2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline)

2011 Writing Group Members; R. Scott Wright; Jeffrey L. Anderson; Cynthia D. Adams; Charles R. Bridges; Donald E. Casey; Steven M. Ettinger; Francis M. Fesmire; Theodore G. Ganiats; Hani Jneid; A. Michael Lincoff; Eric D. Peterson; George J. Philippides; Pierre Theroux; Nanette K. Wenger; James Patrick Zidar

doi:10.1161/CIR.0b013e31820f2f3e

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Table of Contents

Preamble. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2023
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2026
1.1. Methodology and Evidence Review. . . . . . . . . . . . . . . .2026
1.2. Organization of Committee. . . . . . . . . . . . . . . . . . . . .2026
1.3. Document Review and Approval. . . . . . . . . . . . . . . . . .2026
3. Early Hospital Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . .2026
3.2. Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite. . . . . . . . . . . . . . . . . . . . . . . . . . .2026
3.2.1. Recommendations for Antiplatelet Therapy. . . . . .2026
3.2.3. Recommendations for Additional Management of Antiplatelet and Anticoagulant Therapy. . . . . .2026
3.2.3.1. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite. . . . . . . . . . . . . . . . . . . . . . . . .2026
3.2.3.1.1. Thienopyridines. . . . . . . . . . . .2026
3.2.3.1.2. Choice of Thienopyridine for PCI in UA/NSTEMI. . . . . . . . .2031
3.2.3.1.2.1. Timing of Discontinuation of Thienopyridine Therapy for Surgical Procedures. . . . . . . .2031
3.2.3.1.3. Interindividual Variability in Responsiveness to Clopidogrel. . . . . . . . . . . . .2031
3.2.3.1.4 Optimal Loading and Maintenance Dosages of Clopidogrel. . . . . . . . . . . . .2032
3.2.3.1.5. Proton Pump Inhibitors and Dual-Antiplatelet Therapy for Acute Coronary Syndrome. . . . . . . . .2032
3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists. . . . . . . . .2033
3.3. Recommendations for Initial Conservative Versus Initial Invasive Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . .2034
3.3.3.1. Timing of Invasive Therapy. . . . . . . . . . . .2034
5. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care. . . . . . . . . . . .2036
5.2. Long-Term Medical Therapy and Secondary Prevention. . .2036
5.2.1. Recommendations for Convalescent and Long-Term Antiplatelet Therapy. . . . . . . . . . . . . . . . . . . . . .2036
5.2.6. Recommendations for Warfarin Therapy. . . . . . . . .2036
6. Special Groups. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2036
6.2. Recommendations for Diabetes Mellitus. . . . . . . . . . . . .2036
6.2.1.1. Intensive Glucose Control. . . . . . . . . . . . . .2036
6.5. Recommendations for Chronic Kidney Disease. . . . . . . . .2039
6.5.1. Angiography in Patients With Chronic Kidney Disease. . .2039
7. Conclusions and Future Directions. . . . . . . . . . . . . . . . . . . .2040
7.1. Recommendation for Quality of Care and Outcomes for Acute Coronary Syndromes (New Section) . . . . . . . .2040
7.1.1. Quality Care and Outcomes. . . . . . . . . . . . . . . . .2041
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2041
Appendix 1. Author Relationships With Industry and Other Entities. . . .2047
Appendix 2. Reviewer Relationships With Industry and Other Entities . .2048
Appendix 3. Abbreviation List . . . . . . . . . . . . . . . . . . . . . . . .2051
Appendix 4. Dosing Table for Antiplatelet and Anticoagulant Therapy Discussed in This Focused Update to Support PCI in NSTEMI. . . . . . . . . . . . . . . . . . .2052
Appendix 5. Comparisons Among Orally Effective P2Y12 Inhibitors. . .2053
Appendix 6. Flow Chart for Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI. . . . . . . . . . . .2054
Appendix 7. Summary Table. . . . . . . . . . . . . . . . . . . . . . . . .2055
Appendix 8. Selection of Initial Treatment Strategy: Invasive Versus Conservative Strategy. . . . . . . . . . . . . . . . .2060

Preamble

A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based. In an effort to respond promptly to new evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/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. Before the initiation of this focused approach, periodic updates and revisions of existing guidelines required up to 3 years to complete. Now, however, new evidence willbe 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 will be reviewed at least twice a year, and updates will be 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 updated guideline recommendations reflect a consensus of expert opinion after a thorough review, primarily of late-breaking clinical trials identified through a broad-based vetting process as being important to the relevant patient population, as well as other new data deemed to have an impact on patient care (see Section 1.1, Methodology and Evidence Review, for details). This focused update is not intended to represent an update based on a full literature review from the date of the previous guideline publication. Specific criteria/considerations 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
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 relationships with industry or other potential bias
Number of previous trials showing consistent results
Need for consistency with a new guideline or guideline revisions

In analyzing the data and developing the recommendations and supporting text, the focused update writing group used evidence-based methodologies developed by the Task Force that are described elsewhere.¹

The committee reviewed and ranked evidence supporting current recommendations, with the weight of evidence ranked as Level A if the data were derived from multiple randomized clinical trials or meta-analyses. The committee ranked available evidence as Level B when data were derived from a single randomized trial or nonrandomized studies. Evidence was ranked as Level C when the primary source of the recommendation was consensus opinion, case studies, or standard of care. In the narrative portions of these guidelines, evidence is generally presented in chronological order of development. Studies are identified as observational, retrospective, prospective, or randomized when appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and ranked as Level C. An example is the use of penicillin for pneumococcal pneumonia, for which there are no randomized trials and treatment is based on clinical experience. When recommendations at Level C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues where sparse data are available, a survey of current practice among the clinicians on the writing committee was the basis for Level C recommendations and no references are cited. The schema for classification of recommendations and level of evidence is summarized in Table 1, which also illustrates how the grading system provides an estimate of the size and the certainty of the treatment effect. A new addition to the ACCF/AHA methodology is a separation of the Class III recommendations to delineate whether the recommendation is determined to be of “no benefit” or 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 Class I and IIa, Level A or B only have been added.

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Table 1.

