Advances in the Treatment of Stable Coronary Artery Disease and Peripheral Artery Disease

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE

EMCREG-INTERNATIONAL MONOGRAPH PROCEEDINGS FROM THE NOVEMBER 12, 2017 SYMPOSIUM www.emcreg.org ANAHEIM, CA

COLLABORATE | INVESTIGATE | EDUCATE COMPLIMENTARY CME MONOGRAPH

JANUARY 2018

EMCREG-International Monograph January 2018

Editor: W. Brian Gibler, MD President, EMCREG-International Professor of Emergency Medicine Department of Emergency Medicine University of Cincinnati College of Medicine Cincinnati, OH

Associate Editor: Judy M. Racadio, MD

Assistant Editor: Amy L. Hirsch

Production & Graphics Design Manager: Todd W. Roat

JANUARY 2018 Dear Colleagues,

The Emergency Medicine Cardiac Research and Education Group (EMCREG)-International was established in 1989 as an emergency medicine cardiovascular and neurovascular organization led by experts from the United States, Canada, and across the globe. We now have Steering Committee members from the US, Canada, Australia, Belgium, Brazil, France, Netherlands, New Zealand, Japan, Singapore, Sweden, and the United Kingdom. Now in our 28th year, we remain committed to providing you with the best educational programs and enduring material pieces possible. In addition to our usual Emergency Physician audience, we now reach out to our colleagues in Cardiology, Internal Medicine, Family Medicine, Hospital Medicine, and Emergency Medicine with our EMCREG-International University of Cincinnati Office of CME accredited symposia and enduring materials.

In this EMCREG-International Monograph, Advances in the Treatment of Stable Coronary Artery Disease and Peripheral Artery Disease, you will find a detailed discussion regarding the treatment of these two critically important disease entities. This is a Proceedings Monograph based on the 2017 EMCREG-International Satellite Symposium which was held on November 12, 2017, in Anaheim during the American Heart Association Scientific Sessions. For cardiologists, internists, family physicians, hospitalists and emergency physicians, the current approach and evolution of treatment for stable coronary artery disease (CAD) and peripheral artery disease (PAD) are particularly relevant and represent a fertile area for improving care for these patients.

This Monograph is divided into four sections. The first section provides a description of the scientific basis for the current management of patients with stable coronary artery disease. For many patients, this approach uses antiplatelet monotherapy typically aspirin. The use of dual antiplatelet therapy and anticoagulant therapy has also been evaluated in these patients. The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial which was published in late August 2017, is described in detail. This study was terminated prematurely because of the substantial superiority of the aspirin plus low dose rivaroxaban arm in patients with stable CAD and PAD. In the second section of this Monograph, the diagnosis and treatment of PAD is discussed in depth. Antiplatelet monotherapy serves as the predominant treatment for PAD though several other antiplatelet agents have been used as monotherapy or dual antiplatelet therapy. Balancing the positive benefits of these various therapeutic combinations versus the risk of bleeding has made monotherapy with aspirin or clopidogrel a Class Ia recommendation by the American College of Cardiology/American Heart Association Guidelines for PAD. The recently published COMPASS trial demonstrated that dual therapy with aspirin and low dose rivaroxaban was superior to treatment with aspirin only for patients with PAD. In the third section of this Monograph, a detailed discussion of the clotting mechanism emphasizes the cell based nature of the contemporary understanding of thrombosis. The intersection of the protein based clotting cascade with platelets, endothelial cells, and leukocytes represents a cohesive approach to understanding how antiplatelet and anticoagulant agents can prevent pathologic clot formation associated with disease processes such as chronic CAD and PAD. Finally, the clinical and economic value of appropriate anticoagulation with a Factor Xa inhibitor such as rivaroxaban help weave together a coherent approach to understanding the complex disease processes in stable CAD and PAD.

It is our sincere hope that you will find this EMCREG-International Proceedings Monograph from our 2017 EMCREG-International Satellite Symposium during the 2017 American Heart Association Scientific Sessions on the treatment of stable CAD and PAD useful to you in your daily practice as a cardiologist, internist, family physician, hospitalist, and emergency physician. Instructions for obtaining CME from the University of Cincinnati College of Medicine, Office of Continuing Medical Education are available at the conclusion of this January 2018, EMCREG-International Monograph. Thank you very much for your interest in EMCREG-International educational initiatives and we hope you visit our website (www.emcreg.org) for future educational events and publications.

W. Brian Gibler, MD President, EMCREG-International Professor of Emergency Medicine University of Cincinnati College of Medicine Cincinnati, Ohio USA

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE i CONTRIBUTING EDITOR AND AUTHORS:

W. Brian Gibler, MD (Editor) Richard C. Becker, MD President, EMCREG-International Professor of Medicine Department of Emergency Medicine Chief, Division of Cardiovascular Health and Disease University of Cincinnati College of Medicine Director and Physician-in-Chief Cincinnati, OH University of Cincinnati College of Medicine Cincinnati, OH

Deepak L. Bhatt, MD, MPH Christopher B. Granger, MD Professor of Medicine Professor of Medicine Executive Director of Interventional Cardiovascular Programs Division of Cardiology, Department of Medicine Brigham and Women’s Hospital Heart & Vascular Center Director, Cardiac Care Unit Harvard Medical School Duke University Medical Center Boston, MA Durham, NC

Manan Pareek, MD, PhD Manesh R. Patel, MD Postdoctoral Research Fellow Professor of Medicine Brigham and Women’s Hospital Heart & Vascular Center Chief, Division of Cardiology Harvard Medical School Chief, Division of Clinical Pharmacology Boston, MA Duke University Medical Center Durham, NC

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE iii EMCREG-INTERNATIONAL MEMBERS:

W. Brian Gibler, MD, President Jin H. Han, MD Brian J. O’Neil, MD University of Cincinnati Vanderbilt University Medical Center Wayne State University Cincinnati, Ohio Nashville, Tennessee Detroit, Michigan

V. Anantharaman, MD Katherine L. Heilpern, MD Joseph P. Ornato, MD Singapore General Hospital Emory University School of Medicine Medical College of Virginia Singapore Atlanta, Georgia Richmond, Virginia

Tom P. Aufderheide, MD Brian Hiestand, MD, MPH Arthur M. Pancioli, MD Medical College of Wisconsin Wake Forest University University of Cincinnati Milwaukee, Wisconsin Winston Salem, North Carolina Cincinnati, Ohio

Barbra Backus, MD James W. Hoekstra, MD W. Frank Peacock, MD The Hague Medical Center Wake Forest University Baylor College of Medicine The Hague, Netherlands Winston Salem, North Carolina Houston, Texas

Roberto R. Bassan, MD Judd E. Hollander, MD Nicolas R. Peschanski, MD Pro-Cardiaco Hospital Thomas Jefferson University Rouen University Hospital Rio de Janeiro, Brazil Philadelphia, Pennsylvania Upper-Normandy, France

Andra L. Blomkalns, MD Brian R. Holroyd, MD Charles V. Pollack, MA, MD University of Texas Southwestern Medical Center University of Alberta Hospitals Thomas Jefferson University Dallas, Texas Edmonton, Alberta, Canada Philadelphia, Pennsylvania

Richard Body, MB ChB, PhD Shingo Hori, MD Emanuel P. Rivers, MD, PhD Manchester University Hospital Keio University Henry Ford Hospital Manchester, UK Tokyo, Japan Detroit, Michigan

Gerald X. Brogan, MD Raymond E. Jackson, MD Francois P. Sarasin, MD Hofstra North Shore - LIJ William Beaumont Hospital Hospital Cantonal Forest Hills, New York Royal Oak, Michigan Geneva, Switzerland

David F. M. Brown, MD J. Douglas Kirk, MD Harry R. Severance, MD Massachusetts General Hospital U.C. Davis Medical Center University of Tennessee College of Medicine Boston, Massachusetts Sacramento, California Chattanooga, Tennessee

Charles B. Cairns, MD Fatimah Lateef, MD Corey M. Slovis, MD University of Arizona Singapore General Hospital Vanderbilt University Tucson, Arizona Singapore Nashville, Tennessee

Anna Marie Chang, MD Swee Han Lim, MD Alan B. Storrow, MD Thomas Jefferson University Singapore General Hospital Vanderbilt University Philadelphia, Pennsylvania Singapore Nashville, Tennessee

Douglas M. Char, MD Phillip D. Levy, MD Richard L. Summers, MD Washington University School of Medicine Wayne State University University of Mississippi St. Louis, Missouri Detroit, Michigan Jackson, Mississippi

Sean P. Collins, MD Christopher R. Lindsell, PhD Benjamin Sun, MD Vanderbilt University Vanderbilt University Oregon Health & Science University Nashville, Tennessee Nashville, Tennessee Portland, Oregon

Louise Cullen, MB, BS Chad V. Miller, MD Martin Than, MD Royal Brisbane Hospital, Brisbane Wake Forest University Christchurch Hospital Queensland, Australia Winston Salem, North Carolina Christchurch, New Zealand

Deborah B. Diercks, MD Richard M. Nowak, MD James E. Weber, MD University of Texas Southwestern Medical Center Henry Ford Hospital University of Michigan Dallas, Texas Detroit, Michigan Ann Arbor, Michigan

Gregory J. Fermann, MD Masatoshi Oba, MD, PhD University of Cincinnati Osaki Citizens Hospital Cincinnati, Ohio Osaki, Japan

Patrick Goldstein, MD Gunnar Öhlén, MD, PhD Lille University Hospital Karolinska University Hospital Lille, France Stockholm, Sweden iv ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE ACCREDITATION AND DESIGNATION OF CREDIT This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of the University of Cincinnati and EMCREG-International. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. The University of Cincinnati designates this enduring material activity for a maximum of 4.0 AMA PRA Category I Credits™.

Physicians should claim only the credits commensurate with the extent of their participation in the activity. The opinions expressed during this educational activity are those of the faculty and do not necessarily represent the views of the University of Cincinnati. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The University of Cincinnati College of Medicine is committed to resolving all conflicts of interest issues, which may arise as a result of prospective faculty member’s significant relationships with drug or device manufacturer(s). The University of Cincinnati College of Medicine mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the program.

In accordance with the ACCME Standards for Commercial Support the speakers for this course have been asked to disclose to participants the existence of any financial interest/and or relationship(s) (e.g. paid speaker, employee, paid consultant on a board and/or committee for a commercial company) that would potentially affect the objectivity of his/her presentation or whose products or services may be mentioned during their presentation. The following disclosures were made: PLANNING COMMITTEE AND FACULTY DISCLOSURES:

Planning Committee Members: W. Brian Gibler, MD: Advisory Board: AstraZeneca, Entegrion; Shareholder: MyocardioCare, Entegrion Rick Ricer, MD: No relevant relationships Susan P. Tyler: No relevant relationships Barb Forney: No relevant relationships

Speakers: Deepak L. Bhatt, MD, MPH: Grants/Research Support Recipient: Amarin, Amgen, AstraZeneca, Bristol Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company Richard C. Becker, MD: Advisor or Review Panel Member: Ionis, Portola Christopher B. Granger, MD: Grants/Research Support Recipient: Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, FDA, Glaxo SmithKline, Janssen Pharmaceuticals, Medtronic Foundation, Novartis, Pfizer; Consultant: Abbvie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Glaxo SmithKline, Janssen, Medscape, Medtronic, Merck, NIH, Novartis, Pfizer, Sirtex, Verseon Manan Pareek, MD, PhD: Advisory Board: AstraZeneca; Other Relationships: AstraZeneca, Medscape Manesh R. Patel, MD Grants/Research Support Recipient: AstraZeneca, Bayer, Janssen; Advisor or Review Panel Member: AstraZeneca, Bayer, Janssen

Commercial Acknowledgment: This EMCREG-International Monograph is Supported by an educational grant from Janssen Pharmaceuticals, Inc., administered by Janssen Scientific Affairs, LLC. Disclaimer: The opinions expressed during the live activity are those of the faculty and do not necessarily represent the views of the University of Cincinnati. The information is presented for the purpose of advancing the attendees’ professional development. Off Label Disclosure: Faculty members are required to inform the audience when they are discussing off-label, unapproved uses of devices and drugs. Physicians should consult full prescribing information before using any product mentioned during this educational activity. Learner Assurance Statement: The University of Cincinnati is committed to resolving all conflicts of interest issues that could arise as a result of prospective faculty members’ significant relationships with drug or device manufacturer(s). The University of Cincinnati is committed to retaining only those speakers with financial interests that can be reconciled with the goals and educational integrity of the CME activity. EMCREG-International will not be liable to you or anyone else for any decision made or action taken (or not taken) by you in reliance on these materials. This document does not replace individual physician clinical judgment. Clinical judgment must guide each professional in weighing the benefits of treatment against the risk of toxicity. Doses, indications, and methods of use for products referred to in this program are not necessarily the same as indicated in the package insert and may be derived from the professional literature or other clinical courses. Consult complete prescribing information before administering.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE v TABLE OF CONTENTS:

