Inaugural award

RACIAL DISPARITIES RESEARCH ON DIALYSIS ACCESS SURGERY ATTRACTS MVSS AWARD

Black patients were found at significantly higher risk of having additional surgical procedures, including both maintenance and new creations. By Bryan Kay

THE AUTHORS BEHIND A NEW STUDY THAT

found “significant differences” in hemodialysis vascular access outcomes after first-time arteriovenous (AV) fistula or graft creation “directly related” to a patient’s race said the findings speak “to an injustice within the field of vascular surgery.” The research won the Midwestern Vascular Surgical Society’s inaugural MVSS Disparities Research Award at the organization’s 2022 annual meeting in Grand Rapids, Michigan (Sept. 15–17).

The data were presented by Shannon McDonnell, a medical student from Loyola University’s Stritch School of Medicine in Maywood, Illinois, who was mentored by Pegge Halandras, MD, from Loyola University Medical Center. The research team carried out a single-institution, retrospective cohort study of 926 patients undergoing AV procedures from 2007 to 2021, capturing subsequent AV creations and maintenance procedures.

Of the total pool, 45% identified as White and 37% as Black, McDonnell reported. A total of 494 (53%) patients had no additional procedures, 258 (28%) had one additional procedure, 95 (10%) had two additional procedures, and 78 (9%) had three or more procedures.

“Black patients have higher frequency of hypertension, COPD [chronic obstructive pulmonary disease], diabetes and anemia,” McDonnell told MVSS 2022. “Just over half of our patients required only the initial fistula or graft placement. Black patients were at a significantly higher risk of having additional AV access surgical procedures, including both maintenance and new creations as compared to their counterparts of other races.

“Further exploration of these disparities is necessary in order to discover the root of these inequities in care.”

In acknowledging limitations in the study, McDonnell pointed to race’s frequent association with lower socioeconomic status. “Lower socioeconomic status influences a patient’s utilization of healthcare and can lead to poorer outcomes, and worse managed chronic conditions,” she said.

McDonnell also pointed to some reasons why patients may only have one procedure at the study team’s institution, such as a patient receiving a kidney transplant or choosing to continue to dialyze through a catheter instead of undergoing another procedure.

Shannon McDonnell wins the MVSS’ inaugural Disparities Research Award at the 2022 annual meeting

ANNALS OF VASCULAR SURGERY ANNOUNCES SPECIAL ISSUE DEDICATED TO ORIGINAL WORK BY WOMEN

The Annals of Vascular Surgery peer-review journal has announced an upcoming special issue dedicated to original work by women that is set to be guest edited by Caitlin W. Hicks, MD, the associate fellowship program director for vascular surgery and endovascular therapy and associate professor of surgery at Johns Hopkins Medicine in Baltimore, Maryland.

The issue, which will be published in September 2023 to coincide with Women in Medicine Month, will feature original scientific work whose first and last authors identify as women, with men welcomed as co-authors. Hicks will be supported by an all-female editorial team.

“We encourage all women to submit your best original scientific work related to vascular surgery for peer review and possible publication in our special issue,” Hicks said. “Please note that we will not accept review articles, case reports, or commentaries given the high volume of competitive original scientific works that we anticipate.”

Interested researchers are being encouraged to submit an abstract for review by the editorial team, with those selected then offered the opportunity to submit a full manuscript. Issue editors note that abstracts may have been presented at, or submitted to, a meeting, but should be free from embargo by September 2023.

They should be uploaded by Monday, Dec. 5, with all authors notified of their abstract’s selection or rejection by Monday, Dec. 19. Selected manuscript submissions will be due by Feb. 1, 2023. “Annals of Vascular Surgery is excited about the opportunity to highlight the amazing research being performed by women in our specialty,” added Hicks.

Questions about the process should be directed to Hicks directly at chicks11@jhmi.edu, or Annals of Vascular Surgery managing editor Camilla Davies at cdavies.avs@ gmail.com. The full abstract link is: www.surveymonkey. com/r/AVSWomen. —Bryan Kay

WOMEN’S RCT WARRIORS randomized trial aims to examine early EVAR in women

A multinational collaboration of researchers has received endorsement from the Global Cardiovascular Research Funders Forum (GCRFF) Multinational Clinical Trials Initiative for the WARRIORS (Women’s abdominal aortic aneurysm research: Repair immediately or routine surveillance) trial, writes Jocelyn Hudson.

The trial aims to answer the question of whether women should have their aneurysms repaired electively using endovascular aneurysm repair (EVAR) at smaller diameters than men to improve their survival and quality of life. Imperial College London in London, England, is coordinating the study, which will include collaboration with vascular surgeons from Canada, Denmark, The Netherlands, Sweden and the U.S. The researchers note that new partners from locations such as Australia may also be joining. The investigators noted in a press release announcing the endorsement last month that the rationale and need for this trial, which seeks to recruit nearly 1,200 women, stems from the poor outcomes suffered by women with abdominal aortic aneurysms (AAAs). Although women contribute 15–20% of total AAA burden, and one-third of ruptures, they have been significantly under-represented in trials which guide current AAA repair, the investigators detail, adding that women have smaller arteries, a four-fold higher rupture risk and lose eligibility for EVAR at smaller AAA diameters. Treated at the current threshold, the researchers note that a greater proportion receive either higher-risk open surgery or no repair at all. Those that do receive elective repair, do worse, with nearly double the rate of operative mortality (open surgery 6%, EVAR 2.3%), higher postoperative complication rates and longer hospital stays.

“We have learnt that women worry a lot about their AAA and modeling has suggested that repair of AAA at 4cm for women might result in improved quality of life and reduced overall cost,” the investigators write. “These potential benefits, as well as reduction in aneurysm-related mortality, would need to be balanced against the operative risk of early repair.” They state that these areas of uncertainty, regarding the optimal strategy for AAA repair in women, are what the trial seeks to answer.

The endorsement provided by the GCRFF allows the investigators to move forward and seek priority funding from their partner organizations. The team is also hoping for some support from industry for specific as-

“The disadvantage of women with AAA can no longer be ignored, and we hope that you will support us in what will hopefully be a major step towards readdressing the imbalance in AAA outcomes for women and men”

WARRIORS TRIAL INVESTIGATORS

pects of the trial and/or associated registry.

According to the investigators, WARRIORS would be the first randomized trial of AAA management with multinational, wide-ranging, expertise and to have received endorsement from the GCRFF. However, they stress that this is the just the first step.

They elaborate: “To gain funding within each participating country, and to implement the trial successfully, we will need considerable support from the vascular and multidisciplinary community. The disadvantage of women with AAA can no longer be ignored, and we hope that you will support us in what will hopefully be a major step towards readdressing the imbalance in AAA outcomes for women and men. We also hope that this initiative will pave the way to obtain evidence about the management of other underserved patient groups, minorities and rarer diseases managed by vascular surgeons.”

Are your patients with CAD really stable? Consider XARELTO® .

XARELTO® is the ONLY DOAC indicated in combination with aspirin* to significantly reduce the risk of major CV events† in patients with CAD1-8

XARELTO®

(2.5 mg BID) ASPIRIN

(75 mg-100 mg QD)

Tablets not shown to actual size.

Scan QR code for more data:

Arterial Thrombus

*XARELTO® 2.5 mg twice daily + aspirin 75 mg to 100 mg once daily; †Major cardiovascular events include CV death, MI, and stroke. BID = twice daily; DOAC = direct oral anticoagulant; CAD = coronary artery disease; CV = cardiovascular; MI = myocardial infarction; QD = once per day.

INDICATION

XARELTO®, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease (CAD).

IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO® increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. B. Spinal/epidural hematoma

Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal antiinflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug

Interactions

• A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery • Optimal timing between the administration of XARELTO® and neuraxial procedures is

not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS

• Active pathological bleeding • Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS

• Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fi brillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. • Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue in patients with active pathological hemorrhage. – An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable. – Concomitant use of other drugs that impair hemostasis increases risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fi brinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). – Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding: Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO® for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage; active cancer (ie, undergoing acute, in-hospital cancer treatment); active gastroduodenal ulcer or history of bleeding in the three months prior to treatment; or dual antiplatelet therapy. XARELTO® is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. • Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with concurrent use of XARELTO® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profi le of XARELTO®. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO® is low; however, the exact timing to reach a suffi ciently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO®. The next dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO® for 24 hours. Monitor frequently to detect signs or symptoms of neurological impairment, such as midline back pain, sensory and motor defi cits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. • Use in Patients with Renal Impairment: – Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation in patients who develop acute renal failure while on XARELTO®. Clinical effi cacy and safety studies with XARELTO® did not enroll patients with CrCl <30 mL/min or end-stage renal disease (ESRD) on dialysis.

• Use in Patients with Renal Impairment (cont’d): – Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment. – Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment. – Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment. – Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction

of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients

after Recent Lower Extremity Revascularization Due to Symptomatic PAD: For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO® twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min), whose effi cacy and safety outcomes were similar to those with preserved renal function. Clinical effi cacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis. – Pediatric Patients: There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid use of XARELTO® in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO® in these patients. • Use in Patients with Hepatic Impairment: No clinical data are available for adult patients with severe hepatic impairment. Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased. No clinical data are available in pediatric patients with hepatic impairment. • Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of

XARELTO® with known combined P-gp and strong CYP3A inhibitors or inducers. • Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefi t justifi es the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing. Promptly evaluate signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). • Patients with Prosthetic Heart Valves: Use of XARELTO® is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of the

GALILEO study, which reported higher rates of death and bleeding in patients randomized to

XARELTO® compared to those randomized to an antiplatelet regimen. Safety and effi cacy of

XARELTO® have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO® is not recommended in patients with prosthetic heart valves. • Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. • Increased Risk of Thrombosis in Patients with Antiphospholipid Syndrome: Direct-acting oral anticoagulants (DOACs), including XARELTO®, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. • Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase risk of bleeding. • Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase risk of thromboembolic events. • XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin) unless the potential benefi t justifi es the potential risk. • Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase risk of bleeding. • Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefi t outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

USE IN SPECIFIC POPULATIONS

• Pregnancy: The limited available data on XARELTO® in pregnant women are insuffi cient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing. Consider the benefi ts and risks of XARELTO® for the mother and possible risks to the fetus when prescribing to a pregnant woman. – Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate. – Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering use in this setting. – There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insuffi cient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. • Lactation: Rivaroxaban has been detected in human milk. There are insuffi cient data to determine the effects of rivaroxaban on the breastfed child or on milk production.

Consider the developmental and health benefi ts of breastfeeding along with the mother’s clinical need for XARELTO® and any potential adverse effects on the breastfed infant from

XARELTO® or from the underlying maternal condition. • Females and Males of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically signifi cant uterine bleeding, potentially requiring gynecological surgical interventions, identifi ed with oral anticoagulants, including XARELTO®, should be assessed in females of reproductive potential and those with abnormal uterine bleeding. • Pediatric Use: XARELTO® was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth, had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg.

Clinical studies that evaluated safety, effi cacy, and pharmacokinetic/pharmacodynamic data support the use of XARELTO® 10-mg, 15-mg, and 20-mg tablets in pediatric patients.

For the XARELTO® 2.5-mg tablets, there are no safety, effi cacy, and pharmacokinetic/ pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO® 2.5-mg tablets are not recommended for use in pediatric patients.

Although not all adverse reactions identifi ed in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. • Geriatric Use: In clinical trials the effi cacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients.

OVERDOSAGE

• Overdose of XARELTO® may lead to hemorrhage. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

ADVERSE REACTIONS

• Most common adverse reactions in adult patients with XARELTO® were bleeding complications. • Most common adverse reactions in pediatric patients were bleeding, cough, vomiting, and gastroenteritis.

Please read accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS for XARELTO® .

References: 1. XARELTO® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Bevyxxa® [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals. Inc; 2020. 3. Eliquis® [prescribing information]. Princeton, NJ and New York, NY: Bristol-Myers Squibb Company and Pfi zer Inc.; 2021. 4. Bevyxxa® (betrixaban)—Notice of Permanent Discontinuance of Manufacturing in April 2020: Portola Pharmaceuticals, Inc. 5. Pradaxa® [prescribing information]. Ridgefi eld, CT: Boehringer lngelheim Pharmaceuticals, Inc.; 2021. 6. Savaysa® [prescribing information]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2021. 7. Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377[14):1319-1330. 8. Online supplement to: Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl Med. 2017 ;377[14]: 1319-1330.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2022 09/22 cp-330633v1

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4) in Full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in Full Prescribing Information]. B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of XARELTO and neuraxial procedures is not known [see Warnings and Precautions and Adverse Reactions]. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions]. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

XARELTO is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1) in Full Prescribing Information].

Treatment of Deep Vein Thrombosis

XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism

XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism

XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding [see Warnings and Precautions and Clinical Studies (14.5) in Full Prescribing Information].

Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD)

XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.

Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD

XARELTO, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.

Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients

XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.

Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure

XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

CONTRAINDICATIONS

XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions]

WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4) and Clinical Studies (14.1) in Full Prescribing Information].

Risk of Bleeding

XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions]. Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning]. To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/ analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use in Patients with Renal Impairment

Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1) in Full Prescribing Information]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations]. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations]. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations]. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations]. Pediatric Patients There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the use of XARELTO in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO in these patients [see Dosage and Administration (2.2) in Full Prescribing Information and Use in Specific Populations].

Use in Patients with Hepatic Impairment

No clinical data are available for adult patients with severe hepatic impairment. Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations]. No clinical data are available in pediatric patients with hepatic impairment.

Use with P-gp and Strong CYP3A Inhibitors or Inducers

Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions]. Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions].

Risk of Pregnancy-Related Hemorrhage

In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions and Use in Specific Populations].

Patients with Prosthetic Heart Valves

On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves.

Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy

Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome

Direct-acting oral anticoagulants (DOACs), including XARELTO, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

ADVERSE REACTIONS

The following clinically significant adverse reactions are also discussed in other sections of the labeling: • Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and

Warnings and Precautions] • Bleeding Risk [see Warnings and Precautions] • Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 34,947 adult patients were exposed to XARELTO. Hemorrhage The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions]. Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial. Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days

Parameter XARELTO N=7111 n (%/year) Warfarin N=7125 n (%/year) XARELTO vs. Warfarin HR (95% CI)

Major Bleeding† 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20)

Intracranial Hemorrhage (ICH)‡

Hemorrhagic Stroke§

Other ICH 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34)

Gastrointestinal (GI)¶ 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99)

Fatal Bleeding#

ICH 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79) 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96)

Non-intracranial 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding. Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/ Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients. Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies

Parameter

XARELTO†

N=4130 n (%) Enoxaparin/

VKA†

N=4116 n (%)

Major bleeding event

Fatal bleeding Intracranial 40 (1.0) 72 (1.7) 3 (<0.1) 8 (0.2) 2 (<0.1) 4 (<0.1)

Non-fatal critical organ bleeding Intracranial‡ Retroperitoneal‡ Intraocular‡ 10 (0.2) 29 (0.7) 3 (<0.1) 10 (0.2) 1 (<0.1) 8 (0.2) 3 (<0.1) 2 (<0.1)