Applying Classification of Recommendation and Level of Evidence

The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of relationships with industry and other entities (RWI) among the writing group. Specifically, all members of the writing group, as well as peer reviewers of the document, are asked to disclose all current relationships and those existing 12 months before initiation of the writing effort. In response to implementation of a newly revised RWI policy approved by the ACC and AHA, it is also required that the writing group chair plus a majority of the writing group (50%) have no relevant RWI. All guideline recommendations require a confidential vote by the writing group and must be approved by a consensus of the members voting. Members who were recused from voting are noted on the title page of this document and in Appendix 1. Members must recuse themselves from voting on any recommendation to which their RWI apply. Any writing group member who develops a new RWI during his or her tenure is required to notify guideline staff in writing. These statements are reviewed by the Task Force and all members during each conference call and/or meeting of the writing group and are updated as changes occur. For detailed information about guideline policies and procedures, please refer to the ACCF/AHA methodology and policies manual.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' comprehensive disclosure information—including RWI not pertinent to this document—is available online as a supplement to this document. Disclosure information for the Task Force is also available online at www.cardiosource.org/ACC/About-ACC/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The work of the writing group was supported exclusively by the ACCF and AHA without commercial support. Writing group members volunteered their time for this effort.

The ACCF/AHA practice guidelines address patient populations (and healthcare providers) residing in North America. As such, drugs that are currently unavailable in North America are discussed in the text without a specific class of recommendation. For studies performed in large numbers of subjects outside of North America, each writing group reviews the potential impact of different practice patterns and patient populations on the treatment effect and the 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 for the diagnosis, management, and prevention of specific diseases or conditions. These practice guidelines represent a consensus of expert opinion after a thorough review of the available current scientific evidence and are intended to improve patient care. 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. Thus, there are circumstances in which deviations from these guidelines may be appropriate. Clinical decision making should consider the quality and availability 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 better inform patient care; 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.

The recommendations in this focused update will be considered current until they are superseded by another focused update or the full-text guidelines are revised. This focused update is published in the Journal of the American College of Cardiology and Circulation as an update to the full-text guideline,² and it is also posted on the ACC (www.cardiosource.org) and AHA (my.americanheart.org) World Wide Web sites. A revised version of the full-text guideline with links to the focused update is e-published in the May 3, 2011, issues of the Journal of the American College of Cardiology and Circulation. For easy reference, this online-only version denotes sections that have been updated.

1. Introduction

1.1. Methodology and Evidence Review

Late-breaking clinical trials presented at the 2008 and 2009 annual scientific meetings of the ACC, AHA, and European Society of Cardiology, as well as selected other data through April 2010, were reviewed by the standing guideline writing committee along with the parent Task Force and other experts to identify those trials and other key data that may impact guideline recommendations. On the basis of the criteria/considerations noted above, recent trial data and other clinical information were considered important enough to prompt a focused update of the 2007 ACC/AHA Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (UA/NSTEMI).²

To provide clinicians with a comprehensive set of data, whenever deemed appropriate or when published, the absolute risk difference and number needed to treat or harm will be provided in the guideline, along with the confidence interval (CI) and data related to the relative treatment effects such as odds ratio (OR), relative risk (RR), hazard ratio (HR), or 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 Infarction² for policy on clinical areas not covered by the focused update. 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 Committee

For this focused update, all eligible members of the 2007 UA/NSTEMI writing committee were invited to participate; those who agreed (referred to as the 2011 focused update writing group) were required to disclose all RWI relevant to the data under consideration. The committee comprised representatives from ACCF, AHA, American Academy of Family Physicians, American College of Emergency Physicians, American College of Physicians, Society for Cardiovascular Angiography and Interventions, and Society 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 Academy of Family Physicians, American College of Emergency Physicians, American College of Physicians, Society for Coronary Angiography and Interventions, and Society of Thoracic Surgeons, and 25 individual content reviewers, including members of the ACCF Interventional Scientific Council and ACCF Surgeon's 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 American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.

3. Early Hospital Care

3.2. Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite

3.2.1. Recommendations for Antiplatelet Therapy

(See Table 2, and Appendixes 3 to 8 for supplemental information.)

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Table 2.

Recommendations for Early Hospital Care Antiplatelet Therapy

3.2.3. Recommendations for Additional Management of Antiplatelet and Anticoagulant Therapy

(See Table 3, and Appendixes 3 to 8 for supplemental information.)

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Table 3.

Recommendations for Additional Management of Antiplatelet and Anticoagulant Therapy

3.2.3.1. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite

3.2.3.1.1. Thienopyridines.

Thienopyridine 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 guidelines recommended the use of clopidogrel in patients with UA/NSTEMI because it was the only US Food and Drug Administration (FDA)–approved thienopyridine agent at that time. Since the publication of the last guidelines,² the FDA has approved a second thienopyridine agent for use in patients with UA/NSTEMI. The FDA approved the use of prasugrel based on data from a head-to-head comparison with clopidogrel, in which prasugrel was superior in reductions in clinical events but at the expense of an increased risk of bleeding.

The pivotal trial²² for prasugrel, TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction), focused on patients with acute coronary syndrome (ACS) who were referred for percutaneous coronary intervention (PCI). TRITON-TIMI 38 randomly assigned 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 (ASA) 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.

Prasugrel was associated with a significant 2.2% absolute 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. The primary efficacy endpoint occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel (HR for prasugrel versus clopidogrel: 0.81; 95% CI: 0.73 to 0.90; P<0.001).²² Prasugrel decreased cardiovascular 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; 95% CI: 0.67 to 0.85; P<0.001). Rates of cardiovascular death (2.1% versus 2.4%; P=0.31) and nonfatal stroke (1.0% versus 1.0%; P=0.93) were not reduced by prasugrel 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 observed in 2.4% of patients taking prasugrel and in 1.8% of patients taking clopidogrel (HR for prasugrel versus clopidogrel: 1.32; 95% CI: 1.03 to 1.68; P=0.03). The increased RR of major bleeding was 32%. Prasugrel was associated with a significant increase in fatal bleeding (0.4%) compared with clopidogrel (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).²² Also, greater rates of life-threatening bleeding were evident in the prasugrel group than in the clopidogrel group: 1.4% versus 0.9%, respectively (HR for prasugrel: 1.52; 95% CI: 1.08 to 2.13; P=0.01). In the few 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 prasugrel: 4.73; 95% CI: 1.90 to 11.82; P<0.001).²² The net clinical benefit in the TRITON-TIMI 38 study demonstrated a primary efficacy and safety endpoint rate of 13.9% in the clopidogrel group versus 12.2% in the prasugrel group (HR: 0.87; 95% CI: 0.79 to 0.95; 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; 95% CI: 1.02 to 2.32; P=0.04); patients ≥75 years of age had 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 without them.²²

