2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines FREE

Frederick G. Kushner, MD, FACC, FAHA, FSCAI, Co-Chair; Mary Hand, MSPH, RN, FAHA, Co-Chair^⁎; Elliott M. Antman, MD, FACC, FAHA†; Eric R. Bates, MD, FACC, FAHA‡; Donald E. Casey, Jr, MD, MPH, MBA; Lee A. Green, MD, MPH§; Judith S. Hochman, MD, FACC, FAHA∥; Harlan M. Krumholz, MD, SM, FACC, FAHA; Joseph P. Ornato, MD, FACC, FAHA¶; David L. Pearle, MD, FACC, FAHA; Michael A. Sloan, MD, MS, FACC, FAHA; Sidney C. Smith, Jr, MD, FACC, FAHA

Sidney C. Smith, Jr, MD, FACC, FAHA, Chair; Spencer B. King III, MD, MACC, FSCAI, Co-Chair#; Jeffrey L. Anderson, MD, FACC, FAHA^⁎⁎; Steven R. Bailey, MD, FACC, FSCAI††‡‡; James C. Blankenship, MD, FACC, FSCAI††; Alice K. Jacobs, MD, FACC, FAHA, FSCAI§§; Douglass A. Morrison, MD, PhD, FACC, FSCAI††; Eric D. Peterson, MD, MPH, FACC, FAHA^⁎⁎; Patrick L. Whitlow, MD, FACC, FAHA; David O. Williams, MD, FACC, FAHA, FSCAI^⁎⁎

Alice K. Jacobs, MD, FACC, FAHA, Chair 2009–2011; Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair 2006–2008∥∥; Jeffrey L. Anderson, MD, FACC, FAHA, Vice Chair; Christopher E. Buller, MD, FACC; Mark A. Creager, MD, FACC, FAHA; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC, FAHA; Jonathan L. Halperin, MD, FACC, FAHA; Harlan M. Krumholz, MD, SM, FACC, FAHA∥∥; Frederick G. Kushner, MD, FACC, FAHA; Rick Nishimura, MD, FACC, FAHA∥∥; Richard L. Page, MD, FACC, FAHA∥∥; Lynn G. Tarkington, RN; William G. Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA

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 has created a “focused update” process to revise the existing guideline recommendations that are affected by 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 will be 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 as quickly as possible, while maintaining the rigorous methodology that the ACCF and AHA have developed during their 25 years of partnership.

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 a review of other new data deemed to have an impact on patient care (see (5.2.1), 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:

In analyzing the data and developing updated recommendations and supporting text, the focused update writing group used evidence-based methodologies developed by the ACCF/AHA Task Force on Practice Guidelines, which are described elsewhere (1).

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 of the treatment effect and an estimate of the certainty of the treatment effect. Note that a recommendation with level of evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in guidelines do not lend themselves to clinical trials. Although randomized trials may not be available, there may be a very clear clinical consensus that a particular test or therapy is useful and effective. Both the classification of recommendations and level of evidence listed in the focused updates are based on consideration of the evidence reviewed in previous iterations of the guideline and the focused update. Of note, the implications of older studies that have informed recommendations but have not been repeated in contemporary settings are considered carefully.

The ACCF/AHA practice guidelines address patient populations (and healthcare providers) residing in North America. As such, drugs that are not currently available 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 on 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. 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. These guidelines may be used as the basis for regulatory or payer decisions, but the ultimate goals are quality of care and serving the patient's best interests.

Prescribed courses of treatment in accordance with these recommendations are effective only if they are followed by the patient. Because a lack of patient adherence may adversely affect treatment outcomes, healthcare providers should engage the patient in active participation with the prescribed treatment.

The ACCF/AHA Task Force on Practice Guidelines 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 writing committee. Specifically, all members of the writing committee, as well as reviewers of the document, are asked to disclose all such relevant relationships pertaining to the trials and other evidence under consideration (see Appendixes 1, 2, and 3). All guideline recommendations require a confidential vote by the writing group and must be approved by a consensus of the members voting. Members who recused themselves from voting are noted on the title page of this document. Members must recuse themselves from voting on any recommendations to which their relationships with industry and other entities apply. Writing group members who did not participate are not listed as authors of this focused update. 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.

With the exception of the recommendations presented here, the full-text guidelines remain current (2- 3). Only the recommendations from the affected section(s) of the full-text guidelines are included in this focused update. Recommendations from any section of a guideline affected by a change are presented with notation as to whether they are new or have been modified; however, recommendations that remain unchanged in each section are not included in this focused update. When evidence affects recommendations in more than 1 set of guidelines, those guidelines are updated concurrently whenever possible.

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 December 1, 2009, issues of the Journal of the American College of Cardiology and Circulation as an update to the full-text guideline, and it is also posted on the American College of Cardiology (ACC; www.acc.org), AHA (my.americanheart.org), and Society for Cardiovascular Angiography and Interventions (SCAI; scai.org) World Wide Web sites.

Alice K. Jacobs, MD, FACC, FAHA

Chair, ACCF/AHA Task Force on Practice Guidelines

Late-breaking clinical trials presented at the 2007 and 2008 annual scientific meetings of the ACC, AHA, Transcatheter Cardiovascular Therapeutics, the European Society of Cardiology, and the 2009 annual scientific sessions of the ACC 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 ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction and the ACC/AHA 2005 Guidelines for Percutaneous Coronary Intervention, inclusive of their respective 2007 focused updates (2- 5).

