Nonantithrombotic Medical Options in Acute Coronary Syndromes: Old Agents and New Lines on the Horizon Victor Soukoulis, William E. Boden, Sidney C. Smith, Jr and Patrick T. O'Gara Circ Res. 2014;114:1944-1958 doi: 10.1161/CIRCRESAHA.114.302804 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/12/1944
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Acute Coronary Syndromes Compendium Circulation Research Compendium on Acute Coronary Syndromes Acute Coronary Syndromes: Pathology, Diagnosis, Genetics, Prevention, and Treatment Mechanisms of Plaque Formation and Rupture Inflammation and its Resolution as Determinants of Acute Coronary Syndromes Lipoproteins as Biomarkers and Therapeutic Targets in the Setting of Acute Coronary Syndrome Genetics of Coronary Artery Disease Imaging Plaques to Predict and Better Manage Patients With Acute Coronary Events Reperfusion Strategies in Acute Coronary Syndromes Antiplatelet and Anticoagulation Therapy for Acute Coronary Syndromes Nonantithrombotic Medical Options in Acute Coronary Syndromes: Old Agents and New Lines on the Horizon Global Perspective on Acute Coronary Syndrome: A Burden on the Young and Poor Guest Editors: Valentin Fuster and Jason Kovacic
Nonantithrombotic Medical Options in Acute Coronary Syndromes Old Agents and New Lines on the Horizon Victor Soukoulis, William E. Boden, Sidney C. Smith Jr, Patrick T. O’Gara
Abstract: Acute coronary syndromes (ACS) constitute a spectrum of clinical presentations ranging from unstable angina and non–ST-segment elevation myocardial infarction to ST-segment myocardial infarction. Myocardial ischemia in this context occurs as a result of an abrupt decrease in coronary blood flow and resultant imbalance in the myocardial oxygen supply–demand relationship. Coronary blood flow is further compromised by other mechanisms that increase coronary vascular resistance or reduce coronary driving pressure. The goals of treatment are to decrease myocardial oxygen demand, increase coronary blood flow and oxygen supply, and limit myocardial injury. Treatments are generally divided into disease-modifying agents or interventions that improve hard clinical outcomes and other strategies that can reduce ischemia. In addition to traditional drugs such as β-blockers and inhibitors of the renin–angiotensin–aldosterone system, newer agents have expanded the number of molecular pathways targeted for treatment of ACS. Ranolazine, trimetazidine, nicorandil, and ivabradine are medications that have been shown to reduce myocardial ischemia through diverse mechanisms and have been tested in limited fashion in patients with ACS. Attenuating the no-reflow phenomenon and reducing the injury compounded by acute reperfusion after a period of coronary occlusion are active areas of research. Additionally, interventions aimed at ischemic pre- and postconditioning may be useful means by which to limit myocardial infarct size. Trials are also underway to examine altered metabolic and oxygen-related pathways in ACS. This review will discuss traditional and newer anti-ischemic therapies for patients with ACS, exclusive of revascularization, antithrombotic agents, and the use of high-intensity statins. (Circ Res. 2014;114:1944-1958.) Key Words: acute coronary syndrome
■
ischemic preconditioning
■
reperfusion injury
Original received February 9, 2014; revision received March 11, 2014; accepted March 19, 2014. In April 2014, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.38 days. From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (V.S., P.T.O.); Division of Cardiology, Department of Medicine, Albany Stratton Veteran’s Affairs Medical Centre and Albany Medical College, NY (W.E.B.); and Division of Cardiology, University of North Carolina, Chapel Hill (S.C.S.). The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA. 114.302804/-/DC1. Correspondence to Patrick T. O’Gara, MD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail [email protected] © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.114.302804
Downloaded from http://circres.ahajournals.org/ at TECHNISCHE UNIVERSITEIT EINDHO on June 11, 2014 1944
Soukoulis et al Nonantithrombotic Therapies in ACS 1945
Nonstandard Abbreviations and Acronyms ACE-I ACS ARB CAD CBF CCB COR CVR HF LOE LV NSTEMI PCI RCT STEMI UA
angiotensin-converting enzyme inhibitor acute coronary syndromes angiotensin II receptor blocker coronary artery disease coronary blood flow calcium channel blocker Class of Recommendation coronary vascular resistance heart failure Level of Evidence left ventricular non–ST-segment elevation myocardial infarction percutaneous coronary intervention randomized controlled trial ST-segment elevation myocardial infarction unstable angina
