Author + information
- Published online January 15, 2008.
- American College of Cardiology/American Heart Association Task Force on Practice Guidelines,
- Developed in Collaboration With the Canadian Cardiovascular Society,
- Endorsed by the American Academy of Family Physicians,
- 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee,
- Elliott M. Antman, MD, FACC, FAHA, Co-Chair⁎,†,
- Paul W. Armstrong, MD, FACC, FAHA‡,§,
- Lee A. Green, MD, MPH∥,
- Lakshmi K. Halasyamani, MD¶,
- Judith S. Hochman, MD, FACC, FAHA⁎⁎,
- Harlan M. Krumholz, MD, FACC, FAHA††,
- Gervasio A. Lamas, MD, FACC⁎⁎ and
- Sidney C. Smith JR, MD, FACC, FAHA§§
- Mary Hand, MSPH, RN, FAHA, Co-Chair,
- Eric R. Bates, MD, FACC, FAHA,
- Charles J. Mullany, MB, MS, FACC,
- David L. Pearle, MD, FACC, FAHA and
- Michael A. Sloan, MD, FACC
2004 Writing Committee Members
Elliott M. Antman, MD, FACC, FAHA, Chair
Daniel T. Anbe, MD, FACC, FAHA
Paul W. Armstrong, MD, FACC, FAHA
Eric R. Bates, MD, FACC, FAHA
Lee A. Green, MD, MPH
Mary Hand, MSPH, RN, FAHA
Judith S. Hochman, MD, FACC, FAHA
Harlan M. Krumholz, MD, FACC, FAHA
Frederick G. Kushner, MD, FACC, FAHA
Gervasio A. Lamas, MD, FACC
Charles J. Mullany, MB, MS, FACC
Joseph P. Ornato, MD, FACC, FAHA
David L. Pearle, MD, FACC, FAHA
Michael A. Sloan, MD, FACC
Sidney C. Smith, JR, MD, FACC, FAHA
Task Force Members
Sidney C. Smith, JR, MD, FACC, FAHA, Chair
Alice K. Jacobs, MD, FACC, FAHA, Vice-Chair
Cynthia D. Adams, MSN, PHD, FAHA††
Jeffrey L. Anderson, MD, FACC, FAHA††
Christopher E. Buller, MD, FACC
Mark A. Creager, MD, FACC, FAHA
Steven M. Ettinger, MD, FACC
Jonathan L. Halperin, MD, FACC, FAHA††
Sharon A. Hunt, MD, FACC, FAHA††
Harlan M. Krumholz, MD, FACC, FAHA
Frederick G. Kushner, MD, FACC, FAHA
Bruce W. Lytle, MD, FACC, FAHA
Rick Nishimura, MD, FACC, FAHA
Richard L. Page, MD, FACC, FAHA
Barbara Riegel, DNSC, RN, FAHA††
Lynn G. Tarkington, RN
Clyde W. Yancy, MD, FACC
Table of Contents
1.1 Evidence Review......213
1.2 Organization of Committee and Relationships With Industry......214
1.3 Review and Approval......214
3. Beta Blockers......215
3.1 COMMIT/CCS-2 (Metoprolol)......216
4.1 Logistics of Care......217
5. Facilitated PCI......219
6. Immediate or Emergency Invasive Strategy and Rescue PCI......220
7. PCI After Fibrinolysis or for Patients Not Undergoing Primary Reperfusion......223
7.1 The Late Open Artery Hypothesis: Clinical Outcomes......223
7.2 The Late Open Artery Hypothesis: Angiographic Outcomes......223
8. Ancillary Therapy......224
11. Invasive Evaluation......232
12. Secondary Prevention......232
13. Antiplatelet Therapy......237
A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data upon which recommendations are based. In an effort to respond more quickly to new evidence, the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines has created a new “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 ACC and AHA have developed during their more than 20 years of partnership.
These updated guideline recommendations reflect a consensus of expert opinion following a thorough review that consisted primarily of late-breaking clinical trials identified through a broad-based vetting process as important to the relevant patient population and of other new data deemed to have an impact on patient care (see Section 1.1 for details on this focused update). It is important to note that 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:
• Publication in a peer-reviewed journal
• Large, randomized, placebo-controlled trial(s)
• Nonrandomized data deemed important on the basis of results that impact current safety and efficacy assumptions
• Strengths/weakness of research methodology and findings
• Likelihood of additional studies influencing current findings
• Impact on current performance measure(s) and/or likelihood of the need to develop new performance measure(s)
• Requests and requirements 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 other guidelines or guideline revisions
In analyzing the data and developing updated recommendations and supporting text, the focused update writing group used evidence-based methodologies developed by the ACC/AHA Task Force on Practice Guidelines, which are described elsewhere (1,2).