The ST-elevation myocardial infarction (STEMI) and percutaneous coronary intervention (PCI) writing groups together considered the following studies: Two meta-analyses, “A Comparison of Abciximab and Small Molecule Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Primary Percutaneous Coronary Intervention,” (6) and “Benefits From Small Molecule Administration as Compared With Abciximab Among Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary Angioplasty,” (7) FINESSE (Facilitated PCI in Patients With ST-Elevation Myocardial Infarction) (8), the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) (9), BRAVE-3 (Bavarian Reperfusion Alternatives Evaluation-3) (10), MULTISTRATEGY (Multicentre Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study) (11), ON-TIME 2 (Ongoing Tirofiban in Myocardial Infarction Evaluation) (12), TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction) (13), TRANSFER-AMI (Trial of Routine ANgioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction) (14), CARESS-in-AMI (Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction) (15), NICE-SUGAR (Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation) (16), TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study) (17), and EXPIRA (Thrombectomy With Export Catheter in Infarct-Related Artery During Primary Percutaneous Coronary Intervention) (18). Additionally, the PCI writing group considered the CARE (Cardiac Angiography in Renally Impaired Patients) (19), FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study (20), SYNTAX (Synergy Between Percutaneous Intervention With Taxus and Cardiac Surgery) (21), Early ACS (Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes) (22), and TIMACS (Timing of Intervention in Patients With Acute Coronary Syndromes) studies (23). When considering the new data for this focused update, the writing group faced the task of weighing evidence from studies that had enrolled large numbers of subjects outside North America. Although noting that practice patterns and the rigor applied to data collection, as well as the genetic makeup of subjects, may influence the observed magnitude of a treatment's effect, the writing group believed the data were relevant to the formulation of recommendations for management of STEMI and PCI in North America. The writing group also notes that the AHA/ACCF and the Heart Rhythm Society have published updated recommendations for the standardization and interpretation of the electrocardiogram with a separate section on acute ischemia/infarction (24).

To provide clinicians with a comprehensive set of data, whenever possible, the exact event rates in various treatment arms of clinical trials are presented to permit calculation of the absolute risk difference and number needed to treat (NNT) or harm; the relative treatment effects are described either as odds ratio, relative risk (RR), or hazard ratio (HR) depending on the format used in the original publication. Along with all other statistical point estimates, the confidence interval (CI) for those statistics are added when available.

Consult the full-text or executive summary versions of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction or the ACC/AHA/SCAI 2005 Guidelines for Percutaneous Coronary Intervention, as well as their respective 2007 focused updates, for policy on clinical areas not covered by the present focused update (2- 5). Unchanged recommendations from previous iterations of the guidelines are not listed in this document and remain current policy. Individual recommendations updated in this focused update will be incorporated into future revisions of the full-text guidelines.

For this focused update, all members of the 2004 STEMI guideline, 2007 STEMI focused update, 2005 PCI guideline, and 2007 PCI focused update writing committees were invited to participate; those who agreed (referred to as the 2009 Focused Update Writing Group) were required to disclose all relationships with industry and other entities relevant to the data under consideration. The policies used for relationships with industry were those in effect at the initial meeting of this committee, which included disclosure of relationships 12 months prior to initiation and a chair with no relevant relationships except in a situation where more than one chair is named. In this circumstance, one chair will have no relevant relationships and the other may have relationships. Each recommendation required a confidential vote by the writing group members before and after external review of the document. Any writing group member with a relationship with industry relevant to the recommendation was recused from voting on that recommendation. The PCI writing group included 2 representatives from SCAI.

This document was reviewed by 3 official reviewers nominated by the ACCF and 4 official reviewers nominated by the AHA, 1 official reviewer nominated by the SCAI, 6 reviewers from the ACCF Interventional Council, 2 reviewers from the ACCF Imaging Council, and 22 content reviewers. All reviewer information on relationships with industry and other entities was collected and distributed to the writing committee and is published in Appendix 3. This document was approved for publication by the governing bodies of the ACCF, the AHA, and the SCAI (specifically, the PCI portion of the guideline).

(See (Table 2) and Appendix 4.)

In considering the use of intravenous glycoprotein (GP) IIb/IIIa receptor antagonists for STEMI, the writing group noted that much of the evidence favoring the use of these agents was established in the era before dual oral antiplatelet therapy and largely by placebo-controlled comparisons. Contemporary management of STEMI patients involves a complex array of antithrombotics, including dual oral antiplatelet therapy (aspirin [acetylsalicylic acid; ASA] plus a thienopyridine) and an anticoagulant. There is a paucity of trials adequately powered for assessment of clinical end points that have reevaluated the current relative role of intravenous GP IIb/IIIa receptor antagonists with respect to other pharmacological therapy in STEMI patients. Accordingly, a reevaluation of the value of GP IIb/IIIa antagonists in STEMI is appropriate, but the ability to draw definitive conclusions is limited.

At least 3 trials evaluated GP IIb/IIIa antagonists as adjuncts to oral antiplatelet therapy in the setting of primary PCI. The findings of these trials question whether GP IIb/IIIa antagonists provide significant additional benefit to STEMI patients who have received dual-antiplatelet therapy before catheterization. In the BRAVE-3 study, 800 patients presenting within 24 hours of a STEMI were pretreated with 600 mg of clopidogrel and then randomly assigned in a double-blind manner to receive either abciximab or placebo in the intensive care unit before being sent for PCI (10). The primary end point was infarct size measured by single photon emission computed tomography before hospital discharge. At 30 days, the composite of death, recurrent myocardial infarction (MI), stroke, or urgent revascularization of the infarct-related artery was not significantly different in the 2 groups (abciximab 5%, placebo 3.8%; 95% CI 0.7 to 2.6; P=0.4). There was no significant difference in infarct size or major bleeding.

ON-TIME 2 was a randomized, placebo-controlled, multicenter European trial that included 491 patients receiving high-dose tirofiban and 493 receiving placebo within a median of 76 minutes from onset of symptoms (12). Patients receiving high-dose tirofiban (25 mcg/kg bolus followed by 0.15 mcg/kg per min for 18 hours) at first medical contact before transport for primary PCI were also treated with unfractionated heparin (UFH; 5000 U), clopidogrel (600 mg), and ASA. Patients in the high-dose tirofiban group had improved ST-segment resolution (primary end point) before and 1 hour after PCI (P=0.003) compared with those receiving placebo (NNT=100). However, there was no significant difference in Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow or blush grade and no significant difference in major bleeding or minor bleeding. There was no significant difference in death, recurrent MI, or urgent target-vessel revascularization (TVR) between the tirofiban and placebo groups at 30 days (25).

In the HORIZONS-AMI trial (9), patients undergoing primary PCI for STEMI were randomized to treatment with UFH plus a GP IIb/IIIa receptor antagonist (abciximab or double-bolus eptifibatide) or to bivalirudin alone with provisional IIb/IIIa. Aspirin and a thienopyridine were administered before catheterization. (See the full discussion of the trial under 6.3, Recommendations for the Use of Parenteral Anticoagulants.) Seven hundred fifty-seven of the 1661 patients who received UFH received a double bolus of eptifibatide and infusion, whereas 53 of 1661 in the bivalirudin arm received eptifibatide. At 30 days, rates of major bleeding and total adverse events were higher among patients treated with GP IIb/IIIa antagonists and heparin than among those given bivalirudin alone.

