ACCF/AHA Focused Update 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons 2012 WRITING GROUP MEMBERS* Hani Jneid, MD, FACC, FAHA, Chair ; Jeffrey L. Anderson, MD, FACC, FAHA, Vice Chair ; R. Scott Wright, MD, FACC, FAHA, Vice Chair ; Cynthia D. Adams, RN, PhD, FAHA ; Charles R. Bridges, MD, ScD, FACC, FAHA ; Donald E. Casey, Jr, MD, MPH, MBA, FACP, FAHA ; Steven M. Ettinger, MD, FACC ; Francis M. Fesmire, MD, FACEP ; Theodore G. Ganiats, MD#; A. Michael Lincoff, MD, FACC ; Eric D. Peterson, MD, MPH, FACC, FAHA**; George J. Philippides, MD, FACC, FAHA ; Pierre Theroux, MD, FACC, FAHA ; Nanette K. Wenger, MD, MACC, FAHA ; James Patrick Zidar, MD, FACC, FSCAI 2007 WRITING COMMITTEE MEMBERS Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Cynthia D. Adams, RN, PhD, FAHA; Elliott M. Antman, MD, FACC, FAHA; Charles R. Bridges, MD, ScD, FACC, FAHA; Robert M. Califf, MD, MACC; Donald E. Casey, Jr, MD, MPH, MBA, FACP; William E. Chavey II, MD, MS; Francis M. Fesmire, MD, FACEP; Judith S. Hochman, MD, FACC, FAHA; Thomas N. Levin, MD, FACC, FSCAI; A. Michael Lincoff, MD, FACC; Eric D. Peterson, MD, MPH, FACC, FAHA; Pierre Theroux, MD, FACC, FAHA; Nanette K. Wenger, MD, MACC, FAHA; R. Scott Wright, MD, FACC, FAHA *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information. ACCF/AHA Representative. ACCF/AHA Task Force on Practice Guidelines Liaison. Society of Thoracic Surgeons Representative. American College of Physicians Representative. American College of Emergency Physicians Representative. #American Academy of Family Physicians Representative. **ACCF/AHA Task Force on Performance Measures Liaison. Society for Cardiovascular Angiography and Interventions Representative. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0b013e318256f1e0/-/DC1. The online-only Comprehensive Relationships Table is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/ CIR.0b013e318256f1e0/-/DC2. This document was approved by the American College of Cardiology Foundation Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee in March 2012. The American Heart Association requests that this document be cited as follows: Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012;126:875 910. This article is copublished in the Journal of the American College of Cardiology. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and the American Heart Association (my.americanheart.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2012 by the American College of Cardiology Foundation and the American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0b013e318256f1e0 ACCF/AHA TASK FORCE MEMBERS Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair; Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect; Nancy M. Albert, PhD, CCNS, CCRN, FAHA; Mark A. Creager, MD, FACC, FAHA; David DeMets, PhD; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC; Judith S. Hochman, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA; E. Magnus Ohman, MD, FACC; William G. Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA Table of Contents Preamble 876 1. Introduction 879 1.1. Methodology and Evidence Review 879 1.2. Organization of the Writing Group 879 1.3. Document Review and Approval 879 3. Early Hospital Care 879 3.2. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite: Recommendations 879 3.2.1. Antiplatelet Therapy: Recommendations 879 3.2.3. Additional Management of Antiplatelet and Anticoagulant Therapy: Recommendations 879 Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite 879 Inhibitors 879 Receptor Inhibitors for PCI in UA/NSTEMI 881 3.2.3.1.2.1. Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures 882 Variability in Responsiveness to Clopidogrel 882 3.2.3.1.4. Optimal Loading and Maintenance Dosages of Clopidogrel 883 3.2.3.1.5. Proton Pump Inhibitors and Dual Antiplatelet Therapy for ACS 883 3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists 884 3.3. Initial Invasive Versus Initial Conservative Strategies: Recommendations 885 3.3.3.1. Timing of Invasive Therapy 885 5. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care 890 5.2. Long-Term Medical Therapy and Secondary Prevention 890 5.2.1. Convalescent and Long-Term Antiplatelet Therapy: Recommendations 890 5.2.6. Warfarin Therapy: Recommendations 892 6. Special Groups 892 6.2. Diabetes Mellitus: Recommendations 892 6.2.1.1. Intensive Glucose Control 892 6.5. Chronic Kidney Disease: Recommendations 893 6.5.1. Angiography in Patients With CKD 893 7. Conclusions and Future Directions 895 7.1. Quality of Care and Outcomes for UA/NSTEMI: Recommendation 895 7.1.1. Quality Care and Outcomes 895 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 901 Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 903 Appendix 3. Dosing Table for Antiplatelet and Anticoagulant Therapy Discussed in This Focused Update to Support PCI in UA/NSTEMI 906 Appendix 4. Comparisons Among Orally Effective P2Y12 Inhibitors 908 Appendix 5. Flowchart for Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI 909 Appendix 6. Selection of Initial Treatment Strategy: Invasive Versus Conservative Strategy 910 Preamble Keeping pace with the stream of new data and evolving evidence on which guideline recommendations are based is an ongoing challenge to timely development of clinical practice guidelines. In an effort to respond promptly to new evidence, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Task Force on Practice Guidelines (Task Force) has created a focused update process to revise the existing guideline recommendations that are affected by the evolving data or opinion. New evidence is reviewed in an ongoing fashion to more efficiently respond to important science and treatment trends that could have a major impact on patient outcomes and quality of care. Evidence is reviewed at least twice a year, and updates are initiated on an as-needed basis and completed as quickly as possible while maintaining the rigorous methodology that the ACCF and AHA have developed during their partnership of more than 20 years. These focused updates are prompted following a thorough review of late-breaking clinical trials presented at national and international meetings in addition to other new published data deemed to have an impact on patient care (Section 1.1, Methodology and Evidence Review). Through a broad-based vetting process, the studies included are identified as being important to the relevant patient population. The focused update is not intended to be based on a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that may affect changes to current recommendations. Specific criteria/consid- erations for inclusion of new data include the following: publication in a peer-reviewed journal; large, randomized, placebo-controlled trial(s); nonrandomized data deemed important on the basis of results affecting current safety and efficacy assumptions, including observational studies and meta-analyses; strength/weakness of research methodology and findings; likelihood of additional studies influencing current findings; impact on current and/or likelihood of need to develop new performance measure(s); request(s) and requirement(s) for review and update from the practice community, key stakeholders, and other sources free of industry relationships or other potential bias; number of previous trials showing consistent results; and need for consistency with a new guideline or guideline updates or revisions. In analyzing the data and developing recommendations and supporting text, the writing group uses evidence-based method- ologies developed by the Task Force.1 The Class of Recommen- dation (COR) is