voyager pad nejm

Rivaroxaban in patients with symptomatic peripheral artery disease after lower extremity bypass surgery with venous and prosthetic conduits

Affiliations.

• 1 CPC Clinical Research & Community Health, Aurora, CO; Division of Vascular Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO.
• 2 CPC Clinical Research & Community Health, Aurora, CO; Division of Vascular Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO. Electronic address: [email protected].
• 3 Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA.
• 4 Department of Vascular Medicine, Vascular Surgery-Angiology-Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany.
• 5 Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, TX.
• 6 Department of Vascular Surgery, Careggi Polyclinic Hospital, University of Florence, Florence, Italy.
• 7 Department of Surgery, Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine.
• 8 Pauls Stradinš University Hospital, University of Latvia, Riga, Latvia.
• 9 Department of Vascular Surgery, University Medical Center, Utrecht, the Netherlands.
• 10 Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
• 11 Department of Vascular Surgery, ASST dei Sette Laghi, Varese, Italy.
• 12 Section of Vascular Surgery, Dartmouth Hitchcock Medical Center, Lebanon, NH; Section of Vascular Surgery, Geisel School of Medicine at Dartmouth, Hanover, NH.
• 13 Division of Vascular Surgery, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
• 14 Division of Cardiology, Department of Vascular Surgery, Rigshospitalet, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
• 15 Division of Vascular Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO.
• 16 CPC Clinical Research & Community Health, Aurora, CO; Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; State University of New York, Downstate Health Sciences University, Brooklyn, NY.
• 17 Cardioangiologic Center, Agaplesion Bethanien Hospital, Frankfurt am Main, Germany; Center for Thrombosis and Hemostasis, University of Mainz, Mainz, Germany.
• 18 Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
• 19 Duke Clinical Research Institute, Division of Cardiology, Duke University, Durham, NC.
• 20 CPC Clinical Research & Community Health, Aurora, CO; Division of Endocrinology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
• 21 CPC Clinical Research & Community Health, Aurora, CO.
• 22 CPC Clinical Research & Community Health, Aurora, CO; Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
• 23 Bayer AG Research and Development, Wuppertal, Germany.
• 24 Janssen Research and Development, Raritan, NJ.
• 25 CPC Clinical Research & Community Health, Aurora, CO; Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
• PMID: 36470531
• DOI: 10.1016/j.jvs.2022.11.062

Background: Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the 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) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described.

Methods: In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline.

Results: Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (P interaction = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance.

Conclusions: Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.

Trial registration: ClinicalTrials.gov NCT02504216 .

Keywords: Antithrombotic therapy; Bypass; Conduit; Multicenter; Subgroup analysis.

Copyright © 2022 Society for Vascular Surgery. All rights reserved.

Publication types

• Randomized Controlled Trial
• Research Support, Non-U.S. Gov't
• Aspirin / therapeutic use
• Hemorrhage / chemically induced
• Ischemia / diagnostic imaging
• Ischemia / drug therapy
• Ischemia / surgery
• Lower Extremity / blood supply
• Myocardial Infarction* / drug therapy
• Peripheral Arterial Disease* / diagnostic imaging
• Peripheral Arterial Disease* / surgery
• Platelet Aggregation Inhibitors / adverse effects
• Rivaroxaban / adverse effects
• Treatment Outcome
• Rivaroxaban
• Platelet Aggregation Inhibitors

Associated data

• ClinicalTrials.gov/NCT02504216

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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

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ACC.21: VOYAGER PAD analysis shows reduced risk of ischaemic events in PAD patients receiving rivaroxaban

Rivaroxaban (Xarelto, Bayer/Janssen), in addition to low-dose aspirin, should be considered as an adjunctive therapy after lower extremity revascularisation to reduce first and subsequent adverse outcomes, analysis from VOYAGER PAD, presented during a late-breaking trial session at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21, 15–17 May, virtual), indicates. The findings were simultaneously published online in the Journal of the American College of Cardiology ( JACC ).