Two meta-analyses of randomized trials were published that compared small-molecule GP IIb/IIIa antagonists with abciximab in STEMI patients undergoing primary PCI (6- 7). In each case, there was no statistically significant difference in 30-day mortality, reinfarction, or major TIMI bleeding, and there was no significant difference in death or reinfarction at 8 months between groups. There was also no statistically significant difference in postprocedural TIMI flow grade 3 or ST-segment resolution. On the basis of these studies, the present writing group judged that the totality of evidence indicates that the various GP IIb/IIIa antagonists demonstrate similar effectiveness in the setting of primary PCI.

MULTISTRATEGY was an open-label, multicenter, randomized European trial with a 2-by-2 factorial design that randomized 745 STEMI patients undergoing primary PCI to high-dose bolus tirofiban versus abciximab infusion and sirolimus-eluting stent versus bare-metal stent (BMS) (11). The prespecified primary end points were the achievement of 50% resolution of ST-segment elevation at 90 minutes after PCI, powered for noninferiority, and the rate of major adverse cardiac events (MACE) at 8 months, powered for superiority. All patients received ASA at the usual doses, clopidogrel 300 mg orally then 75 mg per day, and UFH. There was a similar rate of at least 50% ST-segment resolution at 90 minutes after primary PCI with abciximab and tirofiban (RR 1.020; 97.5% CI 0.958 to 1.086; P=0.001 for noninferiority). Rates of MACE, including all-cause death, clinical reinfarction, or TVR, and hemorrhagic (major and minor bleeding) complications were similar. The incidence of severe or moderate thrombocytopenia was more common with abciximab than with tirofiban (4.0% versus 0.8%, P=0.004).

In an analysis of the predictors of stent thrombosis after primary PCI in acute MI presented at the 2009 ACC Scientific Sessions, titled “Predictors of Stent Thrombosis After Primary Angioplasty in Acute Myocardial Infarction: The HORIZONS-AMI Trial,” (69) there was no significant difference in the 1-year rate of stent thrombosis with the heparin plus GP IIb/IIIa receptor antagonists compared with eptifibatide and abciximab (3.6% versus 2.8%, P=0.93), which suggests that eptifibatide has the same impact as abciximab on stent thrombosis incidence.

One investigation, FINESSE, addressed the issue of timing of GP IIb/IIIa antagonist administration. This double-blind, randomized, placebo-controlled study of 2453 patients with STEMI explored the use of pre-PCI treatment with a half-dose fibrinolytic agent plus abciximab, pre-PCI abciximab alone, and abciximab at the time of PCI (8). The primary end point was the composite of death due to all causes, ventricular fibrillation that occurred more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization. The results of the trial are discussed in Section 5.1, Triage and Transfer for PCI. This trial showed no benefit (and a tendency toward excess bleeding) with prehospital abciximab compared with abciximab at the time of PCI. The writing group concluded there was no benefit of administration of abciximab before primary PCI, alone or in combination with reteplase. On the basis of this trial and ON-TIME 2, the writing group concluded that the use of GP IIb/IIIa antagonists before primary PCI is of uncertain benefit.

Given the results of the studies cited above, the writing group concluded that in the setting of dual-antiplatelet therapy with UFH or bivalirudin as the anticoagulant, current evidence indicates that adjunctive use of a GP IIb/IIIa antagonist can be useful at the time of primary PCI but cannot be recommended as routine therapy. These agents might provide more benefit in selective use, for example, for the patient with a large thrombus burden or for patients who have not received adequate thienopyridine loading.

(See (Table 3) and Appendix 4.)

Since the publication of the last guidelines (4- 5), evidence has emerged about prasugrel, a thienopyridine that achieves greater inhibition of platelet aggregation than clopidogrel (27). The pivotal trial for prasugrel, TRITON-TIMI 38, focused on patients with ACS who were referred for PCI.

TRITON-TIMI 38 randomly assigned 13 608 patients with moderate- to high-risk ACS, 3534 of whom had STEMI, to receive prasugrel (6813 patients received a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (6795 patients received a 300-mg loading dose and a 75-mg daily maintenance dose) for an average follow-up of 14.5 months. Aspirin was prescribed within 24 hours of PCI. Clinical end points were assessed at 30 and 90 days and then every 3 to 15 months (27).

Prasugrel was associated with a significant 2.2% absolute reduction and a 19% relative reduction in the primary efficacy end point, a composite of the rate of death due to cardiovascular causes (including arrhythmia, congestive heart failure, shock, and sudden or unwitnessed death), nonfatal MI, or nonfatal stroke during the follow-up period. The primary efficacy end point 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). A significant reduction in the primary end point was seen in the prasugrel group by the first prespecified time point, which was 3 days (4.7% in the prasugrel group versus 5.6% in the clopidogrel group; HR 0.82; 95% CI 0.71 to 0.96; P=0.01), and persisted throughout the follow-up period. From Day 3 to the end of the study, the primary end point had occurred in 5.6% of patients receiving prasugrel and in 6.9% of patients receiving clopidogrel (HR 0.80; 95% CI 0.70 to 0.93; P=0.003). Prasugrel decreased cardiovascular death, MI, and stroke by 138 events (NNT=46) (27). The rate of MI with subsequent death due to cardiovascular causes was also reduced in the prasugrel group (P=0.02). The difference in the primary end point 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). There were no significant differences in the 2 treatment groups in the rates of stroke or of death due to cardiovascular causes not preceded by recurrent MI (at 15 months, the nonfatal stroke rate was 1.0% for both prasugrel and clopidogrel; HR for prasugrel=1.02; CI 0.71 to 1.45; P=0.93; the rate of deaths due to cardiovascular causes not preceded by recurrent MI was 2.1% for prasugrel versus 2.4% for clopidogrel; HR 0.89; CI 0.70 to 1.12; P=0.31). There were significant reductions in the rates of ischemic events in the prasugrel group compared with the clopidogrel group: Rates of MI were 7.4% for prasugrel versus 9.7% for clopidogrel (P<0.001); urgent TVR rates were 2.5% for prasugrel versus 3.7% for clopidogrel (P<0.001); and rates of stent thrombosis were 1.1% for prasugrel versus 2.4% for clopidogrel (HR 0.48; 95% CI 0.36 to 0.64; P<0.001).