Intra-articular‡ Non-fatal non-critical organ bleeding§ 0

4 (<0.1) 27 (0.7) 37 (0.9)

Decrease in Hb ≥ 2 g/dL 28 (0.7) 42 (1.0)

Transfusion of ≥2 units of whole blood or packed red blood cells 18 (0.4) 25 (0.6) Clinically relevant non-major bleeding 357 (8.6) 357 (8.7) Any bleeding 1169 (28.3) 1153 (28.0) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients. Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Table 3: Bleeding Events* in EINSTEIN CHOICE

Parameter

XARELTO†

10 mg N=1127 n (%) Acetylsalicylic Acid

(aspirin)† 100 mg

N=1131 n (%)

Major bleeding event

Fatal bleeding

Non-fatal critical organ bleeding

Non-fatal non-critical organ bleeding‡ Clinically relevant non-major (CRNM) bleeding§ 5 (0.4) 0 2 (0.2) 3 (0.3) 22 (2.0)

3 (0.3) 1 (<0.1) 1 (<0.1) 1 (<0.1) 20 (1.8) Any bleeding 151 (13.4) 138 (12.2) * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily. ‡ Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. § Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

XARELTO 10 mg Enoxaparin†

Total treated patients

Major bleeding event

Fatal bleeding

Bleeding into a critical organ

Bleeding that required re-operation

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡

N=4487 n (%)

14 (0.3) 1 (<0.1) 2 (<0.1) 7 (0.2) 4 (0.1)

N=4524 n (%)

9 (0.2) 0 3 (0.1) 5 (0.1) 1 (<0.1)

261 (5.8) 251 (5.6)

Hip Surgery Studies

Major bleeding event

Fatal bleeding

Bleeding into a critical organ

Bleeding that required re-operation

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

Any bleeding event‡

Knee Surgery Study XARELTO 10 mg Enoxaparin†

N=3281 n (%) N=3298 n (%)

7 (0.2) 3 (0.1)

1 (<0.1)

0 1 (<0.1) 1 (<0.1) 2 (0.1) 1 (<0.1)

3 (0.1) 1 (<0.1)

201 (6.1) 191 (5.8)

N=1206 n (%) N=1226 n (%)

Major bleeding event 7 (0.6) 6 (0.5)

Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation

0 1 (0.1) 5 (0.4)

0 2 (0.2) 4 (0.3)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 (0.1) 0

Any bleeding event‡ 60 (5.0) 60 (4.9) * Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. † Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) ‡ Includes major bleeding events Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 5. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo. Table 5 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.

Table 5: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2 Days MAGELLAN Study¶ XARELTO 10 mg N=3218 n (%) Enoxaparin 40 mg / placebo N=3229 n (%)

Major bleeding‡† 22 (0.7) 15 (0.5)

Critical site bleeding Fatal bleeding§ 7 (0.2) 3 (<0.1)

4 (0.1) 1 (<0.1) Clinically relevant non-major bleeding events (CRNM) 93 (2.9) 34 (1.1) * Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. † Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. ‡ Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. § Fatal bleeding is adjudicated death with the primary cause of death from bleeding. ¶ Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital. Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar. Table 6 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

Table 6: Major Bleeding Events in COMPASS - On Treatment Plus 2 Days*

Parameter

Modified ISTH Major Bleeding‡ - Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial - Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH

XARELTO† N=9134 n (%/year) Placebo† N=9107 n (%/year)

XARELTO vs. Placebo HR (95 % CI)

263 (1.6) 144 (0.9) 1.8 (1.5, 2.3) 12 (<0.1) 6 (<0.1) 6 (<0.1) 58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1) 8 (<0.1) 3 (<0.1) 5 (<0.1) 43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1) 1.5 (0.6, 3.7) 2.0 (0.5, 8.0) 1.2 (0.4, 4.0) 1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9)

- Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) 7 (<0.1) 6 (<0.1) 1.2 (0.4, 3.5)

188 (1.1) 91 (0.5) 2.1 (1.6, 2.7)

Major GI bleeding 117 (0.7) 49 (0.3) 2.4 (1.7, 3.4) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. † Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization. CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for XARELTO 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively. Table 7 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.

Table 7: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 Days XARELTO† N=3256 Placebo† N=3248 XARELTO vs. Placebo Parameter n (%) Event rate HR (95 % CI) %/year n (%) Event rate %/year

TIMI Major Bleeding (CABG/non-CABG) 62 (1.9) 0.96 44 (1.4) 0.67 1.4 (1.0, 2.1) Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1.0 (0.3, 3.2) Intracranial bleeding 13 (0.4) 0.20 17 (0.5) 0.26 0.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15% 46 (1.4) 0.71 24 (0.7) 0.36 1.9 (1.2, 3.2) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. † Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 8.

Table 8: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System

Adverse Reaction

EINSTEIN DVT Study

Gastrointestinal disorders

Abdominal pain

General disorders and administration site conditions

Fatigue

Musculoskeletal and connective tissue disorders

Back pain

Muscle spasm

Nervous system disorders

Dizziness

Psychiatric disorders

Anxiety

Depression

Insomnia

EINSTEIN PE Study

Skin and subcutaneous tissue disorders

Pruritus

XARELTO 20 mg N=1718 n (%)

46 (2.7)

24 (1.4)

50 (2.9) 23 (1.3)

38 (2.2)

24 (1.4) 20 (1.2) 28 (1.6) XARELTO 20 mg N=2412 n (%)

53 (2.2) 27 (1.1)

* Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 9.

Enoxaparin/VKA N=1711 n (%)

25 (1.5)

15 (0.9)

31 (1.8) 13 (0.8)

22 (1.3)

11 (0.6) 10 (0.6) 18 (1.1) Enoxaparin/VKA N=2405 n (%)

Table 9: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD 1-3 Studies

Body System

Adverse Reaction

Injury, poisoning and procedural complications

Wound secretion

XARELTO 10 mg N=4487 n (%)

125 (2.8) Enoxaparin†

N=4524 n (%)

89 (2.0)

Musculoskeletal and connective tissue disorders

Pain in extremity Muscle spasm

Nervous system disorders

Syncope

Skin and subcutaneous tissue disorders

Pruritus 74 (1.7) 52 (1.2)

55 (1.2)

96 (2.1) 55 (1.2) 32 (0.7)

32 (0.7)

79 (1.8) Blister 63 (1.4) 40 (0.9) * Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3)

Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weight-adjusted doses of XARELTO or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA). Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the XARELTO group and 3 (1.9%) patients in the comparator group. Table 10 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study. In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the XARELTO group and 5 (10%) female patients in the comparator group.

Table 10: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period*

Parameter XARELTO† N=329 n (%) Comparator Group‡ N=162 n (%)

Major bleeding§

Clinically relevant non-major bleeding¶

Trivial bleeding

0 10 (3.0)

2 (1.2) 1 (0.6) 113 (34.3) 44 (27.2)

Any bleeding 119 (36.2) 45 (27.8) * These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event. † Treatment schedule: body weight-adjusted doses of XARELTO; randomized 2:1 (XARELTO: Comparator). ‡ Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. § Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ¶ Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 11.

Table 11: Other Adverse Reactions* Reported in XARELTO-Treated Patients by ≥5% in EINSTEIN Junior Study

Adverse Reaction XARELTO N=329 n (%) Comparator Group N=162 n (%)

Pain in extremity Fatigue† 23 (7) 23 (7) 7 (4.3) 7 (4.3)

* Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator. † The following terms were combined: fatigue, asthenia. A clinically relevant adverse reaction in XARELTO-treated patients was vomiting (10.6% in the XARELTO group vs 8% in the comparator group). Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of XARELTO for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weightadjusted doses of XARELTO or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the XARELTO group and no patients in the aspirin group. Table 12 shows the number of patients experiencing bleeding events in the UNIVERSE study.