an estimate of the size of the treatment effect considering risks versus benefits in addition to evidence and/or agreement that a given treatment or procedure is or is not useful/effective and in some situations may cause harm. The Level of Evidence (LOE) is an estimate of the certainty or precision of the treatment effect. The writing group reviews and ranks evidence supporting each recommendation with the weight of evidence ranked as LOE A, B, or C using specific definitions that are included in Table 1. Studies are identified as observational, retrospective, prospective, or randomized where appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and ranked as LOE C. When recommenda- tions at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues for which sparse data are available, a survey of current practice among the clinicians on the writing group is the basis for LOE C recommendations, and no references are cited. The schema for COR and LOE is summarized in Table 1, which also provides suggested phrases for writing recommen- dations within each COR. A new addition to this methodology is separation of the Class III recommendations to delineate whether the recommendation is determined to be of no benefit or is associated with harm to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment/strategy with respect to another for COR I and IIa, LOE A or B only. In view of the advances in medical therapy across the spectrum of cardiovascular diseases, the Task Force has designated the term guideline-directed medical therapy (GDMT) to represent optimal medical therapy as defined by ACCF/AHA guideline (primarily Class I) recommended ther- apies. This new term, GDMT, will be used herein and throughout all future guidelines. Because the ACCF/AHA practice guidelines address pa- tient populations (and healthcare providers) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR. For studies performed in large numbers of subjects outside North America, each writing group reviews the potential impact of different practice patterns and patient populations on the treatment effect and relevance to the ACCF/AHA target population to determine whether the findings should inform a specific recommendation. The ACCF/AHA practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. As a result, situations may arise in which deviations from these guidelines may be appropriate. Clinical decision making should consider the quality and avail- ability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise for which additional data are needed to inform patient care more effec- tively; these areas will be identified within each respective guideline when appropriate. Prescribed courses of treatment in accordance with these recommendations are effective only if they are followed. Because lack of patient understanding and adherence may adversely affect outcomes, physicians and other healthcare providers should make every effort to engage the patient s active participation in prescribed medical regimens and lifestyles. In addition, patients should be informed of the risks, benefits, and alternatives to a particular treatment and be involved in shared decision making whenever feasible, particularly for COR IIa and IIb, for which the benefit-to-risk ratio may be lower. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the writing group. All writing group members and peer reviewers of the guideline are required to disclose all current healthcare-related relationships, including those ex- isting 12 months before initiation of the writing effort. In December 2009, the ACCF and AHA implemented a new policy for relationships with industry and other entities (RWI) that requires the writing group chair plus a minimum of 50% of the writing group to have no relevant RWI (Appendix 1 for the ACCF/AHA definition of relevance). These statements are reviewed by the Task Force and all members during each Jneid et al 2012 UA/NSTEMI Focused Update 877 conference call and/or meeting of the writing group and are updated as changes occur. All guideline recommendations require a confidential vote by the writing group and must be approved by a consensus of the voting members. Members are not permitted to draft or vote on any text or recommen- dations pertaining to their RWI. Members who recused them- selves from voting are indicated in the list of writing group members, and specific section recusals are noted in Appendix 1. Authors and peer reviewers RWI pertinent to this guideline are disclosed in Appendixes 1 and 2, respectively. Additionally, to ensure complete transparency, writing group members compre- hensive disclosure information including RWI not pertinent to this document is available as an online supplement. Compre- hensive disclosure information for the Task Force is also available online at http://www.cardiosource.org/ACC/About- ACC/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The work of the writing group is supported exclusively by the ACCF and AHA without commercial support. Writing group members volunteered their time for this activity. In an effort to maintain relevance at the point of care for practicing physicians, the Task Force continues to oversee an ongoing process improvement initiative. As a result, in response to pilot projects, several changes to these guidelines will be apparent, including limited narrative text, a focus on Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. summary and evidence tables (with references linked to abstracts in PubMed), and more liberal use of summary recommendation tables (with references that support LOE) to serve as a quick reference. In April 2011, the Institute of Medicine released 2 reports: Clinical Practice Guidelines We Can Trust and Finding What Works in Health Care: Standards for Systematic Reviews.2,3 It is noteworthy that the ACCF/AHA practice guidelines were cited as being compliant with many of the standards that were proposed. A thorough review of these reports and our current methodology is under way, with further enhancements anticipated. The recommendations in this focused update are consid- ered current until they are superseded in another focused update or the full-text guideline is revised. Guidelines are official policy of both the ACCF and AHA. Jeffrey L. Anderson, MD, FACC, FAHA Chair, ACCF/AHA Task Force on Practice Guidelines 1.1. Methodology and Evidence Review The standing guideline writing committee along with the parent Task Force identified trials and other key data through October 2011 that may impact guideline recom- mendations. On the basis of the criteria/considerations noted in the Preamble and the approval of new oral antiplatelets, a focused update was initiated to provide guidance on how to incorporate these agents into daily practice. Now that multiple agents are available, a com- parison of their use in various settings within clinical practice is provided. This iteration replaces the sections in the 2007 ACC/AHA Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myo- that were updated by the 2011 ACCF/ AHA Focused Update of the Guidelines for the Manage- ment of Patients With Unstable Angina/Non ST-Elevation To provide clinicians with a comprehensive set of data, whenever deemed appropriate or when published, the abso- lute risk difference and number needed to treat or harm are provided in the guideline, along with confidence intervals (CI) and data related to the relative treatment effects such as odds ratio (OR), relative risk (RR), hazard ratio (HR), and incidence rate ratio. Consult the full-text version of the 2007 ACC/AHA Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction4 for policy on clinical areas not covered by the current document. Individual recommendations updated in this focused update will be incorporated into future revisions and/or updates of the full-text guidelines. 