Prasugrel was associated with a significant increase in the rate of bleeding, notably, TIMI 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), which represented an increase in the relative rate of major bleeding of 32%. From the standpoint of safety, prasugrel was associated with an increase of 35 TIMI major and non–coronary artery bypass graft bleeds (number needed to harm=167) (27). 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), which included nonfatal bleeding (1.1% versus 0.9%; HR for prasugrel 1.25; 95% CI 0.87 to 1.81; P=0.23) and fatal bleeding (0.4% versus 0.1%; HR for prasugrel 4.19; 95% CI 1.58 to 11.11; P=0.002). In the few patients who underwent coronary artery bypass graft (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) (27). Despite the increase in bleeding, the net clinical-benefit end point, which included all-cause mortality, ischemic events, and major bleeding events, favored prasugrel (27).

Prasugrel showed superior efficacy in major prespecified subgroups in the overall ACS population. The benefit tended to be greater among the 3146 patients with diabetes (12.2% of whom had the primary end point in the prasugrel group versus 17.0% in the clopidogrel group; HR 0.70; 95% CI 0.58 to 0.85; P<0.001) than among the 10 462 patients without diabetes (9.2% of whom had the primary end point in the prasugrel group versus 10.6% in the clopidogrel group; HR 0.86; 95% CI 0.76 to 0.98; P=0.02). The rate of definite or probable stent thrombosis was significantly reduced in the prasugrel group compared with the clopidogrel group, as noted (27).

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 (TIA) 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 and older 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 less than 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 (27). A pharmacokinetic analysis showed greater exposure to the active metabolite of prasugrel for patients who weighed less than 60 kg and who were 75 years old or older (38).

The US Food and Drug Administration (FDA) approved prasugrel in July 2009 and incorporated the aforementioned subgroup findings into its labeling by citing a contraindication against prasugrel use in patients with a history of TIA or stroke and active pathological bleeding. The FDA further recommends that consideration be given to lowering the maintenance dose of prasugrel to 5 mg in patients who weigh less than 60 kg, with a note that the effectiveness and safety of the 5-mg dose have not been studied prospectively to date. The FDA labeling information includes a general warning against the use of prasugrel in patients older than 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 its effect appears to be greater and its use may be considered (37).

In focusing specifically on patients with STEMI, the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke was significantly reduced in patients assigned to prasugrel at 30 days compared with patients who received clopidogrel (6.5% versus 9.5%; HR 0.68; 95% CI 0.54 to 0.87; P=0.0017), and this trend persisted to 15 months (HR 0.79; 95% CI 0.65 to 0.97; P=0.0221) (13). Furthermore, in the STEMI group, the key secondary end point of cardiovascular death, MI, or urgent TVR was significantly reduced with prasugrel at 30 days (P=0.0205) and 15 months (P=0.0250) (13). At 30 days and 15 months, the individual end points of cardiovascular death and MI, as well as stent thrombosis, were reduced with prasugrel (13).

The interaction testing for efficacy and safety showed no significant difference in bleeding risk regardless of the type of ACS (e.g., UA/NSTEMI versus STEMI). Thus, the STEMI results for efficacy and safety are consistent with the main results of the trial. In a post hoc analysis of patients with anterior MI, event rates at 15 months for the primary end point were lower with prasugrel (9.8% for prasugrel versus 16.3% for clopidogrel; HR 0.57; 95% CI 0.42 to 0.78; P=0.0003). In patients with nonanterior MI, treatment effects did not differ for the primary end point (10.1% for prasugrel versus 9.9% for clopidogrel; HR 1.02; 95% CI 0.78 to 1.34; P=0.8749). The test for heterogeneity of the effect of prasugrel was significant (P=0.0053), which suggests that the benefit might vary by the location of the MI. Data were consistent in both the primary and secondary PCI subgroups (13).

The writing group weighed the current data regarding the use of thienopyridine therapy in patients who remain hospitalized after STEMI and are candidates for CABG and retained the 2007 focused update recommendation of empiric discontinuation of clopidogrel therapy for at least 5 days and at least 7 days in patients receiving prasugrel before planned CABG (2,27,30).

Platelet function testing to determine the degree of platelet inhibition (39) may be used, and if platelet function has normalized, CABG may be performed at an earlier time. Additionally, other strategies of platelet inhibition (GP IIb/IIIa receptor antagonists) may be used if recurrent ischemia is a concern during the waiting period for CABG. Ultimately, the patient's clinical status will determine the risk-to-benefit ratio of CABG compared with awaiting restoration of platelet function.

The results of TRITON-TIMI 38 influenced dosing recommendations for loading and chronic thienopyridine therapy with prasugrel. Sixty milligrams of prasugrel is now recommended as a loading dose for primary PCI in STEMI. For secondary PCI in those patients who have recurrent ischemia or other reasons for planned intervention during their course of treatment, 60 mg of prasugrel may be given after the coronary anatomy has been identified (to avoid dosing those patients who require CABG) either before, during, or within 1 hour of PCI (27). Furthermore, 10 mg of prasugrel may be used in addition to ASA for chronic dual-antiplatelet therapy (27).

Determination of patient groups that should be considered for continuation of dual-antiplatelet treatment beyond 12 months is based on patient-level factors (e.g., age, history of bleeding) and lesion characteristics (e.g., bifurcation, small-diameter vessel) (28).

In previous studies of patients with prior stroke or TIA, use of dual-antiplatelet therapy has been associated with an increased risk of adverse outcomes, notably intracranial bleeding, compared with single-antiplatelet therapy. In the MATCH (Management of Atherothrombosis With Clopidogrel in High-Risk Patients With TIA or Stroke) trial (40) in which patients with prior stroke or TIA and additional risk factors (n=7599) were allocated to clopidogrel 75 mg or combination therapy with clopidogrel 75 mg plus ASA 75 mg per day, there was no significant benefit of combination therapy compared with clopidogrel alone in reducing the primary outcome of the composite of ischemic stroke, MI, vascular death, or rehospitalization due to ischemic events, or any of the secondary outcomes. The risk of major hemorrhage was significantly increased in the combination-therapy group compared with those given clopidogrel alone, with a 1.3% absolute increase in life-threatening bleeding. Although clopidogrel plus ASA is recommended over ASA alone for patients with ACS (41- 43), the results of MATCH do not suggest a similar risk-benefit ratio for stroke and TIA survivors. The AHA/American Stroke Association's Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Stroke contain a Class III recommendation for the use of ASA in combination with clopidogrel in patients with prior stroke or TIA (44). On the other hand, a post hoc analysis from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, which included 9478 patients, suggested that patients with documented prior MI, ischemic stroke, or symptomatic peripheral artery disease derive benefit from dual-antiplatelet therapy with clopidogrel plus ASA (45). Although MATCH and CHARISMA did not involve STEMI patients, the writing group recommended weighing the benefits and risks of prescribing clopidogrel and ASA in patients with a recent history of TIA or stroke. Given prasugrel's greater tendency to cause intensive inhibition of platelet aggregation in general and the findings of increased levels of bleeding compared with clopidogrel in this population, the use of prasugrel as part of a dual-antiplatelet therapy regimen in patients with prior stroke or TIA is contraindicated (37).