The FDA cited a contraindication against use of prasugrel in patients with a history of transient ischemic attack or stroke or with active pathological bleeding.³⁵ The FDA labeling information includes a general warning against the use of prasugrel in patients ≥75 years of age because of concerns of an increased risk of fatal and intracranial 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.³⁵ In focusing specifically on patients with UA/NSTEMI, the rate of the primary efficacy endpoint was significantly reduced in favor of prasugrel (9.9% versus 12.1%; adjusted HR: 0.82; 95% CI: 0.73 to 0.93; P=0.002).²²

The writing group cautions that data on the use of prasugrel come solely from the TRITON-TIMI 38 trial, and its use in clinical practice should carefully follow how it was tested in that study.²² Prasugrel was administered only after a decision to proceed to PCI was made. It is not our recommendation that prasugrel be administered routinely before angiography, such as in an emergency department, or be used in patients who have not undergone PCI. The FDA package 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.³⁵ The writing group acknowledges this flexibility, but it is not our intention to make specific recommendations about which subgroups of patients might benefit from prasugrel instead of clopidogrel. We do wish to caution clinicians about the potential bleeding risks from prasugrel compared with clopidogrel, especially among the subgroups identified in the package insert.^22,35

3.2.3.1.2. Choice of Thienopyridine for PCI in UA/NSTEMI.

These guidelines do not explicitly endorse one of the thienopyridines over the other. There were several reasons for this decision. Although the composite efficacy endpoint favored prasugrel, driven predominantly by a difference in nonfatal MIs, with deaths and nonfatal strokes being similar, bleeding was increased in the prasugrel group.²² In addition, the comparison of the 2 drugs is based on a single large trial. Also, the loading dose of clopidogrel in TRITON-TIMI 38 was lower than is currently recommended in these guidelines.²² Furthermore, some emerging studies suggest there may be some patients who are resistant to clopidogrel, but there is little information about the use of strategies to select patients who might do better with prasugrel. 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 thienopyridine for individual patients.⁸⁶

There may be other options for oral antiplatelet efficacy in the not too distant future. Ticagrelor is a reversible nonthienopyridine P2Y₁₂ receptor antagonist that has been tested in a head-to-head comparison with clopidogrel in PLATO (Study of Platelet Inhibition and Patient Outcomes).⁸⁷ It is not a prodrug like clopidogrel and prasugrel and thus does not require bioactivation.^87,88 Ticagrelor reduced the risks of death and MI but at the expense of an increase in nonprocedural bleeding.⁸⁷ Ticagrelor was not FDA approved or marketed at the time of writing of this update; hence, we could not recommend it for use in patients with UA/NSTEMI, although it may have a future role in patients with UA/NSTEMI.

3.2.3.1.2.1. Timing of Discontinuation of Thienopyridine Therapy for Surgical Procedures.

The writing group weighed the current data on the use of thienopyridine therapy in patients who remain hospitalized after UA/NSTEMI and are candidates for CABG and retained the 2007 recommendation² of empirical discontinuation of clopidogrel therapy for at least 5 days¹³ and advocated a period of at least 7 days in patients receiving prasugrel for its discontinuation before planned CABG.³⁵ Ultimately, the patient's clinical status will determine the risk-to-benefit ratio of CABG compared with awaiting restoration of platelet function.

3.2.3.1.3. Interindividual Variability in Responsiveness to Clopidogrel.

Although clopidogrel in combination with ASA has been shown to reduce recurrent coronary events in the posthospitalized ACS population,^13,17 the response to clopidogrel varies among patients, and diminished responsiveness to clopidogrel has been observed.^89,90 Clopidogrel is a prodrug and requires conversion to R130964, its active metabolite, through a 2-step process in the liver that involves several CYP450 isoenzymes⁸¹; of these, the CYP2C19 isoenzyme is responsible for almost half of the first step formation.⁷⁸ At least 3 major genetic polymorphisms of the CYP2C19 isoenzyme are associated with loss of function: CYP2C19*1, *2, and *3.^78–80 The CYP2C19*2 and *3 variants account for 85% and 99% of the loss-of-function alleles in Caucasians and Asians, respectively.⁷⁸ There are 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 demonstrated an association between an increased risk of adverse cardiovascular events and the presence of ≥1 of the nonfunctioning alleles^{79,81,83,84,89–93} and are well delineated in the ACCF/AHA Clopidogrel Clinical Alert.⁷⁸

Prasugrel, the second FDA-approved thienopyridine 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.^94,95

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,⁸⁶ 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 effectiveness for inhibition of platelet activity. The ACCF/AHA Clopidogrel Clinical Alert expertly summarizes the issues surrounding clopidogrel and the use of genotype testing, as well as the potential for routine platelet function testing.⁷⁸

The FDA label revision does not mandate testing for CYP2C19 genotypes or overall platelet function.⁸⁶ The revision serves to warn clinicians that certain patient subgroups may exhibit reduced clopidogrel-mediated platelet inhibition and emphasizes that clinicians should be aware of alternative treatment strategies to tailor alternative therapies 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. At least 11 ongoing studies are examining whether genotype assessment 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,⁷⁸ 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 studies being conducted now are testing the hypothesis that routine platelet function testing should be used to tailor antiplatelet therapy, and any strong recommendation regarding 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 recommendations 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.⁷⁸ The Class IIb classification of these strategies suggests that a selective, 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.⁷⁸ 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–Organization 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.^28,96 The CURRENT-OASIS trial randomized 25 086 patients with ACS who were intended for PCI and who were not considered 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 ASA (300 to 325 mg daily) with low-dose ASA (75 to 100 mg daily). All patients received ≥300 mg of ASA on Day 1 regardless of randomization after Day 1. The primary endpoint of the trial was the combination of cardiovascular death, myocardial (re)infarction, or stroke at 30 days. Although the overall trial⁹⁶ failed to demonstrate a significant difference in the primary endpoint between the clopidogrel and ASA groups (4.2% versus 4.4%), the PCI subset (n=17 263) did show significant differences in the clopidogrel arm.²⁸ 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 drug-eluting stent versus non–drug-eluting stent subtypes. Higher-dose clopidogrel therapy increased major bleeding in the entire group (2.5% versus 2.0%; P=0.012) and the PCI subgroup (1.1% versus 0.7%; P=0.008). The benefit of higher-dose clopidogrel loading was offset by an increase in major bleeding.⁹⁶

As noted in the Dosing Table (Appendix 4), 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 Acute Coronary Syndrome.