1.2. Organization of the Writing Group For this focused update, members of the 2011 Unstable Angina/Non ST-Elevation Myocardial Infarction (UA/ NSTEMI) focused update writing group were invited and all agreed to participate (referred to as the 2012 focused update writing group). Members were required to disclose all RWI relevant to the data under consideration. The writing group included representatives from the ACCF, AHA, American Academy of Family Physicians, American College of Emer- gency Physicians, American College of Physicians, Society for Cardiovascular Angiography and Interventions, and So- ciety of Thoracic Surgeons. 1.3. Document Review and Approval This document was reviewed by 2 official reviewers each nominated by the ACCF and the AHA, as well as 1 or 2 reviewers each from the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons, and 29 individual content reviewers, including members of the ACCF Interventional Scientific Council. The information on reviewers RWI was distributed to the writing group and is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the ACCF and the AHA and endorsed by the American College of Emergency Physicians, Soci- ety for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. 3. Early Hospital Care 3.2. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite: Recommendations 3.2.1. Antiplatelet Therapy: Recommendations Supplement.) 3.2.3. Additional Management of Antiplatelet and Anticoagulant Therapy: Recommendations Supplement.) 3.2.3.1. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite tor therapy is an important component of antiplatelet therapy in patients with UA/NSTEMI and has been tested in several large trial populations with UA/NSTEMI. The last version of the guideline recommended the use of clopidogrel in patients with UA/NSTEMI because it was the only US Food and Drug Administration (FDA) approved P2Y12 receptor inhibitor in this patient population at that time.6 Since the publication of the last guideline,6 the FDA has approved 2 additional P2Y12 receptor inhibitors for use in patients with UA/NSTEMI. The FDA approved the use of prasugrel and ticagrelor based on data from head-to-head comparison trials with clopidogrel, in which prasugrel and ticagrelor were respectively superior to clopidogrel in reducing clinical events but at the expense of an increased risk of bleeding. The pivotal trial for prasugrel, TRITON TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocar- dial Infarction),7 focused on patients with acute coronary syndrome (ACS) who were referred for percutaneous coro- nary intervention (PCI). TRITON TIMI 38 randomly as- Jneid et al 2012 UA/NSTEMI Focused Update 879 signed 13 608 patients with moderate- to high-risk ACS, of whom 10 074 (74%) had UA/NSTEMI, to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for a median follow-up of 14.5 months. Acetylsalicylic acid (aspirin) was prescribed within 24 hours of PCI. Clinical endpoints were assessed at 30 and 90 days and then at 3-month intervals for 6 to 15 months. Among patients with UA/NSTEMI undergoing PCI, a prasugrel loading dose was administered before, during, or within 1 hour after PCI but only after coronary anatomy had been defined. Patients taking any thienopyridine within 5 days of randomization were excluded. Prasugrel was associated with a significant 2.2% abso- lute reduction and a 19% relative reduction in the primary efficacy endpoint, a composite of the rate of death due to cardiovascular causes (including arrhythmia, congestive heart failure, shock, and sudden or unwitnessed death), nonfatal myocardial infarction (MI), or nonfatal stroke during the follow-up period (see Online Data Supplement). The primary efficacy endpoint occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopi- dogrel (HR for prasugrel versus clopidogrel: 0.81; 95% CI: lar death, MI, and stroke by 138 events (number needed to treat 46). The difference in the primary endpoint was largely related to the difference in rates of nonfatal MI (7.3% for prasugrel versus 9.5% for clopidogrel; HR: 0.76; death (2.1% versus 2.4%; P 0.31) and nonfatal stroke (1.0% versus 1.0%; P 0.93) were not reduced by prasu- grel relative to clopidogrel. Rates of stent thrombosis were significantly reduced from 2.4% to 1.1% (P 0.001) by prasugrel. Prasugrel was associated with a significant increase in the rate of bleeding, notably TIMI (Thrombolysis In Myocardial Infarction) major hemorrhage, which was ob- served in 2.4% of patients taking prasugrel and in 1.8% of patients taking clopidogrel (HR for prasugrel versus clopi- was associated with a significant increase in fatal bleeding compared with clopidogrel (0.4% versus 0.1%; P 0.002). From the standpoint of safety, prasugrel was associated with an increase of 35 TIMI major and non coronary artery graft bypass (CABG) bleeds (number needed to harm 167).7 Also, greater rates of life-threatening bleed- ing were evident in the prasugrel group than in the clopidogrel group: 1.4% versus 0.9%, respectively (HR for patients who underwent CABG, TIMI major bleeding through 15 months was also greater with prasugrel than with clopidogrel (13.4% versus 3.2%, respectively; HR for net clinical benefit in the TRITON TIMI 38 study dem- onstrated a primary efficacy and safety endpoint rate of 13.9% in the clopidogrel group versus 12.2% in the P 0.004). A post hoc analysis suggested there were 3 subgroups of ACS patients who did not have a favorable net clinical benefit (defined as the rate of death due to any cause, nonfatal MI, nonfatal stroke, or non CABG-related nonfatal TIMI major bleeding) from the use of prasugrel or who had net harm: Patients with a history of stroke or transient ischemic attack before enrollment had net harm from prasugrel (HR: 1.54; no net benefit from prasugrel (HR: 0.99; 95% CI: 0.81 to 1.21; P 0.92); and patients with a body weight of 60 kg had no net benefit from prasugrel (HR: 1.03; 95% CI: 0.69 to 1.53; P 0.89). In both treatment groups, patients with at least 1 of these risk factors had higher rates of bleeding than those The FDA approved prasugrel on July 10, 2009, and cited a contraindication against its use in patients with a history of transient ischemic attack or stroke or with active pathological bleeding.8 The FDA labeling information includes a general warning against the use of prasugrel in patients age 75 years because of concerns of an increased risk of fatal and intra- cranial bleeding and uncertain benefit except in high-risk situations (patients with diabetes or a history of prior MI), in which case the net benefit appears to be greater and its use may be considered.8 In focusing specifically on pa- tients with UA/NSTEMI, the rate of the primary efficacy endpoint was significantly reduced in favor of prasugrel The pivotal trial for ticagrelor, PLATO (Study of Platelet Inhibition and Patient Outcomes),9 was a multi- center, international, randomized controlled trial compar- ing ticagrelor with clopidogrel (on a background of aspirin therapy) to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients with ACS (see Online Data Supplement). A total of 18 624 patients hospitalized with an ACS were randomized at 862 centers (from 2006 through 2008). Of those, 11 598 patients had UA/NSTEMI (patients with UA and NSTEMI made up 16.7% and 42.7% of the overall population, respectively), whereas 