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

EMCREG-International Proceedings Monograph from the 2017 American Heart Association Symposium, November 12, 2017 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 and Graphics Design Manager: Todd W. Roat 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 2 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 4 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.DISCLOSURES Dr. W. Brian Gibler has served on the Advisory Boards for AstraZeneca and Entegrion and is a Shareholder for MyocardioCare and Entegrion. Decreasing Major Adverse Clinical Events for Patients With Coronary Artery Disease or Peripheral Artery Disease: The COMPASS Trial Manan Pareek, MD, PhD, Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, MAManan PareekDeepak L. BhattIntroduction: Chronic coronary artery disease (CAD) and peripheral artery disease (PAD) are common manifestations of atherosclerosis. Recent estimates suggest that 16.5 million adults in the United States have chronic CAD.1 The prevalence of PAD is lower, affecting more than 5 million American adults.2 Although CAD is the leading cause of death worldwide, both conditions contribute significantly to loss of disability-adjusted life-years.3,4 Atherosclerosis often manifests in several vascular beds, and the distinct clinical syndromes share many common major risk factors, including older age, smoking, hypertension, hypercholesterolemia, and diabetes mellitus.5 Platelets play pivotal roles in the inflammatory, thrombotic, and atherosclerotic processes. Therefore, targeting various pathways to inhibit platelet activation and aggregation is essential in preventing complications of progressive atherosclerotic disease.6 Single-Agent Antiplatelet Therapy: For more than 3 decades, platelet inhibition with the cyclooxygenase-1 inhibitor aspirin has been a cornerstone in the treatment and prevention of cardiovascular disease.7,8 In the secondary preventive setting, aspirin reduces the risk of myocardial infarction, stroke, or death from vascular causes by an absolute 1.5%.9 However, approximately 1 in 8 patients experiences a recurrent ischemic event while on aspirin.10 The randomized Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial compared clopidogrel, a P2Y12 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, a recent myocardial infarction, or a of the of ischemic stroke, myocardial infarction, or vascular death was significantly in the clopidogrel risk a risk in the PAD risk for the of ischemic stroke, or vascular in of the myocardial on from the of clopidogrel was more at vascular including with diabetes or ischemic clopidogrel was as as as aspirin. the of clopidogrel, the of in Peripheral Artery Disease patients with as or an of or to mg daily or clopidogrel 75 mg once clopidogrel a of the that a of cardiovascular myocardial infarction, or ischemic stroke, with in the 2 Although the of patients with more myocardial and patients with and patients in the and of major and bleeding for the 2 Antiplatelet Therapy: antiplatelet therapy aspirin and a P2Y12 receptor is the for patients with an coronary or coronary and the Clopidogrel for Risk and and trial the use of with clopidogrel 75 mg daily plus aspirin mg daily versus aspirin in patients with established vascular disease or or risk for a of Although the a of myocardial infarction, stroke, or death from cardiovascular was significantly with was a risk in the of patients with established vascular disease for also of versus aspirin patients with myocardial infarction, ischemic stroke, or The risk in the PAD was with that for patients with myocardial or The of bleeding was significantly with for the of cardiovascular or in the of patients because of ischemic stroke, or peripheral artery disease from the myocardial on from of clopidogrel was in the and Outcomes in which the 2 P2Y12 receptor compared in patients with an of was more than clopidogrel in preventing vascular events and a in vascular an in major the of Cardiovascular Events in Patients with Heart Using to on a of in trial the and of in patients with a myocardial and for ischemic Patients mg daily or mg or on of aspirin mg 3 the of cardiovascular myocardial infarction, or was significantly with both compared with mg and mg risk with with diabetes and with to risk of ischemic also the risk of or peripheral artery The of major bleeding was significantly with of or bleeding in the 3 antiplatelet was in the in of in in which patients with a of myocardial infarction, ischemic stroke, or PAD to a antagonist, at a dose of mg daily or on a of or dual antiplatelet in a significantly risk of the a of death from cardiovascular myocardial infarction, or However, this at the of a significantly risk of or including The risk of was particularly patients with and the and to of study in this a of 2 of In patients with the the of patients to significantly of for and peripheral Patients with atherosclerotic disease remain at risk for recurrent cardiovascular events antiplatelet therapy. these also an activation of the has been an interest in the of anticoagulation in this In patients, a superior to and is associated with an risk of However, a 2 trial in patients been that the Xa the risk of ischemic The to Cardiovascular Events in to in with Coronary in trial the of very rivaroxaban of patients randomized to at a dose of or 5 mg or in addition to with aspirin and a or a of the of death from cardiovascular myocardial infarction, or was significantly with both of rivaroxaban