DECREASING MAJOR ADVERSE CLINICAL EVENTS FOR PATIENTS WITH CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE: THE COMPASS TRIAL 1 Manan Pareek, MD, PhD Postdoctoral Research Fellow Brigham and Women’s Hospital Heart & Vascular Center Harvard Medical School Boston, MA Deepak L. Bhatt, MD, MPH Professor of Medicine Executive Director of Interventional Cardiovascular Programs Brigham and Women’s Hospital Heart & Vascular Center Harvard Medical School Boston, MA

IMPROVING THE TREATMENT OF PERIPHERAL ARTERY DISEASE: PROVIDING INDIVIDUALIZED, INNOVATIVE, AND EFFICIENT CARE 5 Manesh R. Patel, MD Professor of Medicine Chief, Division of Cardiology Chief, Division of Clinical Pharmacology Duke University Medical Center Durham, NC

FACTOR Xa MECHANISM OF ACTION - IMPACT ON CLOTTING CASCADE, INFLAMMATION AND PLATELET ACTIVATION 11 Richard C. Becker, MD Professor of Medicine Chief, Division of Cardiovascular Health and Disease Director and Physician-in-Chief University of Cincinnati College of Medicine Cincinnati, OH

CLINICAL AND ECONOMIC VALUE OF RIVAROXABAN IN CORONARY ARTERY DISEASE 15 Christopher B. Granger, MD Professor of Medicine Division of Cardiology, Department of Medicine Director, Cardiac Care Unit Duke University Medical Center Durham, NC

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE vii REDUCING MAJOR ADVERSE CLINICAL EVENTS FOR PATIENTS WITH CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE: THE COMPASS TRIAL

REDUCING MAJOR ADVERSE CLINICAL EVENTS The randomized Clopidogrel versus Aspirin in Patients at Risk of FOR PATIENTS WITH CORONARY ARTERY Ischaemic Events (CAPRIE) trial compared clopidogrel, a P2Y12 DISEASE AND PERIPHERAL ARTERY DISEASE: receptor antagonist, at a dose of 75 mg once daily with aspirin 325 mg once daily in 19,185 patients with a recent ischemic stroke, THE COMPASS TRIAL a recent myocardial infarction, or symptomatic PAD.11 At a mean follow up of 1.9 years, the primary composite endpoint of ischemic Manan Pareek, MD, PhD stroke, myocardial infarction, or vascular death was significantly Postdoctoral Research Fellow Brigham and Women’s Hospital Heart & Vascular Center lower in the clopidogrel group (relative risk reduction, 8.7%; 95% Harvard Medical School, Boston, MA confidence interval [CI], 0.3-16.5; p=0.04). Subgroup analyses revealed a greater risk reduction in the PAD subgroup (Figure 1). Furthermore, the benefit of clopidogrel was more pronounced Deepak L. Bhatt, MD, MPH Professor of Medicine among subjects at high vascular risk, including those with diabetes 12,13 Executive Director of Interventional Cardiovascular Programs or multiple prior ischemic events. Importantly, clopidogrel was Brigham and Women’s Hospital Heart & Vascular Center as least as safe as aspirin. Harvard Medical School, Boston, MA FIGURE Relative Risk Reduction (95% Con dence Interval) for the Primary Endpoint Objectives 01 (a Composite of Ischemic Stroke, Myocardial Infarction, or Vascular Death) in Subgroups 1. Describe old and recent literature regarding antiplatelet therapy of the CAPRIE Trial in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD). MI -3.7% (-22.1 to 12.0) 2. Summarize recent data regarding very low-dose anticoagulation in patients with CAD and PAD. Stroke 7.3% (-5.7 to 18.7) 3. Describe the tradeoff between ischemic events and bleeding events in patients with CAD and PAD treated with antithrombotic 23.8% (8.9 to 36.2) therapy. PAD

All patients 8.7% (0.3 to 16.5) Introduction -40 -20 0 20 40 Chronic coronary artery disease (CAD) and peripheral artery dis- Aspirin better Clopidogrel better ease (PAD) are common manifestations of atherosclerosis. Recent estimates suggest that 16.5 million adults in the United States CAPRIE: Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; MI: myocardial infarction; PAD: peripheral artery disease. Reprinted with permission 1 have chronic CAD. The prevalence of PAD is lower, affecting more from CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel than five million American adults.2 While CAD is the leading cause versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996, of death worldwide, both conditions contribute significantly to loss 348:9038:329-1339. of disability-adjusted life-years.3,4 Atherosclerosis often manifests in several vascular beds, and the distinct clinical syndromes share Given the theoretical advantages of ticagrelor over clopidogrel, the many common major risk factors, including older age, smok- Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) ing, hypertension, hypercholesterolemia, and diabetes mellitus.5 investigators randomly assigned 13,885 patients with symptomatic Platelets play pivotal roles in the inflammatory, thrombotic, and PAD, defined as previous lower limb revascularization or an ankle- atherosclerotic processes. Therefore, targeting various pathways to brachial index of 0.80 or less, to receive ticagrelor 90 mg twice inhibit platelet activation and aggregation is essential in preventing daily or clopidogrel 75 mg once daily.14 Poor clopidogrel metaboliz- complications of progressive atherosclerotic disease.6 ers per cytochrome P-450 2C19 genotyping were excluded. At a median of 30 months, the primary efficacy endpoint, i.e., a com- Single Agent Antiplatelet Therapy posite of cardiovascular death, myocardial infarction, or ischemic stroke, had occurred with similar rates in the two groups (ticagrelor For more than three decades, platelet inhibition with the cyclooxy- versus clopidogrel, hazard ratio, 1.02; 95% CI, 0.92-1.13; p=0.65). genase-1 inhibitor aspirin has been a cornerstone in the treatment While the subset of patients with previous revascularization experi- and prevention of cardiovascular disease.7,8 In the secondary enced more myocardial infarctions and acute limb ischemia events, preventive setting, aspirin reduces the risk of myocardial infarction, there were no differences between patients treated with ticagrelor stroke, or death from vascular causes by an absolute 1.5%.9 How- versus clopidogrel.15 More patients in the ticagrelor group experi- ever, approximately one in eight patients experiences a recurrent enced dyspnea and any bleeding, but rates of major bleeding, fatal ischemic event while on aspirin.10 bleeding, and intracranial bleeding were similar for the two drugs.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 1 REDUCING MAJOR ADVERSE CLINICAL EVENTS FOR PATIENTS WITH CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE: THE COMPASS TRIAL

Dual Antiplatelet Therapy clopidogrel in preventing vascular events and provided a reduction in vascular death, without an increase in overall major bleeding.20 Dual antiplatelet therapy (DAPT) comprising aspirin and a P2Y12 Consequently, the Prevention of Cardiovascular Events in Patients receptor antagonist is the best-established regimen for patients with with Prior Heart Attack Using Ticagrelor Compared to Placebo on an acute coronary syndrome (ACS) or those undergoing percutane- a Background of Aspirin-Thrombolysis in Myocardial Infarction 16,17 ous coronary intervention and stent implantation. Accordingly, 54 (PEGASUS-TIMI 54) trial examined the efficacy and safety of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabili- extended DAPT in 21,162 patients with a previous myocardial zation, Management, and Avoidance (CHARISMA) trial tested the infarction and additional high-risk features for ischemic events.21 use of DAPT with clopidogrel 75 mg daily plus aspirin 75-162 mg Patients received ticagrelor (90 mg twice daily or 60 mg twice daily versus aspirin alone in 15,603 patients with either established daily) or placebo, on top of aspirin 75-150 mg daily. At 3 years, vascular disease (documented CAD, cerebrovascular disease, or the primary efficacy endpoint of cardiovascular death, myocardial symptomatic PAD) or multiple atherothrombotic risk factors for infarction, or stroke was significantly reduced with both ticagrelor 18 a median of 28 months. While the primary efficacy endpoint, a regimens as compared with placebo: ticagrelor 90 mg (hazard ratio, composite of myocardial infarction, stroke, or death from cardio- 0.85; 95% CI, 0.75-0.96; p=0.008) and ticagrelor 60 mg (hazard vascular causes, was not significantly reduced with DAPT (relative ratio, 0.84; 95% CI, 0.74-0.95; p=0.004). Absolute risk reductions risk, 0.93; 95% CI, 0.83-1.05; p=0.22), there was a significant risk with extended DAPT were greater among subjects with diabetes reduction in the subgroup of patients with established vascular and those with PAD, due to their higher baseline risk of ischemic disease (p=0.045 for interaction). A post hoc analysis also showed events.22 Ticagrelor also reduced the risk of acute limb ischemia or greater efficacy of DAPT versus aspirin alone among patients with peripheral artery revascularization. The rate of major bleeding was 19 prior myocardial infarction, ischemic stroke, or symptomatic PAD. significantly greater with ticagrelor, but rates of intracranial hemor- The relative risk reduction in the PAD subgroup was consistent rhage or fatal bleeding were similar in the three groups. with that observed for patients with myocardial infarction or stroke (Figure 2). The primary safety endpoint of severe bleeding was not An alternative DAPT strategy was tested in the Thrombin Receptor significantly increased with DAPT. Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 (TRA 2°P-TIMI 50) trial, in which 26,449 patients FIGURE Hazard Ratio (95% Con dence Interval) for with a history of myocardial infarction, ischemic stroke, or symp- the Primary Endpoint (a Composite of 02 Cardiovascular Death, Myocardial Infarction, tomatic PAD were randomly assigned to receive either vorapaxar, a or Stroke) in the Subgroup of Patients Enrolled protease-activated receptor 1 antagonist, at a dose of 2.5 mg daily Because of Myocardial Infarction, Ischemic or placebo, on a background of antiplatelet therapy.23 Vorapaxar re- Stroke, or Peripheral Artery Disease from the sulted in a significantly lower three-year risk of the primary efficacy CHARISMA Trial endpoint, a composite of death from cardiovascular causes, myocardial infarction, or stroke (hazard ratio, 0.87; 95% CI, 0.80-0.94; MI 0.77% (0.61 to 0.98) p<0.001). However, this came at the expense of a significantly increased risk of moderate or severe bleeding, including intracranial Ischemic stroke 0.78% (0.62 to 0.98) hemorrhage. The risk of intracranial hemorrhage was particularly pronounced among patients with previous stroke and prompted the PAD 0.87% (0.67 to 1.13) data and safety monitoring board to recommend discontinuation of study drug in this subgroup after a median of two years of follow up. In patients with PAD, vorapaxar did not reduce the primary All patients 0.83% (0.72 to 0.96) endpoint; however, the group of patients assigned to vorapaxar experienced significantly lower rates of hospitalization for acute limb 0.5 0.75 1 1.5 2 24 Aspirin better ischemia and peripheral revascularization. Clopidogrel + Aspirin better CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Very Low-Dose Anticoagulation Stabilization, Management, and Avoidance; MI: Myocardial infarction; PAD: peripheral artery disease. Reprinted with permission from Bhatt DL, Flather MD, Hacke W, Beger PB, et al. Patients With Prior Myocardial Infarction, Stroke, Patients with atherosclerotic disease remain at high risk for recur- or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial. J Amer Coll rent cardiovascular events despite antiplatelet therapy. Since these Cardiol. 2007, 49:19:1982-1988. individuals also display an increased activation of the coagulation system, there has been an interest in examining the role of oral DAPT using ticagrelor instead of clopidogrel was tested in the anticoagulation in this setting.25 Platelet Inhibition and Patient Outcomes (PLATO) trial, in which the two P2Y12 receptor antagonists were compared in patients In stented patients, a vitamin K antagonist does not offer superior with an ACS. Twelve months of ticagrelor was more effective than protection to DAPT and is associated with an increased risk of

2 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE REDUCING MAJOR ADVERSE CLINICAL EVENTS FOR PATIENTS WITH CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE: THE COMPASS TRIAL bleeding.26 However, a Phase 2 safety trial in patients who had FIGURE Primary and Selected Secondary E cacy been stabilized after ACS suggested that the direct factor Xa inhibi- Endpoints in the COMPASS Trial tor, rivaroxaban, might decrease the risk of ischemic endpoints.27 03 (All Study Patients) The subsequent Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary MI 0.86% (0.70 to 1.05)