Proton pump inhibitor (PPI) medications* have been found to interfere with the metabolism of clopidogrel. When clopidogrel is started, PPIs are often prescribed prophylactically to prevent gastrointestinal complications such as ulceration and related bleeding⁹⁷ due to dual-antiplatelet therapy, in particular ASA and clopidogrel.⁹⁰ Coupled with concern about the gastrointestinal precautions, there has been increased emphasis on the prevention of premature discontinuation of dual-antiplatelet therapy, particularly in patients who have received a drug-eluting stent for whom 12 months of antiplatelet therapy is recommended.⁹⁸

There have been retrospective reports of adverse cardiovascular outcomes (eg, readmission for ACS) when the antiplatelet regimen of clopidogrel and ASA is accompanied by PPIs assessed as a group compared with use of this regimen without a PPI.^90,99,101 In a retrospective cohort study 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.⁹⁰ Other post hoc study analyses^83,102 and a retrospective data analysis from the National Heart, Lung, and Blood Institute Dynamic Registry,¹⁰³ in which PPIs were assessed as a class in combination with a clopidogrel and an ASA 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, respectively.^83,103

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, lansoprazole, or rabeprazole. Notably, the PPI omeprazole has been reported to significantly decrease the inhibitory effect of clopidogrel on platelet aggregation.^104,105 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 2C19.⁹⁹

Other studies have examined the thienopyridine agent 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 combination of clopidogrel and lansoprazole, whereas platelet aggregation was unaffected after a prasugrel dose.¹⁰⁶

Another study¹⁰¹ 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 trial¹⁰⁷ and the TRITON-TIMI 38 trial.²² The findings indicated that first, PPI treatment attenuated the pharmacodynamic 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 a preliminary report of a randomized study (the COGENT [Clopidogrel and the Optimization of Gastrointestinal Events] study¹⁰⁸; see Appendix 7), omeprazole was compared with placebo in 3627 patients starting dual-antiplatelet therapy with ASA and clopidogrel. No difference was found in the primary composite cardiovascular endpoint between clopidogrel plus omeprazole and clopidogrel plus placebo (HR: 1.02), but gastrointestinal bleeding complications were reduced.¹⁰⁸ Clearly, 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 bisulfate⁸⁶ 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 omeprazole (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.⁸⁶ Most recently, the ACC has released a statement on the use of PPI agents in combination with clopidogrel. The expert consensus 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 clopidogrel.¹⁴

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.^{18–21,109–115} 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 supported the upstream use of a GP IIb/IIIa inhibitor as a second agent in combination with ASA 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.^{19,20,25,110,111,113} These studies did not directly test in a randomized fashion the selection of an oral thienopyridine versus an intravenous 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 ASA and a thienopyridine.

The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome) trial³⁷ 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 to12 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–MB 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 investigators' discretion (75% intended early use), and if used, a loading dose of 300 mg was recommended. For patients beginning 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 administer early clopidogrel (ie, at or before randomization).³⁷

The primary endpoint (a 30-day composite of all-cause death, MI, recurrent ischemia requiring urgent revascularization, 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; 95% CI: 0.80 to 1.06; P=0.23). Secondary endpoint (all-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 characteristics, including early clopidogrel administration, and the primary 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 Catheterization and Urgent Intervention Triage strategY) trial,¹⁶ 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 occurred in 7.1% of the patients assigned to upstream administration and in 7.9% of patients assigned to deferred selective administration (RR: 1.12; 95% CI: 0.97 to 1.29; P=0.13),¹⁶ and thus the noninferiority hypothesis was not achieved. Major bleeding was lower in the deferred-use group versus the upstream 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,^{27,37,112,114,115} these 2 most recent studies more strongly support a strategy of selective rather than provisional use of GP IIb/IIIa inhibitor therapy as part of triple-antiplatelet therapy. Data from EARLY ACS³⁷ 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 ≥75 years of age, in whom the potential benefit may be significantly offset by the potential risk of bleeding.

3.3. Recommendations for Initial Conservative Versus Initial Invasive Strategies

(See Table 4, and Appendixes 3, 6, and 8 for supplemental information.)

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Table 4.

Recommendations for Initial Invasive Versus Initial Conservative Strategies

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 otherwise 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 periprocedural 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 recommendation in this guideline.