7026 patients had STEMI. The primary efficacy endpoint was the time to first occurrence of the composite of vascular death, MI, or stroke. The primary safety endpoint was the first occur- rence of any major bleeding event. The randomized treat- ment was scheduled to continue for 12 months; however, patients were allowed to leave the trial at 6 to 9 months if the event-driven study achieved its targeted number of primary events. Overall, the median duration of study drug administration was 277 days. Using a double-blind, double-dummy design, ticagrelor (180-mg loading dose followed by 90 mg twice daily) was compared with clopidogrel (300- to 600-mg loading dose followed by 75 mg daily).9 At 24 hours after randomization, 79% of patients treated with clopidogrel received at least 300 mg, and nearly 20% received at least 600 mg. Overall, 64.3% of patients underwent PCI during the index hospitalization and 60.6% had stent implantation. Median times from the start of hospitalization to initiation of study treatment were 4.9 and 5.3 hours for ticagrelor and clopidogrel, respectively. At 12 months, ticagrelor was associated with a 1.9% absolute reduction and 16% relative reduction in the primary composite outcome compared with clopidogrel which was driven by lower rates of MI (5.8% versus 6.9%; benefits of ticagrelor appeared consistent across most subgroups studied, with no significant interaction being observed between the treatment effect and type of ACS. In focusing specifically on patients with UA/NSTEMI, ti- cagrelor was associated with a significant reduction in the primary efficacy endpoint among NSTEMI patients CI: 0.73 to 0.94) but not among UA patients (n 3112 1.22), although caution is urged against overinterpreting subgroup analyses. The benefits of ticagrelor in PLATO appeared within the first 30 days, persisted for up to 360 days, and were evident irrespective of clopidogrel pretreat- ment and whether patients had invasive or medical man- agement planned. Notably, ticagrelor was associated with a 1.4% absolute reduction in all-cause mortality (4.5% lower rates of definite stent thrombosis (1.3% versus 1.90%; HR: 0.67; 95% CI: 0.50 to 0.91). There were no significant differences between the ticagre- lor and clopidogrel groups in rates of major bleeding (the primary safety endpoint: composite of major life-threatening and other major bleeding events, PLATO study criteria; CI: 0.48 to 1.59).9 There were also no differences in major bleeding in patients undergoing CABG, in whom clopidogrel and ticagrelor were discontinued before the procedure for 5 days and 24 to 72 hours, respectively, per study protocol. Ticagrelor, however, was associated with a higher rate of non CABG-related major bleeding (4.5% versus 3.8%, P 0.03). In addition, ticagrelor caused a higher incidence of 2.02; although not necessitating drug discontinuation except in a few cases), mild increases in creatinine and uric acid levels, and a higher rate of ventricular pauses 3 seconds in the first week (5.8% versus 3.6%, P 0.01; but without causing differences in syncope or pacemaker implantation). Overall, discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (7.4% versus 6.0%; P 0.001). Patients with a history of bleeding were excluded in PLATO, and 4% of patients had a prior history of nonhemorrhagic stroke.9 The efficacy and safety of ticagrelor in patients with prior tran- sient ischemic attack or stroke were not reported in PLATO,9 and the balance of risks and benefits of ticagrelor in this patient population remains unclear. A separate analysis was performed for the 5216 patients in PLATO admitted with ACS and prespecified as planned for noninvasive management (constituting 28% of the overall PLATO study population).10 Compared with clopidogrel, ticagrelor was associated with a lower incidence of the 0.73 to 1.00; P 0.04) and overall mortality without increas- ing major bleeding. These results indicate the benefits of intensified P2Y12 inhibition with ticagrelor applied broadly for patients regardless of the intended or actualized manage- The benefits of ticagrelor in PLATO appeared to be attenuated in patients weighing less than the median weight for their sex and those not taking lipid-lowering therapies at randomization.9 There was a significant interaction between treatment and geographic region, with patients enrolled in North America having no statistically significant differences between ticagrelor and clopidogrel with respect to the pri- mary efficacy endpoint.9 Extensive additional analyses were conducted to explore potential explanations for this interac- tion between treatment effect in PLATO and geographic region and whether this could be explained by specific patient characteristics or concomitant therapies.11 Mahaffey and colleagues11 noted that a significantly higher proportion of patients in the United States received a median aspirin dose of 300 mg daily compared with the rest of the world (53.6% versus 1.7%). Indeed, of all 37 baseline and postrandomiza- tion variables explored, only aspirin maintenance dose ap- peared to explain a substantial fraction of the regional interaction. Of note, subgroup analysis consistently showed the same aspirin-dose effect outside the United States. With- out being able to fully rule out the play of chance or other factors related to clinical care in North America as explana- tions for the regional interaction, PLATO concluded that a low aspirin maintenance dose ( 100 mg daily) is likely to be associated with the most favorable outcomes when using the potent P2Y12 inhibitor ticagrelor in patients with ACS.11 Because of its reversible inhibition of the P2Y12 receptor, ticagrelor is associated with more rapid functional recovery of circulating platelets and, consequently, a faster offset of effect than clopidogrel. Although this may represent a poten- tial advantage for patients with ACS undergoing early CABG, it may theoretically pose a problem for noncompliant patients (especially given its twice-daily dosing regimen). The FDA approved ticagrelor on July 20, 2011.12 The FDA also issued a Boxed Warning indicating that aspirin daily maintenance doses of 100 mg decrease the effec- tiveness of ticagrelor, cautioned against its use in patients with active bleeding or a history of intracranial hemor- rhage, and advocated a Risk Evaluation and Mitigation Strategy, a plan to help ensure that the benefits of ticagrelor outweigh its risks. As part of that plan, the manufacturer is mandated to conduct educational outreach programs to alert physicians about the risk of using higher doses of aspirin. Dual antiplatelet therapy with aspirin and either clopi- dogrel or prasugrel has increased the risk of intracranial hemorrhage in several clinical trials and patient populations (especially in those with prior stroke).7,13a,13b,13c In PLATO, the number of patients with prior stroke was small, limiting the power to detect treatment differences in intracranial bleeding in this subgroup.13d Patients with prior stroke or TIA have been excluded from PEGASUS (Prevention of Cardio- vascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of an ongoing trial of ticagrelor versus placebo in addition to aspirin in patients with stable coronary artery disease. Until further data become available, it seems prudent to weigh the possible increased risk of intracranial bleeding when considering the addition of ticagrelor to aspirin in patients with prior stroke or TIA.13f 3.2.3.1.2. Choice of P2Y12 Receptor Inhibitors for PCI in UA/NSTEMI. The writing group cautions that data on the use of prasugrel and ticagrelor