Syndrome-TIMI 51 (ATLAS-ACS TIMI 51) trial tested the role of Stroke 0.58% (0.44 to 0.76) very low-dose rivaroxaban after ACS.28 A total of 15,526 patients were randomized to rivaroxaban, at a dose of either 2.5 mg or Cardiovascular death 0.78% (0.64 to 0.96) 5 mg twice daily, or placebo, in addition to DAPT with low-dose Death from any cause 0.82% (0.71 to 0.96) aspirin and a thienopyridine (clopidogrel or ticlopidine). At a mean Primary compositie endpoint 0.76% (0.66 to 0.86) of 13 months, the primary composite efficacy endpoint of death from cardiovascular causes, myocardial infarction, or stroke, was Net clinical benet 0.80% (0.70 to 0.91) significantly reduced with both doses of rivaroxaban (hazard ratio, 0.5 0.75 1 1.5 0.84; 95% CI, 0.74-0.96; p=0.008), albeit at the expense of more Rivaroxaban + aspirin better Aspirin better major bleeding and intracranial hemorrhage. The 2.5 mg rivaroxa- COMPASS: Cardiovascular Outcomes for People Using Anticoagulation Strategies; ban dose was associated with lower bleeding rates than 5 mg, as MI: myocardial infarction. well as decreased rates of death from cardiovascular causes and FIGURE Primary and Selected Secondary E cacy all-cause mortality compared to the 5 mg dose. Endpoints in the COMPASS Trial 04 (Subgroup with Peripheral Artery Disease) These intriguing findings for very low-dose anticoagulation finally culminated in the Cardiovascular Outcomes for People Using Anti- MI 0.76% (0.53 to 1.09) coagulation Strategies (COMPASS) trial, in which 27,395 individuals Stroke 0.54% (0.33 to 0.87) with stable atherosclerotic vascular disease (CAD or PAD) without Cardiovascular death 0.82% (0.59 to 1.14) an indication for DAPT or anticoagulation were randomly assigned Primary compositie endpoint 0.72% (0.57 to 0.90) to receive rivaroxaban 2.5 mg twice daily plus aspirin 100 mg MALE 0.54% (0.35 to 0.84) once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily.29 The trial was stopped early, after a mean follow up of 23 Major amputation 0.30% (0.11 to 0.80) months, owing to a consistent benefit in favor of the combination Key composite endpoint 0.69% (0.56 to 0.85) therapy arm. Thus, the primary endpoint, a composite of cardio- Net clinical benet 0.72% (0.59 to 0.87) vascular death, stroke, or myocardial infarction, was significantly 0.25 0.5 0.75 1 1.5 2 reduced with rivaroxaban plus aspirin versus aspirin alone (hazard Rivaroxaban + aspirin better Aspirin better ratio, 0.76; 95% CI, 0.66-0.86; p<0.001), but not with rivaroxaban MALE: major adverse limb events; MI: myocardial infarction; PAD: peripheral artery alone versus aspirin alone (hazard ratio, 0.90; 95% CI, 0.79-1.03; disease. Figures 3 and 4 reprinted with permission from Eikelboom JW, Connolly SJ, p=0.12). Rivaroxaban-aspirin significantly lowered the individual Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. endpoints of cardiovascular death, death from any cause, and N Engl J Med. 2017;Epub ahead of print. stroke (Figure 3). In 7,470 participants included with PAD, major limb events were substantially lowered as well (Figure 4). As Summary and Conclusions expected, major bleeding was significantly increased with rivaroxa- Patients with stable atherosclerotic disease derive benefit from sec- ban-aspirin versus aspirin (hazard ratio, 1.70; 95% CI, 1.40-2.05; ondary prevention with antiplatelet drugs. In this setting, clopidogrel p<0.001) and with rivaroxaban versus aspirin (hazard ratio, 1.51; is superior to aspirin. After an ACS event or percutaneous coronary 95% CI, 1.25-1.84; p<0.001). However, the combination regimen intervention, DAPT with aspirin and a P2Y12 receptor antagonist did not significantly increase fatal or intracranial hemorrhage and is the preferred regimen. In many ACS patients at high risk for was associated with significant net clinical benefit (hazard ratio, recurrent cardiovascular events and at low bleeding risk, extending 0.80; 95% CI, 0.70-0.91; p<0.001). DAPT beyond 12 months may be advantageous. The COMPASS trial has challenged the traditional antiplatelet-only paradigm by demonstrating a considerable ischemic benefit and, importantly, a reduction in cardiovascular mortality and all-cause mortality with very low-dose anticoagulation added to aspirin in patients with stable CAD and PAD. Still, as with any antithrombotic regimen, its use in clinical practice will require careful balancing of the risk of ischemia versus bleeding. Further analyses from the COMPASS trial are likely to identify individuals who will benefit the most from this new therapeutic approach.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 3 REDUCING MAJOR ADVERSE CLINICAL EVENTS FOR PATIENTS WITH CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE: THE COMPASS TRIAL

References

1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. 16. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, et Heart Disease and Stroke Statistics-2017 Update: A Report From the al. Effects of clopidogrel in addition to aspirin in patients with acute American Heart Association. Circulation. 2017;135(10):e146-e603. coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502. 2. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National 17. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Health and Nutrition Examination Survey, 1999-2000. Circulation. et al. Effects of pretreatment with clopidogrel and aspirin followed 2004;110(6):738-43. by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281):527-33. 3. GBD 2016 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and 18. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. healthy life expectancy (HALE) for 195 countries and territories, 1990- Clopidogrel and aspirin versus aspirin alone for the prevention of 2016: a systematic analysis for the Global Burden of Disease Study atherothrombotic events. N Engl J Med. 2006;354(16):1706-17. 2016. Lancet. 2017;390(10100):1260-344. 19. Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, et 4. GBD 2016 Causes of Death Collaborators. Global, regional, and al. Patients with prior myocardial infarction, stroke, or symptomatic national age-sex specific mortality for 264 causes of death, 1980- peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2016: a systematic analysis for the Global Burden of Disease Study 2007;49(19):1982-8. 2016. Lancet. 2017;390(10100):1151-210. 20. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held 5. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, et al. C, et al. Ticagrelor versus clopidogrel in patients with acute coronary International prevalence, recognition, and treatment of cardiovascular syndromes. N Engl J Med. 2009;361(11):1045-57. risk factors in outpatients with atherothrombosis. JAMA. 2006;295(2):180-9. 21. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. 6. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and N Engl J Med. 2015;372(19):1791-800. thrombus formation. Circ Res. 2007;100(9):1261-75. 22. Bhatt DL, Bonaca MP, Bansilal S, Angiolillo DJ, Cohen M, Storey RF, et 7. Lewis HD, Jr., Davis JW, Archibald DG, Steinke WE, Smitherman TC, al. Reduction in Ischemic Events With Ticagrelor in Diabetic Patients Doherty JE, 3rd, et al. Protective effects of aspirin against acute With Prior Myocardial Infarction in PEGASUS-TIMI 54. J Am Coll Cardiol. myocardial infarction and death in men with unstable angina. Results 2016;67(23):2732-40. of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309(7):396-403. 23. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. 8. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, et N Engl J Med. 2012;366(15):1404-13. al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985;313(22):1369-75. 24. Bonaca MP, Scirica BM, Creager MA, Olin J, Bounameaux H, Dellborg M, et al. Vorapaxar in patients with peripheral artery disease: results 9. Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, Collins from TRA°2 P-TIMI 50. Circulation. 2013;127(14):1522-9, 9e1-6. R, Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual 25. Bhatt DL, Hulot JS, Moliterno DJ, Harrington RA. Antiplatelet and participant data from randomised trials. Lancet. 2009;373(9678):1849- anticoagulation therapy for acute coronary syndromes. Circ Res. 60. 2014;114(12):1929-43.

10. Antithrombotic Trialists Collaboration. Collaborative meta-analysis 26. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, et al. of randomised trials of antiplatelet therapy for prevention of A clinical trial comparing three antithrombotic-drug regimens after death, myocardial infarction, and stroke in high risk patients. BMJ. coronary-artery stenting. Stent Anticoagulation Restenosis Study 2002;324(7329):71-86. Investigators. N Engl J Med. 1998;339(23):1665-71.

11. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel 27. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE F, et al. Rivaroxaban versus placebo in patients with acute coronary Steering Committee. Lancet. 1996;348(9038):1329-39. syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374(9683):29-38. 12. Ringleb PA, Bhatt DL, Hirsch AT, Topol EJ, Hacke W. Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events I. Benefit of clopidogrel 28. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et over aspirin is amplified in patients with a history of ischemic events. al. Rivaroxaban in patients with a recent acute coronary syndrome. Stroke. 2004;35(2):528-32. N Engl J Med. 2012;366(1):9-19.

13. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Amplified 29. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Am J Cardiol. 2002;90(6):625-8. Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-30.

14. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N Engl J Med. 2017;376(1):32-40.

15. Jones WS, Baumgartner I, Hiatt WR, Heizer G, Conte MS, White CJ, et al. Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease. Circulation. 2017;135(3):241-50.

4 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE IMPROVING THE TREATMENT OF PERIPHERAL ARTERY DISEASE: PROVIDING INDIVIDUALIZED, INNOVATIVE, AND EFFICIENT CARE

IMPROVING THE TREATMENT OF PERIPHERAL FIGURE Age-Standardized Mortality Rate for Patients ARTERY DISEASE: PROVIDING INDIVIDUALIZED, 01 with Peripheral Artery Disease, 2014 INNOVATIVE, AND EFFICIENT CARE

Manesh R. Patel, MD Professor of Medicine Chief, Division of Cardiology Co-Director, Duke Heart Center Duke University, Durham, NC

Objectives

1. Describe the symptoms and health risks associated with peripheral artery disease (PAD). 2. Summarize the current medical approach to treating patients with PAD. Reprinted with permission from Roth et al, Trends and Patterns of Geographic 3. Outline the significant results of recent trials of antithrombotic Variation in Cardiovascular Mortality Among US Counties, 1980-2014. JAMA therapy in patients with PAD. 2010;317(19): 1976-1992 JAMA 2010;317(19):1976-1992.

Introduction index (ABI) is the guideline recommended and most frequently used diagnostic test to determine the presence of PAD; the degree Atherosclerotic peripheral artery disease (PAD) affects more than of hemodynamic abnormality is often used along with symptoms to 200 million adults worldwide1 and an estimated eight million determine treatment strategies. people in the United States. The prevalence of peripheral artery disease (PAD) in patients over 70 years of age or over 55 with Medical treatment of patients with PAD has traditionally involved diabetes is estimated near 30% from the Partners study (Figure 1). antiplatelet monotherapy (e.g., aspirin or clopidogrel) and moder- Lower extremity PAD is considered a manifestation of systemic ate- to high-intensity statin medication to reduce cardiovascular risk atherosclerosis that affects the arteries of the lower limbs. Despite over time.10 Although PAD is generally considered a coronary artery recent advances in diagnosis and treatment, 5-10% of patients with disease (CAD) risk equivalent, antiplatelet and statin medications PAD have recurrent events and millions die from cardiovascular dis- are used significantly less frequently in patients with PAD than ease each year.2 Many medical strategies are considered important in patients with CAD. As such, there is significant opportunity to for patients with PAD. These include smoking cessation, diabetes improve treatment rates and compliance with antiplatelet and statin control, blood pressure management, exercise therapy for claudica- medications in patients with PAD.11,12 In patients with persistent tion, and antithrombotic medications. Antithrombotic medications symptoms despite background medical therapy, cilostazol and have been proven to reduce cardiovascular morbidity and mortal- supervised exercise training for intermittent claudication have ity in a number of scenarios, including acute coronary syndrome, been shown to improve walking distance and quality of life.13,14 atrial fibrillation, and percutaneous coronary intervention.3-7 Statin Until recently, supervised exercise training has been seldom used therapy is considered a cornerstone treatment to reduce the occur- by eligible patients due to lack of insurance reimbursement and rence of major adverse cardiovascular events in patients with stable sparse availability around the country. In May 2017, however, the atherosclerotic disease.8,9 The evidence base for PAD therapies has Centers for Medicare and Medicaid Services announced a National evolved recently. The cardiovascular risk of patients with PAD, risk Coverage Determination that will reimburse providers for supervised reduction strategies, recent antithrombotic trial data, and opportuni- exercise training in patients with intermittent claudication. ties for care improvement moving forward will be reviewed here. There are few proven medical therapies for patients with critical PAD Patient Population and Treatment Opportunities limb ischemia (CLI), the most severe form of PAD. In patients with limb threatening ischemia, non-invasive and invasive imaging is rec- Most patients with PAD are asymptomatic, and those with symp- ommended to define the burden and severity of obstructive disease, toms can present with a variety of complaints including atypical leg and revascularization is frequently recommended to preserve limb pain, intermittent claudication (leg pain that occurs with exertion function and mobility. Typically only 30% of patients who undergo a and improves with rest), ischemic rest pain, ulceration, or gan- limb amputation have an arterial diagnostic study of any kind per- grene.10 The symptom presentation often dictates how patients are formed prior to the amputation. The heterogeneity that exists in the identified and brought to clinical specialties. The ankle-brachial application of these diagnostic and interventional strategies is also