at the of more major bleeding and The rivaroxaban dose was associated with bleeding than 5 and of death from cardiovascular causes and compared with the for very anticoagulation in the Cardiovascular Outcomes for People Using Strategies (COMPASS) in which with stable atherosclerotic vascular disease or an for or anticoagulation to rivaroxaban mg daily plus aspirin mg once rivaroxaban 5 mg or aspirin mg once The trial was a of to a in of the therapy the a of cardiovascular stroke, or myocardial infarction, was significantly with rivaroxaban plus aspirin versus aspirin with rivaroxaban versus aspirin significantly the of cardiovascular and In with major events as major bleeding was significantly with versus aspirin and with rivaroxaban versus aspirin However, the significantly or and was associated with clinical and secondary in the COMPASS trial study myocardial on from and secondary in the COMPASS trial with peripheral artery major myocardial on from and Patients with stable atherosclerotic disease from secondary prevention with antiplatelet In this setting, clopidogrel is superior to aspirin. an event or coronary with aspirin and a P2Y12 receptor is the In many patients at risk for recurrent cardiovascular events and at low bleeding The COMPASS trial has the by a ischemic of cardiovascular and with very anticoagulation to aspirin in patients with stable CAD or PAD. as with use in clinical practice will of the risk of versus from the COMPASS trial are to will the from this therapeutic Dr. Manan the Advisory AstraZeneca and Dr. Deepak L. the Advisory Cardiology, Cardiology, of Research of Cardiovascular American Heart Association for Clinical Research Harvard Clinical Research Clinical Research of Medicine, Research American College of Associate Clinical and for Clinical Research Harvard Clinical Research clinical trial in Harvard Heart Clinical Research trial in of of the American College of Associate Research for the COMPASS and Medical of Cardiovascular Clinical Steering Committee Research and Committee Research The Cardiovascular to Heart Medical American College of the Treatment of Peripheral Artery Disease: and MD, of Cardiology, University Medical Center, peripheral artery disease (PAD) more than million adults and an 8 million in the United The prevalence of PAD in patients or of with diabetes is from the study PAD is a of that the of the recent in diagnosis and of patients with PAD have recurrent events and from cardiovascular disease are important for patients with PAD. diabetes therapy for and have been to cardiovascular and in a of including coronary and coronary therapy is a cornerstone treatment to the of major cardiovascular events in patients with stable atherosclerotic The for PAD has The cardiovascular risk of patients with risk recent trial and for care will for patients with peripheral artery with from and Treatment patients with PAD are and with can with a of including that with and with ischemic or The often how patients are and to clinical The is the and used to the of the of is often used with to treatment Medical treatment of patients with PAD has antiplatelet monotherapy aspirin or and to to cardiovascular risk Although PAD is a coronary artery disease (CAD) risk antiplatelet and are used significantly in patients with PAD than in patients with is to treatment and with antiplatelet and in patients with In patients with and for have been to and of has been used by patients to of and the In 2017, the for and a that will for in patients with are for patients with the of PAD. In patients with and is to the and of disease and is to and only of patients a have an study of the The that in the of these and is also across the Finally, in patients, the of patients with at 1 is the for at this Antiplatelet Therapy: compared with patients with other of atherosclerotic including patients with PAD have a risk of cardiovascular myocardial and In the of for PAD patients a risk of cardiovascular stroke, or for an the risk of major typically as major or from to on age, and major of the to PAD has significantly in the United States, an important because are at 1 and at 3 major in peripheral vascular have significantly the 2 in in peripheral vascular with from Antiplatelet have been the of treatment for patients with atherosclerotic vascular the American College of Cardiology/American Heart Association a Class Ia recommendation for antiplatelet monotherapy with aspirin mg or clopidogrel mg to the of stroke, and vascular death in patients with the for antiplatelet therapy in patients with PAD are from and are more the a Class recommendation for antiplatelet therapy in these patients. the and of dual antiplatelet therapy in patients with PAD based on a from the Clopidogrel for Risk and and dual antiplatelet therapy for patients with PAD a Class are to the risk of in stable patients with PAD have platelet and and clopidogrel, and and Aspirin has been the therapy used by vascular because of low and patients remain at risk for events such as and aspirin With the of and clopidogrel, in patients, including with PAD. The use of was to an risk of and clopidogrel was to the risk of vascular or by in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) the of clopidogrel for aspirin in clinical practice to the use of has been in patients with atherosclerotic disease including of and clinical important to patients with PAD. with Clinical Trial is a inhibitor that to and has been in the of coronary and stable atherosclerotic disease or as an addition to