The schema for class of recommendation and level of evidence is summarized in Table 1, which also illustrates how the grading system provides estimates of the size of the treatment effect and 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 class of recommendation and level of evidence listed in the focused updates are based on consideration of the evidence reviewed in previous iterations of the guidelines as well as the focused update. Of note, the implications of older studies that have informed recommendations but have not been repeated in contemporary settings are carefully considered.
The ACC/AHA practice guidelines address patient populations (and health care 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 committee reviews the potential impact of different practice patterns and patient populations on the treatment effect and on the relevance to the ACC/AHA target population to determine whether the findings should inform a specific recommendation.
The ACC/AHA practice guidelines are intended to assist health care 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 health care 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 goal is quality of care and serving the patient’s best interests.
Prescribed courses of treatment in accordance with these recommendations are only effective if they are followed by the patient. Because lack of patient adherence may adversely affect treatment outcomes, health care providers should make every effort to engage the patient in active participation with prescribed treatment.
The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual, potential, or perceived conflict of interest arising from industry relationships or personal interests of a writing committee member. All writing committee members and peer reviewers were required to provide disclosure statements of all such relationships pertaining to the trials and other evidence under consideration (see Appendixes 1 and 2). Final recommendations were balloted to all writing committee members. Writing committee members with significant (greater than $10 000) relevant relationships with industry (RWI) were required to recuse themselves from voting on that recommendation. Writing committee members who did not participate are not listed as authors of this focused update.
With the exception of the recommendations presented here, the full guidelines remain current. Only the recommendations from the affected section(s) of the full guidelines are included in this focused update. For easy reference, all recommendations from any section of guidelines impacted by a change are presented with a notation as to whether they remain current, are new, or have been modified. When evidence impacts recommendations in more than 1 set of guidelines, those guidelines are updated concurrently.
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 January 15, 2008, issue of the Journal of the American College of Cardiology and the January 15, 2008, issue of Circulation as an update to the full-text guidelines and is also posted on the ACC (www.acc.org) and AHA (www.americanheart.org) Web sites. Copies of the focused update are available from both organizations.
Sidney C. Smith, Jr., MD, FACC, FAHA, Chair, ACC/AHA Task Force on Practice Guidelines, Alice K. Jacobs, MD, FACC, FAHA, Vice-Chair, ACC/AHA Task Force on Practice Guidelines
1.1 Evidence Review
Late-breaking clinical trials presented at the 2005 and 2006 annual scientific meetings of the ACC, AHA, and European Society of Cardiology, as well as selected other data, 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 might impact guidelines 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 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction [see Chen ZM et al. (3); Chen ZM et al. (4); ASSENT-4 PCI (5); Antman EM et al. (6); Yusuf S et al. (7); Bhatt DL et al. (8); Sabatine MS et al. (9); Bennett JS et al. (10); Smith SC Jr et al. (11); OAT (12,13) and TOSCA (14)].
When considering the new data for this focused update, the writing group faced the task of weighing evidence from studies enrolling 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, might influence the observed magnitude of a treatment effect, the writing group believed the data were relevant to formulation of recommendations for management of ST-elevation myocardial infarction (STEMI) in North America. The reasons for this decision include that 1) a broad array of management strategies was represented, including substantial proportions of subjects who received some form of reperfusion therapy, 2) concomitant treatments with proven efficacy (e.g., aspirin, beta blockers, inhibitors of the renin-angiotensin-aldosterone system, and statins) were used in the majority of patients, and 3) it was considered an impractical expectation that the tens of thousands of patients with STEMI needed to meet the estimated sample size for contemporary clinical trials be enrolled exclusively at North American sites.
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 (ARD) and number needed to treat (NNT) or harm (NNH); the relative treatment effects are described either as odds ratio (OR), relative risk (RR), or hazard ratio (HR), depending on the format in the original publication.