Table 12: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days

Parameter XARELTO* N=64 n (%) Aspirin* N=34 n (%)

Major Bleeding†

Epistaxis leading to transfusion Clinically relevant non-major (CRNM) bleeding§

Trivial bleeding 1 (1.6) 1 (1.6) 0 0

4 (6.3)

3 (8.8) 21 (32.8) 12 (35.3)

Any bleeding 23 (35.9) 14 (41.2) * Treatment schedule: body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg); randomized 2:1 (XARELTO: Aspirin). † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. § Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 13.

Table 13: Other Adverse Reactions* Reported by ≥5% of XARELTO-Treated Patients in UNIVERSE Study (Part B)

Cough Vomiting Gastroenteritis†

Rash†

Adverse Reaction XARELTO N=64 n (%)

Aspirin N=34 n (%)

10 (15.6) 3 (8.8) 9 (14.1) 3 (8.8) 8 (12.5) 1 (2.9) 6 (9.4) 2 (5.9)

* Adverse reaction with Relative Risk >1.5 for XARELTO versus aspirin. † The following terms were combined:

Gastroenteritis: gastroenteritis, gastroenteritis viral

Rash: rash, rash maculo-papular, viral rash

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

DRUG INTERACTIONS General Inhibition and Induction Properties

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems

Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Anticoagulants and NSAIDs/Aspirin

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy

Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see Warnings and Precautions]. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss. Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate. Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting. Data Human Data There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta. Animal Data Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Lactation

Risk Summary Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).

Data Animal Data Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

Females and Males of Reproductive Potential

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including XARELTO should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

Pediatric Use

The safety and effectiveness of XARELTO have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, openlabel, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg [see Dosage and Administration (2.2) in Full Prescribing Information, Adverse Reactions, Clinical Pharmacology (12.3) and Clinical Studies (14.8) in Full Prescribing Information]. The safety and effectiveness of XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose pharmacokinetic properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure [see Dosage and Administration (2.2) in Full Prescribing Information, Adverse Reactions, Clinical Pharmacology (12.3) and Clinical Studies (14.9) in Full Prescribing Information]. Clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients. For the XARELTO 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

Geriatric Use

Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3) and Clinical Studies (14) in Full Prescribing Information].

Renal Impairment

In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Nonvalvular Atrial Fibrillation Patients with Chronic Kidney Disease not on Dialysis In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Patients with End-Stage Renal Disease on Dialysis Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF. Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min. Prophylaxis of DVT Following Hip or Knee Replacement Surgery The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. In the RECORD 1-3 trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding Patients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min a dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min. Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD Patients with Chronic Kidney Disease not on Dialysis Patients with a CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information], whose efficacy and safety outcomes were similar to those with preserved renal function. Patients with End-Stage Renal Disease on Dialysis No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. Pediatric Use No dosage adjustment is required in patients 1 year of age or older with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m2). There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the use of XARELTO in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO in these patients [see Dosage and Administration (2.2) in Full Prescribing Information].

Hepatic Impairment

In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127% were observed in adult subjects with moderate hepatic impairment (Child-Pugh B). The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. No clinical data are available in pediatric patients with hepatic impairment.

OVERDOSAGE

Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Active Ingredient Made in Germany Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany © 2011-2021 Janssen Pharmaceutical Companies cp-62545v11

ADVOCACY SVS weighs in on 2023 Medicare payment rules for physicians and hospital outpatient services

By Trisha Crishock, Megan Marcinko and Jill Rathbun

The Society for Vascular Surgery (SVS) has submitted comment letters in response to the proposed rules issued by the Centers for Medicare and Medicaid Services (CMS) on the Medicare Physician Fee Schedule (MPFS) and the Medicare Hospital Outpatient Perspective Payment System (OPPS) and Ambulatory Surgical Center (ASC) Payment System.

Both proposed rules are for calendar year (CY) 2023.

Each year CMS announces proposed rules for the MPFS and the OPPS, usually in July, and provides a 60-day comment period when the public can submit input on the proposed rules. After reviewing the comments, CMS issues final rules on the MPFS and OPPS, typically on or around Nov. 1; rules taken effect on Jan. 1 of the following calendar year.

Members of the SVS Coding and Performance Measures committees review these rules each year and assist in developing the SVS comment letters submitted to CMS.

This year’s MPFS and OPPS proposed rules contained several important issues that impact vascular surgeons.

MPFS rule comment letter

In the comments on the CY 2023 MPFS proposed rule, SVS members stressed the need for stability in Medicare physician payment. CMS proposes to reduce the MPFS conversion factor by nearly 4.5%, rebase and revise the Medicare Economic Index (MEI) and move forward with year two of the four-year implementation of the clinical labor-pricing update finalized in the CY 2022 MPFS rule. This will result in payment cuts that are unsustainable for vascular surgeons.

This recurring scenario with the annual MPFS payment rule that necessitates congressional action to mitigate Medicare cuts demonstrates that the Medicare physician payment system is broken. Factors that adversely impact the physician payment system are the lack of an annual inflationary update and the statutory budget-neutrality requirements that trigger across-the-board decreases in payment for all physicians when increases are provided for any physician fee schedule service. Updates to the conversion factor have consistently failed to keep up with inflation, in large part due to the fee schedule budget-neutrality requirements. We strongly stated to CMS that “our policy-makers, both within the administration and in Congress, have a duty to ensure a Medicare system that provides financial stability through a baseline positive annual update reflecting inflation in practice costs, and eliminate, replace or revise budget-neutrality requirements to allow for appropriate changes in spending growth.”

Percutaneous arteriovenous fistula creation

We requested that CMS reconsider its rejection of the RVS Update Committee (RUC)-recommended work relative value units (wRVUs) of 7.50 for Current Procedural Terminology (CPT) code 368X1 and 9.60 for 368X2. CMS proposed work RVUs of 7.20 for CPT code 368X1 and 9.30 for CPT code 368X2 do not accurately reflect the intensity of the physician work associated with these services. We believe the RUC-recommended values for these codes account for the complexity and intensity of the procedures and are supported through the survey data collected. We urged CMS to accept the RUC-recommended work RVUs of 7.50 for CPT code 368X1 and 9.60 for CPT code 368X2.

SVS commended CMS for accepting the RUC-recommended increased work values for the hospital inpatient and observation codes. However, we reiterated our strong objection to CMS’ continued refusal to incorporate the 2021 office evaluation and management (E/M) visit increases to the visits bundled into global surgery payment.

CMS requested public comment on strategies to improve the accuracy of payment for the global surgical packages. We expressed strong opposition to the CMS position that physicians are not performing the follow-up care with their patients that is included in the global surgical package. Noting the many flaws of the RAND study, which CMS uses to defend its position that physicians are not seeing patients for follow-up care, we urged CMS to follow the established process of identifying individual codes as potentially misvalued if there is concern with the postoperative visits assigned to a particular service. A blanket approach to address all 010-day and 090-day global surgical packages inappropriately impacts physicians performing surgeries.

Quality Payment Program

In response to several CMS proposed changes to the Quality Payment Program (QPP) Merit-Based Incentive Payment System (MIPS) benchmark and reporting requirements, we raised our continued concerns about increased reporting requirements and how they conflict with CMS’ goals of reducing administrative burden within the MIPS program. Annual program changes increase the administrative burden and complexity of the MIPS program and divert physician time and resources from providing patient care. Physicians who comply with MIPS reporting requirements should be offered a bonus potential for having increased reporting requirements as an incentive to do that work instead of being penalized. We urged CMS to hold harmless all eligible clinicians and groups from a MIPS penalty during the 2023 performance year due to the ongoing circumstances of the COVID-19 pandemic. These flexibilities should be continued until COVID cases are markedly reduced.