The ISAR-COOL (Intracoronary Stenting with Antithrombotic Regimen Cooling-Off) trial¹¹⁹ carried out at 2 hospitals between 2000 and 2002 randomized 410 patients with unstable chest pain and either electrocardiographic ST-segment depression or elevated troponin levels to undergo coronary angiography within 6 hours of presentation (median 2.4 hours) or after 3 to 5 days (median 86 hours) of antithrombotic pretreatment.¹¹⁹ Patients with “large MI,” defined by ST-segment elevation or creatine kinase–MB isoenzyme activity >3 times normal, were excluded. Underlying medical therapy in both treatment arms included ASA, clopidogrel, UFH, and tirofiban. 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–MB elevation >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 catheterization, with identical event rates in the 2 arms after angiography. 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 patterns was provided in the 2009 publication of the large-scale multicenter TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial,³⁸ which compared early versus delayed angiography and intervention in patients with non–ST-segment elevation ACS. Patients were included if they presented within 24 hours of onset of unstable ischemic symptoms with advanced age (≥60 years), elevated cardiac biomarkers, or ischemic electrocardiographic changes, and were randomized to undergo angiography as rapidly as possible and within 24 hours of randomization (median 14 hours) versus after a minimum delay of 36 hours (median 50 hours). Anticoagulation included ASA, clopidogrel in >80% of patients, heparin or fondaparinux, and GP IIb/IIIa inhibitors in 23% of patients. Although the trial was initially powered for enrollment of 4000 patients to detect a 25% reduction in the primary endpoint of death, new MI, or stroke at 6 months, the steering committee chose to terminate enrollment at 3031 patients because of recruitment challenges. Among the overall trial population, there was only a nonsignificant trend toward a reduced incidence of the primary clinical endpoint, from 11.3% in the delayed intervention group to 9.6% in the early intervention arm (for early intervention: 0.85; 95% CI: 0.68 to 1.06; P=0.15). However, a prospectively defined secondary endpoint of death, MI, or refractory ischemia was significantly reduced by early intervention from 12.9% to 9.5% (HR: 0.72; 95% CI: 0.58 to 0.89; P=0.003), mainly because of a difference in the incidence of refractory ischemia (3.3% versus 1.0% in the delayed versus early intervention arms, respectively; P<0.001). The occurrence of refractory ischemia was associated with a >4-fold increase in risk of subsequent MI. Moreover, significant heterogeneity was observed in the primary endpoint when stratified according to a prespecified estimation of baseline risk according to the Global Registry of Acute Coronary Events (GRACE) score. Patients in the highest tertile of the GRACE risk score (>140) experienced a sizeable and significant reduction in the incidence of the primary ischemic endpoint, from 21.0% to 13.9% (HR: 0.65; 95% CI: 0.48 to 0.89; P=0.006), whereas no difference in outcome (6.7% versus 7.6% in the delayed and early groups, respectively; HR: 1.12; 95% CI: 0.81 to 1.56; P=0.48) was observed among patients in the lower 2 risk tertiles (GRACE score ≤140).³⁸

Results of the TIMACS trial suggested superior outcome among patients managed by early rather than delayed intervention in the setting of UA/NSTEMI, although the reduction in the primary endpoint did not reach statistical significance for the overall trial population. Nevertheless, refractory ischemia was reduced by an early approach, as were the risks of death, MI, and stroke among patients at the highest tertile of ischemic risk as defined by the GRACE risk score.³⁸

To assess whether a more aggressive strategy of very early intervention, analogous to the standard of primary PCI for STEMI, would lead to improved outcomes in patients with non–ST-elevation ACS, the ABOARD (Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes) study investigators¹²⁰ compared angiography and intervention performed immediately on presentation with intervention carried out on the next working day. A total of 352 patients with unstable ischemic symptoms, ECG changes, or troponin elevation were randomized at 13 hospitals to immediate (at a median 70 minutes after enrollment) versus delayed (at a median 21 hours) angiography and revascularization. Background antithrombotic therapy consisted of ASA, clopidogrel with a loading dose of ≥300 mg, abciximab during PCI, and the anticoagulant of the investigator's choice. The primary trial endpoint was peak troponin I value during the hospitalization period. Immediate intervention conferred no advantage with regard to the primary endpoint (median troponin I value 2.1 versus 1.7 ng/mL in the immediate and delayed intervention groups, respectively), nor was there even a trend toward improved outcome in the prespecified clinical secondary endpoint of death, MI, or urgent revascularization by 1 month (13.7% versus 10.2%, in the immediate and delayed intervention groups, respectively; P=0.31).¹²⁰

These 3 trials, taken together with earlier studies, do provide support for a strategy of early angiography and intervention to reduce ischemic complications in patients who have been selected for an initial invasive strategy, particularly among those at high risk (defined by a GRACE score >140), whereas a more delayed approach is reasonable in low- to intermediate-risk patients. The “early” time period in this context is considered to be within the first 24 hours after hospital presentation, although there is no evidence that incremental benefit is derived by angiography and intervention performed within the first few hours of hospital admission. The advantage of early intervention was achieved in the context of intensive background antithrombotic therapy.

5. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care

5.2. Long-Term Medical Therapy and Secondary Prevention

5.2.1. Recommendations for Convalescent and Long-Term Antiplatelet Therapy

(See Table 5, and Appendixes 3 and 4 for supplemental information.)

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Table 5.

Recommendations for Convalescent and Long-Term Antiplatelet Therapy

5.2.6. Recommendations for Warfarin Therapy

(See Table 6 and Appendix 3.)

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Table 6.

Recommendations for Warfarin Therapy

6. Special Groups

6.2. Recommendations for Diabetes Mellitus

(See Table 7 and Appendix 3.)

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Table 7.

Recommendations for Diabetes Mellitus

6.2.1.1. Intensive Glucose Control

As detailed in the 2004 STEMI guideline,¹⁴⁷ 2007 UA/NSTEMI guideline revision,² and 2009 STEMI and PCI focused update,³² randomized trial evidence supported use of insulin infusion to control hyperglycemia. A clinical trial of intensive versus conventional glucose control in critically ill patients raised uncertainty about the optimal level to target when achieving glucose control. NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation), a large international randomized trial (n=6104) of adults admitted to the intensive care unit with either medical or surgical conditions, compared intensive glucose control (target glucose range, 81 to 108 mg/dL) with conventional glucose control (to achieve a glucose level of <180 mg/dL, with reduction and discontinuation of insulin if the blood glucose level dropped below 144 mg/dL).¹⁴³ Time-weighted glucose levels achieved were 115±18 mg/dL in the intensive group versus 144±23 mg/dL in the conventional group. The risk of death was increased at 90 days in the intensive group by 2.6% (27.5% versus 24.9%; OR: 1.14; 95% CI: 1.02 to 1.08; P=0.02; number needed to harm=38). The result remained the same after adjusting for potential confounders. There were significantly more episodes of treatment-related hypoglycemia in the intensely managed group (6.8% versus 0.5%; P=0.001), although the contribution of hypoglycemia to excess mortality is uncertain.^143,144 Overall, the hospital course and proximate causes of death were similar in the 2 groups. Excess deaths in the intensive management group were predominantly of cardiovascular causes (absolute difference: 5.8%; P=0.02). More patients in the intensive group than in the conventional group were treated with corticosteroids.

Because NICE-SUGAR¹⁴³ enrolled critically ill medical and surgical patients, the degree to which its results can be extrapolated to the management of patients with UA/NSTEMI is unclear. Although recent data from a small, mechanistic clinical trial^148,149 suggest that glucose control may reduce inflammation and improve left ventricular ejection fraction (LVEF) in patients with acute MI, it remains uncertain whether acute glucose control will improve patient outcomes.