Although clopidogrel in combination with ASA has been shown to reduce recurrent coronary events in the posthospitalized ACS population (32,43,46), the response to clopidogrel varies among patients, and clopidogrel resistance has been observed (43). Information is accumulating about the variations in the antiplatelet effect of clopidogrel in patients with loss-of-function alleles in the gene encoding CYP450 2C19 (32,46- 50). These patients form a subgroup in which failure of clopidogrel effectiveness has been linked to adverse clinical outcomes (30,47- 51). In TRITON-TIMI 38 and 3 of the cohort studies (47,49,52), patients who were carriers of a reduced-function CYP450 2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and increased rates of cardiovascular events (e.g., death, MI, stroke), including stent thrombosis (53), compared with the extensive metabolizers (54). In another cohort study with 2208 patients (50), the increased event rate was observed only in poor metabolizers. (Prasugrel has a higher level of inhibition of platelet aggregation than clopidogrel and a more rapid onset of action [(55)]. Its metabolism is not affected by the 2C19 allele variant [56].)

Accordingly, the effective clopidogrel dose for an individual undergoing PCI for STEMI may not be known. A large randomized trial (57) is attempting to determine whether adjustment of clopidogrel therapy on the basis of platelet function testing with a point-of-care assay safely improves outcomes after PCI with DES. As noted in the drug dosing table (Appendix 4), the current recommended loading dose for clopidogrel is uncertain. In addition, a period of several hours is required to metabolize clopidogrel to its active metabolite, which leaves a window of time during which there is a reduced level of effectiveness even in responders.

With regard to clopidogrel loading for PCI after a patient has received fibrinolytic therapy, there are no studies that have formally tested a 600-mg (or higher) clopidogrel loading dose administered with fibrinolytic treatment. The only study that tested any clopidogrel dose with a fibrinolytic was the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28) study, which randomized 3491 patients 75 years of age and younger who were receiving fibrinolytic therapy within 12 hours of STEMI to clopidogrel (300-mg oral loading dose; 75-mg oral daily maintenance dose) or placebo (58). As described in the 2007 STEMI focused update (4), patients who received clopidogrel had a reduced rate of an occluded infarct artery, accomplished by preventing infarct-related reocclusion rather than by facilitating early reperfusion.

When considering a loading dose of clopidogrel for PCI after a patient has received a fibrinolytic agent, the available level of evidence is limited (Level of Evidence: C), and consensus opinion suggests it is dependent on how many hours have elapsed since fibrinolytic therapy was administered before PCI. For patients who have received any fibrinolytic agent and subsequently proceed to PCI within 24 hours, a dose of 300 mg of clopidogrel as a loading dose is suggested. If the patient received a fibrin-specific fibrinolytic agent and then proceeds to PCI after 24 hours has elapsed, a loading dose of 300 to 600 mg may be considered. If at least 48 hours has elapsed after treatment with a non–fibrin-specific fibrinolytic agent, a dose of 300 to 600 mg may be considered.

Prasugrel has not been studied in patients who have received fibrinolytic therapy. Thus, for STEMI patients undergoing nonprimary PCI who received prior fibrinolytic therapy without a thienopyridine, only a loading dose with clopidogrel should be given as the thienopyridine of choice.

The guidelines do not endorse explicitly one of the thienopyridines over the other. There were several reasons for this decision. Although the composite efficacy end point favored prasugrel, driven predominantly by a difference in nonfatal MIs, with deaths and nonfatal strokes being similar, bleeding was increased in the prasugrel group (27). 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. Furthermore, there are some emerging studies that 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. There is not yet experience with the use of prasugrel in routine community practice. As a result, the writing group believes that there is some uncertainty regarding the net benefit and risks of 1 drug over another for a given patient. Considerations of efficacy in the prevention of thrombosis and risk of an adverse effect related to bleeding, as well as experience with a given medication, may best guide decisions about the choice of thienopyridine for individual patients.

Proton pump inhibitors (PPIs) are often prescribed prophylactically when clopidogrel is started, to prevent gastrointestinal complications such as ulceration and related bleeding (59) due to dual-antiplatelet therapy, in particular ASA and clopidogrel (32). 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 stent (BMS or DES), for whom 12 months of antiplatelet therapy is recommended (28). PPI medications^⁎) have been found to interfere with the metabolism of clopidogrel (34).

Although there are studies that show a pharmacodynamic interaction on ex vivo platelet function testing, to date there are no convincing randomized clinical trial data for an important clinical drug–drug interaction. Retrospective claims-based reports suggesting clinical harm, some detailed below, may be confounded by different baseline characteristics and lack of compliance data. There have been retrospective reports of adverse cardiovascular outcomes (e.g., readmission for ACS) when the antiplatelet regimen of clopidogrel and ASA is accompanied by PPIs, assessed as a group, compared with the use of this regimen without a PPI (32- 34,60). 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 point during follow-up of 8205 patients discharged for ACS was associated with an increased risk of death or rehospitalization for ACS (32). Other post hoc study analyses (50,61) and a retrospective data analysis from the NHLBI Dynamic Registry (62) 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, after ACS, or in a general post-PCI population, respectively (50,61- 62).

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, which includes omeprazole, lansoprazole, and rabeprazole. The PPI omeprazole notably has been reported to significantly decrease the inhibitory effect of clopidogrel on platelet aggregation (63- 64). One study reported that the PPI pantoprazole was not associated with recurrent MI among patients receiving clopidogrel, possibly because of its lack of inhibition of CYP450 2C19 (33).

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 it was unaffected after a prasugrel dose (56).