Rupert Bauersachs, director of vascular medicine at the Darmstadt Clinic (Darmstadt, Germany) and lead author of the study told ACC.21 attendees that the use of rivaroxaban significantly reduced the occurrence of total severe events of the heart, limb or brain and issues related to other vascular complications in patients with symptomatic peripheral arterial disease (PAD) who underwent lower extremity revascularisation. The findings underscore the broad benefits of this strategy in this high-risk patient population, he said.

“To our knowledge, this is the first time that the addition of low-dose rivaroxaban to aspirin has been clearly shown to reduce the occurrence of both first and total adverse events in patients with PAD who have undergone lower extremity revascularisation but remain at high risk for a heart attack, stroke or recurrent arterial blockage in a limb,” Bauersachs said. “The benefits we saw in the trial for total events were statistically significant and entirely consistent with those for first events. Rivaroxaban 2.5mg twice daily with aspirin should be considered as adjunctive therapy after revascularisation to reduce first and subsequent adverse outcomes.”

Recent data have shown that, after lower extremity revascularisation, there is a four-fold risk of acute limb ischaemia, Bauersachs told ACC.21 attendees, adding that this is associated with a high incidence of limb-related complications.

“There is a need for greater awareness that PAD is a distinct disease state and that patients with PAD have a high risk for cardiovascular adverse events and are generally a very vulnerable population, especially in the post-revascularisation setting,” Bauersachs said. “Care for these patients is often fragmented because the surgeon or interventionalist who performs the revascularisation may not follow them for complications or recurrences. They deserve to receive optimal treatment to reduce the risk of recurrences.”

The randomised, double blind VOYAGER PAD trial enrolled 6,564 patients in 34 countries who had PAD and had undergone lower extremity revascularisation. The patients’ median age was 67 years and 74% were men.

Patients were randomly assigned to receive either rivaroxaban or a placebo in addition to daily aspirin. The trial’s primary endpoint was timed to the first event of a composite of acute limb ischaemia, major amputation of vascular aetiology, myocardial infarction (MI), ischaemic stroke or cardiovascular death. Another prespecified endpoint was the total number of vascular events, including recurrent primary endpoint events as well as other vascular events. The median follow-up time was 28 months after revascularisation.

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 seen in patients who received rivaroxaban compared with those who received the placebo. The current study reports on the total number of vascular events, with over 4,700 occurring in the 6,564 patients randomised over three years.

“There were 342 fewer adverse events in the rivaroxaban group than in the placebo group, which translates to an absolute reduction in risk of 12.5%,” Bauersachs said. “In a high-risk population, that is a big gain in avoiding the need for patients to come back with vascular complications.”

The 6,564 study participants experienced a total of 4,714 vascular events during the study period with 2,301—or about one-third—experiencing at least one vascular event, Bauersachs said.

“So, during approximately three years of follow-up, about two to three out of six patients with PAD had a vascular event in spite of high utilisation of background medical therapy. This overall rate of vascular events is eye-opening and speaks to the high vulnerability of this patient population,” Bauersachs said. “First events are just the tip of the iceberg.”

A limitation of the study is that the trial was designed to assess the occurrence of first adverse events following lower extremity revascularisation, Bauersachs said. Therefore, in a double blinded trial, patients may come off study treatment or go on to other therapies after an event, which can attenuate the observed benefit. Assessment of the total number of adverse events, however, was a prespecified secondary endpoint and despite this limitation, the findings were statistically significant and robust in absolute terms.

VOYAGER PAD was funded by pharmaceutical companies Bayer and Janssen, who in a press release highlighting the presentation of the results, said that the analysis showed a very high burden of subsequent events and a consistent 14% reduction in both primary endpoint events and total vascular events over a median of 2.5 years.