SVS responded to CMS’ request for information (RFI) on the potential development of a quality measure which would assess the percentage of patients with diabetes who receive neurologic and vascular assessment of their lower extremities to determine ulcer risk and if they receive a follow-up plan of care. We expressed general support for a new measure related to diabetes control that includes a neurologic and vascular assessment and suggested that including a referral to a specialist would enhance the measure’s effectiveness in reducing diabetes-related lower-extremity amputation. However, we noted such a measure would not be appropriate for specialists who are seeing patients after an ulcer has been identified. This measure would be appropriate for primary care providers at the group level within the same specialty and those treating the patients’ underlying conditions who have frequent contact with the patients. the recent Supreme Court decision on American Hospital Association v Becerra, which requires CMS to apply a rate of ASP (average sales price) +6% to drugs and biologicals. We urged CMS to provide as much detail as possible in the final rule related to the conversion factor modifications that will impact HOPPS payments as a result of the revised 340B drug payment policy, and provide opportunities for public input regarding how it will conduct retrospective policy changes if such changes are necessary.

In CMS’ comprehensive Ambulatory Payment Classification (APC) methodology, if two J1 services are reported together and meet specific frequency and cost criteria, a complexity adjustment can be applied, thus moving the payment rate to the next highest APC. We requested that CMS allow a complexity adjustment for CPT code pair 37187 (venous thrombectomy) and 37248 (venous balloon angioplasty) based on frequency and cost data. CMS currently recognizes CPT code pair 37187 (venous thrombectomy) with 37238 (venous stent) for complexity adjustment consideration. In the 2020 OPPS/ ASC final rule, CMS established a prior authorization process for certain hospital outpatient department (HOPD) services, which is now being applied to vein ablation. We are concerned that CMS continues to misinterpret an increase in the volume of utilization for certain procedures in the HOPD setting as “unnecessary,” when such increases may reflect an appropriate site-of-service shift, a change in practice guidelines, decreases in corresponding/related services, or changes in coverage determinations.

We urged CMS to holistically review data (i.e., site of service, guidelines, coverage determinations, etc.) prior to expanding prior authorization requirements.

Temporarily office-based

CMS reviewed CY 2021 volume and utilization data for several procedures, including two vascular duplex scan procedures (CPT codes 93985 and 93986).

Based on low volume, CMS is proposing to continue to designate these two vascular duplex scan procedures as temporarily office-based for CY 2023. We expressed appreciation for CMS’ proposal to extend the temporary designation for CY 2023 to allow for further analysis before determining if it is appropriate to permanently designate them as office-based.

Additionally, SVS opposes CMS’ proposal to change the terminology currently applied to “skin substitutes” to “wound care management products” and encouraged CMS to work with specialty societies and the American Medical Association CPT Editorial Panel to address terminology confusion.

CMS will review the SVS comment letters along with those submitted by other stakeholders and members of the public and will issue final CY 2023 rules for both the MPFS and the OPPS later this fall.

Information on the finalized rules will be provided in SVS publications. Resources will be available to assist SVS members in understanding and preparing for the implementation of the new Medicare MPFS and OPPS payment policies in the new year.

Read the full letters at vascular.org/ FeeSchedule23Comment and vascular.org/

HOPPS23Comment.

VASCULAR ACCESS REGISTRY DATA HIGHLIGHT LONG-TERM TRENDS IN HEMODIALYSIS ACCESS PROFILE OF FAILED KIDNEY TRANSPLANT PATIENTS

NEW FINDINGS, RECENTLY

published in the Journal of Vascular Access (JVA), provide insight into the hemodialysis access profile of failed kidney transplant patients treated in the Catalonia region of Spain over an 18-year period.

Researchers Ramon Roca-Tey, MD, a senior consultant in nephrology from Hospital Universitari Mollet in Barcelona, Spain, and colleagues note that data on vascular access use in failed kidney transplant patients returning to hemodialysis are limited. In the present study, therefore, the investigators sought to analyze the vascular access profile of this patient group, the factors associated with the likelihood of hemodialysis reinitiation through an arteriovenous fistula (AVF), and the effect of vascular access in use at the time of kidney transplant on kidney graft outcomes.

In their report, Roca-Tey et al write that they examined data from the Catalan Renal Registry on failed kidney transplant patients restarting hemodialysis and incidence hemodialysis patients with native kidney failure over the period from 1998–2016.

The authors report in JVA that the vascular access profile of 675 failed kidney transplant patients at hemodialysis reinitiation compared with that before kidney transplant, and with 16,731 incident patients starting hemodialysis was 79.3% vs. 88.6% and 46.2% (p=0.001 and p<0.001) for AVF; 4.4% vs. 2.6% and 1.1% (p=0.08 and p<0.001) for arteriovenous graft (AVG); 12.4% vs. 5.5% and 18% (p=0.001 and p<0.001) for tunneled central catheter; and 3.9% vs. 3.3% and 34.7% (p=0.56 and p<0.001) for non-tunneled catheter. In addition, they reveal that the likelihood of hemodialysis reinitiation by AVF was significantly lower in patients with cardiovascular disease, a kidney transplant duration of more than fiveyears, those dialyzed through AVG or tunneled central catheter before kidney transplant, and those of the female sex.

The authors add that analysis of Kaplan-Meier curves showed a greater kidney graft survival in patients dialyzed through arteriovenous access than in patients using catheters just before kidney transplantation. Finally, Cox regression analysis showed that patients on hemodialysis through arteriovenous access at the time of kidney transplantation had lower probability of kidney graft loss compared to those with catheters, Roca-Tey and colleagues write.

The authors conclude that the vascular access profile of failed kidney transplant patients returning to hemodialysis and incident patients starting hemodialysis was different. They also note that, compared to before a kidney transplant, the proportion of failed kidney transplant patients restarting hemodialysis with an AVF decreased significantly at the expense of a tunneled central catheter, and that patients on hemodialysis through arteriovenous access at the time of a kidney transplant showed greater kidney graft survival compared with those using a catheter.

“If our results are confirmed in further studies, including a larger number of kidney transplant patients and not simply patients returning to hemodialysis, routine arteriovenous access closure after a successful kidney transplantation should not be performed”

RAMON ROCA-TEY

According to the researchers, there are two clinical implications that can be derived from their findings. “To reduce the proportion of failed kidney transplant patients returning to hemodialysis with a central line, better vascular access management is needed,” they state, outlining the first implication. The second implication, Roca-Tey et al believe, arises from the impact of arteriovenous access on kidney graft outcomes. They elaborate: “If our results are confirmed in further studies, including a larger number of kidney transplant patients and not simply patients returning to hemodialysis, routine arteriovenous access closure after a successful kidney transplantation should not be performed.”

In the discussion of their data, the authors state that a number of factors limit the strength of their findings. They highlight the use of a population registry database for this study as a key weakness, for example. “The variables used are restricted in number and can have low clinical specificity,” they note, giving the example that the number of litigated accesses, as well as those with spontaneous thrombosis and not salvaged, were not recorded. Furthermore, the researchers acknowledge a weakness pertaining to the effect of vascular access on kidney graft survival—a secondary aim of the study. They write: “Kidney transplant patients who returned to hemodialysis were considered instead of all kidney transplant patients, and this may be a bias in our study.”—Jamie Bell

O C T O B E R 2 3 - 2 4 , 2 0 2 2 R O S E M O N T , I L L I N O I S

VASCULAR.ORG/CPVI

MIDWESTERN VASCULAR CEA, TCAR ‘CONTINUE TO SHOW SUPERIOR OUTCOMES’ TO TRANSFEMORAL STENTING

Researchers led by a vascular team in Indianapolis found that carotid endarterectomy (CEA) remains the most-used strategy in carotid revascularization, with CEA and TCAR showing decreased odds of stroke or death compared to TF-CAS.