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 5 IMPROVING THE TREATMENT OF PERIPHERAL ARTERY DISEASE: PROVIDING INDIVIDUALIZED, INNOVATIVE, AND EFFICIENT CARE geographically variable across the country.15,16 Finally, in Medicare asymptomatic patients with PAD is derived from small studies and patients the mortality rate of patients with CLI at one year is nearly is more heterogeneous, the ACC/AHA guidelines place a Class IIa 50%, signaling the need for therapies aimed at this population.17 recommendation for antiplatelet therapy in these patients. There remains uncertainty about the long-term safety and efficacy of dual Dual Antiplatelet Therapy antiplatelet therapy in patients with PAD based on a single subgroup analysis from the Clopidogrel for High Atherothrombotic Risk When compared with patients with other forms of atherosclerotic and Ischemic Stabilization, Management and Avoidance (CHARIS- disease, including CAD, patients with PAD have a higher risk of MA) study, thus prolonged dual antiplatelet therapy for all patients cardiovascular death, myocardial infarction (MI), and stroke. In the with PAD remains a Class IIb recommendation. Reduction of Atherothrombosis for Continued Health (REACH) registry, PAD patients had a 21.1% annual risk of cardiovascular death, There are multiple antithrombotic targets to reduce the risk of myocardial infarction, stroke, or hospitalization for an atherothrom- atherothrombosis in stable patients with PAD (Figure 3). Therapies botic cause.18 Also, the risk of major adverse limb events, typically have targeted platelet activity and receptors and include aspirin, defined as major amputation or surgical intervention, varies from clopidogrel and ticagrelor, and vorapaxar (targeting thromboxane, 2-10% annually depending on age, symptom classification, con- P2Y12, and protease-activated receptor-1 [PAR-1], respectively). comitant medical therapy, and prior revascularization procedures. Aspirin has been the dominant therapy used by vascular physicians because of its low cost, availability, and safety; however, patients Importantly, major amputation of the lower extremities due to PAD remain at high risk for life threatening events such as MI and stroke has decreased significantly in the United States, but it remains an despite aspirin therapy.20 With the introduction of ticlopidine21 and important public health concern since mortality rates are nearly clopidogrel, multiple studies were performed in high-risk patients, 50% at one year and 70% at three years after major amputation in including those with PAD. The use of ticlodipine was truncated due Medicare patients.19 Lower extremity peripheral vascular interven- to an excess risk of thrombotic thrombocytopenic purpura, and tions have increased significantly over the last two decades while clopidogrel was found to reduce the risk of vascular death, MI, (Figure 2). or stroke by 23.8% in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial,22 the substitution of clopi- FIGURE Trends in Peripheral Vascular Intervention dogrel for aspirin did not routinely occur in clinical practice due to 02 (PVI) in U.S. Medicare Bene ciaries cost. More recently, the use of oral anticoagulants has been studied in patients with atherosclerotic disease including PAD. 250 231.6 228.5 209.7 215.4  Recent Antithrombotic Clinical Trial Data 200 187.8 186.4   184.7 Vorapaxar is a PAR-1 inhibitor that binds to platelets and has been 174.3 178.0  150 165.3   154.8 151.6 studied in the setting of acute coronary syndrome and stable atherosclerotic disease (prior MI or PAD) as an addition to baseline  Inpatient 100 Outpatient antiplatelet therapy. In the pivotal Thrombin Receptor Antagonist O ce in Secondary Prevention of Atherothrombotic Ischemic Events Age- and Sex-Adjusted Rate 50 37.8 (TRA°2P)-TIMI 50 study, 26,449 patients (3,787 with PAD) were

f PVI per 100,000 Medicare Beneficiaries 18.4 19.7 23

o 13.2 6.0 4.1 randomized to vorapaxar or placebo. Eighty-eight percent of 0 these patients were receiving aspirin therapy, 37% were taking a 2006 2007 2008 2009 2010 2011 thienopyridine, and 28% were receiving dual antiplatelet therapy on Reprinted with permission from Jones WS et al, Trends in Settings of Peripheral study entry. In the overall cohort, vorapaxar reduced the incidence Vascular Intervention and the Effect of Changes in the Outpatient Prospective of the composite endpoint (cardiovascular death, MI, or stroke) Payment System. J Am Coll Cardiol 2015;65(9):920-7. by 1.2%. In the PAD cohort, the risk reduction for the primary composite endpoint was not statistically significant (11.3% versus Risk Reduction from Antithrombotic Agents 11.9%; hazard ratio, 0.94; 95% confidence interval [CI] 0.78 – 1.14; p=0.53). Vorapaxar did reduce the risk of hospitalization Antiplatelet therapies have been the center of treatment for patients for acute limb ischemia and peripheral revascularization, but the with atherosclerotic vascular disease; the American College of hazard of GUSTO (Global Utilization of Streptokinase and t-PA Cardiology/American Heart Association (ACC/AHA) guidelines for Occluded Coronary Arteries) moderate and severe bleeding place a Class Ia recommendation for antiplatelet monotherapy and intracranial hemorrhage was statistically significantly higher with aspirin (75-325 mg daily) or clopidogrel (75 mg daily) to with vorapaxar. In 2014, the U.S. Food and Drug Administration reduce the incidence of MI, stroke, and vascular death in patients approved the use of vorapaxar in patients with prior MI or PAD with symptomatic PAD.10 Since the data for antiplatelet therapy in albeit with a warning for bleeding on the label.

6 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE IMPROVING THE TREATMENT OF PERIPHERAL ARTERY DISEASE: PROVIDING INDIVIDUALIZED, INNOVATIVE, AND EFFICIENT CARE

In the recently published Cardiovascular Outcomes for People Us- FIGURE Mechanisms of Anti-Thrombotic ing Anticoagulation Strategies (COMPASS) trial, a total of 27,395 Medications and Clinical Endpoints patients with stable atherosclerotic vascular disease (CAD, PAD, or 03 Important to Patients with PAD both) were randomized to three arms (aspirin 100 mg daily versus

Additional factors: rivaroxaban 5 mg twice daily versus aspirin 100 mg daily plus riva- Shear stress Collagen / vWF roxaban 2.5 mg twice daily) at 602 centers worldwide.26 The study In mamation Aspirin was terminated earlier than expected due to overwhelming efficacy in the aspirin and low-dose rivaroxaban arm. Over approximately Vorapaxar TXA2 two years of follow up, patients randomized to aspirin plus rivaroxa- Clopidogrel ban 2.5 mg twice daily had a significantly lower rate of the primary PAR-1 TP Prasugrel Ticagrelor composite endpoint (MI, ischemic stroke, cardiovascular death) Cangrelor when compared with aspirin alone (4.1% versus 5.4%; hazard P2Y12 TF + FVIIa ratio, 0.76; 95% CI, 0.66-0.86; p<0.001). There was a significantly higher rate of major bleeding in the aspirin plus rivaroxaban group Prothrombin when compared with aspirin alone (3.1% versus 1.9%; hazard ratio, Factor Xa 1.70; 95% CI, 1.40-2.15; p<0.001). Nevertheless, there was an 18% risk reduction in all-cause mortality in favor of aspirin and Rivaroxaban Granule ADP low-dose rivaroxaban (3.4% versus 4.1%; hazard ratio, 0.82; 95% CI Apixaban Secretion 0.71-0.96; p<0.001).

Fibrin + Platelet Aggregation Dabigatran Thrombin In a simultaneous report, rivaroxaban was shown to have similar efficacy in the PAD cohort from the COMPASS trial. In 7,470 patients Fibrinogen Platelet-Fibrin Clot Ischemic Events who met inclusion criteria based on a prior history of PAD, 55.2% had symptomatic limbs, 25.7% had carotid disease, and 19.1% had Reprinted with permission. vWF: von Willebrand Factor; TxA2: thromboxane A2; a low ABI. The rate of the primary composite endpoint was reduced TP: thromboxane receptor; TF: tissue factor; ADP: adenosine diphosphate. with aspirin plus rivaroxaban 2.5 mg twice daily when compared with aspirin alone (5.1% versus 6.9%; hazard ratio, 0.72; 95% CI, 0.57-0.90; p<0.001). The risk of major bleeding was also very simi- Another antiplatelet agent, ticagrelor, has been tested extensively in lar to the main trial results, with aspirin plus rivaroxaban 2.5 mg patients with PAD. The Prevention of Cardiovascular Events in Pa- twice daily being associated with a significantly higher rate of major tients with Prior Heart Attack Using Ticagrelor Compared to Placebo bleeding when compared with aspirin alone (3.1% versus 1.9%; haz- on a Background of Aspirin - Thrombolysis in Myocardial Infarction ard ratio, 1.61; 95% CI, 1.12-2.31; p<0.001). However, this finding 54 (PEGASUS-TIMI 54) trial enrolled 21,162 patients with a prior is also significant in that PAD patients did not have an elevated risk history of MI, of which 1,143 had PAD.24 Patients were randomized of major bleeding when compared to patients without PAD. in a 1:1:1 fashion to ticagrelor 90 mg twice daily versus ticagrelor 60 mg twice daily versus placebo on a background of aspirin. PAD In aggregate, these recent trial results provide some insight into the patients in the ticagrelor 60 mg arm had a statistically significant potential pathobiology of cardiovascular and limb events in patients reduction in cardiovascular death, MI, or stroke, but the reduction with PAD. These recent data demonstrated no improvement in with the ticagrelor 90 mg dose was not statistically significant. cardiovascular outcomes with more potent mono antiplatelet Hospitalization for acute limb ischemia or peripheral revasculariza- therapy (EUCLID). Subgroups of studies with dual therapy versus tion was significantly reduced in the ticagrelor 90 mg arm but the mono antiplatelet therapy show some benefit (PEGASUS, CHA- reduction in the 60 mg arm was not statistically significant.24 RISMA). Finally, there is now evidence that dual pathway therapy The Examining Use of Ticagrelor in Peripheral Artery Disease with antiplatelet and antithrombotic therapy (COMPASS PAD) may (EUCLID) trial randomized 13,885 symptomatic patients with PAD provide the most significant cardiovascular and limb protection in a 1:1 fashion to ticagrelor or clopidogrel monotherapy.25 Patients for PAD patients. Table 1 summarizes clinical trials of antithrom- were followed for approximately 30 months, and there was no dif- botic agents in patients with stable peripheral arterial disease and ference between the two groups in terms of the primary composite patients undergoing peripheral revascularization. endpoint of cardiovascular death, MI, or stroke (10.8% versus 10.6%; hazard ratio, 1.02; 95% CI, 0.92-1.13; p=0.65). Both major bleeding (1.6% versus 1.6%; hazard ratio, 1.10; 95% CI 0.84-1.43; p=0.49) and hospitalization for acute limb ischemia (1.7% versus 1.7%; hazard ratio, 1.03; 95% CI 0.79-1.33; p=0.85) were also similar between treatment groups.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 7 IMPROVING THE TREATMENT OF PERIPHERAL ARTERY DISEASE: PROVIDING INDIVIDUALIZED, INNOVATIVE, AND EFFICIENT CARE