come solely from the TRITON TIMI 38 and PLATO trials, respectively, and their use in clinical practice should carefully follow how they were tested in these studies.7,9 Prasugrel was administered only after a decision to proceed to PCI was made, whereas ticagrelor was studied in all-comer patients with UA/NSTEMI, including invasively and medically managed patients. The writing group does not recommend that prasugrel be administered routinely to patients with UA/NSTEMI before angiography, Jneid et al 2012 UA/NSTEMI Focused Update 881 such as in an emergency department, or used in patients with UA/NSTEMI who have not undergone PCI. The FDA pack- age label suggests that it is reasonable to consider selective use of prasugrel before catheterization in subgroups of patients for whom a decision to proceed to angiography and PCI has already been established for any reason.8 The writing group acknowledges this flexibility, but it is not its intention to make more specific recommendations about which sub- groups of patients might benefit from prasugrel or ticagrelor instead of clopidogrel. The writing group does wish to caution clinicians about the potential increased bleeding risks associated with prasugrel and ticagrelor compared with clopi- dogrel in specific settings and especially among the sub- groups identified in the package insert and clinical trials.7 9,12 This guideline explicitly does not endorse one of the P2Y12 receptor inhibitors over the other. There were several reasons for this decision. Although the composite efficacy endpoint in TRITON TIMI 38 favored prasugrel, driven predominantly by a difference in nonfatal MIs (mostly asymptomatic), with deaths and nonfatal strokes being similar, bleeding was increased in the prasugrel group.7 On the other hand, the composite efficacy endpoint in PLATO favoring ticagrelor over clopidogrel was driven by differences in both vascular death and nonfatal MIs, with stroke rates being similar. Ticagre- lor was also associated with a notable reduction in all-cause mortality in PLATO. Compared with clopidogrel, ticagrelor was associated with a higher rate of non CABG-related major bleeding and slightly more frequent discontinuation of the study drug due to adverse events.9 On the other hand, prasugrel was associated with a significant increase in the rate of TIMI major hemorrhage, TIMI major and non-CABG bleeding, as well as higher fatal and life-threatening bleeding. There was a signifi- cant interaction between the treatment effect in PLATO and the geographic region, with lack of benefit in the United States for ticagrelor versus clopidogrel (with the explanation depending on a post hoc analysis of aspirin maintenance dose, as noted in the preceding text)11 (see Online Data Supplement). It must be recognized, however, that the 2 newer P2Y12 receptor inhibitors were studied in different patient popula- tions and that there is no head-to-head comparative trial of these agents. Also, the loading dose of clopidogrel in TRITON TIMI 38 was lower than is currently recommended in this guideline.7 Furthermore, some emerging studies sug- gest there may be some patients who are resistant to clopi- dogrel, but there is little information about the use of strategies to select patients who might do better with newer P2Y12 receptor inhibitors. Considerations of efficacy in the prevention of thrombosis and risk of an adverse effect related to bleeding and experience with a given medication may best guide decisions about the choice of P2Y12 receptor inhibitor for individual patients14 (Appendix 4). 3.2.3.1.2.1. Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures. The writing group weighed the current data on the use of P2Y12 receptor inhibitor therapy in patients who remain hospitalized after UA/NSTEMI and are candidates for CABG and retained the 2007 recommendation4 of empirical discontinuation of clopi- dogrel therapy for at least 5 days13 and advocated a period of at least 7 days in patients receiving prasugrel and a period of at least 5 days in patients receiving ticagrelor for their respective discontinuation before planned CABG.8,12 Ulti- mately, the patient s clinical status will determine the risk- to-benefit ratio of CABG compared with awaiting restoration of platelet function. It is the opinion of the writing group that physicians and patients should be cautioned against early discontinuation of P2Y12 receptor inhibitors for elective noncardiac procedures. Given the increased hazard of recurrent cardiovascular events from premature discontinuation of P2Y12 inhibitors and the increased bleeding risk in patients undergoing procedures on therapy (eg, colonoscopy with biopsy, dental procedures), it is advisable to consult a cardiologist and preferably defer elective noncardiac procedures until the patient finishes the appropriate course of P2Y12 receptor inhibition therapy, especially in UA/NSTEMI patients who received 12 months of treatment with dual antiplatelet therapy after deployment of a drug-eluting stent (DES).15 3.2.3.1.3. Interindividual Variability in Responsiveness to Clopidogrel. Although clopidogrel in combination with as- pirin has been shown to reduce recurrent coronary events in the posthospitalized ACS population,13,16 the response to clopidogrel varies among patients, and diminished respon- siveness to clopidogrel has been observed.17,18 Clopidogrel is a prodrug and requires conversion to R130964, its active metabolite, through a 2-step process in the liver that involves several CYP450 isoenzymes19; of these, the CYP2C19 isoen- zyme is responsible for almost half of the first step forma- tion.20 At least 3 major genetic polymorphisms of the CYP2C19 isoenzyme are associated with loss of function: ants account for 85% and 99% of the loss-of-function alleles in Caucasians and Asians, respectively.20 There are racial and ethnic differences in the prevalence of these loss-of-function alleles among Caucasians, African Americans, Asians, and Latinos, but all of these groups have some expression of them. Data from a number of observational studies have dem- onstrated an association between an increased risk of adverse cardiovascular events and the presence of 1 of the nonfunc- tioning alleles17,18,20,21,23 27 and are well delineated in the ACCF/AHA Clopidogrel Clinical Alert.20 Prasugrel, the second FDA-approved P2Y12 receptor in- hibitor for use in ACS, is also a prodrug that requires conversion to its active metabolite. Prasugrel requires a single CYP-dependent step for its oxidation to the active metabolite, and at least 2 observational studies have demonstrated no significant decrease in plasma concentrations or platelet inhibition activity in carriers of at least 1 loss-of-function allele of the CYP2C19 isoenzyme.28,29 On the other hand, ticagrelor, the latest FDA-approved P2Y12 receptor inhibitor, is a nonthienopyridine, reversible, direct-acting oral antago- nist of the P2Y12 receptor that does not require transformation to an active metabolite.30 Since the FDA announced a Boxed Warning on March 12, 2010, about the diminished effectiveness of clopidogrel in patients with an impaired ability to convert the drug into its active form,14 there has been much interest in whether clinicians should perform routine testing in patients being treated with clopidogrel. The routine testing could be for genetic variants of the CYP2C19 allele and/or for overall effective- ness for inhibition of platelet activity. The ACCF/AHA Clopidogrel Clinical Alert expertly summarizes the issues surrounding clopi- dogrel and the use of genotype testing, as well as the potential for