Another study (35) 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 trial (65) and the TRITON-TIMI 38 trial (27). The findings indicated that first, PPI treatment attenuated the pharmacodynamic effects of clopidpgrel and, to a lesser extent, those of prasugrel. Secondly, 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.

The FDA communication concerning an ongoing safety review of clopidogrel bisulfate (66) advises that healthcare providers avoid the use of clopidogrel in patients with impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity. 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.

Further research with thienopyridines and PPI combinations, particularly drugs that are not dependent on CYP450 2C19, is needed. Consideration may be given to the use of H2 antagonists as an alternative to PPIs in the setting of dual-antiplatelet therapy, although they cannot be relied on to protect as well as PPIs, and there are few data about their use with ASA (59). The FAMOUS (Famotidine for the Prevention of Peptic Ulcers in Users of Low-Dose Aspirin) trial, a phase II, double-blind, randomized, placebo-controlled trial, found that among patients with a history of coronary heart disease, diabetes mellitus, or cerebrovascular disease who were taking low-dose ASA, 12 weeks of famotidine 20 mg twice daily (n=204) compared with placebo twice daily (n=200) was beneficial in reducing the incidence of peptic ulcer or esophagitis during follow-up endoscopy at 12 weeks. The rate of occurrence of a gastric ulcer at endoscopy at 12 weeks was 3.4% in the famotidine group versus 15% in the placebo group (P=0.0002), duodenal ulcer occurred in 0.5% versus 8.5% (P=0.0045), and erosive esophagitis was seen in 4.4% versus 19% (P<0.0001), respectively. Of note, in the famotidine group, clopidogrel use was 19% and dipyridamole use was 6% (67). The writing committee concluded that additional data, notably randomized controlled clinical trial data that have been peer reviewed and published, are needed before an official recommendation can be made about the use of dual antiplatelet therapy with PPIs in the setting of ACS.

(See (Table 4) and Appendix 4.)

Parenteral anticoagulants include intravenous UFH, bivalirudin, enoxaparin, and fondaparinux. Bivalirudin was briefly cited in the 2007 STEMI focused update. The HORIZONS-AMI trial, which was reported subsequently, was a prospective, open-label, randomized, multicenter, international trial that included 3602 patients with STEMI undergoing primary PCI. Patients were randomized to treatment with UFH plus a GP IIb/IIIa receptor antagonist or to bivalirudin alone (with provisional abciximab or double-bolus eptifibatide). The primary efficacy end point was a composite of net adverse clinical events, including major bleeding plus MACE, a composite of cardiovascular death, reinfarction, TVR for ischemia, and stroke within 30 days. Bivalirudin alone resulted in a lower incidence of net adverse clinical events at 30 days (9.2% versus 12.1%; RR 0.76; 95% CI 0.63 to 0.92; P=0.005; NNT=34) and at 1 year (15.7% versus 18.3%, HR 0.84; 95% CI 0.71 to 0.98; P=0.3) (9). The difference was driven by a significant decrease in major bleeding complications with bivalirudin at 30 days (4.9% versus 8.3%, P=0.001; number needed to harm=33) and 1 year (5.8% versus 9.2%, P=0.001). There was a statistically significant 1% increase in stent thrombosis (n=17) within the first 24 hours with bivalirudin but no subsequent difference (1.3% versus 0.3%, P<0.001). More deaths at 30 days occurred after major bleeding (n=26) than after reinfarction (n=10) or definite stent thrombosis (n=5) (9). Treatment with bivalirudin resulted in significantly lower 30-day rates of death due to cardiac causes (1.8% versus 2.9%; RR 0.62; 95% CI 0.40 to 0.95; P=0.03) and death due to all causes (2.1% versus 3.1%; RR 0.66; 95% CI 0.44 to 1.00; P=0.047 compared with UFH plus GP IIb/IIIa inhibitors). At 1 year, MACE rates were identical, but there was a decrease in all-cause mortality with bivalirudin (3.4% versus 4.8%, P=0.03) (68).

Concerns about the trial include its open-label design and the administration of UFH before randomization in 66% of patients in the bivalirudin arm and 76% of patients in the UFH plus GP IIb/IIIa receptor antagonist arm. Only 615 patients received bivalirudin monotherapy, and only 60% of patients in the trial received a 600-mg clopidogrel loading dose. Major bleeding as defined in the publication included hematomas of 5 cm, intracranial hemorrhage, and bleeding that required surgery. Additionally, the study put forth a composite primary end point that combined efficacy and safety. Although there were no statistically significant interactions at 30 days between the treatment assignment and preprocedural UFH use or clopidogrel loading dose with respect to MACE or major bleeding, the occurrence of an increase in early stent thrombosis with bivalirudin and the excess bleeding with UFH and GP IIb/IIIa inhibitors may be related to the degree of platelet inhibition and antithrombin activity associated with these treatment doses.

A preliminary report suggested that the use of bivalirudin alone (P=0.005) and a lower loading dose of clopidogrel (300 versus 600 mg; P=0.01) were independent predictors of acute and subacute stent thrombosis rates, respectively (69). Probability values for secondary end points may not have been adjusted for multiple looks.

Therefore, the writing group now considers bivalirudin useful for primary PCI in STEMI whether or not the patient received pretreatment with UFH. The risk of acute stent thrombosis associated with bivalirudin appeared to be mitigated by the prior use of UFH and the risk of subacute stent thrombosis by the use of a 600-mg loading dose of clopidogrel. These data should be confirmed by prospective studies.

(See (Table 5) and Appendix 5.)

The 2007 STEMI Focused Update describes several strategies for reperfusion, among them facilitated PCI and rescue PCI (4). These terms are no longer used for the recommendations in this update so that the contemporary therapeutic choices that lead to reperfusion as part of the treatment of patients presenting with STEMI can be described without these potentially misleading labels.

A brief review of facilitated PCI, however, is needed. This strategy involves full- or half-dose fibrinolytic therapy with or without a GP IIb/IIIa receptor antagonist, followed by immediate PCI. Two studies addressed this issue: ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention) (70), which was described in detail in the 2007 PCI and STEMI focused updates, and FINESSE (71- 72), which was a randomized, double-blind clinical trial of 2452 patients randomized within 6 hours of symptom onset to receive reduced-dose reteplase plus abciximab followed by PCI (combination-facilitated PCI), abciximab alone followed by PCI (abciximab-facilitated PCI), or placebo (primary PCI).