PAD: peripheral arterial dis- TABLE Clinical Trials of Anti-thrombotic Agents in Patients with Stable Peripheral Arterial 01 Disease and Patients Undergoing Peripheral Revascularization ease; POPADA: Prevention of Progression of Arterial Disease Stable PAD 1 vs. 0 (Antiplatelet agent) 1 vs. 1 (Antiplatelet agent) and Diabetes; STIMS: Swedish Ticlopidine Multicentre Study; Aspirin for Asymptomatic TRIAL POPADAD Atherosclerosis Trialists STIMS CAPRIE EUCLID CAPRIE: Clopidogrel versus Aspirin Description ASA 100 mg daily vs. ASA 100 mg daily vs. Ticlopidine vs. ASA 100 mg daily vs. Ticagrelor vs. Clopidogrel in Patients at Risk of Ischaemic Control Control Placebo Clopidogrel 13,885 patients Events; EUCLID: Examining Use 1,276 patients 3,350 patients 687 patients 6,452 patients of Ticagrelor in Peripheral Artery Major Vascular death, MI, Fatal or non-fatal MI/ *All-cause mortality: Vascular death, MI, or CV death, MI, or stroke: adverse stroke: stroke or 18.5% vs.26.1% ischemic stroke: 10.8% vs. 10.6% Disease; CHARISMA: Clopidogrel cardiac 18.2% vs. 18.3% revascularization: for High Atherothrombotic Risk and events HR 0.98, 95% CI .76-1.26 HR 1.03, 95% CI 0.84-1.27 HR 0.76, 95% CI 0.64-0.91 HR 1.02, 95% CI .92-1.13 Ischemic Stabilization, Management Major Major amputation: Not reported Not reported Not reported Not reported and Avoidance; TRA2°P: Thrombin adverse 2% vs. 2% limb Receptor Antagonist in Secondary events Prevention of Atherothrombotic Acute Not reported Not reported Not reported Not reported 1.7% vs. 1.7% limb HR 1.03, 95% CI .79-1.33 Ischemic Events; PEGASUS: Preven- ischemia tion of Cardiovascular Events in

Major Not reported HR 1.71, 95% CI 0.99-2.97 *Ticlopidine group Not reported for PAD TIMI Major Bleeding: Patients with Prior Heart Attack Us- bleeding had 5% rate of subgroup 1.6% vs. 1.6% ing Ticagrelor Compared to Placebo hemorrhagic event on a Background of Aspirin; WAVE: 2 vs. 1 (Antiplatelet and Anticoagulant) 2 vs. 2 (Antiplatelet and Anticoagulant) Warfarin Antiplatelet Vascular Evaluation; COMPASS: Cardiovas- TRIAL CHARISMA TRA2°P PEGASUS WAVE COMPASS Description ASA vs. ASA/Clopidogrel Vorapaxar vs. placebo on Ticagrelor 90mg BID Antiplatelet (ASA, Rivaroxaban 2.5 mg BID + cular Outcomes for People Using 3,096 patients background of antiplatelet vs. Ticagrelor 60 BID clopidogrel or ASA 100 mg daily vs. Anticoagulation Strategies; CASPAR: (88% aspirin, 28% on vs. placebo on ticlopidine) + warfarin Rivaroxaban 5 mg BID vs. Clopidogrel and Acetyl Salicylic Acid ASA & thienopyridine) background of ASA vs. Antiplatelet ASA 100 mg daily 3787 patients 1,143 patients 2,161 patients 7,470 patients in Bypass Surgery for Peripheral Arterial Disease; VOYAGER: Efficacy Major CV death, MI, or stroke: CV death, MI, or stroke: CV death, MI, stroke: CV death, MI, or stroke: CV death, MI, or stroke: adverse 7.6% vs. 8.9% 11.3% vs. 11.9% Ticagrelor 60mg 12.2% vs. 13.3% 5.1% vs. 6.9% and Safety of Rivaroxaban in Reduc- cardiac HR 0.85, 95% CI .66-1.08 HR 0.94, 95% CI .78–1.14 HR 0.69,95% CI .47–.99 HR 0.92,95% CI 0.73-1.16 HR 0.72, 95% CI .57-.90 ing the Risk of Major Thrombotic events Ticagrelor 90mg HR 0.81 Vascular Events in Subjects with 95% CI 0.57– 0.15 Symptomatic Peripheral Artery Major Not reported Not reported Not reported Not reported 1.2% vs. 2.2% Disease Undergoing Peripheral adverse HR 0.54, 95% CI .35-.84 Revascularization Procedures of the limb events Lower Extremity; ePAD: Edoxaban in Peripheral Arterial Disease; ASA: Acute Not reported 2.3% vs. 3.9% Ticagrelor 60mg Not reported Not reported limb HR 0.58, 95% CI 0.39–0.86 HR 0.67, 95% CI .24–.87 aspirin; MI: myocardial infarction; ischemia Ticagrelor 90mg CV: cardiovascular; HR: hazard HR 0.45,95% CI .14–1.45 ratio; CI: confidence interval; RR: Major GUSTO Severe GUSTO Mod/Sev TIMI Major bleeding: Life threatening bleeding: ISTH Major bleeding: relative risk; TIMI: Thrombolysis bleeding bleeding: bleeding: Ticagrelor 60mg: 4.0% vs. 1.2% 3.1% vs. 1.9% 1.7% vs. 1.5% 7.4% vs. 4.5% HR 1.18,95% CI .29–4.70 RR 3.41, 95% CI 1.84- 6.35 HR 1.61, 95% CI 1.12-2.31 in Myocardial Infarction; GUSTO: HR 0.97, 95% CI .56-1.66 HR 1.62, 95% CI 1.21–2.18 Ticagrelor 90 mg: Global Utilization of Streptokinase HR 1.46,95% CI .39–5.43 and t-PA for Occluded Coronary Post-Revasc 2 vs. 1 (Antiplatelet and Anticoagulant) 2 vs. 2 (Antiplatelet and Anticoagulant) Arteries; ISTH: International Society TRIAL CASPAR VOYAGER ePAD on Thrombosis and Haemostasis; Description Clopidogrel vs. placebo Rivaroxaban vs. placebo ASA/Edoxaban vs. BID: twice daily on background of ASA on background of ASA ASA/Clopidogrel 851 patients 6,500 patients 203 patients Major *Death Not available – Not reported adverse 24 patients vs. 17 trial ongoing cardiac HR 1.44, 95% CI .77-2.68 events Major *Primary endpoint Not available – Not reported adverse (graft occlusion, major trial ongoing limb amputation or death) events HR 0.98, 95% CI .78-1.23 Acute Not reported Not available – Not reported limb trial ongoing ischemia Major GUSTO Severe Not available – TIMI Major bleeding: bleeding bleeding: trial ongoing 0 patients (E) vs. 2.1% vs. 1.2% 2 patients (C)

8 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE IMPROVING THE TREATMENT OF PERIPHERAL ARTERY DISEASE: PROVIDING INDIVIDUALIZED, INNOVATIVE, AND EFFICIENT CARE

Ongoing Clinical Trial 10. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive The Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Summary: A Report of the American College of Cardiology/American Heart Thrombotic Vascular Events in Subjects with Symptomatic Peripheral Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;69(11):1465-508. Artery Disease Undergoing Peripheral Revascularization Procedures 11. Subherwal S, Patel MR, Chiswell K, Tidemann-Miller BA, Jones WS, Conte of the Lower Extremity (VOYAGER PAD) study is a 1:1 randomized, MS, et al. Clinical trials in peripheral vascular disease: pipeline and trial placebo-controlled trial of rivaroxaban 2.5 mg twice daily or placebo designs: an evaluation of the ClinicalTrials.gov database. Circulation. on a background of aspirin 100 mg daily after peripheral surgical 2014;130(20):1812-9. and/or endovascular revascularization. VOYAGER will enroll over 12. Armstrong EJ, Chen DC, Westin GG, Singh S, McCoach CE, Bang H, et al. Adherence to guideline-recommended therapy is associated with 6,500 patients and should be reported in early 2019. decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease. J Am Heart Assoc. Conclusion 2014;3(2):e000697. 13. Jones WS, Schmit KM, Vemulapalli S, Subherwal S, Patel MR, Hasselblad In conclusion, PAD is a systemic manifestation of atherosclerosis V, et al. Treatment Strategies for Patients With Peripheral Artery Disease. that affects over 200 million people worldwide. Proven therapies Rockville (MD); 2013. such as blood pressure reduction, statin therapy, and smoking 14. Vemulapalli S, Dolor RJ, Hasselblad V, Schmit K, Banks A, Heidenfelder B, et al. Supervised vs unsupervised exercise for intermittent claudication: A cessation are variable and used less in patients with PAD compared systematic review and meta-analysis. Am Heart J. 2015;169(6):924-37 e3. to patients with CAD. Antithrombotic therapy for patients with PAD 15. Vemulapalli S, Greiner MA, Jones WS, Patel MR, Hernandez AF, Curtis has recently evolved and monotherapy with clopidogrel has been LH. Peripheral arterial testing before lower extremity amputation among shown to be similar to ticagrelor. Rivaroxaban 2.5 mg twice daily in Medicare beneficiaries, 2000 to 2010. Circ Cardiovasc Qual Outcomes. 2014;7(1):142-50. addition to aspirin was shown to reduce cardiovascular events and 16. Soden PA, Zettervall SL, Curran T, Vouyouka AG, Goodney PP, Mills JL, limb events when compared to aspirin alone. Clinicians and pa- et al. Regional variation in patient selection and treatment for lower tients will need to have personalized discussions on how to reduce extremity vascular disease in the Vascular Quality Initiative. J Vasc Surg. their cardiovascular and limb risk for clinical events. 2017;65(1):108-18. 17. Iida O, Takahara M, Soga Y, Azuma N, Nanto S, Uematsu M, et al. References Prognostic Impact of Revascularization in Poor-Risk Patients With Critical Limb Ischemia: The PRIORITY Registry (Poor-Risk Patients With and Without 1. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Revascularization Therapy for Critical Limb Ischemia). JACC Cardiovasc et al. Comparison of global estimates of prevalence and risk factors for Interv. 2017;10(11):1147-57. peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382(9901):1329-40. 18. Steg PG, Bhatt DL, Wilson PW, D'Agostino R, Sr., Ohman EM, Rother J, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. 2. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, et al. Comparative JAMA. 2007;297(11):1197-206. determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304(12):1350-7. 19. Jones WS, Patel MR, Dai D, Subherwal S, Stafford J, Calhoun S, et al. Temporal trends and geographic variation of lower-extremity amputation in 3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb patients with peripheral artery disease: results from U.S. Medicare 2000- S, et al. Prasugrel versus clopidogrel in patients with acute coronary 2008. J Am Coll Cardiol. 2012;60(21):2230-6. syndromes. N Engl J Med. 2007;357(20):2001-15. 20. Jones WS, Patel MR, Dai D, Vemulapalli S, Subherwal S, Stafford J, et al. 4. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. High mortality risks after major lower extremity amputation in Medicare Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N patients with peripheral artery disease. Am Heart J. 2013;165(5):809-15. Engl J Med. 2009;361(11):1045-57. 21. Jones WS, Mi X, Qualls LG, Vemulapalli S, Peterson ED, Patel MR, et al. 5. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Trends in settings for peripheral vascular intervention and the effect of Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. changes in the outpatient prospective payment system. J Am Coll Cardiol. 2011;365(10):883-91. 2015;65(9):920-7.

6. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et 22. Antithrombotic Trialists Collaborative meta-analysis of randomised trials of al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. antiplatelet therapy for prevention of death, myocardial infarction, & stroke 2011;365(11):981-92. in high risk patients. BMJ. 2002;324(7329):71-86.

7. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, 23. Janzon L. The STIMS trial: the ticlopidine experience and its clinical et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting applications. Swedish Ticlopidine Multicenter Study. Vasc Med. stents. N Engl J Med. 2014;371(23):2155-66. 1996;1(2):141-3.

8. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study 24. Bonaca MP, Bhatt DL, Storey RF, Steg PG, Cohen M, Kuder J, et of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a al. Ticagrelor for Prevention of Ischemic Events After Myocardial randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22. Infarction in Patients With Peripheral Artery Disease. J Am Coll Cardiol. 2016;67(23):2719-28. 9. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary 25. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, et al. disease. N Engl J Med. 2005;352(14):1425-35. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N Engl J Med. 2017;376(1):32-40.

26. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 9 FACTOR Xa MECHANISM OF ACTION- IMPACT ON CLOTTING CASCADE, INFLAMMATION AND PLATELET ACTIVATION

FACTOR Xa MECHANISM OF ACTION - IMPACT ON Prothrombinase Assembly on Platelet Surfaces CLOTTING CASCADE, INFLAMMATION AND Platelets play a critical role in localizing and controlling the burst of PLATELET ACTIVATION thrombin generation leading to fibrin formation. Procoagulant phospholipids (microparticles), particularly phosphatidylserine, stimulate Richard C. Becker, MD, FAHA prothrombinase assembly by several orders of magnitude. Factor Stonehill Endowed Chair and Professor of Medicine; Chief, X activation requires a phospholipid surface; however, recent work Division of Cardiovascular Health and Disease; Director and Physician-in-Chief, University of Cincinnati College of Medicine, suggests that thrombin-stimulated platelets also expose non-lipid Cincinnati, OH binding sites for fVIIIa, fIXa and fXa. The platelet receptor for fXa may include membrane bound fVa, effector protease receptor Objectives (EPR-1), and an anion-exposed binding site in complex with glycoprotein Ib. 1. Discuss the contemporary paradigm of thrombosis, including the role of neutrophil extracellular traps (NETs), histones and Emerging Paradigms in Thrombosis DNA-histone complexes. 2. List the inflammatory and proliferative effects of Factor Xa and A traditional perspective of thrombosis begins with vessel wall inju- describe the interplay between inflammation and thrombosis. ry and exposure of subendothelial proteins, including collagen and 3. Describe the evidence that attenuation of inflammation is benefi- tissue factor, to circulating cellular and non-cellular components. cial in patients who are at risk for a cardiovascular event. Adhesion and activation of platelets, mediated by their interaction with von Willebrand protein and collagen, respectively, coupled with Introduction tissue factor-mediated activation of coagulation proteins results in thrombin generation and fibrin formation. The events as they take A contemporary view of thrombosis emphasizes the importance place on cell surfaces are summarized above. While this time-hon- of cellular surface biochemistry and the integrated contribution of ored paradigm remains firm and soundly based, emerging evidence platelets, leukocytes, nucleic acids, histones and perturbed endo- suggests that thrombosis is much more complex and dynamic than thelial cells. Initiation of coagulation occurs on tissue-factor (TF) originally believed. Several novel triggers, templates and facilita- bearing cells, while amplification (or priming) requires activation of tors, such as cell-free nucleic acids (cfNAs), histones, DNA-histone platelets and coagulation proteases. The final phase, propagation, complexes, polyphosphates, and microvesicles, have recently been is determined by thrombin generation on platelet surfaces. The cell- identified and require inclusion in the expanding universe of throm- based model of thrombosis highlights specific phases or biochemi- bosis as a dominant phenotype of human conditions, disorders and cal stages rather than a traditional view of independent coagulation diseases. pathways or cascades. Accordingly, tissue factor is considered the key element for initiation of thrombosis, wherein its ability to Neutrophil extracellular traps (NETs) are platforms of intact chroma- complex with factor VIIa (fVIIa) and activate factor X (fXa) ultimately tin fibers with antimicrobial proteins that are produced by neutro- causes thrombin generation. Although thrombin is a pivotal enzyme phils to ‘‘trap and disarm’’ microbes in the extracellular in thrombosis, the importance of fXa and its diverse effects on milieu. These NETs have been shown to interact with the vascular thrombin generation, inflammatory processes, smooth muscle cell endothelium, platelets, red blood cells, and coagulation factors, proliferation and endothelial cell activation represents a point of each of which are known to participate actively in thrombus forma- convergence for each component part. tion. Specifically, NETs have been shown to induce endothelial cell death via interactions with NET-associated proteases or cationic Factor X proteins, including histones. Histones, in turn, can induce pore Factor X (fX) is a vitamin K-dependent glycoprotein synthesized in formation and influx of ions into cells by binding to their cellular the liver and subsequently secreted into the plasma as a precursor membranes. These interactions promote increased intracellular to an active serine protease fXa. The human protein is composed calcium levels, endothelial activation and Weibel-Palade content of a light chain and a heavy chain linked by a single disulfide bond. release of von Willebrand factor and other prothrombotic constitu- The catalytic domain of fXa is contained within the heavy chain. ent proteins.

Factor X is activated by excision of a small peptide from its heavy Beyond their ability to bind endothelial cells and cause activation, chain. The cleavage of an alanine-isoleucine peptide bond by either NETs directly activate platelets. NETs have been shown in flow TF-fVIIa or fVIIIa-fIXa complex liberates the 52 amino acid peptide, systems to bind platelets and facilitate aggregation. These proper- providing a potentially measureable marker of fX activation. Under ties are believed to be the result of both direct and indirect effects, optimal conditions (high concentrations of TF), the TF-fVIIa complex as platelets are known to bind with histones through phospholipids, can activate fX and, in essence, bypass the contribution of fVIII-fIX. carbohydrates, and toll-like receptors (TLRs). In addition, platelets

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 11 FACTOR Xa MECHANISM OF ACTION- IMPACT ON CLOTTING CASCADE, INFLAMMATION AND PLATELET ACTIVATION

can bind double-and single-stranded DNA in vitro, representing an Factor Xa: Inflammatory and Proliferative Effects alternative mechanism for NET-induced platelet activation. Factor Xa binds to human umbilical vein endothelial cells via a Also, NETs may provoke thrombus formation through direct stimula- single class of binding sites with a dissociation constant value of tion of both the contact and TF-mediated coagulation pathways 6.6 ± 0.8 nM and density of 57460 ± 5200 sites per cell. The bind- (Figure 1). In vitro, NETs have been shown to stimulate fibrin for- ing kinetics are considered “pseudo” first order with association mation and deposition as well as to co-localize with fibrin in blood and dissociation constants of 0.15 × 106 m−1 s−1 and 4.0 × 10−4 clots. The NETs contain neutrophil elastase, which can effectively s−1, respectively. FXa binding to vascular endothelial cells is not cleave TF pathway inhibitor and augment fXa activation. By binding influenced by thrombin, fVa, antithrombin or TF pathway inhibitor to TF pathway inhibitor, NETs also attenuate the endothelium’s but is blocked by antibodies specific for EPR-1, supporting its role primary means to regulate TF. Last, NETs can stimulate thrombin in fXa-endothelial cell interactions. The binding of fXa is associated generation and fibrin formation through fXII-mediated contact with the following events: 1) increased intracellular calcium; 2) activation. Similar to cfNAs, DNA-histone complexes have prothrom- increased phosphoinositide turnover; 3) tissue factor expression; botic properties. The responsible mechanisms, however, are likely 4) tissue plasminogen activator release; 5) plasminogen activator the product of inflammatory states and cellular damage rather than inhibitor release; 6) interleukin-6 and -8 release; 7) cellular pro- functional pathways. liferation; 8) expression of E-selectin, ICAM-1 (intercellular adhesion molecule) and VCAM-1 (vascular cell adhesion molecule); and 9) FIGURE Neutrophil Extracellular Traps (NETS) May Provoke Thrombus Formation Through Direct nitric oxide release. The ability of indirect and direct antagonists to 01 Stimulation of Both The Contact and inhibit fXa-mediated cellular effects, without impacting its surface Tissue Factor-Mediated Coagulation Pathways binding capacity, suggests strongly that catalytic activity is the determining feature (Figure 2). Macrophages localized within ath- eromatous plaques can synthesize fX. An ability of fXa to promote smooth muscle cell proliferation suggests that local prothrombotic responses may also influence arterial remodeling following injury. The mitogenic response to fXa probably involves PAR-2. Functional PAR-2, an auto-activating tethered ligand, is widely distributed in human vascular endothelial cells and smooth muscle cells. FXa also exerts mitogenic effects through platelet-derived growth factor. Leukocyte proliferation has been observed following fX activation. In turn, pro-inflammatory cytokines that activate fX (fXa) are released. FXa also promotes recruitment of mast cells and their secretion of ROS: reactive oxygen species; RBCs: red blood cells. Reprinted with permission vasoactive mediators including histamine and serotonin. from Becker, RC. Aspirin and the Prevention of Venous Thromboembolism. N Engl J Med. 2012, 366; 21. FIGURE Integrated Cellular and Protein Clotting Pathways Demonstrate the Importance of DNA-Histone Complexes 02 Cellular Involvement in This Complex Process Histones are cationic proteins that are normally found bound to DNA within the nucleus of a cell, specifically within nucleosomes. Similar to cfNAs, histones and DNA-histone complexes can be released into the circulation from dying or damaged cells. Although release of both DNA-histone complexes and NETs are hypothesized to serve primarily anti-inflammatory and pathogen restricting or constraining roles, recent studies have identified functions for these complexes in thrombosis.

Circulating histones and DNA-histone complexes have been observed in several acute and chronic inflammatory conditions. In addition, extracellular histones function as late mediators of cell M: monocyte; SMC: smooth muscle cell; TF: tissue factor; NETS: neutrophil extracellular traps; MPs: mononuclear phagocytes; TLRs: toll-like receptors; damage and organ dysfunction in sepsis. Histones may provoke PLTs: platelets; DAMPS: danger-associated molecular patterns; ROS: reactive thrombin generation by activating platelets through stimulation oxygen species; LPS: lipopolysaccharide; TNF: tumor necrosis factor; PAR: of TLR2 and TLR4. In addition, histone-DNA complexes augment proteinase activated receptors; IL: interleukin; MCP: ; VWF: von Willebrand factor; thrombin generation more than histones alone. Considered col- PF: platelet factor; TM: thrombomodulin; PDGF: platelet-derived growth factor; lectively, these data support the existence of an integrated and ICAM: intercellular adhesion molecule; VCAM: vascular cell adhesion molecule Reprinted with permission from Foley JH, Conway EM. Cross Talk Pathways complex interface of inflammation, host-defenses and coagulation. Between Coagulation and Inflammation. Circ Res. 2016;118:1392-1408.

12 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE FACTOR Xa MECHANISM OF ACTION- IMPACT ON CLOTTING CASCADE, INFLAMMATION AND PLATELET ACTIVATION

Translating the Anticoagulant and Anti-inflammatory 3. Qi H, Yang S, Zhang L. Neutrophil Extracellular Traps and Endothelial Effects of Factor Xa Inhibition to Patient Care Dysfunction in Atherosclerosis and Thrombosis. Front Immunol. 2017;8:928. Systemic inflammation has been implicated in coronary artery dis- 4. Helseth R, Solheim S, Arnesen H, Seljeflot I, Opstad TB. The Time ease and common phenotypes including acute coronary syndrome. Course of Markers of Neutrophil Extracellular Traps in Patients Investigation of plaques points to inflammatory mechanisms as Undergoing Revascularisation for Acute Myocardial Infarction or Stable key regulators of fibrous cap fragility and the overall thrombogenic Angina Pectoris. Mediators Inflamm. 2016;2016:2182358. capacity of necrotic lipid core constituents. Activated macrophages, 5. Koklic T, Chattopadhyay R, Majumder R, Lentz BR. Factor Xa neutrophils and monocytes elaborate enzymes that degrade dimerization competes with prothrombinase complex formation on extracellular matrix proteins that, in turn, pave the way for plaque platelet-like membrane surfaces. Biochem J. 2015;467(1):37-46. instability and rupture. 6. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Clinical trials performed over the past decade suggest strongly that Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-30. attenuating inflammation exerts a beneficial effect among patients at risk for coronary artery disease-related events. In addition, the re- 7. Granger V, Faille D, Marani V, Noel B, Gallais Y, Szely N, et al. Human cently completed, presented and published CANTOS trial, in which blood monocytes are able to form extracellular traps. J Leukoc Biol. 2017;102(3):775-81. over 10,000 patients with prior myocardial infarction and elevated high-sensitivity C-reactive protein level received a monoclonal 8. Kovalenko TA, Panteleev MA, Sveshnikova AN. Substrate delivery antibody targeting interleukin-1β or placebo in addition to evidence- mechanism and the role of membrane curvature in factor X activation by extrinsic tenase. J Theor Biol. 2017;435:125-33. based therapy, supports the inflammatory hypothesis of coronary artery disease and its natural history.11 9. Wisler JW, Becker RC. Antithrombotic therapy: new areas to understand efficacy and bleeding. Expert Opin Ther Targets. 2014;18(12):1427- The COMPASS trial was a randomized, double-blind study of 34. 27,395 patients with stable atherosclerotic vascular disease who 10. Wisler JW, Becker RC. Oral factor Xa inhibitors for the long-term received either rivaroxaban, a direct inhibitor of the pleuri-potent co- management of ACS. Nat Rev Cardiol. 2012;9(7):392-401. agulation protease fXa, at a dose of 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg daily. 11. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al, for the CANTOS Trial Group. Antiinflammatory The primary outcome measure was a composite of cardiovascular Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. death, stroke or myocardial infarction. The study was stopped for 2017;377(12):1119-31. superiority of the rivaroxaban plus aspirin group after a mean follow up of 23 months.

Summary Factor Xa is a coagulation protease that has procoagulant, proin- flammatory and proliferative effects. Its importance in atherosclerotic vascular disease is based on these properties that are known to underlie the pathobiology of atherosclerotic plaque development, rupture and thrombosis as the causal underpinnings for the transi- tion from stable to unstable disease and resulting clinical events. The findings from COMPASS support the importance of factor Xa and its inhibition as a viable, readily available and safe therapeutic strategy for patients with atherosclerotic vascular disease at risk for cardiovascular death, stroke and myocardial infarction.