By Bryan Kay

THOSE WERE AMONG THE MAIN

findings delivered by Hanaa Dakour Aridi, MD, an integrated vascular surgery resident at Indiana University in Indianapolis, during the 2022 annual meeting of the Midwestern Vascular Surgical Society (MVSS) in Grand Rapids, Michigan (Sept. 15–17), after a analysis of regional variation in patient selection, practice patterns and outcomes based on techniques used in carotid revascularization logged in the Vascular Quality Initiative (VQI) from 2016–2021.

The research team divided 19 geographic regions into three quantiles based on the average annual volume of carotid procedures performed: low (956 cases), medium (1,533) and high (1,845) centers. They looked at a total of 126,768 carotid revascularization cases, with most patients asymptomatic. CEA was the most common procedure (>60%) across all regional groups, with 13% performed using transfemoral carotid artery stenting (TF-CAS) and 17% with transcarotid artery revascularization (TCAR).

“Overall, there was a trend towards increased utilization of TCAR since its introduction in 2016 up to 2021,” Aridi told MVSS 2022. “This seems to have been mirrored by an increase in the percentage of CEA cases.”

Aridi reported the research team found no significant differences in stroke and death between CEA and TCAR across the three regional volume groups. “However, TF-CAS was associated with a higher odds of stroke and death compared to CEA, and TCAR was associated with a decreased odds of stroke or death compared to TF-CAS,” she said. “These variations were also seen when we analyzed the regions individually.”

Despite significant variation in clinical practice, Aridi concluded, “no significant regional variation was observed in the outcomes of carotid revascularization. TCAR and CEA continue to show superior outcomes to TF-

Hanaa Dakour Aridi takes to the MVSS 2022 podium

CAS across all regional groups. Our study identifies some gaps in adherence to societal guidelines, mainly in terms of intraoperative procedural variability that can potentially lead to worse outcomes. It also highlights the need for uniformity in management of patients with carotid artery disease.”

Raghu Motaganahalli, MD, the study’s senior author, told Vascular Specialist: “What we are seeing is TCAR has grown at the cost of CEA, not at the cost of TF-CAS,” further noting, “We would love to see growth happening at the cost of TF-CAS because it is probably at a higher risk of stroke and complications.” “TF-CAS was associated with a higher odds of stroke and death compared to CEA, and TCAR was associated with a decreased odds of stroke or death compared to TF-CAS” HANAA DAKOUR ARIDI

FROM THE COVER: STUDY: COMBINED ANTIPLATELET, NOAC USE LINKED TO WORSE LIMB OUTCOMES AFTER SUPRAINGUINAL BYPASS

continued from page 1

Zaidi noted that rates of antiplatelet usage were “pretty steady” over the eightyear study period, whereas warfarin use “steadily decreased,” with NOAC administration “steadily increasing.”

Univariate analysis showed that at one year, “the NOACplus-antiplatelet group had a statistically significantly reduced primary patency rate compared to antiplatelet alone.”Multivariate analysis demonstrated that NOAC use, prior bypass, diabetes and acute ischemic limb presentation “all were independently significant predictors of a reduced primary [and] primary assisted patency at one year.” Likewise, secondary patency rates showed a similar finding, Zaidi stated.

Further, at 12 months, univariate analysis showed NOAC use associated with a lower major adverse limb event-free survival rate compared to the antiplatelet group. “We found several independent predictors on multivariate analysis— NOAC use, prior bypass, patient being nonambulatory, rest pain or tissue loss and acute ischemic limb presentation—of increased major adverse limb events,” said Zaidi.

NOAC use was also associated with reduced major amputation-free survival at one year, he continued, with multivariate analysis showing that non-ambulatory status, having an axillary bypass graft origin, tissue loss or acute ischemic limb presentation were associated with increased rates of major amputation.

Univariate analysis demonstrated that overall survival in the NOAC group was 89% at one year compared to 91.3% in the antiplatelet group, Zaidi added. “We did find that warfarin ultimately had similar outcomes as NOAC therapy but, ultimately, did not include it in the final analysis due to its decreased usage over time,” he noted.

“Combined antiplatelet and NOAC therapy after suprainguinal bypass was associated with worse limb outcomes and patency but equivalent statistically significant survival compared to antiplatelet therapy alone,” Zaidi concluded. “NOAC use in suprainguinal bypass has typically been extrapolated from infrainguinal data and can’t be recommended for routine use based on our experience. Additional prospective investigations are required to determine the role of NOACs and optimal antithrombotic therapy after suprainguinal bypass.” The questioner from the floor who noted some concern over the findings asked whether the study was dealing with equivalent patients. “I’m a little concerned that, if you publish this, you’re probably not comparing apples to apples; you’re going to give the recommendation that patients shouldn’t go on [rivaroxaban], or whatever,” he said.

“NOAC use in suprainguinal bypass has typically been extrapolated from infrainguinal data”

SYED ZAIDI

In response, Zaidi explained that the message was more “to be discriminating” about “who should get NOACs, [and] who shouldn’t.”

Rising from the audience to explain further, senior author Robinson said he wanted to add some caveats. “We do know NOACs are being used a lot, and we don’t have a lot of data for their use. You bring up a lot of good points: Certainly, we can’t identify hypercoagulant states. Do we know every anatomic aspect of these patients in the VQI? No ...

“There is a fair bit of data you can control for, and I think using both propensity score matching and pretty aggressive multivariate analysis within that—you can’t do much better shy of a randomized trial is the bottom line. If you look at the randomized trials, we actually don’t have any of that information either.”

Expanding on where the study might lead, Robinson added, “I do think [this study] adds a little bit, mostly being that it’s hypothesis-generating.”

Study probes use of NOACs such as rivaroxaban

AORTIC DISSECTION Mortality drops for acute type A aortic dissection, still high for patients not receiving surgery

By Jocelyn Hudson

THE CHANCE OF A PATIENT SURVIVING AFTER AN

acute type A aortic dissection has improved significantly, but mortality remains high if not recognized early and repaired surgically. This is according to new research from a team at Michigan Medicine at the University of Michigan in Ann Arbor, Michigan.

A team of researchers examined early mortality rates for more than 5,600 patients admitted to hospital and examined hourly with acute type A aortic dissection between 1996 and 2018 from the International Registry for Acute Aortic Dissection (IRAD).

Findings published in JAMA Cardiology reveal that 5.8% of patients with acute type A aortic dissection died within the first two days after hospital arrival, a mortality rate of 0.12% per hour. The rate is significantly lower than that reported in the 1950s, which estimated that 37% of patients died within the first 48 hours, with an increasing mortality rate of 1–2% per hour.

“We believe that advances in diagnosis and management, especially a focus on early surgical repair, may have contributed in part to these improvements in mortality for acute aortic dissection,” said Kim Eagle, MD, senior author of the paper and director of the University of Michigan Health Frankel Cardiovascular Center.

Of all the patients, 91% either received surgery or were intended for surgery, with the others managed medically due to advanced age and complications such as stroke and kidney failure. Nearly 24% of those receiving medical treatment alone died within two days, compared to 4.4% of patients treated with surgical repair—a death rate more than five times higher.