ASSENT-4 patients treated with fibrinolytic therapy before PCI had increased rates of adverse outcomes, including in-hospital death (6% versus 3%). The investigators theorized that suboptimal antithrombotic therapy (i.e., the lack of a heparin infusion after bolus administration, no upfront loading dose of clopidogrel, and prohibition of IIb/IIIa use except for bailout) and a short time from fibrinolytic therapy to PCI contributed in part to the adverse clinical outcomes.

FINESSE (8) showed that neither PCI preceded by abciximab and reteplase nor PCI preceded by abciximab alone was superior to abciximab used at the time of PCI among patients presenting within 4 hours of medical contact. Neither the primary end point (a composite of death due to all causes, ventricular function more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization) nor mortality was significantly different among the groups. Although the study was terminated early because of recruitment challenges, there was less than a 2% chance that the primary treatment group difference would be significant if the trial had been allowed to continue to its planned completion.

The indications for rescue PCI have been defined by a combination of clinical and electrocardiographic clues that an infarct artery has not reperfused. These are relief of pain and resolution of ST-segment elevation. Although complete relief of pain and complete resolution of ST elevation are reasonably predictive of reperfusion after fibrinolytic therapy, this is not a common occurrence. In the 2007 STEMI Focused Update, the writing committee held that at 90 minutes after initiation of fibrinolytic therapy, if there was less than 50% ST-segment resolution in the lead that showed the greatest degree of ST elevation at presentation, then fibrinolytic therapy had likely failed to reperfuse the patient (4). If the judgment was made that fibrinolytic therapy had not resulted in reperfusion after 90 minutes, then PCI performed at that time was labeled rescue PCI.

The 2007 STEMI Focused Update (4) recommended rescue PCI in the following cases: Fibrinolytic-treated STEMI patients meeting high-risk criteria (i.e., cardiogenic shock [less than 75 years of age, Class I; 75 years of age or older, Class IIa]); hemodynamic or electrical instability; persistent ischemic symptoms; and for certain moderate- and high-risk patients who did not strictly meet the above criteria (Class IIb). These recommendations were based on results of the REACT (Rescue Angioplasty Versus Conservative Treatment of Repeat Thrombolysis) trial (74) which showed a clear benefit of rescue PCI (over repeated doses of fibrinolytics or medical management) in moderate- to high-risk patients with failed reperfusion, as well as a meta-analysis of 8 rescue PCI trials (including REACT) (73- 76). The 2007 focused update acknowledged that the expected benefits of rescue PCI are greater the earlier it is initiated after the onset of ischemic symptoms.

Two new trials have helped inform this update: The CARESS-in-AMI trial and the TRANSFER-AMI trial. CARESS-in-AMI (15) studied 600 STEMI patients 75 years of age or younger with at least 1 high-risk feature (extensive ST-segment elevation, new-onset left bundle-branch block, previous MI, Killip class greater than 2, or left ventricular ejection fraction 35% or less) who were treated initially at non-PCI hospitals with half-dose reteplase, abciximab, heparin, and ASA within 12 hours of symptom onset (3). All patients were randomized to immediate transfer for PCI or to standard treatment with transfer for rescue PCI if needed. PCI was performed in 85.6% of patients in the immediate PCI group, and rescue PCI was performed in 30.3% of the standard treatment/transfer for rescue PCI group. There was a shorter median time from fibrinolytic therapy to transfer to a PCI-capable center in the immediate versus the rescue PCI group (110 versus 180 minutes, P<0.0001). Antiplatelet therapy with ASA and clopidogrel was used less frequently in the standard care/rescue arm than in the early intervention group. The primary outcome (composite of all-cause mortality, reinfarction, and refractory myocardial ischemia within 30 days of randomization) occurred significantly less often (4.4% versus 10.7%, P=0.004) in the immediate PCI group than in the standard care/rescue PCI group (NNT=17). There were no significant differences in the rates of major bleeding at 30 days (3.4% versus 2.3%, P=0.47) or stroke (0.7% versus 1.3%, P=0.50) between groups. These results suggest that high-risk STEMI patients treated at non-PCI hospitals with a preparatory pharmacological strategy of half-dose fibrinolytic therapy, abciximab, heparin, and ASA have improved outcomes when transferred immediately to a PCI facility rather than when medical therapy is continued with transfer for rescue PCI only if there is evidence of failed reperfusion.

The TRANSFER-AMI study (14) further tested the pharmacoinvasive strategy concept in high-risk STEMI patients. Accordingly, 1059 patients who presented to a non–PCI-capable hospital within 12 hours of symptom onset of STEMI who had at least 1 high-risk feature (greater than or equal to 2 mm of ST-segment elevation in 2 anterior leads, systolic blood pressure less than 100 mm Hg, heart rate higher than 100 bpm, Killip class II to III, 2 mm or more of ST-segment depression in the anterior leads, or 1 mm or more of ST elevation in right-sided lead V₄ indicative of right ventricular involvement for inferior MIs; anterior MI alone with 2 mm or more of ST-segment elevation in 2 or more leads also qualified) and who were treated with fibrinolytic therapy were randomized to a pharmacoinvasive strategy (immediate transfer for PCI within 6 hours of fibrinolytic therapy) or to standard treatment after fibrinolytic therapy, which included rescue PCI as required for ongoing chest pain and less than 50% resolution of ST elevation at 60 to 90 minutes or hemodynamic instability. Standard-treatment patients who did not require rescue PCI remained at the initial hospital for at least 24 hours, and coronary angiography within the first 2 weeks was encouraged.

All patients received standard-dose tenecteplase, ASA, and either UFH or enoxaparin. Clopidogrel loading (300 mg for patients 75 years of age or younger and 75 mg for those older than 75 years of age) was strongly encouraged in all study patients. GP IIb/IIIa receptor antagonists were administered at the PCI-capable hospitals according to standard practice at the institution. The primary end point of the trial was the 30-day composite of the first occurrence of death, reinfarction, recurrent ischemia, new or worsening heart failure, and cardiogenic shock.

The median time to administration of tenecteplase from onset of symptoms was approximately 2 hours in both groups, whereas the median time from tenecteplase administration to catheterization was 2.8 hours in the pharmacoinvasive group and 32.5 hours in the standard-treatment group. Coronary angiography was performed in 98.5% versus 88.7% and PCI in 84.9% versus 67.4% of the pharmacoinvasive and standard-treatment groups, respectively.