antiplatelet therapy. In the pivotal in of in patients with randomized to or of these patients aspirin a and dual antiplatelet therapy on study In the the of the or by In the PAD the risk for the was the risk of for and peripheral the of of and for Coronary and bleeding and was significantly with In the and the use of in patients with or PAD with a for bleeding on the antiplatelet has been in patients with PAD. The of Cardiovascular Events in Patients with Heart Using to on a of in trial patients with a of of which Patients randomized in a to mg daily versus mg daily versus on a of aspirin. PAD patients in the mg arm a in cardiovascular or stroke, the with the mg dose was for or peripheral was significantly in the mg the in the mg arm was The of in Peripheral Artery Disease trial randomized patients with PAD in a to or clopidogrel Patients for approximately and was the 2 in of the of cardiovascular or major bleeding and for also treatment In the recently published Cardiovascular Outcomes for People Anticoagulation Strategies (COMPASS) a of patients with stable atherosclerotic vascular disease or randomized to 3 mg daily rivaroxaban 5 mg daily aspirin mg daily plus rivaroxaban mg at The study was terminated than to in the aspirin and rivaroxaban approximately 2 of patients randomized to aspirin plus rivaroxaban mg daily a significantly of the ischemic stroke, cardiovascular compared with aspirin was a significantly of major bleeding in the aspirin plus rivaroxaban compared with aspirin was an risk in in of aspirin and rivaroxaban In a rivaroxaban was to have in the PAD from the COMPASS In patients based on a of and a low The of the was with aspirin plus rivaroxaban mg daily compared with aspirin The risk of major bleeding was also very to the trial with aspirin plus rivaroxaban mg daily associated with a significantly of major bleeding compared with aspirin However, this is also in that PAD patients have an risk of major bleeding compared with patients PAD. In these recent trial into the of cardiovascular and events in patients with PAD. recent demonstrated in cardiovascular with more antiplatelet therapy of with dual therapy versus antiplatelet therapy and Finally, is now that dual therapy with antiplatelet and therapy the cardiovascular and for PAD patients. 1 clinical of agents in patients with stable peripheral disease and patients peripheral Clinical of in Patients With Stable Peripheral Disease and Patients Peripheral Clinical The and of in the Risk of Major Vascular Events in with Peripheral Artery Disease Peripheral of the study is a trial of rivaroxaban mg daily or on a of aspirin mg daily peripheral will patients and in In PAD is a of that million such as and are and used in patients with PAD compared to patients with therapy for patients with PAD has recently and monotherapy with clopidogrel has been to to mg daily in addition to aspirin was to cardiovascular events and events compared with aspirin and patients will to have on how to cardiovascular and risk for clinical Dr. the and or and Factor Xa of on and MD, of Cardiovascular and Disease, University of Cincinnati College of Medicine, Cincinnati, contemporary of emphasizes the of and the of platelets, and endothelial of on cells, activation of and The is by on platelet contemporary understanding of emphasizes the of with from cell-based of or than a of pathways or is the for of to complex with and causes Although is a pivotal in the of and on and endothelial activation represents a of for Factor Factor is a in the and into the as a to an The protein is of a and a by a The of is the Factor is by of a from The of an by or complex the providing a of conditions of the complex can in the of on Platelets play a in and the of leading to particularly by several of Factor activation a recent that also for and The platelet receptor for and an in complex with in of with and of including and to and and activation of platelets, by with protein and with activation of in and The events as on are Although this and that is much more complex and than and such as and have recently been and in the of as a of and are of with that are by to and in the have been to with the vascular platelets, cells, and factors, of which is to in have been to endothelial death with or including in can formation and of into by to endothelial and of and other to endothelial and cause have been in to and are to the of both and as are to with and In can and in an mechanism for platelet formation of both the and pathways In have been to formation and and to with in The which can inhibitor and to also the to can and formation to have The are the of and than formation of both the and with from are that are to the of a to and can into the from or Although of both and is to and or recent have for these in thrombosis. and have been in several and chronic In as late of and in by of and In more than these the of an and complex of and Factor and Factor Xa to endothelial a of with a value of and of The are first with and of and to vascular endothelial is by or inhibitor is by for in The of is associated with the inhibitor and of and vascular and The of and to inhibit that is the can of to that also The to an is in vascular endothelial and also has been In that are also of and of including and and protein clotting pathways the of in this complex platelet vascular with from the and of Factor Xa to has been in coronary artery disease and common including coronary of to as of and the of and that in the for and Clinical the suggest that a patients at risk for