“The VOYAGER PAD trial is the first and only study of antithrombotic therapy in the past 20 years to demonstrate a significant benefit in patients with PAD after lower extremity revascularisation,” James List, global therapeutic area head, Cardiovascular & Metabolism, Janssen Research & Development, was quoted as saying in the release. “With these new data, we now have a full picture of evidence demonstrating the potential of Xarelto in treating patients through various stages of PAD—chronic, symptomatic, those requiring revascularisation and beyond.”

“Even years after revascularisation, patients with PAD continue to have a markedly high risk for future thrombotic events due to excessive thrombin generation and platelet aggregation,” added Marc P Bonaca, Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, (Aurora, USA). “This analysis from VOYAGER PAD looked beyond the first event and found subsequent thrombotic event reduction with rivaroxaban plus aspirin, underscoring the importance of long-term prevention in these high-risk patients.”

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May 16, 2021

VOYAGER PAD Shows Rivaroxaban Reduces First and Total Ischemic Events in Patients With PAD

May 16, 2021—Findings from the VOYAGER PAD trial demonstrated that rivaroxaban, in addition to low-dose aspirin, significantly reduced the occurrence of total severe events of the heart, limb, or brain and issues related to other vascular complications in patients with symptomatic peripheral artery disease (PAD) who underwent lower extremity revascularization.

“To our knowledge, this is the first time that the addition of low-dose rivaroxaban to aspirin has been clearly shown to reduce the occurrence of both first and total adverse events in patients with PAD who have undergone lower extremity revascularization but remain at high risk for a heart attack, stroke, or recurrent arterial blockage in a limb,” commented the study’s lead author Rupert Bauersachs, MD, in a press release from the American College of Cardiology (ACC).

Dr. Bauersachs, who presented the study’s findings virtually at ACC.21, the ACC’s 70th annual scientific sessions, continued, “The benefits we saw in the trial for first events were statistically significant and entirely consistent with those for total events. Rivaroxaban 2.5 mg twice daily with aspirin should be considered as adjunctive therapy after revascularization to reduce first and subsequent adverse outcomes.” The findings expand on earlier data and underscore the broad absolute benefits of this strategy in this high-risk patient population, noted the investigators in the ACC announcement.

This study was simultaneously published online by Dr. Bauersachs et al in the Journal of the American College of Cardiology . VOYAGER PAD was funded by Bayer AG and the Janssen Pharmaceutical Companies of Johnson & Johnson, which market rivaroxaban as Xarelto.

As summarized in the ACC announcement, the randomized, double-blinded VOYAGER PAD trial enrolled 6,564 patients in 34 countries who had PAD and had undergone lower extremity revascularization. The patients’ median age was 67 years, and 74% were men. Patients were randomly assigned to receive rivaroxaban or a placebo in addition to daily aspirin.

The trial’s primary endpoint was timed to the first event of a composite of acute limb ischemia, leg amputation caused by blood vessel disease, heart attack, stroke, or death due to cardiovascular causes. Another prespecified endpoint was the total number of vascular events, including recurrent primary endpoint events as well as other vascular events like blood clots in the leg veins or lungs or the need for repeat vascular procedures. The median follow-up time was 28 months after patients underwent revascularization.

At ACC.20/WCC—the ACC’s annual scientific session together with World Congress of Cardiology held in March 2020, the VOYAGER PAD investigators reported that the trial met its primary endpoint, with a 15% statistically significant reduction in the risk of a first major adverse limb or cardiovascular event seen in patients who received rivaroxaban compared with those who received the placebo. Marc P. Bonaca, MD, et al published those findings in The New England Journal of Medicine (2020;382:1994-2004).

The current findings presented at ACC.21 report on the total number of vascular events, which totaled 4,714 in the 6,564 study participants during the 3-year study period, with 2,301 patients (approximately one-third) experiencing at least one vascular event, stated Dr. Bauersachs.