A consensus statement by the American Association of Clinical Endocrinologists and the American Diabetes Association¹⁵⁰ summarized that “although hyperglycemia is associated with adverse outcomes after acute MI, reduction of glycemia per se and not necessarily the use of insulin is associated with improved outcomes. It remains unclear, however, whether hyperglycemia is a marker of underlying health status or is a mediator of complications after acute MI. Noniatrogenic hypoglycemia has also been associated with adverse outcomes and is a predictor of higher mortality.”

There is a clear need for a well-designed, definitive randomized trial of target-driven glucose control in UA/NSTEMI patients with meaningful clinical endpoints so that glucose treatment thresholds and glucose targets can be determined. Until such a trial is completed, and on the basis of the balance of current evidence,^150–152 the writing group concluded that it was prudent to change the recommendation for the use of insulin to control blood glucose in UA/NSTEMI from a more stringent to a more moderate target range in keeping with the recent 2009 STEMI and PCI Focused Update (Class IIa, Level of Evidence: B)³² and recommend treatment for hyperglycemia >180 mg/dL while avoiding hypoglycemia. The writing group believed that the 2007 recommendation² regarding long-term glycemic control targets failed to reflect recent data casting doubt on a specific ideal goal for the management of diabetes in patients with UA/NSTEMI.

Diabetes is another characteristic associated with high risk for adverse outcomes after UA/NSTEMI. The 2007 UA/NSTEMI guidelines² state that patients with diabetes are at high risk and in general should be treated similarly to patients with other high-risk features. However, the 2011 writing group noted that diabetes was not listed as a high-risk feature for which an invasive strategy was specifically preferred, in contrast to the inclusion of chronic kidney disease (CKD) and diabetes mellitus as characteristics favoring an invasive approach in the 2007 European Society of Cardiology guidelines for management of UA/NSTEMI.¹⁵³ To revisit this question for diabetes, the writing group reviewed results of the published analysis of patients with diabetes in the FRISC-II (FRagmin and Fast Revascularization during InStability in Coronary artery disease) trial.²⁶ Overall, the FRISC II trial demonstrated a benefit with invasive management compared with conservative management in patients with UA/NSTEMI. There were similar reductions in the risk of MI/death at 1 year in the diabetic subgroup randomized to an invasive strategy (OR: 0.61 [0.36 to 1.04]) compared with patients who did not have diabetes randomized to an invasive strategy (OR: 0.72 [0.54 to 0.95]). The risk of death was also reduced by randomization to an invasive strategy among patients with diabetes (OR: 0.59 [95% CI: 0.27 to 1.27]) and without diabetes (OR: 0.50 [95% CI: 0.27 to 0.94]). Subgroup analysis of the TACTICS-TIMI-18 (Treat Angina with aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction 18) study in patients with diabetes, available in abstract form, was consistent with this finding.¹⁵⁴ Thus, diabetes, as well as the often concurrent comorbidity of CKD (Section 6.5, “Recommendations for Chronic Kidney Disease”), is not only a high-risk factor but also benefits from an invasive approach. Accordingly, diabetes has been added to the list of characteristics for which an early invasive strategy is generally preferred (Appendix 8).

6.5. Recommendations for Chronic Kidney Disease

(See Table 8, and Appendixes 3 and 7 for supplemental information.)

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Table 8.

Recommendations for Chronic Kidney Disease

6.5.1. Angiography in Patients With Chronic Kidney Disease

Since the 2007 UA/NSTEMI Guidelines were published,² several larger randomized trials have been published that reported no difference in contrast-induced nephropathy (CIN) when iodixanol was compared with various other low-osmolar contrast media (LOCM).^163–166 These and other randomized trials comparing isosmolar iodixanol with LOCM have been summarized in 2 mutually supportive and complementary meta-analyses involving 16 trials in 2763 patients¹⁶⁷ and 25 trials in 3260 patients,¹⁶⁸ respectively. When more recent trials were combined with the older studies, the data supporting a reduction in CIN favoring iodixanol were no longer significant (summary RR: 0.79; 95% CI: 0.56 to 1.12; P=0.29¹⁶⁷; summary RR: 0.80; 95% CI: 0.61 to 1.04; P=0.10,¹⁶⁸ respectively). However, subanalyses showed variations in relative renal safety by specific LOCM: A reduction in CIN was observed when iodixanol was compared to ioxaglate, the only ionic LOCM (RR: 0.58; 95% CI: 0.37 to 0.92; P=0.022¹⁶⁷), and to iohexol, a nonionic LOCM (RR: 0.19; 95% CI: 0.07 to 0.56; P<0.0002¹⁶⁷), but no difference was noted in comparisons of iodixanol with iopamidol, iopromide, or ioversol,¹⁶⁷ and a single trial favored iomeprol.¹⁶⁶ A pooled comparison of iodixanol with all nonionic LOCM other than iohexol indicated equivalent safety (RR: 0.97; 95% CI: 0.72 to 1.32; P=0.86¹⁶⁸). Results were consistent regardless of ancillary preventive therapies (hydration, acetylcysteine), route of administration (intravenous or intra-arterial), age, sex, dose, or preexisting CKD or diabetes. Of further interest, findings were similar in the 8 studies (n=1793 patients) performed in the setting of coronary angiography.¹⁶⁷ These results have been incorporated into the 2009 STEMI/PCI Focused Update recommendations.³² A more recent study comparing iodixanol versus iopamidol provides additional supportive evidence.¹⁶⁹ However, even these clinical inferences must be tempered by the relative paucity of head-to-head trials comparing CIN rates among the various contrast media and the variability in results (eg, for iohexol versus other low-osmolar comparators).^170–173 Further, the assumption that a transient rise in serum creatinine after 24 to 48 hours is a reliable predictor of the more serious but somewhat delayed development of renal failure requiring hospitalization or dialysis has been challenged. A nationwide Swedish survey¹⁷⁴ of hospitalizations for renal failure after coronary procedures in 57 925 patients found that this risk was paradoxically higher with iodixanol (1.7%) than ioxaglate (0.8%) or iohexol (0.9%; P<0.001). Although the result was observational, hence subject to selection bias, it persisted in analyses of high-risk patient subsets (patients with diabetes, prior history of renal failure), in multivariable analysis, and in hospitals crossing over from ioxaglate to iodixanol. Iodixanol's greater viscosity was speculated but not demonstrated to be a possible mechanism for the observed effect. Thus, an overall summary of the current database, updated since previous guideline recommendations,^2,32 is that strength and consistency of relationships between specific isosmolar or low-osmolar agents and CIN or renal failure are not sufficient to enable a guideline statement on selection among commonly used low-osmolar and isosmolar media. Instead, the writing group recommends focusing on operator conduct issues shown to be important to protect patients, that is, (1) proper patient preparation with hydration, and (2) adjustment of maximal contrast dose to each patient's renal function and other clinical characteristics.