routine platelet function testing.20 The FDA label revision does not mandate testing for CYP2C19 genotypes or overall platelet function.14 The revi- sion serves to warn clinicians that certain patient subgroups may exhibit reduced clopidogrel-mediated platelet inhibi- tion and emphasizes that clinicians should be aware of alternative treatment strategies to tailor alternative thera- pies when appropriate. A number of commercially available genetic test kits will identify the presence of 1 of the loss-of-function CYP2C19 alleles, but these tests are expensive and not routinely covered by most insurance policies. Additionally, there are no prospective studies that demonstrate that the routine use of these tests coupled with modification of antiplatelet therapy improves clinical outcomes or reduces subsequent clinical events. A recent meta-analysis demonstrated an association between the CYP2C19 genotype and clopidogrel responsiveness but no significant association of genotype with cardiovascular events.31 Several ongoing studies are examining whether genotype assess- ment with attendant alteration in antiplatelet therapy for those with loss-of-function alleles can improve clinical outcomes. On the basis of the current evidence, it is difficult to strongly recommend genotype testing routinely in patients with ACS, but it might be considered on a case-by-case basis, especially in patients who experience recurrent ACS events despite ongoing therapy with clopidogrel. Some argue that clinicians should consider routine testing of platelet function, especially in patients undergoing high- risk PCI,20 to maximize efficacy while maintaining safety. Again, no completed prospective studies have examined such an approach to guide such a sweeping change in clinical management. At least 4 randomized clinical evaluation stud- ies being conducted now are testing the hypothesis that routine platelet function testing should be used to tailor antiplatelet therapy, and any strong recommendation regard- ing more widespread use of such testing must await the results of these trials. The lack of evidence does not mean lack of efficacy or potential benefit, but the prudent physician should maintain an open yet critical mind-set about the concept until data are available from 1 of the ongoing randomized clinical trials examining this strategy. Our recommendations for the use of genotype testing and platelet function testing seek to strike a balance between not imposing an undue burden on clinicians, insurers, and society to implement these strategies in patients with UA or NSTEMI and that of acknowledging the importance of these issues to patients with UA/NSTEMI. Our recommen- dations that the use of either strategy may have some benefit should be taken in the context of the remarks in this update, as well as the more comprehensive analysis in the ACCF/AHA Clopidogrel Clinical Alert.20 The Class IIb recommendation of these strategies suggests that a selec- tive, limited approach to platelet genotype assessment and platelet function testing is the more prudent course until better clinical evidence exists for us to provide a more scientifically derived recommendation. 3.2.3.1.4. Optimal Loading and Maintenance Dosages of Clopidogrel. Some have suggested that the loading and maintenance doses of clopidogrel should be altered to account for potential reduced responsiveness to clopidogrel therapy or that some subgroups of high-risk patients should be treated preferentially with prasugrel.20 Accordingly, the optimal loading and short-term maintenance dosing for clopidogrel in patients with UA/NSTEMI undergoing PCI is uncertain. Loading and short-term maintenance doses of clopidogrel were studied in CURRENT OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent Events Organiza- tion to Assess Strategies in Ischemic Syndromes), with published data demonstrating a potential benefit of higher- dose clopidogrel in patients with definite UA/NSTEMI undergoing an invasive management strategy.32,33 The CURRENT OASIS 7 trial randomized 25 086 patients with ACS who were intended for PCI and who were not consid- ered to be at high risk for bleeding to receive higher-dose clopidogrel (600 mg loading, 150 mg daily for 6 days, 75 mg daily thereafter) versus standard-dose clopidogrel (300 mg loading, 75 mg daily) as part of a 2 2 design that also compared maintenance higher-dose aspirin (300 to 325 mg daily) with low-dose aspirin (75 to 100 mg daily). All patients received 300 mg of aspirin on Day 1 regardless of random- ization after Day 1. The primary endpoint of the trial was the combination of cardiovascular death, myocardial (re)infarc- tion, or stroke at 30 days. Although the overall trial33 failed to demonstrate a significant difference in the primary endpoint between the clopidogrel and aspirin groups (4.2% versus 4.4%), the PCI subset (n 17 263) did show significant differences in the clopidogrel arm.32 The primary outcome was reduced in the PCI subgroup randomized to higher-dose clopidogrel (3.9% versus 4.5%; P 0.035), and this was largely driven by a reduction in myocardial (re)infarction (2.0% versus 2.6%; P 0.017). Definite stent thrombosis was reduced in the higher-dose clopidogrel group (0.7% versus 1.3%; P 0.0001), with consistent results across DES versus non-DES subtypes. Higher-dose clopidogrel therapy in- creased major bleeding in the entire group (2.5% versus P 0.008). The benefit of higher-dose clopidogrel loading was offset by an increase in major bleeding.32 The findings from the prespecified PCI subgroup analysis32 should be interpreted with caution and considered hypothesis generat- ing, because the primary endpoint of the CURRENT OASIS 7 trial was not met and given that the P value for interaction (P 0.026) between treatment effect and PCI was of border- line statistical significance. As noted in the dosing table (Appendix 3), the current recommended loading dose for clopidogrel is uncertain. In addition, several hours are required to metabolize clopidogrel to its active metabolite, leaving a window of time where there is a reduced level of effectiveness even in patients who respond to clopidogrel. 3.2.3.1.5. Proton Pump Inhibitors and Dual Antiplatelet Therapy for ACS. Proton pump inhibitor (PPI) medications have been found to interfere with the metabolism of clopi- dogrel. When clopidogrel is started, PPIs are often prescribed prophylactically to prevent gastrointestinal (GI) complica- tions such as ulceration and related bleeding34 due to dual antiplatelet therapy, in particular aspirin and clopidogrel.17 Coupled with concern about the GI precautions, there has been increased emphasis on the prevention of premature discontinuation of dual antiplatelet therapy, particularly in patients who have received a DES for whom 12 months of antiplatelet therapy is recommended.15 There have been retrospective reports of adverse cardio- vascular outcomes (eg, readmission for ACS) when the antiplatelet regimen of clopidogrel and aspirin is accompa- nied by PPIs assessed as a group compared with use of this regimen without a PPI.17,35,36 In a retrospective cohort study Jneid et al 2012 UA/NSTEMI Focused Update 883 from the Veterans Affairs medical records and pharmacy database, concomitant clopidogrel and PPI therapy (with omeprazole, rabeprazole, lansoprazole, or pantoprazole) at any time during follow-up of 8205 patients discharged for ACS was associated with an increased risk of death or rehospitalization for ACS.17 Other post hoc study analyses25 and a retrospective data analysis from the National Heart, Lung, and Blood Institute Dynamic