Pathophysiology of Myocardial Ischemia Myocardial ischemia derives from an imbalance between myocardial oxygen supply and demand. Because myocardial oxygen extraction is near maximal in the resting state, any increase in tissue oxygen delivery in response to increased demand occurs mainly through an increase in coronary blood flow (CBF).1,2 In the setting of an acute coronary syndrome (ACS), ischemia is driven in large measure by an abrupt decrease in CBF consequent to the formation of a fully or partially obstructing platelet-fibrin thrombus at the site of rupture or erosion of a vulnerable plaque.3 CBF can be further compromised by reactive constriction of vascular smooth muscle cells, leading to deleterious increases in coronary vascular resistance (CVR) at the arteriolar level and further narrowing of the larger, epicardial conduit artery. CVR is mediated by a host of factors, including paracrine factors released from activated platelets, adenosine, local availability of nitric oxide (NO), prostacyclin, endothelin, hypoxia, acidosis, ATPsensitive K+ channels, neurohumoral agonists, neural tone, and vascular shear stress.4,5 An intact and functional endothelium serves as the gatekeeper. Atherosclerosis leads to a reduction in NO availability and paradoxical increases in CVR on exposure to substances such as acetylcholine, which would otherwise cause vasodilation and a fall in CVR in normal arterial segments.6 Myocardial compressive forces also contribute to CVR. Nutrient supply to the more vulnerable subendocardium can be compromised by increases in left ventricular (LV) diastolic pressure with a resultant decrease in the coronary driving pressure, which is represented by the difference between the aortic and LV diastolic pressures. Isolated reductions in aortic diastolic pressure, as seen in patients with significant aortic regurgitation or in some elderly patients with aggressively treated systolic hypertension, may also decrease coronary driving pressure. Higher LV diastolic pressures in the context of ischemia can further reduce coronary driving pressure. Because the majority of left coronary artery blood flow occurs
during diastole, decreases in diastolic filling times at rapid heart rates will also reduce CBF. Myocardial oxygen supply is additionally influenced by the oxygen-carrying capacity of blood, and severe anemia (hemoglobin
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/12/1944
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ at TECHNISCHE UNIVERSITEIT EINDHO on June 11, 2014
Acute Coronary Syndromes Compendium Circulation Research Compendium on Acute Coronary Syndromes Acute Coronary Syndromes: Pathology, Diagnosis, Genetics, Prevention, and Treatment Mechanisms of Plaque Formation and Rupture Inflammation and its Resolution as Determinants of Acute Coronary Syndromes Lipoproteins as Biomarkers and Therapeutic Targets in the Setting of Acute Coronary Syndrome Genetics of Coronary Artery Disease Imaging Plaques to Predict and Better Manage Patients With Acute Coronary Events Reperfusion Strategies in Acute Coronary Syndromes Antiplatelet and Anticoagulation Therapy for Acute Coronary Syndromes Nonantithrombotic Medical Options in Acute Coronary Syndromes: Old Agents and New Lines on the Horizon Global Perspective on Acute Coronary Syndrome: A Burden on the Young and Poor Guest Editors: Valentin Fuster and Jason Kovacic
Nonantithrombotic Medical Options in Acute Coronary Syndromes Old Agents and New Lines on the Horizon Victor Soukoulis, William E. Boden, Sidney C. Smith Jr, Patrick T. O’Gara
Abstract: Acute coronary syndromes (ACS) constitute a spectrum of clinical presentations ranging from unstable angina and non–ST-segment elevation myocardial infarction to ST-segment myocardial infarction. Myocardial ischemia in this context occurs as a result of an abrupt decrease in coronary blood flow and resultant imbalance in the myocardial oxygen supply–demand relationship. Coronary blood flow is further compromised by other mechanisms that increase coronary vascular resistance or reduce coronary driving pressure. The goals of treatment are to decrease myocardial oxygen demand, increase coronary blood flow and oxygen supply, and limit myocardial injury. Treatments are generally divided into disease-modifying agents or interventions that improve hard clinical outcomes and other strategies that can reduce ischemia. In addition to traditional drugs such as β-blockers and inhibitors of the renin–angiotensin–aldosterone system, newer agents have expanded the number of molecular pathways targeted for treatment of