With respect to patient preparation, the writing group reviewed several trials addressing the optimal preparatory regimen of hydration and pharmacotherapy. The basic principle of hydration follows from experimental studies and clinical experience, with isotonic or half-normal saline alone being the historical gold standards.^{157,158,175–177} More recently, sodium bicarbonate has been tested as the hydrating solution. Some trials have reported superiority of sodium bicarbonate over saline in preventing CIN.^178–181 Similarly, some have reported a benefit of N-acetylcysteine administration as adjunctive therapy to hydration,^178,182 whereas others have not.^183,184 Thus, although the writing group found the evidence compelling for adequate hydration preparatory to angiography with contrast media, it found the evidence insufficient to recommend a specific regimen.

With respect to limitation of contrast dose by renal function, mounting evidence points to renal-function–specific limits on maximal contrast volumes that can be given without significantly increasing the baseline risk of provoking CIN. In a contemporary study, Laskey et al studied 3179 consecutive patients undergoing PCI and found that a contrast volume to creatinine clearance ratio >3.7 was a significant and independent predictor of an early and abnormal increase in serum creatinine.¹⁶⁰ In an earlier trial, administration of a contrast volume of 5 mL×body weight (kg)/serum creatinine (mg/dL), applied to 16 592 patients undergoing cardiac catheterization, was associated with a 6-fold increase in the likelihood of patients developing CIN requiring dialysis.¹⁵⁹

Patients with CKD are consistently underrepresented in randomized controlled trials of cardiovascular disease.¹⁸⁵ The impact of an invasive strategy has been uncertain in this group. The SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) study included a cohort of 23 262 patients hospitalized for NSTEMI in Sweden between 2003 and 2006 who were ≤80 years of age.¹⁶¹ This contemporary nationwide registry of nearly all consecutive patients examined the distribution of CKD and the use of early revascularization after NSTEMI and evaluated whether early revascularization (by either PCI or CABG) within 14 days of admission for NSTEMI altered outcomes at all stages of kidney function.

In SWEDEHEART, all-cause mortality was assessed at 1 year and was available in >99% of patients. Moderate or more advanced CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m²) was present in 5689 patients (24.4%). After multivariable adjustment, the 1-year mortality in the overall cohort was 36% lower with early revascularization (HR: 0.64; 95% CI: 0.56 to 0.73; P<0.001).¹⁶¹ The magnitude of the difference in 1-year mortality was similar in patients with normal estimated glomerular filtration rate (early revascularization versus medically treated: 1.9% versus 10%; HR: 0.58; 95% CI: 0.42 to 0.80; P=0.001), mild CKD (2.4% versus 10%; HR: 0.64; 95% CI: 0.52 to 0.80; P<0.001), and moderate CKD (7% versus 22%; HR: 0.68; 95% CI: 0.54 to 0.86; P=0.001). The benefit of an invasive therapy was not evident in patients with severe CKD stage IV (22% versus 41%; HR: 0.91; 95% CI: 0.51 to 1.61; P=0.780) or in those with CKD stage V kidney failure or receiving dialysis (44% versus 53%; HR: 1.61; 95% CI: 0.84 to 3.09; P=0.150). Early revascularization was associated with increased 1-year survival in UA/NSTEMI patients with mild to moderate CKD, but no association was observed in those with severe or end-stage kidney disease.¹⁶¹

The findings from SWEDEHEART are limited by their nonrandomized nature and the potential for selection bias despite the intricate multivariable adjustment.¹⁶¹ On the other hand, SWEDEHEART captured unselected patients with more comorbidities and is therefore more reflective of real-world patients.

Recently, a collaborative meta-analysis of randomized controlled trials that compared invasive and conservative treatments in UA/NSTEMI was conducted to estimate the effectiveness of early angiography in patients with CKD.¹⁶² The meta-analysis demonstrated that an invasive strategy was associated with a significant reduction in rehospitalization (RR: 0.76; 95% CI: 0.66 to 0.87; P<0.001) at 1 year compared with conservative strategy. The meta-analysis did not show any significant differences with regard to all-cause mortality (RR: 0.76; 95% CI: 0.49 to 1.17; P=0.21), nonfatal MI (RR: 0.78; 95% CI: 0.52 to 1.16; P=0.22), and the composite of death/nonfatal MI (RR: 0.79; 95% CI: 0.53 to 1.18; P=0.24).¹⁶²

Our recommendation is that an early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) is a reasonable strategy in patients with mild and moderate CKD. Clinicians should exercise judgment in all populations with impaired kidney function when considering whether to implement an invasive strategy. Such implementation should be considered only after careful assessment of the risks, benefits, and alternatives for each individual patient.

The observational data with regard to patients with mild to severe CKD also support the recognition that CKD is an underappreciated high-risk characteristic in the UA/NSTEMI population. The increased risk of mortality associated with mild, moderate, and severe CKD remains evident across studies.^{155,156,162,186} Indeed, the risks of short- and long-term mortality are increased as the gradient of renal dysfunction worsens.^156,162,186 The optimal role of early revascularization in this heterogeneous population of patients remains an important topic of research and investigation as discussed earlier in this update.

7. Conclusions and Future Directions

7.1. Recommendation for Quality of Care and Outcomes for Acute Coronary Syndromes (New Section)

(See Table 9 and Appendix 3.)

View this table:

Table 9.

