigned to rivaroxaban vs placebo and the hazard ratio (HR) and associated 95% CI.

CAD indicates coronary artery disease; eGFR, estimated glomerular filtration rate; and HR, hazard ratio.

This cohort study reports 3 novel findings on the risk of VTE and benefit associated with rivaroxaban in patients with PAD after LER. First, the rate of VTE after LER was approximately 0.6% per year, which is approximately 2-fold that seen in stable atherosclerosis populations, 11 , 14 and both patient factors (eg, age, obesity) and severity of PAD (eg, prior amputation) were associated with VTE risk. Second, the pattern of risk for VTE was not front-loaded, as might be anticipated in the postprocedural setting, but rather was linear and continuous, suggesting that VTE was a consequence of the disease state rather than the procedure. Third, in addition to the arterial benefits described in the VOYAGER PAD trial, rivaroxaban was also associated with a lower rate of VTE, underscoring the broad thrombotic benefits of this strategy in patients at heightened thrombotic risk.

Although atherothrombosis, or atherosclerosis-associated arterial thrombosis, and VTE are often considered separate entities, an evolving body of literature suggests an association between atherosclerotic vascular disease and VTE. In a large population-based case-control study, risk for subsequent MI and stroke was 20% to 40% higher among patients with VTE compared with controls, and VTE was associated with 1.9-fold increased risk of MI and 2.7-fold increased risk of stroke. 9 Conversely, patients with a history of symptomatic atherosclerotic cardiovascular disease have also been found to be at increased risk of VTE. 11 , 17 In addition, arterial and venous thrombosis share common risk factors, such as age and obesity, 18 and data suggest that thrombophilia and inflammation may play a role in both conditions. 19 , 20 , 21 Statins, which have anti-inflammatory properties, 22 have been associated with 20% to 30% decreased risk of VTE, 23 , 24 , 25 and there was an observed trend for reduction in VTE associated with PCSK9-inhibitor use in acute coronary syndromes, with the risk of VTE related to reduction in the proinflammatory lipoprotein(a), 26 but not low-density lipoprotein cholesterol. 27 Further evidence for shared pathobiology in atherothrombosis and VTE comes from the finding of increased platelet activation in patients with VTE, 28 , 29 suggesting cross-talk between platelet function and coagulation. Consistent with this finding is the additional 29% reduction in VTE associated with more intensive antiplatelet therapy demonstrated in TRA°2P-TIMI 50 and PEGASUS-TIMI 54. 11 , 12 , 13

Given this association between atherosclerosis and VTE, we examined VTE as a potential complication after LER for symptomatic PAD. In patients with stable atherosclerotic vascular disease with mixed CAD and PAD assigned to placebo in a pooled analysis of the TRA°2P-TIMI 50 and PEGASUS-TIMI 54 trials and in the COMPASS trial, the rate of VTE was approximately 0.3% per year. 11 , 12 , 13 , 14 In contrast, the risk of VTE among patients in the placebo group in VOYAGER PAD was almost 2-fold higher (approximately 0.6% per year). In this population, patient factors, such as older age and greater weight, as well as greater PAD severity, as evidenced by history of lower extremity amputation, were associated with VTE risk. These findings provide a more complete understanding of the true spectrum of thrombotic risk facing patients with PAD undergoing revascularization and may help to identify patients at higher risk for VTE after LER. Although attention has been focused on postprocedure arterial complications, VTE events are not benign and can be associated with significant morbidity, mortality, and cost. 30 , 31 In our analysis, 44% of VTE complications required inpatient treatment, and 15% of patients died within 30 days of their VTE event. Increased risk of death after incident VTE within the first year, as well as long-term up to 30 years after, has also been observed. 32

Beyond raising awareness of the heightened risk for VTE after LER, our results also provide insight into the underlying pathophysiology of VTE in this population. We hypothesized that VTE risk might be higher immediately after LER, perhaps related to procedure-associated hypercoagulability and reduced mobility. However, we observed a linear and continuous pattern of risk for VTE after LER. This pattern suggests that VTE risk is related to PAD itself, rather than only to procedure- or hospitalization-related factors. Along with the observed post-LER VTE risk that was almost 2-fold that in patients with stable vascular disease, these results suggest that more severe atherosclerosis (eg, symptomatic PAD treated with LER) is associated with VTE risk and further support an association between atherosclerosis and venous thrombotic events.