ACS. Ranolazine, trimetazidine, nicorandil, and ivabradine are medications that have been shown to reduce myocardial ischemia through diverse mechanisms and have been tested in limited fashion in patients with ACS. Attenuating the no-reflow phenomenon and reducing the injury compounded by acute reperfusion after a period of coronary occlusion are active areas of research. Additionally, interventions aimed at ischemic pre- and postconditioning may be useful means by which to limit myocardial infarct size. Trials are also underway to examine altered metabolic and oxygen-related pathways in ACS. This review will discuss traditional and newer anti-ischemic therapies for patients with ACS, exclusive of revascularization, antithrombotic agents, and the use of high-intensity statins. (Circ Res. 2014;114:1944-1958.) Key Words: acute coronary syndrome
■
ischemic preconditioning
■
reperfusion injury
Original received February 9, 2014; revision received March 11, 2014; accepted March 19, 2014. In April 2014, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.38 days. From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (V.S., P.T.O.); Division of Cardiology, Department of Medicine, Albany Stratton Veteran’s Affairs Medical Centre and Albany Medical College, NY (W.E.B.); and Division of Cardiology, University of North Carolina, Chapel Hill (S.C.S.). The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA. 114.302804/-/DC1. Correspondence to Patrick T. O’Gara, MD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail [email protected] © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.114.302804
Downloaded from http://circres.ahajournals.org/ at TECHNISCHE UNIVERSITEIT EINDHO on June 11, 2014 1944
Soukoulis et al Nonantithrombotic Therapies in ACS 1945
Nonstandard Abbreviations and Acronyms ACE-I ACS ARB CAD CBF CCB COR CVR HF LOE LV NSTEMI PCI RCT STEMI UA
angiotensin-converting enzyme inhibitor acute coronary syndromes angiotensin II receptor blocker coronary artery disease coronary blood flow calcium channel blocker Class of Recommendation coronary vascular resistance heart failure Level of Evidence left ventricular non–ST-segment elevation myocardial infarction percutaneous coronary intervention randomized controlled trial ST-segment elevation myocardial infarction unstable angina
Pathophysiology of Myocardial Ischemia Myocardial ischemia derives from an imbalance between myocardial oxygen supply and demand. Because myocardial oxygen extraction is near maximal in the resting state, any increase in tissue oxygen delivery in response to increased demand occurs mainly through an increase in coronary blood flow (CBF).1,2 In the setting of an acute coronary syndrome (ACS), ischemia is driven in large measure by an abrupt decrease in CBF consequent to the formation of a fully or partially obstructing platelet-fibrin thrombus at the site of rupture or erosion of a vulnerable plaque.3 CBF can be further compromised by reactive constriction of vascular smooth muscle cells, leading to deleterious increases in coronary vascular resistance (CVR) at the arteriolar level and further narrowing of the larger, epicardial conduit artery. CVR is mediated by a host of factors, including paracrine factors released from activated platelets, adenosine, local availability of nitric oxide (NO), prostacyclin, endothelin, hypoxia, acidosis, ATPsensitive K+ channels, neurohumoral agonists, neural tone, and vascular shear stress.4,5 An intact and functional endothelium serves as the gatekeeper. Atherosclerosis leads to a reduction in NO availability and paradoxical increases in CVR on exposure to substances such as acetylcholine, which would otherwise cause vasodilation and a fall in CVR in normal arterial segments.6 Myocardial compressive forces also contribute to CVR. Nutrient supply to the more vulnerable subendocardium can be compromised by increases in left ventricular (LV) diastolic pressure with a resultant decrease in the coronary driving pressure, which is represented by the difference between the aortic and LV diastolic pressures. Isolated reductions in aortic diastolic pressure, as seen in patients with significant aortic regurgitation or in some elderly patients with aggressively treated systolic hypertension, may also decrease coronary driving pressure. Higher LV diastolic pressures in the context of ischemia can further reduce coronary driving pressure. Because the majority of left coronary artery blood flow occurs
during diastole, decreases in diastolic filling times at rapid heart rates will also reduce CBF. Myocardial oxygen supply is additionally influenced by the oxygen-carrying capacity of blood, and severe anemia (hemoglobin