References

1. Muller MP, Wang Y, Morrissey JH, Tajkhorshid E. Lipid specificity of the membrane binding domain of coagulation factor X. J Thromb Haemost. 2017;15(10):2005-16.

2. Nehaj F, Sokol J, Ivankova J, Mokan M, Kovar F, Stasko J, et al. First Evidence: TRAP-Induced Platelet Aggregation Is Reduced in Patients Receiving Xabans. Clin Appl Thromb Hemost. 2017:1076029617734310.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 13 CLINICAL AND ECONOMIC VALUE OF RIVAROXABAN IN CORONARY ARTERY DISEASE

CLINICAL AND ECONOMIC VALUE OF FIGURE Secondary Prevention with Warfarin and RIVAROXABAN IN CORONARY ARTERY DISEASE 01 Aspirin versus Aspirin Alone after Acute Coronary Syndrome Christopher B. Granger, MD Professor of Medicine Death 0.96 (0.77–1.20) Duke Clinical Research Institute Division of Cardiology MI 0.56 (0.46–0.69) Duke University Medical Center, Durham, NC Ischemic stroke 0.46 (0.27–0.77) Objectives Major bleeding event 2.48 (1.67–3.68) 1. Discuss the balance between the benefits of antithrombotic therapy and the risk of increased bleeding in patients with Minor bleeding event 2.65 (2.14–3.29) atherosclerotic vascular disease. 0.05 1.0 5.0 2. Describe the efficacy and safety of non-vitamin K oral Warfarin + Rate ratio ASA better anticoagulants (NOACs) as compared to warfarin. ASA better 3. Discuss the significant results from the COMPASS trial of MI: myocardial infarction; ASA: aspirin; CI: confidence interval. Reprinted with rivaroxaban plus aspirin versus aspirin alone in patients with permission from Rothberg MB, Celestin C, Flore LD, Lawler E, et al. Warfarin stable coronary artery disease. plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta- Analysis with Estimates of Risk and Benefit. Ann Intern Med. 2005;143(4):241- 4. Describe the potential cost implications of using low-dose 25. rivaroxaban in addition to aspirin to treat patients with atherosclerotic vascular disease. In recent years, non-vitamin K antagonist oral anticoagulants (NOACs), which have the advantage of less life-threatening bleeding Introduction than warfarin, have been tested for treatment of vascular disease. The APPRAISE-2 trial found reduced rates of MI and stent thrombo- Coronary heart disease is the number one cause of death and sis with apixaban in addition to dual antiplatelet therapy after acute disability in the world and is projected to continue to be so for the coronary syndromes (ACS). This reduction in events was accom- 1 foreseeable future. An estimated 16.5 million Americans have panied by more bleeding, including intracranial hemorrhage.6 The coronary heart disease based on current data from the National ATLAS-2 investigators used a different strategy, testing low-dose ri- 2 Health and Nutrition Examination Survey (NHANES). varoxaban in addition to dual antiplatelet therapy in 93% of patients without a history of stroke. They showed benefit that exceeded risk, The combination of control of risk factors and use of effective with a reduction in mortality using the lower dose of rivaroxaban medical treatments cut the death rate from coronary heart disease (2.5 mg twice daily) added to antiplatelet therapy.7 There was also 3 in half over 20 years from 1980 to 2000. Patients with peripheral a reduction in stent thrombosis with rivaroxaban added to antiplate- artery disease have fewer available options that improve outcomes. let therapy. This trial showed that oral Xa inhibitor therapy can Thus, there remains a major need for more effective treatments for provide overall benefit in patients with ACS. Benefit from oral factor patients with peripheral vascular disease. IIa (thrombin) inhibition for patients with ACS is less clear. There is a modestly higher rate of MI with dabigatran than with warfarin Oral Anticoagulation Prevents Vascular Events and across the randomized trials of atrial fibrillation and venous throm- Causes Bleeding boembolic disease.8 Phase II trials have suggested that targeting thrombin may provide some benefit following ACS, although these Although antiplatelet therapy has been the mainstay of antithrom- trials have not progressed to Phase III. botic therapy for patients with stable vascular disease, there is strong evidence that oral anticoagulation with warfarin provides Rivaroxaban or Dabigatran with Clopidogrel - Safer than protection against myocardial infarction (MI). This benefit is coun- Warfarin Triple Therapy terbalanced by increased bleeding, and the net effect, including the effect on mortality, is neutral (Figure 1).4 A similar pattern has Two completed trials have tested oral anticoagulation with warfarin been seen in chronic heart failure without atrial fibrillation where versus NOACs - rivaroxaban in the PIONEER trial9 (Figure 2 and warfarin reduces stroke but causes bleeding, resulting in a net neu- Table 1) and dabigatran in the RE-DUAL trial10 for stroke prevention tral effect on mortality.5 Therefore oral anticoagulation has been in patients with atrial fibrillation who underwent stent placement shown to reduce arterial vascular events, but at a cost in bleeding and were also treated with P2Y12 inhibitor therapy. These trials that counterbalances the benefits. Because of this reduction in net found that NOACs with P2Y12 inhibitors (without aspirin) are safer clinical benefit, warfarin is not used for these patients. than the combination of warfarin, aspirin and P2Y12 inhibitors.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 15 CLINICAL AND ECONOMIC VALUE OF RIVAROXABAN IN CORONARY ARTERY DISEASE

Rivaroxaban 15 mg daily without aspirin or 2.5 twice daily with as- Oral Anticoagulation and Coronary Disease Events in pirin and dabigatran 110 mg or 150 mg twice daily appeared to be Patients with Atrial Fibrillation nearly equally effective at preventing thrombotic events, although the number of thrombotic events was too small to have high confi- A substantial portion of the populations in the clinical trials of dence in those findings. The 110 mg twice daily dose of dabigatran NOACs versus warfarin for atrial fibrillation also had coronary without aspirin had numerically more MIs and stent thromboses artery disease. In the ROCKET-AF trial, 17% of the population had 13 than warfarin with aspirin, although the differences were not statis- prior MI. Not surprisingly, these patients were at higher risk for tically significant. The use of rivaroxaban 15 mg daily or dabigatran ischemic events as well as for bleeding, and they were more likely 150 mg twice daily with a P2Y12 inhibitor, but without aspirin be- to be on concomitant aspirin. Overall, the rates of ischemic events yond the first few days after coronary stenting appears to result in tended be lower with rivaroxaban than with warfarin, with a 14% comparable rates of stent thrombosis compared to “triple therapy” reduction in hazard with rivaroxaban, p=0.05. The hazard ratio of with warfarin, clopidogrel and aspirin. The observation that aspirin myocardial infarction with rivaroxaban versus warfarin was 0.81 may not be required to prevent stent thrombosis in the presence of (95% confidence interval [CI], 0.63-1.06). These findings, as well a NOAC and P2Y12 inhibitor was also seen in the GEMINI trial11 in as similar findings with apixaban and edoxaban, suggest that factor which low dose rivaroxaban and clopidogrel had comparable rates Xa inhibitors are at least as effective as warfarin at preventing coro- of stent thrombosis as aspirin and clopidogrel. The AUGUSTUS nary events with lower risk of life-threatening bleeding. trial will test, in a full factorial design, the impact of aspirin versus placebo combined with either warfarin or apixaban12 in patients Rivaroxaban in Patients with Stable Coronary Disease with atrial fibrillation and coronary stenting and/or ACS. Whether patients with coronary disease without atrial fibrillation FIGURE Clinically Signi cant Bleeding Events may benefit from low dose rivaroxaban with or without aspirin, 02 in the PIONEER Trial compared to aspirin alone, was tested in the COMPASS trial. Overall, 91% of the trial population had coronary artery disease; 30 20% of these were women. Half of those with prior MI had their 26.7% 25 infarction within five years of enrollment, and only 5% within one year. Importantly, the patients were on good background medical 20 18% VKA + DAPT therapy to reduce vascular events, with 92% on lipid lowering drugs 16.8% 15 Riva + DAPT and 72% on angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers. 10 Riva + PGY12

5 Riva + P2Y12 v. VKA + DAPT Riva + DAPT v. VKA + DAPT HR=0.59 (95% CI: 0.47-0.76) HR=0.63 (95% CI: 0.50-0.80) The 26% relative risk reduction in the primary outcome of p <0.001 p <0.001 Requiring Medical Attention (%) Requiring Medical Attention cardiovascular death, MI, or stroke with low dose rivaroxaban plus

TIMI Major, TIMI Minor, or Bleeding TIMI Minor, TIMI Major, 0 0 30 60 90 180 270 360 aspirin versus aspirin alone in the coronary disease subgroup Days (p<0.0001) was similar to the effect in the overall trial (Figure TABLE Major Adverse Cardiac Events in the 3). The hazard ratio for major bleeding was 1.66 (p<0.0001) with 01 PIONEER Trial rivaroxaban plus aspirin versus aspirin. In the coronary disease population, the 1.3% absolute reduction in cardiovascular death, Kaplan-Meier Estimates Hazard Ratio (95% CI) MI and stroke was counterbalanced by a 1.2% absolute increase Riva + Riva + VKA + Riva + P2Y12 vs. Riva + DAPT Overall P2Y12 DAPT DAPT in major bleeding. The overall impact on mortality becomes key VKA + DAPT vs. VKA + DAPT (N=694) (N=704) (N=695) to understanding the net effect. There was a 23% relative risk Adverse CV 1.08 (0.69-1.68) 0.93 (0.59-1.48) 41 (6.5%) 36 (5.6%) 36 (6.0%) Event p=0.750 p=0.765 reduction in all-cause mortality in the coronary disease population 1.29 (0.59-2.80) 1.19 (0.54-2.62) 15 CV Death 15 (2.4%) 14 (2.2%) 11 (1.9%) (p=0.001), providing strong evidence of an overall benefit. p=0.523 p=0.664

0.86 (0.46-1.59) 0.75 (0.40-1.42) MI 19 (3.0%) 17 (2.7%) 21 (3.5%) p=0.625 p=0.374 With respect to ischemic heart disease outcomes in the coronary 1.07 (0.39-2.96) 1.36 (0.52-3.58) Stroke 8 (1.3%) 10 (1.5%) 7 (1.2%) p=0.891 p=0.530 disease population, MI was not significantly reduced (hazard ratio,

Stent 1.20 (0.32-4.45) 1.44 (0.40-5.09) 0.86; 95% CI, 0.70-1.05) perhaps related to small numbers, but 5 (0.8%) 6 (0.9%) 4 (0.7%) Thrombosis p=0.790 p=0.574 the hazard of a broader ischemic heart disease composite (MI, Adverse CV 1.08 (0.69-1.68) 0.93 (0.59-1.48 Events + Stent 41 (6.5%) 36 (5.6%) 36 (6.0%) coronary heart disease death, sudden death, resuscitated cardiac P=0.750 p=0.765 Thrombosis arrest, or unstable angina) was reduced by 17% (p=0.03, Table 2).15 The 46% relative risk reduction (p<0.0001) in stroke in this Riva: rivaroxaban; DAPT: dual antiplatelet therapy; VKA: vitamin K antagonist; CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial population, similar to in the overall trial, was the most striking infarction. Figures 2 and 3 reprinted with permission from Gibson MC, Mehran effect on major clinical outcomes. R, Bode C, Halperin J, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423-34.