Interestingly, concomitant CAD was not identified as a factor associated with VTE in this analysis. Prior studies have demonstrated that among patients with stable atherosclerotic disease, polyvascular disease (ie, disease in more than 1 vascular territory) is associated with greater risk of major adverse cardiovascular events compared with disease in a single vascular territory. 33 , 34 However, most patients in those studies had CAD; thus, the term polyvascular has often referred to the addition of PAD to CAD. In this study, CAD was not informative for risk: having baseline CAD in addition to PAD was not associated with greater risk of VTE. While this may be related to the presence of CAD in only approximately one-third of the population and low numbers of events, the data also suggest that perhaps in this population, the burden of atherosclerosis overall is not as important as the burden of PAD specifically. This is consistent with the identification of prior major lower extremity amputation reflecting severe PAD as a baseline characteristic associated with VTE. Functional limitations and decreased mobility associated with PAD may also contribute to increased risk of VTE in this setting. Furthermore, prior data have demonstrated that, in contrast to CAD, pathological manifestations of PAD are related to thrombosis irrespective of the extent of atherosclerosis, 35 providing additional support for greater thrombotic risk associated with PAD than other atherosclerotic diseases.

Although antiplatelet agents remain first-line therapy for atherosclerotic vascular disease, most recently, greater intensity of antithrombotic therapy with dual pathway inhibition combining a factor Xa inhibitor with aspirin has been studied for the prevention of thrombotic complications in patients with vascular disease. In COMPASS, 14 rivaroxaban 2.5 mg twice daily plus low-dose aspirin was associated with lower VTE risk in patients with stable atherosclerotic disease who were only treated with single antiplatelet therapy. Our study from VOYAGER PAD demonstrates that even in the higher risk, acute setting of LER for symptomatic PAD, among patients often treated with dual antiplatelet therapy, rivaroxaban plus aspirin was associated with a 39% reduction in VTE, with an effect apparent early after the procedure and irrespective of clopidogrel or statin use at randomization. These findings should be considered hypothesis-generating, since VTE was a low-event secondary outcome. Taken together with the primary results of VOYAGER PAD, 15 these results suggest that this strategy of dual pathway inhibition may be associated with long-term protection against the spectrum of venous and arterial post-LER thrombotic complications. Importantly, both potential benefit and risk should be considered when selecting patients for more intensive antithrombotic therapy after LER. For example, older age, a factor associated with VTE risk in this study, is also a risk factor for bleeding procedural complications. However, the events prevented with rivaroxaban after LER extend beyond VTE, and there is an overall net benefit for use of rivaroxaban in this setting among older patients, with an estimated 38 ischemic events prevented at a cost of 8 TIMI major bleeds without intracranial hemorrhage or fatal bleeding among 1000 patients aged 75 years and older treated for 3 years with rivaroxaban plus aspirin after LER. 36

Limitations

This study has several limitations. First, VTE was a secondary end point in VOYAGER PAD and was investigator reported; however, VTE was prospectively ascertained, and this analysis was prespecified. Second, adjusted models accounted for known baseline characteristics, but postrandomization variables were not included, and residual confounding may exist. Third, although associated factors were modeled, formal predictive modeling, including cross-validation, was not performed owing to the number of events. Fourth, the number of VTE events was small, which may have resulted in overfitting of models, and fifth, the median time to death after VTE likely reflects a combination of fatal VTE events and nonfatal VTE events. Sixth, although the P value associated with rivaroxaban effect on VTE was P  < .05, it should be considered nominal, given its position in the hierarchy of testing of secondary outcomes in VOYAGER PAD.

Conclusions

This cohort study found that patients with symptomatic PAD undergoing LER were at heightened risk for VTE, with almost 2-fold the risk observed in patients with stable vascular disease. Postprocedure VTE risk accrued in a linear, continuous fashion, suggesting that risk was related more to PAD rather than the procedure. VTE was associated with poor prognosis, and patient and PAD characteristics may help clinicians identify patients at risk for VTE events. Rivaroxaban plus aspirin was associated with lower risk of VTE after LER. Combined with the arterial benefits reported in VOYAGER PAD, these findings highlight the broad thrombotic benefits of this approach in patients with PAD.

Supplement.

eTable. Candidate Variables for Factors Associated With VTE

• Today's news
• Reviews and deals
• Climate change
• 2024 election
• Fall allergies
• Health news
• Mental health
• Sexual health
• Family health
• So mini ways
• Unapologetically
• Buying guides

Entertainment

• How to Watch
• My watchlist
• Stock market
• Biden economy
• Personal finance
• Stocks: most active
• Stocks: gainers
• Stocks: losers
• Trending tickers
• World indices
• US Treasury bonds
• Top mutual funds
• Highest open interest
• Highest implied volatility
• Currency converter
• Basic materials
• Communication services
• Consumer cyclical
• Consumer defensive
• Financial services
• Industrials
• Real estate
• Mutual funds
• Credit cards
• Balance transfer cards
• Cash back cards
• Rewards cards
• Travel cards
• Online checking
• High-yield savings
• Money market
• Home equity loan
• Personal loans
• Student loans
• Options pit
• Fantasy football
• Pro Pick 'Em
• College Pick 'Em
• Fantasy baseball
• Fantasy hockey
• Fantasy basketball
• Download the app
• Daily fantasy
• Scores and schedules
• GameChannel
• World Baseball Classic
• Premier League
• CONCACAF League
• Champions League
• Motorsports
• Horse racing
• Newsletters

New on Yahoo

• Privacy Dashboard

15 men brought to military enlistment office after mass brawl in Moscow Oblast

Local security forces brought 15 men to a military enlistment office after a mass brawl at a warehouse of the Russian Wildberries company in Elektrostal, Moscow Oblast on Feb. 8, Russian Telegram channel Shot reported .