In the ACC announcement, Dr. Bauersachs commented, “There were 342 fewer adverse events in the rivaroxaban group than in the placebo group, which translates to an absolute reduction in risk of 12.5%. In a high-risk population, that is a big gain in avoiding the need for patients to come back with vascular complications.”

He continued, “So, during approximately 3 years of follow-up, about 2 to 3 out of 6 patients with PAD had a vascular event in spite of high utilization of background medical therapy. This overall rate of vascular events is eye-opening and speaks to the high vulnerability of this patient population. First events are just the tip of the iceberg.”

Dr. Bauersachs advised that a limitation of the study is that the trial was designed to assess the occurrence of first adverse events after lower extremity revascularization. Therefore, in a double-blinded trial, patients may come off study treatment or go on to other therapies after an event, which can attenuate the observed benefit. However, assessment of the total number of adverse events was a prespecified secondary endpoint, and despite this limitation, the findings were statistically significant and robust in absolute terms.

“There is a need for greater awareness that PAD is a distinct disease state and that patients with PAD have a high risk for cardiovascular adverse events and are generally a very vulnerable population, especially in the postrevascularization setting. Care for these patients is often fragmented because the surgeon who performs the revascularization may not follow them for complications or recurrences. They deserve to receive optimal treatment to reduce the risk of recurrences,” concluded Dr. Bauersachs in the ACC announcement.

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New VOYAGER PAD Analyses Reinforce Benefit of XARELTO® (rivaroxaban) Plus Aspirin Across High-Risk and Complex Patient Populations with Peripheral Artery Disease (PAD)

Data presentations at aha 2023 meeting reinforce treatment with xarelto ® plus aspirin consistently reduces major cardiovascular events (mace) as well as major adverse limb events (male) in complex patients with pad janssen continues commitment to supporting pad patients with ongoing research to help understand this undertreated and underdiagnosed disease 1.

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TITUSVILLE, NJ, November 14, 2023 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced data from two new analyses from the Phase 3 VOYAGER PAD clinical trial reinforcing the benefit of XARELTO® (rivaroxaban [2.5 mg twice daily plus aspirin 100 mg once daily]) over standard of care (aspirin alone). Data from the two analyses demonstrate the role of XARELTO® in treating both high-risk and fragile patients and those with and without comorbid coronary artery diseases (CAD). Results were presented at the American Heart Association’s (AHA) 2023 Scientific Sessions, hosted in Philadelphia, Pennsylvania, November 11-13, 2023.

“These analyses reinforce the consistency of the favorable benefit-risk profile of XARELTO® plus aspirin for patients with vascular disease, regardless of comorbidity. For example, patients categorized as ‘fragile’ are often undertreated due to concerns about benefit-risk, particularly with antithrombotic treatments,” said Marc P. Bonaca*, M.D., Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. “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.”

Impact of XARELTO® plus Aspirin on Total Vascular Events in Fragile Patients with PAD

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 this analysis, fragile patients are defined as age greater than 75 years, or weight less than 50 kg or baseline eGFR less than 50 mL/min/1.732. XARELTO® plus aspirin (2.5 mg 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 placebo (aspirin alone). In fragile patients treated with XARELTO® 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 XARELTO® plus aspirin experienced a MALE compared to 9.7% of patients treated with placebo.

XARELTO® plus aspirin also reduced the occurrence of total vascular events in fragile patients over time, with an absolute rate of 82.1 events per 100 patients at three years compared to 99.3 events per 100 patients in those treated with placebo at three years. A similar benefit was also seen in non-fragile patients, with a rate of 70.4 events per 100 patients at three years in those treated with XARELTO® plus aspirin compared to 81.6 events per 100 patients in those treated with placebo at three years. Importantly, thrombolysis in myocardial infarction (TIMI) major bleeding was consistent in both the fragile and non-fragile treatment groups. XARELTO® plus aspirin demonstrated a consistent, numerical increase in TIMI major bleeding for both the fragile (HR 1.66; 95% CI 0.87-3.19) and the non-fragile (HR 1.37; 95% CI 0.83-2.24, p-interaction 0.65) patients.