Registry, in which PPIs were assessed as a class in combination with a clopidogrel and an aspirin regimen, have not found an effect of PPI therapy on the clinical effect of clopidogrel in ACS patients, post-ACS patients, and a general post-PCI population, Some studies have suggested that adverse cardiovascular outcomes with the combination of clopidogrel and a PPI are explained by the individual PPI, in particular, the use of a PPI that inhibits CYP450 2C19, including omeprazole, lansopra- zole, or rabeprazole. Notably, the PPI omeprazole has been reported to significantly decrease the inhibitory effect of clopidogrel on platelet aggregation.38,39 One study reported that the PPI pantoprazole was not associated with recurrent MI among patients receiving clopidogrel, possibly due to pantoprazole s lack of inhibition of CYP450 2C19.35 Other studies have examined the P2Y12 receptor inhibitor prescribed with the PPI. One open-label drug study evaluated the effects of the PPI lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg per day. The data suggest that inhibition of platelet aggregation was reduced in patients who took the combina- tion of clopidogrel and lansoprazole, whereas platelet aggre- gation was unaffected after a prasugrel dose.40 Another study36 assessed the association of PPIs with the pharmacodynamics and clinical efficacy of clopidogrel and prasugrel, based on populations from 2 randomized trials, the PRINCIPLE (Prasugrel In Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation) TIMI-44 trial41 and the TRITON TIMI 38 trial.7 The findings indi- cated that first, PPI treatment attenuated the pharmacody- namic effects of clopidogrel and, to a lesser extent, those of prasugrel. Second, PPI treatment did not affect the clinical outcome of patients given clopidogrel or prasugrel. This finding was true for all PPIs that were studied, including omeprazole and pantoprazole. Observational trials may be confounded by selection bias. In the COGENT (Clopidogrel and the Optimization of Gas- trointestinal Events) study,42 omeprazole was compared with placebo in 3627 patients starting dual antiplatelet therapy with aspirin and clopidogrel. No difference was found in the primary composite cardiovascular endpoint between clopi- dogrel plus omeprazole and clopidogrel plus placebo (HR: 1.02), but GI bleeding complications were reduced.42 CO- GENT had several shortcomings (see Online Data Supple- ment), and more controlled, randomized clinical trial data are needed to address the clinical impact of conjunctive therapy with clopidogrel and PPIs. The FDA communication on an ongoing safety review of clopidogrel bisulfate14 advises that healthcare providers should reevaluate the need for starting or continuing treatment with a PPI, including omeprazole, in patients taking clopidogrel. The FDA notes there is no evidence that other drugs that reduce stomach acid, such as H2 blockers or antacids, interfere with the antiplatelet activity of clopidogrel. Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke. Healthcare providers should reevaluate the need for starting or continuing treatment with a PPI, including omepra- zole (over the counter), in patients taking clopidogrel. Patients taking clopidogrel should consult their healthcare provider if they are currently taking or considering taking a PPI, including omeprazole.14 The ACCF has released a statement on the use of PPI agents in combination with clopidogrel. The expert consen- sus statement does not prohibit the use of PPI agents in appropriate clinical settings, yet highlights the potential risks and benefits from use of PPI agents in combination with 3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists. The efficacy of glycoprotein (GP) IIb/IIIa inhibitor therapy has been well established during PCI procedures and in patients with UA/NSTEMI, particularly among high-risk patients such as those with elevated troponin biomarkers, those with diabetes, and those undergoing revascularization.44 54 The preponderance of the evidence supporting the use of GP IIb/IIIa inhibitor therapy predated the trials that established the benefits of clopidogrel, early invasive therapy, and contemporary medical treatments in patients with UA/NSTEMI. These studies sup- ported the upstream use of a GP IIb/IIIa inhibitor as a second agent in combination with aspirin for dual antiplatelet therapy in patients with UA/NSTEMI, especially in high-risk subsets such as those with an initial elevation in cardiac troponins, those with diabetes, and in those undergoing revascularization.47,48,50 52,55 These studies did not directly test in a randomized fashion the selection of an oral thienopyridine versus an intravenous (IV) GP IIb/IIIa inhibitor as the second antiplatelet agent in UA/NSTEMI. Contemporary clinical trials have therefore been needed to define the optimal timing of initiation of GP IIb/IIIa inhibitor therapy in patients with UA/NSTEMI, whether upstream (at presentation and before angiography) or deferred (at the time of angiography/PCI), and its optimal application (whether routine, selective, or provisional) and to clarify the relative benefit and risk of GP IIb/IIIa inhibitor therapy as a third antiplatelet agent in combination with aspirin and a thienopyridine. The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non ST-Segment Elevation Acute Coronary Syndrome) trial56 tested the hypothesis that a strategy of early routine administration of the GP IIb/IIIa inhibitor eptifibatide would be superior to delayed provisional administration in reducing ischemic complications among high-risk patients with UA/NSTEMI. The study investigators enrolled 9492 patients who presented within 24 hours of an episode of ischemic rest discomfort of at least 10 minutes duration. The study subjects were randomized within 8 to 12 hours after presentation and assigned to an invasive treatment strategy no sooner than the next calendar day. To qualify as having high-risk UA/NSTEMI, the subjects were required to have at least 2 of the following: ST-segment depression or transient ST-segment elevation, elevated biomarker levels (creatine kinase myocardial band or troponin), or age 60 years. The study subjects were randomized in a double-blind design to receive either early routine administration of eptifibatide (double bolus followed by standard infusion) or delayed provisional eptifibatide at the time of PCI. Eptifibatide infusion was given for 18 to 24 hours after PCI in both groups. For patients who underwent PCI, the total duration of the infusion was 96 hours. For patients who did not receive PCI for whatever reason, the duration of infusion was 96 hours. The study infusion was stopped 2 hours before surgery for those undergoing CABG. Early clopidogrel was allowed at the inves- tigators discretion (75% intended early use), and if used, a loading dose of 300 mg was recommended. For patients begin- ning clopidogrel during PCI (intended in 25% of study subjects, but actually implemented in 11%), a dose of 600 mg was permitted. Randomization to 1 of 3 antithrombotic regimens was stratified according to the intention of the investigator to admin- ister early clopidogrel (ie, at or before randomization).56 The primary endpoint (a 30-day composite of all-cause death, MI, recurrent ischemia requiring urgent revasculariza- tion, or thrombotic bailout at 96 hours) occurred in 9.3% of patients in the early therapy arm versus 10.0% of patients in the provisional GP IIb/IIIa inhibitor therapy arm (OR: 0.92; cause death or MI within 30 days) event rates were 11.2% versus 12.3% (OR: 0.89; 95% CI: 0.79 to 1.01; P 