29 people were also taken to police stations. Among the arrested were citizens of Kyrgyzstan.

A mass brawl involving over 100 employees and security personnel broke out at the Wildberries warehouse in Elektrostal on Dec. 8.

Read also: Moscow recruits ‘construction brigades’ from Russian students, Ukraine says

We’re bringing the voice of Ukraine to the world. Support us with a one-time donation, or become a Patron !

Read the original article on The New Voice of Ukraine

Recommended Stories

Tigers take jab at lions' former rival aaron rodgers in scoreboard trivia game.

The Detroit Tigers' scoreboard operator had some fun at Aaron Rodgers' expense during Sunday's game with the Milwaukee Brewers.

Giants TE Darren Waller retires after 1 season with team, describes scary medical situation that preceded decision

The Giants traded a third-round pick to acquire Waller from the Raiders in 2023.

Angel Reese's 'weak' ejection from Sky-Liberty game draws attention, offer from Bulls' Lonzo Ball

Reese was ejected after two very quick whistles from referee Charles Watson.

Top RBs for 2024 fantasy football, according to our experts

The Yahoo Fantasy football analysts reveal their first running back rankings for the 2024 NFL season.

Sparks rookie Cameron Brink: 'There's a privilege' for WNBA's younger white players

The Sparks rookie had plenty to say about her WNBA rookie class, headlined by Caitlin Clark.

NBA Finals: Kristaps Porziņģis vows to play in Game 3 after apparent Game 2 injury: 'I'll die out there'

Kristaps Porziņģis acknowledged that "something happened" but declined to elaborate on an apparent Game 2 injury. He's adamant that he'll play in Game 3.

Formula 1: Max Verstappen wins chaotic Canadian Grand Prix

This was not your typical Verstappen snoozer.

Belmont Stakes 2024 winner, results: Dornoch scores upset victory at Saratoga giving former MLBer Jayson Werth a win on the track

The 156th running of the Belmont Stakes is headed to Saratoga

Iowa basketball player Ava Jones retires due to injuries from car accident that killed her father

Ava Jones and her family were hit by an allegedly impaired driver two days after she committed to the Hawkeyes.

Vikings reveal 'Winter Warrior' alternate all-white uniforms to be worn on Week 15

The Minnesota Vikings revealed their all-white "Winter Warrior" uniforms that the team will wear for Week 15's matchup with the Chicago Bears.

Rivian's path to survival is now remarkably clear

Rivian has had a lot on its plate as it transitioned from pitch mode to selling EVs. It created an electric pickup and an electric SUV while prepping a monster IPO. It now plans to sell an even cheaper SUV that could make Rivian a dominant EV player for years to come.

Sky's Chennedy Carter has 'no regrets' about foul on Caitlin Clark; Angel Reese will 'take the bad guy role'

The Sky have broken their silence about the flagrant foul on Caitlin Clark, and they had a lot to say.

GameStop stock soars as 'Roaring Kitty' announces livestream, reveals $382 million unrealized gain

First X, then Reddit, now YouTube. GameStop's most bullish enthusiast announced a livestream, and the stock surged.

Opposing players aren't fond of Caitlin Clark ... which should be good for the WNBA

Watching Clark fight through adversity and rack up rivals will only bring more eyeballs to the league.

NFL denies Packers RB Josh Jacobs' claim that wearing green isn't allowed in Brazil game due to potential violence

No, the Packers and Eagles aren't being told to not wear green for a game in Brazil.

Ryan Garcia arrested for alleged felony vandalism at Beverly Hills hotel

It has been a bizarre two months for the star boxer.

2025 Ford Expedition spy photos reveal major exterior overhaul

2025 Ford Expedition full-size SUV spy photos show a significantly changed exterior that takes cues from the recently updated F-150 pickup truck.

Bobby Witt Jr. comes through in 9th as Royals erase 8-0 deficit to stun Mariners

MLB hadn't seen a comeback like this since 1995.

Lashinda Demus will get her Olympic gold medal ... 12 years later

Demus will receive her gold medal at a ceremony at the foot of the Eiffel Tower during the 2024 Summer Olympics.