16 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE CLINICAL AND ECONOMIC VALUE OF RIVAROXABAN IN CORONARY ARTERY DISEASE

Cost Implications of Rivaroxaban for Patients with Stable FIGURE Primary E cacy and Safety Outcome in the Coronary Disease 03 Coronary Artery Disease Subgroup of the COMPASS Trial The overall effects of rivaroxaban plus aspirin versus aspirin alone Primary outcome: cardiovascular death, MI, stroke compare favorably to other commonly used treatments to improve 1010 Low-dose rivaroxaban + aspirin vs. aspirin alone outcome for patients with vascular disease, such as antiplatelet HR 0.74, 95% CI 0.65-0.86, P≤ 0.0001 therapy, lipid lowering agents and blood pressure lowering agents. 88 Rivaroxaban alone vs. aspirin alone Preliminary data regarding the cost impact of rivaroxaban in the HR 0.89, 95% CI 0.78-1.02, P=0.09 COMPASS trial have been presented.16 Examining direct costs of 66 care, not including costs of the drug, rivaroxaban plus aspirin resulted

44 in substantially lower health care costs than aspirin alone, driven largely by lower costs related to the reduction in stroke. There were Cumulative incidence risk (%) incidence Cumulative Low-dose rivaroxaban + aspirin larger differences favoring rivaroxaban in patients with peripheral 22 Rivaroxaban alone Aspirin alone artery or polyvascular arterial disease. Formal cost effectiveness 00 analyses are ongoing. 0 1 2 3 Time (years) Summary Major Bleeding 1010 Coronary heart disease continues to be the most important cause Low-dose rivaroxaban + aspirin vs. aspirin alone HR 1-66 (95% CI 1.23-2.03), P≤0.0001 of death and disability in the United States and around the world. 88 Low-dose rivaroxaban + aspirin Rivaroxaban alone vs. aspirin alone There is now another treatment proven to prevent vascular events Rivaroxaban alone HR 1-51 (95% CI 1.23-1.24), P≤0.0001 Aspirin alone in patients with stable coronary disease – low dose rivaroxaban 66 added to aspirin -- with an even larger absolute benefit for patients

44 who have both coronary disease and concomitant peripheral or cerebrovascular disease. The net benefit of low dose rivaroxaban Cumulative incidence risk (%) incidence Cumulative

22 Rivaroxaban alone with aspirin, compared to aspirin alone, is underscored by the 24% Aspirin alone relative risk reduction in all-cause mortality. 00

0 1 2 3 Time (years) References

HR: hazard ratio; CI: confidence interval. Reprinted with permission from 1. Global Health Estimates 2015: Deaths by cause, age and sex, by Eikelboom JW, Connolly SJ, Dagenais B, Shestkovsak O, et al. Rivaroxaban with or country and by region, 2000-2015. Geneva: World Health Organization; without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319- 2016. (http://www.who.int/healthinfo/global_burden_disease/en/ 30. accessed November 26, 2017). 2. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. TABLE Coronary Disease Outcomes in the Coronary Heart Disease and Stroke Statistics-2017 Update: A Report From the 02 Disease Subgroup in the COMPASS Trial American Heart Association. Circulation. 2017;135(10):e146-e603. 3. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, Rivaroxaban and Aspirin Rivaroxaban and aspirin et al. Explaining the decrease in U.S. deaths from coronary disease, aspirin N=8,261 vs. aspirin 1980-2000. N Engl J Med. 2007;356(23):2388-98. Event N=8,313 N N HR 4. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus p (%) (%) (95% CI) aspirin after myocardial infarction or the acute coronary syndrome: 169 195 0.86 meta-analysis with estimates of risk and benefit. Ann Intern Med. Myocardial infarction (MI) 0.15 (2%) (2%) (0.70-1.05) 2005;143(4):241-50. 234 273 0.85 MI or sudden cardiac death 0.065 (3%) (3%) (0.71-1.01) 5. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, MI, coronary heart disease Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and death, SCD, resuscitated 264 314 0.83 sinus rhythm. N Engl J Med. 2012;366(20):1859-69. 0.028 cardiac arrest, or unstable (3%) (4%) (0.71-0.98) angina 6. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N HR: hazard ratio; CI: confidence interval. Reprinted with permission from Engl J Med. 2011;365(8):699-708. Eikelboom JW, Connolly SJ, Dagenais B, Shestkovsak O, et al. Rivaroxaban with or 7. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319- al. Rivaroxaban in patients with a recent acute coronary syndrome. N 30. Engl J Med. 2012;366(1):9-19. 8. Douxfils J, Buckinx F, Mullier F, Minet V, Rabenda V, Reginster JY, et al. Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2014;3(3):e000515.

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 17 CLINICAL AND ECONOMIC VALUE OF RIVAROXABAN IN CORONARY ARTERY DISEASE

9. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423-34. 10. Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377(16):1513-24. 11. Ohman EM, Roe MT, Steg PG, James SK, Povsic TJ, White J, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet. 2017;389(10081):1799-808. 12. AUGUSTUS Trial: https://clinicaltrials.gov/ct2/show/NCT02415400. 13. Mahaffey KW, Stevens SR, White HD, Nessel CC, Goodman SG, Piccini JP, et al. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J. 2014;35(4):233-41. 14. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-30. 15. Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo- controlled trial. Lancet. 2017. 16. Lamy A. Cost impact of rivaroxaban plus aspirin versus aspirin in the COMPASS trial. American Heart Association Scientific Sessions, Anaheim, CA, November 2017. http://professional. heart.org/professional/EducationMeetings/MeetingsLiveCME/ ScientificSessions/UCM_497351_SS17-Late-Breaking-Clinical-Trials. jsp#compass.

18 ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE Continuing Medical Education Post-Test Answer Form and Evaluation ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE B. The primary endpoint was significantly reduced in the rivaroxaban alone arm compared to aspirin alone. Based on the information presented in this monograph, please C. Major bleeding was significantly increased in the rivaroxaban choose one correct response for each of the following questions plus aspirin arm compared to aspirin alone. or statements. Record your answers on the answer sheet found D. Major bleeding was significantly increased in the rivaroxaban on the last page. To receive Category I credit, complete the post- alone arm compared to aspirin alone. test and record your responses on the following answer sheet and complete the evaluation. A passing grade of 80% is needed to 4. Which of the following is NOT used for DAPT in patients receive credit. with acute coronary syndrome? A. Rivaroxaban TEST ALSO AVAILABLE ONLINE: www.emcreg.org/testing B. Ticagrelor *Immediate CME Certificate online with passing grade. C. Aspirin D. Clopidogrel Hardcopy test can be returnd by E-mail, Fax or Mail using the included return envelope. See following page for information. 5. Which of the following antithrombotic agents produced Please return the CME no later than January 15, 2019. an increase in intracranial bleeding in patients with previous stroke that was significant enough to result in QUESTIONS: discontinuing the study drug in that group? A. Ticagrelor 1. All of the following statements regarding trials with B. Rivaroxaban dual antiplatelet therapy (DAPT) are true EXCEPT: C. Vorapaxar A. The CHARISMA trial showed that DAPT with clopidogrel and D. Clopidogrel aspirin reduces the risk of the primary endpoint (myocardial infarction [MI], stroke, or death from cardiovascular causes) in patients with established vascular disease. 6. All of the following statements regarding treatment for patients with peripheral artery disease (PAD) are true B. In the PLATO trial, twelve months of clopidogrel was more EXCEPT: effective than ticagrelor in preventing vascular events and provided a reduction in vascular death. A. Diabetes control and smoking cessation are necessary. C. In the PEGASUS-TIMI 54 trial, ticagrelor plus aspirin reduced B. Statin medications are a mainstay of therapy. the risk of acute limb ischemia or peripheral artery revascu- C. Supervised exercise therapy is used for patients with larization as compared to aspirin alone. persistent claudication. D. In the TRA 2°P-TIMI trial, vorapaxar resulted in a signifi- D. A diagnostic arterial study must be performed to define the cantly lower 3-year risk of the primary endpoint (MI, stroke, severity of obstructive vascular disease prior to limb or death from cardiovascular causes), but a significantly amputation. increased risk of moderate or severe bleeding. 7. In the PEGASUS-TIMI 54 trial, which of the following 2. Which of the following statements regarding medi- antiplatelet regimens resulted in a significant reduction cal therapy for patients with atherosclerotic vascular in the primary endpoint of cardiovascular death, MI, or disease is TRUE? stroke in the subgroup of patients with PAD? A. Aspirin is superior to clopidogrel for prevention of cardiovas- A. Aspirin alone cular events in patients with stable atherosclerotic disease. B. Ticagrelor 60 mg twice daily plus aspirin B. Vitamin K antagonists are superior to DAPT for prevention of cardiovascular events in patients with coronary stents. C. Ticagrelor 90 mg twice daily plus aspirin C. After an acute coronary syndrome event or percutaneous D. Ticagrelor 90 mg twice daily without aspirin coronary intervention, dual therapy with aspirin and rivaroxaban is the preferred regimen. 8. In the TRA°2P-TIMI 50 trial, patients with atherosclero- D. Low dose anticoagulation with rivaroxaban reduced cardio- sis who were treated with vorapaxar experienced all of vascular mortality and all-cause mortality when added to the following EXCEPT: aspirin in patients with stable coronary artery disease and A. Significantly increased rate of moderate to severe bleeding peripheral artery disease. B. Significantly increased rate of intracranial hemorrhage C. Significantly reduced rate of cardiovascular events in 3. The following findings regarding the COMPASS trial are patients with PAD all true EXCEPT: D. Significantly reduced rate of hospitalization for acute limb A. The primary endpoint (cardiovascular death, MI, or stroke) ischemia and peripheral revascularization was significantly reduced in the rivaroxaban plus aspirin arm compared to aspirin alone. (Continued Next page)

ADVANCES IN THE TREATMENT OF STABLE CORONARY ARTERY DISEASE AND PERIPHERAL ARTERY DISEASE 19 Continuing Medical Education Post-Test Answer Form and Evaluation 9. All of the following statements regarding the cohort 16. Over the twenty year period from 1980 to 2000, the of patients with PAD in the COMPASS trial are true death rate from coronary heart disease: EXCEPT: A. Decreased by 50% A. Aspirin plus rivaroxaban 2.5 mg twice daily significantly B. Decreased by 25% reduced the rate of the primary composite endpoint (car- C. Increased by 25% diovascular death, MI, stroke) when compared with aspirin alone. D. Did not change B. Aspirin plus rivaroxaban 2.5 mg twice daily significantly 17. All of the following statements regarding oral anticoag- reduced the rate of limb events compared with aspirin alone. ulation for patients with atherosclerotic heart disease C. Aspirin plus rivaroxaban 2.5 mg twice daily was associated are true EXCEPT: with a significantly higher rate of major bleeding when compared with aspirin alone. A. Non-vitamin K antagonist oral anticoagulants (NOACs) are D. Patients with PAD had a significantly higher incidence of ma- associated with less life-threatening bleeding than warfarin. jor bleeding than patients without peripheral arterial disease. B. Factor Xa inhibitors are likely at least as effective as warfarin at preventing coronary events. 10. Which of the following statements regarding evidence C. Aspirin may not be required to prevent stent thrombosis in from recent antithrombotic therapy trials is TRUE? the presence of a NOAC and P2Y12 inhibitor. A. Ticagrelor monotherapy significantly reduces the rate of D. Oral factor IIa inhibitors significantly reduce cardiovascular cardiovascular events in patients with PAD compared to events following acute coronary syndrome. clopidogrel monotherapy. B. Dual antiplatelet therapy has not been shown to be benefi- 18. In the coronary disease population in the COMPASS cial in patients with PAD. trial, what was the effect on all-cause mortality noted C. A combination of antiplatelet and anticoagulant therapy may in the rivaroxaban plus aspirin group compared to the provide the most significant cardiovascular and limb protec- aspirin alone group? tion for PAD patients. A. 46% relative risk reduction D. Clopidogrel has similar efficacy to aspirin for reducing the B. 23% relative risk reduction risk of cardiovascular events in patients with atherosclerotic C. 23% relative risk increase vascular disease. D. No significant difference 11. Factor Xa: A. Is a coagulation protein 19. In the coronary disease population in the COMPASS B. Functions at the convergence of the contact activation and trial, the rate of which of the following events did NOT tissue factor-mediated pathways of coagulation. significantly decrease in the rivaroxaban plus aspirin C. Can be inhibited effectively by medications given IV, subcuta- group compared to the aspirin alone group? neously or by mouth A. Myocardial infarction D. All of the above B. Stroke 12. Factor Xa plays a role in both thrombosis and C. Ischemic heart disease composite inflammation. D. All-cause mortality A. True B. False 20. All of the following statements regarding oral antico- 13. A contemporary paradigm of thrombosis includes agulation trials in patients with vascular disease are which of the following: true EXCEPT: A. Cell-free DNA A. The ATLAS-2 trial demonstrated a reduction in mortality B. Histones with low dose rivaroxaban (2.5 mg twice daily) added to antiplatelet therapy. C. Histone-DNA complexes B. The PIONEER and RE-DUAL trials demonstrated that the D. All of the above combination of warfarin, aspirin and P2Y12 inhibitors is 14. There is emerging evidence that medications that safer than NOACs with P2Y12 inhibitors (without aspirin). target inflammation in patients at risk for cardiovascu- C. The GEMINI trial demonstrated comparable rates of stent lar events are effective. thrombosis in patients treated with rivaroxaban and clopidogrel as in those treated with aspirin and clopidogrel. A. True B. False D. The COMPASS trial demonstrated a 26% relative risk reduc- 15. Factor Xa inhibition, particularly when achieved in tion in the primary outcome (MI, stroke, or cardiovascular combination with a low-dose aspirin, reduces cardio- death) in patients with coronary disease treated with vascular events in patients at risk. rivaroxaban plus aspirin versus aspirin alone. A. True B. False

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