The primary end point of the trial occurred in 11.0% of the pharmacoinvasive group compared with 17.2% of the standard-treatment group (RR 0.64; 95% CI 0.47 to 0.84; P=0.004). Importantly, the incidence of TIMI major and minor bleeding and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) (77) moderate and severe bleeding was not different between groups, although there was a higher incidence of GUSTO mild bleeding in the pharmacoinvasive group (13.0% compared with 9.0% in the standard-treatment group, P=0.036). The authors concluded that after treatment with fibrinolytic therapy in STEMI patients presenting to hospitals without PCI capability, transfer to a PCI center to undergo coronary angiography and PCI should be initiated immediately without waiting to determine whether reperfusion has occurred. These results lend further support to the routine, early transfer of high-risk, fibrinolytic-treated patients to a PCI center for early PCI supported by contemporary antiplatelet and antithrombotic therapy.

On the basis of this evidence, a pathway has been suggested for the care of STEMI patients that has been divided into those patients presenting to a PCI-capable facility and those presenting to a non–PCI-capable facility (Appendix 5). Those seen at a PCI-capable facility should be moved expeditiously to the catheterization laboratory, with appropriate antithrombotic therapy for catheterization and PCI if appropriate. There has been discussion about whether the recommended door-to-balloon time (or first medical contact–to-balloon time) should be greater than 90 minutes, with the recognition that in certain patients, the mortality advantage of primary PCI compared with fibrinolytic therapy is maintained with more prolonged door-to-balloon times (78). However, the writing groups continue to believe that the focus should be on developing systems of care to increase the number of patients with timely access to primary PCI rather than extending the acceptable window for door-to-balloon time (79). Moreover, in a study of 43 801 patients with STEMI undergoing primary PCI within the National Cardiovascular Data Registry, any delay in time to reperfusion after arrival at the hospital was associated with a higher adjusted risk of in-hospital mortality in a continuous, nonlinear fashion (30 minutes=3.0%, 60 minutes=3.5%, 90 minutes=4.3%, 120 minutes=5.6%, 150 minutes=7.0%, and 180 minutes=8.4%; P<0.001) (80). Rather than accepting a 90-minute door-to-balloon benchmark for primary PCI, these data suggest an as-soon-as-possible standard.

Those patients presenting to a non–PCI-capable facility should be triaged to fibrinolytic therapy or immediate transfer for PCI. This decision will depend on multiple clinical observations that allow judgment of the mortality risk of the STEMI, the risk of fibrinolytic therapy, the duration of the symptoms when first seen, and the time required for transport to a PCI-capable facility (3). If primary PCI is chosen, the patient will be transferred for PCI. If fibrinolytic therapy is chosen, the patient will receive the agent(s), and a judgment as to whether the patient is high risk or not will be made. If high risk, the patient should receive appropriate antithrombotic therapy and be moved immediately to a PCI-capable facility for diagnostic catheterization and consideration of PCI. If not high risk, the patient may be moved to a PCI-capable facility after receiving antithrombotic therapy or may be observed in the initial facility.

Patients best suited for transfer for PCI are those STEMI patients who present with high-risk features, those with high bleeding risk from fibrinolytic therapy, and patients presenting late, that is, more than 4 hours after onset of symptoms. The decision to transfer is a judgment made after consideration of the time required for transport and the capabilities of the receiving hospital (2,5). Patients best suited for fibrinolytic therapy are those who present early after symptom onset with low bleeding risk. After fibrinolytic therapy, if the patient is not at high risk, transfer to a PCI-capable facility may be considered, especially if symptoms persist and failure to reperfuse is suspected.

The duration of symptoms should continue to serve as a modulating factor in selecting a reperfusion strategy for STEMI patients. Although patients at high risk (e.g., those with congestive heart failure, shock, and contraindications to fibrinolytic therapy) are best served with timely PCI, “inordinate delays between the time from symptom onset and effective reperfusion with PCI may prove deleterious, especially among the majority of STEMI patients at relatively low risk” (p 1299) (81). Accordingly, each community and each facility in that community should have an agreed-upon plan for how STEMI patients are to be treated. This includes which hospitals should receive STEMI patients from emergency medical services units capable of obtaining diagnostic ECGs, management at the initial receiving hospital, and written criteria and agreements for expeditious transfer of patients from non–PCI-capable to PCI-capable facilities (82).

The development of regional systems of STEMI care is a matter of utmost importance (83- 84). 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 (85). 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 National Cardiovascular Data Registry ACTION Registry, the AHA's “Get With The Guidelines” quality improvement program, and those performance-measurement systems required by the Joint Commission and the Centers for Medicare and Medicaid Services (86- 89). More recently, the AHA has promoted its “Mission: Lifeline” initiative, which was developed to encourage closer cooperation and trust among prehospital emergency services, and cardiac care professionals (90). The evaluation of STEMI care delivery across traditional care-delivery boundaries with these tools and other resources is imperative to identify systems problems and to enable the application of modern quality improvement methods, such as Six Sigma, to make necessary improvements (70,91- 93) .

(See Table 6.) (94- 96)

As detailed in the 2004 STEMI guideline and the 2007 UA/NSTEMI guideline revision, randomized trial evidence supported the use of insulin infusion to control hyperglycemia (3,97). A recently published randomized clinical trial of intensive versus conventional glucose control in critically ill patients raised uncertainty regarding the optimal level to target when achieving glucose control. NICE-SUGAR, 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 less than 180 mg/dL, with reduction and discontinuation of insulin if the blood glucose level dropped below 144 mg/dL) (16). Time-weighted glucose levels achieved were 115±18 mg/dL in the intensive glucose control group versus 144±23 mg/dL in the conventional glucose control group. The risk of death was increased at 90 days in the intensive glucose control group by 2.6% (27.5% versus 24.9%; odds ratio 1.14; 95% CI 1.02 to 1.08; P=0.02; number needed to harm=38). The result remained the same after adjustment 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 (94,98). Overall, the hospital course and proximate causes of death were similar in the 2 groups. Excess deaths in the intensive-control group were predominantly due to cardiovascular causes (absolute difference 5.8%; P=0.02). More patients in the intensive-control group than in the conventional-control group were treated with corticosteroids.

Because NICE-SUGAR enrolled critically ill medical and surgical patients, the degree to which its results can be extrapolated to the management of patients with STEMI is unclear. Although recent data from a small, mechanistic cl