2025 Toyota Crown Signia First Drive: Venza replacement puts efficiency and fashion first

Our first drive review of the 2025 Toyota Crown Signia where we tell you all about it and give initial driving impressions.

• Bahasa Indonesia
• Eastern Europe
• Moscow Oblast

Elektrostal

Elektrostal Localisation : Country Russia , Oblast Moscow Oblast . Available Information : Geographical coordinates , Population, Altitude, Area, Weather and Hotel . Nearby cities and villages : Noginsk , Pavlovsky Posad and Staraya Kupavna .

Information

Find all the information of Elektrostal or click on the section of your choice in the left menu.

• Update data

Elektrostal Demography

Information on the people and the population of Elektrostal.

Elektrostal Geography

Geographic Information regarding City of Elektrostal .

Elektrostal Distance

Distance (in kilometers) between Elektrostal and the biggest cities of Russia.

Elektrostal Map

Locate simply the city of Elektrostal through the card, map and satellite image of the city.

Elektrostal Nearby cities and villages

Elektrostal weather.

Weather forecast for the next coming days and current time of Elektrostal.

Elektrostal Sunrise and sunset

Find below the times of sunrise and sunset calculated 7 days to Elektrostal.

Elektrostal Hotel

Our team has selected for you a list of hotel in Elektrostal classified by value for money. Book your hotel room at the best price.

Elektrostal Nearby

Below is a list of activities and point of interest in Elektrostal and its surroundings.

The Unique Burial of a Child of Early Scythian Time at the Cemetery of Saryg-Bulun (Tuva)

<< Previous page

Pages:  379-406

In 1988, the Tuvan Archaeological Expedition (led by M. E. Kilunovskaya and V. A. Semenov) discovered a unique burial of the early Iron Age at Saryg-Bulun in Central Tuva. There are two burial mounds of the Aldy-Bel culture dated by 7th century BC. Within the barrows, which adjoined one another, forming a figure-of-eight, there were discovered 7 burials, from which a representative collection of artifacts was recovered. Burial 5 was the most unique, it was found in a coffin made of a larch trunk, with a tightly closed lid. Due to the preservative properties of larch and lack of air access, the coffin contained a well-preserved mummy of a child with an accompanying set of grave goods. The interred individual retained the skin on his face and had a leather headdress painted with red pigment and a coat, sewn from jerboa fur. The coat was belted with a leather belt with bronze ornaments and buckles. Besides that, a leather quiver with arrows with the shafts decorated with painted ornaments, fully preserved battle pick and a bow were buried in the coffin. Unexpectedly, the full-genomic analysis, showed that the individual was female. This fact opens a new aspect in the study of the social history of the Scythian society and perhaps brings us back to the myth of the Amazons, discussed by Herodotus. Of course, this discovery is unique in its preservation for the Scythian culture of Tuva and requires careful study and conservation.

Keywords: Tuva, Early Iron Age, early Scythian period, Aldy-Bel culture, barrow, burial in the coffin, mummy, full genome sequencing, aDNA

Information about authors: Marina Kilunovskaya (Saint Petersburg, Russian Federation). Candidate of Historical Sciences. Institute for the History of Material Culture of the Russian Academy of Sciences. Dvortsovaya Emb., 18, Saint Petersburg, 191186, Russian Federation E-mail: [email protected] Vladimir Semenov (Saint Petersburg, Russian Federation). Candidate of Historical Sciences. Institute for the History of Material Culture of the Russian Academy of Sciences. Dvortsovaya Emb., 18, Saint Petersburg, 191186, Russian Federation E-mail: [email protected] Varvara Busova  (Moscow, Russian Federation).  (Saint Petersburg, Russian Federation). Institute for the History of Material Culture of the Russian Academy of Sciences.  Dvortsovaya Emb., 18, Saint Petersburg, 191186, Russian Federation E-mail:  [email protected] Kharis Mustafin  (Moscow, Russian Federation). Candidate of Technical Sciences. Moscow Institute of Physics and Technology.  Institutsky Lane, 9, Dolgoprudny, 141701, Moscow Oblast, Russian Federation E-mail:  [email protected] Irina Alborova  (Moscow, Russian Federation). Candidate of Biological Sciences. Moscow Institute of Physics and Technology.  Institutsky Lane, 9, Dolgoprudny, 141701, Moscow Oblast, Russian Federation E-mail:  [email protected] Alina Matzvai  (Moscow, Russian Federation). Moscow Institute of Physics and Technology.  Institutsky Lane, 9, Dolgoprudny, 141701, Moscow Oblast, Russian Federation E-mail:  [email protected]

Shopping Cart Items: 0 Cart Total: 0,00 € place your order

Price pdf version

student - 2,75 € individual - 3,00 € institutional - 7,00 €

Copyright В© 1999-2022. Stratum Publishing House