Role of XARELTO® Plus Aspirin on Myocardial Infarction in Patients with PAD with and without Concomitant CAD Following Lower Extremity Revascularization (LER)

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.2 Patients with PAD are also at a heightened risk of MACE, defined as myocardial infarction (MI), ischemic stroke, or cardiovascular death. In this analysis, 14.1% of patients with PAD and CAD treated with XARELTO® 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 XARELTO® plus aspirin experienced a MACE versus 9.8% of patients treated with placebo. Overall, XARELTO® plus aspirin showed a consistent benefit in reducing MACE in patients with and without CAD.

In this analysis, patients with CAD (HR 2.23; CI 1.10-4.53) and patients without CAD (HR 1.15; CI 0.72-1.84) had higher rates of TIMI major bleeding with XARELTO® plus aspirin compared to placebo plus aspirin. The rates of intracerebral hemorrhage (ICH) and fatal bleeding were similar across both patient groups. Overall, the safety of XARELTO® plus aspirin in patients with PAD was consistent regardless of CAD with no significant interactions.

“At Janssen, we work tirelessly to bring the latest research and clinical practice insights to healthcare providers and their patients to help improve cardiovascular care for all,” said Avery Ince, M.D., Ph.D., Vice President, Medical Affairs, Cardiovascular & Metabolism, Janssen Scientific Affairs, LLC. “These new findings continue to support the use of XARELTO® with its positive benefit-risk profile in many types of patients, including those who are high-risk and considered harder to treat.”

In August 2021, the U.S. Food and Drug Administration (FDA) approved an expanded PAD indication for XARELTO® (2.5 mg twice daily plus aspirin 75 - 100 mg once daily) 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.

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® (rivaroxaban [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® plus aspirin 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® plus aspirin 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:

Unexpected bleeding or bleeding that lasts a long time, such as:

• 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

Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like XARELTO ® , and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

• 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)

Are pregnant or plan to become pregnant. It is not known if XARELTO® will harm your unborn baby.

• 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:

Atrial Fibrillation that is not caused by a heart valve problem:

• 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.

Blood clots in the veins of your legs or lungs:

• 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 miss a dose:
• 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.

Hip or knee replacement surgery:

• Take XARELTO® 1 time a day with or without food.

Blood clots in people hospitalized for an acute illness:

• 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.

Reducing the risk of serious heart problems, heart attack and stroke in coronary artery disease:

• 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.

If your child vomits or spits up:

• 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: Oncology, Immunology, Neuroscience, Cardiovascular, Pulmonary Hypertension and Retina.

Learn more at www.janssen.com . Follow us at @JNJInnovMed and @JanssenUS Janssen Scientific Affairs, LLC, is a Johnson & Johnson company.

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 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 Janssen Scientific Affairs, LLC nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

• Afzal N, Sohn S, Scott CG, Liu H, Kullo IJ, Arruda-Olson AM. Surveillance of Peripheral Arterial Disease Cases Using Natural Language Processing of Clinical Notes. AMIA Jt Summits Transl Sci Proc . 2017;2017:28-36. Accessed October 20, 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543345/#r2-2609862 .
• Beckman, JA, Schneider PA, Conte MS. Advances in revascularization for peripheral artery disease: revascularization in PAD. Circ Res. 2021;128.12: 1885-1912. Accessed October 27, 2023. https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.121.318261

*Dr. Marc Bonaca is the lead study author of the VOYAGER PAD analysis entitled “Impact of Low-dose Rivaroxaban plus Aspirin on Total Vascular Events in Fragile Patients with Peripheral Artery Disease: Insights from VOYAGER PAD” and “Impact of Low-dose Rivaroxaban plus Aspirin on Myocardial Infarction in Patients with Peripheral Artery Disease with and without Concomitant Coronary Artery Disease: Insights from VOYAGER PAD,” and was provided payment for his participation in the study; he has not been compensated for contributing to this press release.