Consult the full-text version or executive summary of the 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (15) 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 and Relationships With Industry
For this focused update, all members of the 2004 STEMI writing committee were invited to participate; those who agreed (referred to as the 2007 focused update writing group) were required to disclose all RWI relevant to the data under consideration (2). Focused update writing group members who had no significant relevant RWI wrote the first draft of the focused update; the draft was then reviewed and revised by the full writing group. Each recommendation required a confidential vote by the writing group members before external review of the document. Any writing committee member with a significant (greater than $10 000) relationship with industry relevant to the recommendation was recused from voting on that recommendation.
1.3 Review and Approval
This document was reviewed by 3 outside reviewers nominated by the ACC and 3 outside reviewers nominated by the AHA, as well as 1 reviewer each from the American Academy of Family Physicians and the Canadian Cardiovascular Society (CCS) and 58 individual content reviewers. All reviewer RWI information was collected and distributed to the writing committee and is published in this document (see Appendix 2 for details).
This document was approved for publication by the governing bodies of the American College of Cardiology Foundation and the American Heart Association and endorsed by the American Academy of Family Physicians and the Canadian Cardiovascular Society.
Analysis of retrospective data (16) has raised a question about the potentially adverse effects of morphine in patients with unstable angina (UA)/non–ST-elevation myocardial infarction (NSTEMI). As a result, the recommendation for morphine pain relief has been reduced to a Class IIa recommendation for that patient population. Use of morphine remains a Class I recommendation for patients with STEMI, however, because STEMI patients should either have received reperfusion or are not candidates for reperfusion, and continuing pain requires relief in either case (Table 2).
Because of the known increased risk of cardiovascular events among patients taking cyclooxygenase-2 (COX-2) inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs) (17–19), these drugs should be discontinued immediately at the time of STEMI (see 2004 STEMI Guidelines, Section 7.12.5, for additional discussion) (3,15,20,21). A substudy analysis from the ExTRACT TIMI-25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction) trial (22) demonstrated an increased risk of death, reinfarction, heart failure, or shock among patients who were taking NSAIDs within 7 days of enrollment. Longer-term management considerations and a discussion of the gradient of risk with the various NSAIDS are found in Section 7.12.5 of the 2004 STEMI Guidelines (15).
3 Beta Blockers
The 2004 STEMI Guidelines recommendations (Table 3) were based on studies that showed a reduced incidence of subsequent reinfarction and recurrent ischemia in patients receiving both fibrinolytic therapy and intravenous (IV) beta blockers. However, uncertainty about the use of IV beta blockers in the setting of fibrinolytic therapy has increased following 2 later randomized trials of IV beta blockade (23,24), a post-hoc analysis of the use of atenolol in the GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) trial (25), and a review of early beta-blocker therapy in myocardial infarction (MI) (26) that did not find significant reductions in mortality (15).
3.1 COMMIT/CCS-2 (Metoprolol)
The COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study) (4) randomized 45 852 patients within 24 hours of onset of suspected MI to receive metoprolol (up to 3 doses of 5 mg IV each in the first 15 minutes, followed by 200 mg orally daily) or matching placebo. Fifteen minutes after the IV doses, a 50-mg tablet of metoprolol or placebo was administered orally and repeated every 6 hours during Days 0 to 1 of hospitalization. From Day 2 onward, 200 mg of controlled-release metoprolol or placebo was administered orally daily (this is the Food and Drug Administration [FDA]-approved regimen for metoprolol in MI) until discharge from the hospital or up to a maximum of 4 weeks in hospital (in survivors, the mean was 15 days). The 2 prespecified co-primary outcomes were the composite of death, reinfarction, or cardiac arrest and death from any cause during the scheduled treatment period.
Neither of the co-primary study end points was significantly reduced by allocation to metoprolol. For every 1000 patients treated, allocation to metoprolol was associated with 5 fewer episodes of reinfarction, 5 fewer episodes of ventricular defibrillation, but 11 more episodes of cardiogenic shock. The excess of cardiogenic shock was seen chiefly from Days 0 to 1 after hospitalization, whereas the reductions in reinfarction and ventricular fibrillation appeared from Day 2 onward.