“Patients who were managed medically were likely not surgical candidates due to their comorbidities,” said Bo Yang, MD, a professor of cardiothoracic surgery at University of Michigan Medical School, in a press release announcing the results of the study. Yang was not involved in the study, the release notes. “The medically managed patients could die from aortic dissection-associated complications—such as malperfusion, cardiac tamponade, aortic rupture and acute aortic insufficiency, which can be treated with surgery—or from their existing medical conditions, which could be worsened by the aortic dissection.”

Only 1% of patients deemed suitable for surgery died before the procedure. These patients died after an average of

“With this new information, it is clear that the ‘cost,’ or risk, of a four-to-six-hour delay caused by transfers is more than offset by the lower risk of surgery at experienced hospitals”

KIM EAGLE

nearly nine hours from being admitted to the hospital, exceeding the six-hour median time to surgery for all patients.

Interhospital transfer is needed in more than 70% of aortic dissection cases, causing inherent delays. Before this study, Eagle says, it was thought that early death from this condition was so prohibitive that operating urgently, even in hospitals with limited volume of aortic dissection surgery and resources, was the preferred strategy.

However, there is evidence that surgery at a low-volume hospital can double the risk of dying while undergoing repair compared to the highest volume providers. Additionally, mortality rates for open repair of acute type A aortic dissection are nearly three times higher when the operation is not performed by a dedicated aortic surgeon.

“Hospital mortality at a high-volume center like U-M [University of Michigan], where aortic dissection patients are taken care only by highly experienced aortic surgeons, can be as low as 5%, while the same patient operated on at a low-volume center may be 20% or higher,” Eagle said. “With this new information, it is clear that the ‘cost,’ or risk, of a four-to-six-hour delay caused by transfers is more than offset by the lower risk of surgery at experienced hospitals.”

Cases are rare. Approximately three in 100,000 people suffer aortic dissection each year. The condition most commonly affects older men, and a person experiencing the tear may feel a “knife-like, tearing pain through the back,” according to IRAD.

It is estimated that up to 50% of patients will die before ever reaching the hospital, making the overall mortality for aortic dissection substantially higher, the press release from Michigan Medicine points out.

“There is a need to identify the high-risk population of aortic dissection, such as those with a family history of aortic aneurysm and dissection, especially at a younger age, or known pathogenic genetic variants, so that we can replace the proximal aorta electively to prevent acute type A aortic dissection,” Yang said. “For young people under 55 years old with severe chest pain, we have to prove if patients have aortic dissection or otherwise.”

EASTERN VASCULAR STUDY SUGGESTS LOWER RATES OF AORTIC RUPTURE, MORTALITY AFTER TEVAR FOR UNCOMPLICATED TBAD IN SUBACUTE PHASE COMPARED TO MEDICAL MANAGEMENT

By Bryan Kay

THORACIC ENDOVASCULAR AORTIC

repair (TEVAR) carried out for uncomplicated type B aortic dissection (TBAD) saw worse mortality and aortic-related outcomes when performed in the acute phase compared to those treated in the subacute phase and those managed medically.

That was the chief conclusion of an investigation of TEVAR timing presented at the 2022 Eastern Vascular Society (EVS) annual meeting in Philadelphia (Sept. 29–Oct. 1) by Matthew Muller and colleagues from Albert Einstein College of Medicine in New York City. Patients with acute uncomplicated TBAD between 2007 and 2019 were identified using the TriNetX Analytics Network, a federated network of nationwide healthcare organizations with de-identified data.

The study looked at 17,018 patients with TBAD, with 918 (5.4%) undergoing acute TEVAR, 328 (1.9%) subacute, and 15,772 (92.7%) being treated nonoperatively.

After 1:1 propensity matching, the research team found that the acute TEVAR group had higher rates of endovascular reintervention (7.76% vs. 1.09%; p<0.001) and aortic rupture at 30 days (3.93% vs. 1.09%; p<0.001) and three years (9.51% vs. 3.93%; p<0.001), when compared to medical management. The subacute group had significantly higher rates of endovascular intervention at three years when compared to medical management (9.17% vs. 3.06%; p=0.001). The rate of aortic rupture at three years was significantly higher in the acute TEVAR group compared to the subacute TEVAR group (10.2% vs. 3.51%; p=0.001). There were no significant differences in 30-day and three-year mortality rates, or three-year rates of open reintervention, between the three groups.

Muller told the EVS gathering that the acute TEVAR group was found to have higher rates of mortality compared to both the medical management and subacute TEVAR groups but this finding was not found to be

Matthew Muller presents at EVS 2022

statistically significant. Additionally, the subacute TEVAR group had lower three-year mortality rates compared to the medical management group, but this, too, was not found to be statistically significant. “Our data shows that when TEVAR is performed in the subacute phase, there are lower rates of aortic rupture and mortality compared to medical management,” Muller concluded. “These are similar findings to previously discussed studies looking at the timing of TEVAR with regards to both complicated and uncomplicated type B aortic dissections.”

NEW ENGLAND VASCULAR NESVS meeting features paper showing relationship between increased distance from medical center and higher treatment costs among complex aortic patients

Research detailing that patients traveling farther for complex aortic surgery have higher procedural costs, postoperative imaging costs, and comprehensive one-year costs was among the new science being presented at the 2022 annual meeting of the New England Society for Vascular Surgery (NESVS) in Newport, Rhode Island (Oct. 14–16). By Bryan Kay

INVESTIGATORS, INCLUDING FIRST-

named author Zach M. Feldman, MD, a vascular surgery resident at Massachusetts General Hospital in Boston, and senior author Mark F. Conrad, MD, drew the conclusion after conducting a retrospective review of all patients in the Vascular Quality Initiative (VQI) and Vascular Implant Surveillance and Interventional Outcomes Network (VISION) databases undergoing complex endovascular aortic repair (EVAR).

Between 2011 and 2018, they looked at 8,782 patients, including 4,822 with complex EVARs, 2,672 complex thoracic EVARs (TEVARs), and 1,288 complex open abdominal aortic aneurysm (AAA) repairs. Median travel distance was 22.8 miles, with the research team establishing that patients traveling farther were more likely female and to have had prior aortic surgery. “These patients should be targeted for increased care coordination for improved outcomes and healthcare system burden,” the researchers concluded.

Elsewhere, a team from the University of Massachusetts Medical School in Worcester led by Andres Schanzer, MD, delivered data on their initial experience with the emerging Fiber Optic RealShape (FORS) imaging technology.

They presented findings from 21 procedures carried out with FORS guidance that were matched to 63 non-FORS procedures. Ninety-five FORS cannulation tasks were attempted (87 visceral target artery, eight contralateral bifurcated gate), they reported, with technical success achieved in 81 cannulations (85%). Furthermore, 15 (16%) were completed without any fluoroscopy, they added. “Use of FORS guidance was associated with lower median procedural and fluoroscopy times, dose area product, and air kerma.”