Media Contacts: Leal Morehouse Phone: (617) 487-3060 [email protected]

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

Investor Relations: Raychel Kruper [email protected]

First refuelling for Russia’s Akademik Lomonosov floating NPP

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The FNPP includes two KLT-40S reactor units. In such reactors, nuclear fuel is not replaced in the same way as in standard NPPs – partial replacement of fuel once every 12-18 months. Instead, once every few years the entire reactor core is replaced with and a full load of fresh fuel.

The KLT-40S reactor cores have a number of advantages compared with standard NPPs. For the first time, a cassette core was used, which made it possible to increase the fuel cycle to 3-3.5 years before refuelling, and also reduce by one and a half times the fuel component in the cost of the electricity produced. The operating experience of the FNPP provided the basis for the design of the new series of nuclear icebreaker reactors (series 22220). Currently, three such icebreakers have been launched.

The Akademik Lomonosov was connected to the power grid in December 2019, and put into commercial operation in May 2020.

Electricity generation from the FNPP at the end of 2023 amounted to 194 GWh. The population of Pevek is just over 4,000 people. However, the plant can potentially provide electricity to a city with a population of up to 100,000. The FNPP solved two problems. Firstly, it replaced the retiring capacities of the Bilibino Nuclear Power Plant, which has been operating since 1974, as well as the Chaunskaya Thermal Power Plant, which is more than 70 years old. It also supplies power to the main mining enterprises located in western Chukotka. In September, a 490 km 110 kilovolt power transmission line was put into operation connecting Pevek and Bilibino.

Image courtesy of TVEL

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Some results uranium dioxide powder structure investigation

• Processes of Obtaining and Properties of Powders
• Published: 28 June 2009
• Volume 50 , pages 281–285, ( 2009 )

Cite this article

• E. I. Andreev 1 ,
• K. V. Glavin 2 ,
• A. V. Ivanov 3 ,
• V. V. Malovik 3 ,
• V. V. Martynov 3 &
• V. S. Panov 2  

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Features of the macrostructure and microstructure of uranium dioxide powders are considered. Assumptions are made on the mechanisms of the behavior of powders of various natures during pelletizing. Experimental data that reflect the effect of these powders on the quality of fuel pellets, which is evaluated by modern procedures, are presented. To investigate the structure of the powders, modern methods of electron microscopy, helium pycnometry, etc., are used. The presented results indicate the disadvantages of wet methods for obtaining the starting UO 2 powders by the ammonium diuranate (ADU) flow sheet because strong agglomerates and conglomerates, which complicate the process of pelletizing, are formed. The main directions of investigation that can lead to understanding the regularities of formation of the structure of starting UO 2 powders, which will allow one to control the process of their fabrication and stabilize the properties of powders and pellets, are emphasized.

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Elektrostal’ Polytechnical Institute (Branch), Moscow Institute of Steel and Alloys, ul. Pervomaiskaya 7, Elektrostal’, Moscow oblast, 144000, Russia

E. I. Andreev

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Original Russian Text © E.I. Andreev, K.V. Glavin, A.V. Ivanov, V.V. Malovik, V.V. Martynov, V.S. Panov, 2009, published in Izvestiya VUZ. Poroshkovaya Metallurgiya i Funktsional’nye Pokrytiya, 2008, No. 4, pp. 19–24.

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Andreev, E.I., Glavin, K.V., Ivanov, A.V. et al. Some results uranium dioxide powder structure investigation. Russ. J. Non-ferrous Metals 50 , 281–285 (2009). https://doi.org/10.3103/S1067821209030183

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Published : 28 June 2009

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DOI : https://doi.org/10.3103/S1067821209030183

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