coronary artery In the recently and published Outcomes in which patients with myocardial and protein a targeting or in addition to the of coronary artery disease and The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was a study of patients with stable atherosclerotic vascular disease a inhibitor of the at a dose of mg daily plus aspirin mg rivaroxaban 5 mg or aspirin mg The was a of cardiovascular stroke, or myocardial The study was for superiority of the rivaroxaban plus aspirin a of Factor Xa is a that has and in atherosclerotic vascular disease is based on these that are to the of atherosclerotic and as the for the from stable to disease and clinical The from COMPASS the of Xa and inhibition as a and therapeutic for patients with atherosclerotic vascular disease at risk for cardiovascular stroke, and myocardial Dr. the or and Clinical and of in Coronary Artery Disease MD, Department of Medicine, Clinical Research and of Cardiology, University Medical Center, Coronary disease is the cause of death and in the and is to to for the 16.5 million have coronary disease based on current from the and The of of risk and use of the death from coronary disease in from to Patients with peripheral artery disease have available that a major for more for patients with peripheral vascular disease. Anticoagulation Vascular Events and Although antiplatelet therapy has been the of therapy for patients with stable vascular is that anticoagulation with provides myocardial This is by and the including the on is has been in chronic reduces causes in a on Therefore, anticoagulation has been to vascular at a in bleeding that the of this in clinical is used for these prevention with and aspirin versus aspirin coronary with from recent which have the of bleeding than have been for treatment of vascular disease. The for of Events 2 trial of and with in addition to dual antiplatelet therapy coronary syndromes This in events was by more including The to Cardiovascular Events in to in with Coronary used a rivaroxaban in addition to dual antiplatelet therapy in of patients a of that with a in the dose of rivaroxaban mg to antiplatelet was also a in with rivaroxaban to antiplatelet therapy. This trial that Xa inhibitor therapy can in patients with from inhibition for patients with is is a of with than with across the randomized of and have that targeting these have to or With Therapy: have anticoagulation with versus rivaroxaban in the Treatment Strategies of and a Treatment in with Coronary 2 and and in the of with versus with in Patients with Coronary for prevention in patients with and also with P2Y12 inhibitor therapy. that with P2Y12 are than the of and P2Y12 Major Adverse Cardiac Events in the bleeding events in the dual antiplatelet with from mg daily aspirin or daily with aspirin and mg or mg daily to at preventing the of events was to have in The mg daily dose of aspirin more and than with the The use of rivaroxaban mg daily or mg daily with a P2Y12 aspirin the first coronary to in of compared to with clopidogrel, and aspirin. The that aspirin to prevent in the of a and P2Y12 inhibitor was also in the to the of in to Clopidogrel or in With Coronary in which rivaroxaban and clopidogrel of as aspirin and 2 2 Clinical Trial to the of and Aspirin Aspirin in Patients With and Coronary or Coronary trial will in a the of aspirin versus with or in patients with and coronary Anticoagulation and Coronary Disease Events in Patients With substantial of the in the clinical of versus for also coronary artery disease. In the Factor Xa with for of and Trial in of the these patients at risk for ischemic events and for and more to on aspirin. the of ischemic events to with rivaroxaban than with with a in with The of with rivaroxaban versus was and with and suggest that Xa are at as as at preventing coronary events with risk of in Patients With Stable Coronary Disease: patients with coronary disease from rivaroxaban with or compared to aspirin was in the Cardiovascular Outcomes for People Using Strategies (COMPASS) of the trial coronary artery of these of with 5 of and only 1 the patients on therapy to vascular with on and on or receptor The risk in the of cardiovascular or with rivaroxaban plus aspirin versus aspirin in the coronary disease was to the in the trial The for major bleeding was with rivaroxaban plus aspirin versus aspirin. In the coronary disease the absolute in cardiovascular and was by a absolute in major The on to understanding the was a risk in in the coronary disease providing of an and in the coronary artery disease of the COMPASS with from to ischemic disease in the coronary disease was significantly to the of a ischemic disease coronary disease or was by The risk in in this to in the was the on major clinical Coronary Disease Outcomes in the Coronary Disease in the COMPASS of for Patients With Stable Coronary Disease: The of rivaroxaban plus aspirin versus aspirin to other used to for patients with vascular such as antiplatelet and regarding the of rivaroxaban in the COMPASS trial have been of including of the rivaroxaban plus aspirin in care than aspirin by to the in rivaroxaban in patients with peripheral artery or disease. are Coronary disease to the important cause of death and in the United States and the is now treatment to prevent vascular events in patients with stable coronary rivaroxaban to an absolute for patients have both coronary disease and peripheral or disease. The of rivaroxaban with compared to aspirin is by the risk in Dr. the Clinical Research and and