Meanwhile, a team from Beth Israel Deaconess Medical Center in Boston, led by Marc Schermerhorn, MD, demonstrated use of FORS in internal iliac artery navigation in a video presentation. “Much of the attention garnered by FORS is for use in complex aortic surgery … however, we have found that the FORS system is also particularly useful for navigation of the internal iliac artery,” they reported. The video showed two examples of internal iliac artery navigation with the FORS system. “Specifically, they demonstrate the ability to employ extreme angles that would either not be possible with conventional fluoroscopy or subject personnel to high radiation doses,” the team add. “The FORS system is also particularly useful for navigation of the internal iliac artery”

PAD ‘SIGNIFICANT’ INCREASE IN ATHERECTOMY USE IN US LARGELY DRIVEN BY OFFICE-BASED PROCEDURES, VQI DATA SHOW

In the United States, atherectomy use in peripheral vascular interventions (PVIs) “more than doubled” from 2010 to 2019, with officebased procedures a “major driver” of this increase. This is according to published U.S. data from the Vascular Quality Initiative (VQI), which also revealed wide regional variability in the use of atherectomy. By Jocelyn Hudson

According to authors Tonga Nfor, MD, a cardiologist at Aurora St Luke’s Medical Center, in Milwaukee, Wisconsin, and colleagues, small, older studies have indicated that the use of atherectomy devices has become common in PVIs despite what they describe as the “paucity of strong clinical guidelines.” The study, published in the Journal of Vascular Surgery (JVS), was a retrospective analysis of prospectively-collected data from the VQI registry, which the investigators say provides a “unique opportunity” to fill knowledge gaps in this field of research using real-world data originating across the U.S. The team identified all patients who had undergone endovascular PVIs for occlusive lower-extremity arterial disease from 2010 to 2019. Procedures in which an atherectomy device had been used as the primary or secondary device were classified as the atherectomy group, Nfor et al write.

In the study period, the authors note that a total of 205,377 PVIs were performed for 152,693 unique patients. The key finding, they report in JVS, is that, during the 10-year study period, 16.6% of the PVIs had used atherectomy, with the data showing that use “significantly increased” from 8.5% in 2010 to 19.7% in 2019.

Geographic variation was evident in the study results, with Nfor and colleagues stating that they found a significant difference in the prevalence of atherectomy use across 17 geographic regions, ranging from 8.2% to 29%.

These regions were further split into North, East, South, and West, the authors write, revealing that the observed frequency of atherectomy use in PVIs during the 10-year period was highest in the South at 22.5%, followed by the West (19.9%), North (17.3%), and East (12.6%; p<0.0001).

According to the study authors, the strongest predictor of use was performance of PVI in an office setting (odds ratio [OR], 10.08; 95% confidence interval [CI], 9.17–11.09) or ambulatory center (OR, 4; 95% CI, 3.65–4.39) versus a hospital setting. Furthermore, the geographic trend in atherectomy use followed the distribution of the proportion of office-based PVI procedures—South (6.1%), followed by the West (4%), North (3.9%), and East (0.5%).

They note that the presence of severe (OR, 2.6; 95% CI, 2.4–2.85) or moderate (OR, 1.5; 95% CI, 1.4–1.69) lesion calcification was also predictive of atherectomy use.

The researchers also examined the reimbursement aspect of the atherectomy discussion. For angioplasty performed in a hospital, the physician total relative value units (RVUs) was 12.94, averaging about $466, they report. For the same procedure performed in an office-based laboratory [OBL], the total RVU was 100.68 (procedure total), translating to $3,628.

Nfor et al further reveal that, when angioplasty was performed with atherectomy in a hospital, the physician RVU was 17.61, averaging $635. However, when atherectomy with angioplasty was performed in an OBL, the reimbursement increased to 345 RVU—approximately $12,444.

The authors, however, point out that these total RVU reimbursement figures for office and ambulatory center procedures includes the technical and facility fees.

“To provide patients with the highest quality of care, physicians must allow their decision-making to be guided only by the clinical factors and the best interest of the patient, and should be mindful of any biases that might influence their practice, including the reimbursement structure and financial incentives,” the researchers stress.

Caitlin Hicks

of complications.

Despite the financial incentives that exist, the authors acknowledge that clinical considerations “play an important role in interventional decisions that guide patient care.”

For example, the investigators note that patients in the hospital setting will tend to have more acute disease with greater urgency and a greater risk

Routine use of atherectomy for infrainguinal PVI called into question

In a commentary on Nfor and colleagues’ report, Caitlin Hicks, MD, a vascular surgeon from Johns Hopkins University School of Medicine, Baltimore, Maryland, underscores the “overwhelming message” of the analysis: that atherectomy is being overused in the U.S.

“This is not an attack on physicians who work in OBLs,” Hicks stresses at the outset of her commentary, but rather a “statement of the facts,” of which she assembles four from this latest addition to the available research: ◆ Atherectomy use for infrainguinal PVI has been “increasing rapidly” in the U.S. ◆ No high-quality evidence is available that atherectomy improves outcomes compared with alternative endovascular therapies ◆ Atherectomy is much more frequently used in OBL settings than in hospital-based settings ◆ And reimbursement for atherectomy procedures is substantially higher than that for stenting and balloon angioplasty in the outpatient setting

CANADIAN VASCULAR Virtual visits versus in-person: Telemedicine study detects ‘substantial’ cost savings for patients

By Bryan Kay

VIRTUAL CONSULTATIONS ARE COMPARABLE TO

care received in-person when it comes to general, clinical, process and patient satisfaction outcomes, a systematic review and meta-analysis of all primary studies evaluating telemedicine in vascular surgery has demonstrated.

“In considering, telemedicine’s effectiveness moving forward, one thing we have to keep in the back of our minds is: Are there other healthcare costs to the system with the use of virtual consultations?” first-named investigator, Arshia Javidan, MD, observed in an interview with Vascular Specialist, after delivering data from the study at the 2022 annual meeting of the Canadian Society for Vascular Surgery (CSVS) in Vancouver (Sept. 9–10). “So, for example, are additional investigations, or potentially unnecessary investigations, being ordered when we’re seeing a patient virtually, not doing a physical exam or not seeing anything in person, as opposed to a video camera, that may include additional costs later.” Javidan, from the division of vascular surgery at the University of Toronto in Toronto, was part of a research team led by Faysal Naji, MD, from the department of vascular surgery at McMaster University in Hamilton.

Some 22 studies were included in the review and involved around 29,000 patients. The study group’s limited meta-analysis of three randomized-controlled trials (RCTs) assessing diabetic foot ulcers did not detect any statistically significant differences in terms of ulcer healing, mortality or amputation rates, they noted. “In terms of other clinical outcomes, we grouped together what we were able to find based off the data available,” Javidan said. “This had to do with readmission rates, with surveys evaluating patient-reported outcome measures. And, largely, across clinical outcomes measured, there were no appreciable differences—meaning that telemedicine and virtual consultations were really no better or no worse across the board between virtual care and in-patient care.”

From a cost savings point of view, continued Javidan, the study found that patients were saving time, money and fuel through the use of virtual consultations. In terms of travel distance savings, the number “was relatively substantial at between 31 and 150 miles, 39 to 115 minutes of travel time,

“[In terms of savings, the numbers] were relatively substantial at between 31 and 150 miles, 39 to 115 minutes of travel time, and 2.2 to 12 gallons of

fuel saved” ARSHIA JAVIDAN

and 2.2 to 12 gallons of fuel saved.” Among seven studies evaluating patient satisfaction, patients generally felt telemedicine was either comparable or better than in-person visits, Javidan and colleagues found.

The researchers had felt there was a need to assess the merits of telemedicine—particularly through the lens of vascular surgery practice—from a higher level after analyzing a plethora of level three and four evidence, mostly in the form of cohort studies and case series. “There was no real review out there summarizing things, putting things together and aggregating results,” Javidan said.

Naji added, “As COVID calmed down a little bit, we noticed that telemedicine was still being used, kind of begging the question that maybe there were some hidden benefits to these shifts in practice patterns that we weren’t identifying.”

Summing up their findings at CSVS 2022, the research team noted: “Telemedicine has the potential to augment vascular surgery practice while reducing resource use for patients and providers alike. Additional high-quality evidence comparing telemedicine to in-person clinical encounters is required to further elucidate the effect that telemedicine and virtual consultations have on clinical outcomes.”

Arshia Javidan (left) and Faysal Naji

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