0.08). Early routine eptifibatide administration was associated with a greater risk of TIMI major hemorrhage (2.6% versus 1.8%; P 0.02). Severe or moderate bleeding, as defined by the GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) criteria, also occurred more commonly in the early eptifibatide group (7.6% versus 5.1%; P 0.001). Rates of red blood cell transfusion were 8.6% and 6.7% in the early-eptifibatide and delayed-eptifibatide groups, respectively (P 0.001). There were no significant interactions with respect to prespecified baseline characteris- tics, including early clopidogrel administration, and the pri- mary or secondary efficacy endpoints. In a subgroup analysis, early administration of eptifibatide in patients who underwent PCI was associated with numerically fewer ischemic events. A second contemporary study, the ACUITY (Acute Cath- eterization and Urgent Intervention Triage Strategy) trial,57 examined in part the optimal strategy for the use of GP IIb/IIIa inhibitors in moderate- and high-risk ACS patients undergoing early invasive therapy. A total of 9207 patients were randomized to 1 of 3 antithrombin regimens: unfractionated heparin (UFH) or enoxaparin plus GP IIb/IIIa inhibitor therapy; bivalirudin plus GP IIb/IIIa inhibitor therapy; or bivalirudin alone. Patients assigned to the heparin (UFH or enoxaparin) plus GP IIb/IIIa inhibitor therapy or to the bivalirudin plus GP IIb/IIIa inhibitor therapy were also randomized to immediate upstream routine GP IIb/IIIa inhibitor therapy or deferred selective use of GP IIb/IIIa inhibitor therapy at the time of PCI. A clopidogrel loading dose of 300 mg was required in all cases no later than 2 hours after PCI, and provisional GP IIb/IIIa inhibitor use was permitted before angiography in the deferred group for severe breakthrough ischemia. The composite ischemic endpoint oc- curred in 7.1% of the patients assigned to upstream administra- tion and in 7.9% of patients assigned to deferred selective thus the noninferiority hypothesis was not achieved. Major bleeding was lower in the deferred-use group versus the up- stream group (4.9% to 6.1%; P 0.001 for noninferiority and P 0.009 for superiority). Although early GP IIb/IIIa inhibitor therapy as dual antiplatelet therapy also reduced complications after PCI, supporting its continued role in patients undergoing PCI,49,53,54,56,58 these 2 most recent studies56,57 more strongly support a strategy of selective rather than routine upstream use of GP IIb/IIIa inhibitor therapy as part of triple antiplate- let therapy. Data from EARLY ACS56 highlight the potential bleeding risks of upstream use of a GP IIb/IIIa inhibitor as part of triple antiplatelet therapy. The use of a GP IIb/IIIa inhibitor should be undertaken when the risk-benefit ratio suggests a potential benefit for the patient. The use of these agents as part of triple antiplatelet therapy may therefore not be supported when there is a concern for increased bleeding risk or in non high-risk subsets such as those with a normal baseline troponin level, those without diabetes, and those aged 75 years, in whom the potential benefit may be significantly offset by the potential risk of bleeding (Tables 2 and 3). 3.3. Initial Invasive Versus Initial Conservative Strategies: Recommendations (See Table 4, and Appendixes 5 and 6 for supplemental information.) 3.3.3.1. Timing of Invasive Therapy Among initially stabilized patients with UA/NSTEMI for whom an early invasive strategy of coronary angiography is chosen, optimal timing of angiography has not been well defined. Early or immediate catheterization with revascularization of unstable coronary lesions may prevent ischemic events that would oth- erwise occur during medical therapy. Conversely, pretreatment with intensive antithrombotic therapy may diminish thrombus burden and passivate unstable plaques, improving the safety of percutaneous revascularization and reducing the risk of peripro- cedural ischemic complications. Three trials have compared different strategies of early versus delayed intervention in patients with UA/NSTEMI and form the basis of the updated recommendations in this guideline. The ISAR-COOL (Intracoronary Stenting with Antithrom- botic Regimen Cooling-Off) trial122 carried out at 2 hospitals between 2000 and 2002 randomized 410 patients with unstable chest pain and either electrocardiographic ST-segment depres- sion or elevated troponin levels to undergo coronary angiogra- phy within 6 hours of presentation (median 2.4 hours) or after 3 to 5 days (median 86 hours) of antithrombotic pretreatment.122 Patients with large MI, defined by ST-segment elevation or creatine kinase myocardial band isoenzyme activity 3 times normal, were excluded. Underlying medical therapy in both treatment arms included aspirin, clopidogrel, UFH, and tiro- fiban. By 30 days follow-up, the primary endpoint of death or large MI (defined by new electrocardiographic Q waves, left bundle-branch block, or creatine kinase myocardial band eleva- tion 5 times normal) occurred in 11.6% of patients randomized to delayed catheterization versus 5.9% of those in the early angiography group (P 0.04). Differences between treatment groups were observed exclusively in the period before catheter- ization, with identical event rates in the 2 arms after angiogra- phy. Although providing evidence that a strategy of cooling- off for 3 to 5 days before angiography does not improve outcome in this setting, the findings of this trial were limited because of the small sample size and the prolonged delay before angiography in the medical pretreatment arm. Information more relevant to contemporary practice pat- terns was provided in the 2009 publication of the large-scale multicenter TIMACS (Timing of Intervention in Acute Cor- onary Syndromes) trial,107 which compared early versus delayed angiography and intervention in patients with non Jneid et al 2012 UA/NSTEMI Focused Update 885 Table 2. Recommendations for Antiplatelet Therapy 2012 Focused Update Recommendations 2012 Comments Class I 1. Aspirin should be administered to UA/NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it.59 66 (Level of Evidence: A) 2011 recommendation remains current. 2. A loading dose followed by daily maintenance dose of either clopidogrel13,67,68 (Level of Evidence: B), prasugrel* (in PCI-treated patients)7 (Level of Evidence: C), or ticagrelor 9 (Level of Evidence: C) should be administered to UA/NSTEMI patients who are unable to take aspirin because of hypersensitivity or major GI intolerance. modified (included prasugrel and ticagrelor). 3. Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected (Appendix 6) should receive dual antiplatelet therapy on presentation.13,16,45,69 (Level of Evidence: A) Aspirin should be initiated on presentation.59,61 66 (Level of Evidence: A) The choice of a second antiplatelet therapy to be added to aspirin on presentation includes 1 of the following (note that there are no data for therapy with 2 concurrent P2Y12 receptor inhibitors, and this is not recommended in the case of aspirin allergy): modified (included ticagrelor). Before PCI: Clopidogrel13,16 (Level of Evidence: B); or Ticagrelor 9 (Level of Evidence: B); or An IV GP IIb/IIIa inhibitor.45,50,51,70,71 (Level of Evidence: A) IV eptifibatide and tirofiban are the preferred GP IIb/IIIa inhibitors.50,51 (Level of Evidence: B) At the time of PCI: Clopidogrel if not started before PCI13,16 (Level of Evidence: A); or Prasugrel*7 (Level of Evidence: B); or Ticagrelor 9 (Level of Evidence: B); or An IV GP IIb/IIIa inhibitor.46,50,51 (Level of Evidence: A) 4. 