Recommendation for Quality Care and Outcomes for Acute Coronary Syndromes (New Section)

7.1.1. Quality Care and Outcomes

The development of regional systems of ACS care is a matter of utmost importance.^187–189 This includes encouraging the participation of key stakeholders in collaborative efforts to evaluate care using standardized performance and quality-improvement measures, such as those endorsed by the ACC and the AHA for ACS.¹⁸⁹ Standardized quality-of-care data registries designed to track and measure outcomes, complications, and adherence to evidence-based processes of care for ACS are also critical: programs such as the NCDR (National Cardiovascular Data Registry) ACTION Registry-GWTG, the AHA's Get With The Guidelines (GWTG) quality-improvement program, and those performance-measurement systems required by the Joint Commission and the Centers for Medicare and Medicaid Services.^190–193 More recently the AHA has promoted its Mission: Lifeline initiative, which was developed to encourage closer cooperation and trust among prehospital emergency services personnel and cardiac care professionals.¹⁹⁰ The evaluation of ACS care delivery across traditional care-delivery boundaries with these tools and other resources is imperative to identify systems problems and enable the application of modern quality-improvement methods, such as Six Sigma, to make necessary improvements.^194–197 The quality improvement data coming from registries like the ACTION-GTWG may prove pivotal in addressing opportunities for quality improvement at the local, regional, and national level, including the elimination of healthcare disparities and conduct of comparative effectiveness research.

Staff

American College of Cardiology Foundation

John C. Lewin, MD, Chief Executive Officer

Janet Wright, MD, FACC, Senior Vice President, Science and Quality

Charlene L. May, Senior Director, Science and Clinical Policy

Lisa Bradfield, CAE, Director, Science and Clinical Policy

Sue Keller, BSN, MPH, Senior Specialist, Evidence-Based Medicine

Erin A. Barrett, MPS, Senior Specialist, Science and Clinical Policy

Leigh Maltese, Senior Specialist, Science and Clinical Policy

American Heart Association

Nancy Brown, Chief Executive Officer

Rose Marie Robertson, MD, FAHA, Chief Science Officer

Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations

Mark D. Stewart, MPH, Science and Medicine Advisor, Office of Science Operations

Appendix

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Appendix 1.

Author Relationships With Industry and Other Entities—2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline)

View this table:

Appendix 2.

Reviewer Relationships With Industry and Other Entities—2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline)

View this table:

Appendix 3.

Abbreviation List

View this table:

Appendix 4.

Dosing Table for Antiplatelet and Anticoagulant Therapy Discussed in This Focused Update to Support PCI in NSTEMI

View this table:

Appendix 5.

Comparisons Among Orally Effective P2Y12 Inhibitors

View this table:

Appendix 6.

Flowchart for Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI

View this table:

Appendix 7.

Summary Table

View this table:

Appendix 8.

Selection of Initial Treatment Strategy: Invasive Versus Conservative Strategy²

Footnotes

Developed in Collaboration With the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons
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
ACCF/AHA Task Force Members
Alice K. Jacobs, MD, FACC, FAHA, Chair; Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect; Nancy Albert, PhD, CCNS, CCRN, FAHA; Mark A. Creager, MD, FACC, FAHA; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC; Jonathan L. Halperin, MD, FACC, FAHA; Judith S. Hochman, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA; Erik Magnus Ohman, MD, FACC; William G. Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA
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 December 2010.
The American Heart Association requests that this document be cited as follows: Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:2022–2060.
This article has been 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 also available at http://www.americanheart.org/presenter.jhtml?identifier=3003999 by selecting either the “topic list” link or the “chronological list” link (No. KB-0193). To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay{at}wolterskluwer.com.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.
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.americanheart.org/presenter.jhtml?identifier=4431. A link to the “Permission Request Form” appears on the right side of the page.
↵* PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole (which are all available by prescription). Omeprazole is also sold over the counter for frequent heartburn.

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2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline)

2011 Writing Group Members, R. Scott Wright, Jeffrey L. Anderson, Cynthia D. Adams, Charles R. Bridges, Donald E. Casey, Steven M. Ettinger, Francis M. Fesmire, Theodore G. Ganiats, Hani Jneid, A. Michael Lincoff, Eric D. Peterson, George J. Philippides, Pierre Theroux, Nanette K. Wenger and James Patrick Zidar

Circulation. 2011;123:2022-2060, originally published May 9, 2011
https://doi.org/10.1161/CIR.0b013e31820f2f3e

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Quality and Outcomes
- Statements and Guidelines

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2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline)

A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

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Preamble

1. Introduction

1.1. Methodology and Evidence Review

1.2. Organization of Committee

1.3. Document Review and Approval

3. Early Hospital Care

3.2. Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite

3.2.1. Recommendations for Antiplatelet Therapy

3.2.3. Recommendations for Additional Management of Antiplatelet and Anticoagulant Therapy

3.2.3.1. Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite

3.2.3.1.1. Thienopyridines.

3.2.3.1.2. Choice of Thienopyridine for PCI in UA/NSTEMI.

3.2.3.1.2.1. Timing of Discontinuation of Thienopyridine Therapy for Surgical Procedures.

3.2.3.1.3. Interindividual Variability in Responsiveness to Clopidogrel.

3.2.3.1.4. Optimal Loading and Maintenance Dosages of Clopidogrel.

3.2.3.1.5. Proton Pump Inhibitors and Dual-Antiplatelet Therapy for Acute Coronary Syndrome.

3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists.

3.3. Recommendations for Initial Conservative Versus Initial Invasive Strategies

3.3.3.1. Timing of Invasive Therapy

5. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care

5.2. Long-Term Medical Therapy and Secondary Prevention

5.2.1. Recommendations for Convalescent and Long-Term Antiplatelet Therapy

5.2.6. Recommendations for Warfarin Therapy

6. Special Groups

6.2. Recommendations for Diabetes Mellitus

6.2.1.1. Intensive Glucose Control

6.5. Recommendations for Chronic Kidney Disease

6.5.1. Angiography in Patients With Chronic Kidney Disease

7. Conclusions and Future Directions

7.1. Recommendation for Quality of Care and Outcomes for Acute Coronary Syndromes (New Section)

7.1.1. Quality Care and Outcomes

Staff

American College of Cardiology Foundation

American Heart Association

Appendix

Footnotes

References

This Issue

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