Allocation to metoprolol produced an average relative increase in cardiogenic shock of 30%, with higher rates for those greater than 70 years of age, or with systolic blood pressure less than 120 mm Hg, or with presenting heart rate greater than 110 bpm, or with Killip class greater than 1. On average across the whole study population, the absolute reduction in arrhythmia-related deaths and the absolute increase in cardiogenic shock–related deaths were of similar magnitude. No apparent difference was noted between the 2 treatment groups in the other attributed causes of death, either individually or in aggregate. Metoprolol allocation was associated with significantly more persistent hypotension and more cases of bradycardia.
Though patients at high or low risk could be identified, the authors noted that they were not able to identify any subgroups in which the benefits clearly outweighed the risks.
This focused update expands on the concepts introduced in the 2004 STEMI Guidelines, underscoring the potential risk of administering IV beta blockers to patients with severe heart failure or cardiogenic shock. There are several circumstances in which it can be useful (Class IIa) to administer an IV beta blocker acutely to a STEMI patient (Table 3), and these situations are discussed below. It is reasonable to administer IV beta-blocker therapy on Days 0 to 1 of hospitalization for STEMI when hypertension is present and the patient is not at an increased risk of cardiogenic shock on the basis of the risk factors defined above. Patients with sinus tachycardia or atrial fibrillation should have left ventricular (LV) function rapidly evaluated before administration of IV beta blockers (or other negative inotropes, such as non-dihydropyridine calcium channel blockers). From Day 2 onward, when beneficial effects on reinfarction and ventricular fibrillation are seen, administration of 200 mg of controlled-release oral metoprolol daily appears to be safe in hemodynamically stable patients with STEMI who are free of contraindications. It is prudent to initiate a dose of 50 mg of metoprolol orally every 6 hours, transitioning to a dose equivalent to 200 mg per day orally or the maximum tolerated dose. It should be noted that long-term use of oral beta blockers is strongly recommended (Class I, Level of Evidence: A) for secondary prevention in patients at highest risk, such as those with low ejection fraction, heart failure, or postshock, once they have stabilized, with gradual dose titration (27) (see the 2004 STEMI Guidelines, Sections 7.4.1 and 7.12.7) (15).
The results of the COMMIT-CCS 2 trial raise questions about the safety of early use of IV beta blockers, particularly in high-risk populations, and led the writing group to reexamine the overall evidence base for beta-blocker therapy. The evidence base for this therapy was developed more than 25 years ago in a treatment environment that differs from contemporary practice. Moreover, no study included an oral beta blocker–only arm. The writing group consensus, however, was not to change the classification of the current early oral beta-blocker recommendation but to restrict it to patients who are not at high risk for complications. In addition, because of the absence of a study that specifically evaluated oral therapy alone, the Level of Evidence has been changed from A to B. Nevertheless, early (within 24 hours) oral beta-blocker therapy remains a Class I recommendation for those patients who are not at high risk for complications. Whether this change should affect current performance measures is beyond the scope of this document. The findings of potential risk of beta-blocker therapy in COMMIT emphasize the importance of continually monitoring these patients throughout hospitalization for signs and symptoms of complications of therapy, as noted in other sections of the original guidelines (Sections 126.96.36.199, 7.4.1, and 7.12.7). Because of the uncertainty about the benefit of oral beta blockers early on (e.g., in COMMIT-CCS 2, Days 0 to 1), the writing group recommends further research and additional examination at the time of the next revision to the STEMI Guidelines.
4.1 Logistics of Care
Regardless of the mode of reperfusion, the overarching concept is to minimize total ischemic time, which is defined as the time from onset of symptoms of STEMI to initiation of reperfusion therapy. It is increasingly clear that 2 types of hospital systems provide reperfusion therapy: those with percutaneous coronary intervention (PCI) capability and those without PCI capability. When PCI capability is available, the best outcomes are achieved by offering this strategy 24 hours per day, 7 days per week (28). The systems goal should be a first medical contact–to-balloon time within 90 minutes (Table 4,Figure 1). There should be an ongoing program of outcomes analysis and periodic case review to identify process-of-care strategies that will continually improve time to treatment and facilitate rapid and appropriate treatment. A comprehensive effort in this regard is the AHA Mission Lifeline program, a community-based national initiative to improve the quality of care and outcomes of patients with STEMI by improving health care system readiness and response to STEMI (29). The “Door-to-Balloon (D2B): An Alliance for Quality” campaign (www.d2balliance.org), launched by the ACC in collaboration with many organizations, including the AHA, aims to improve the timeliness of primary PCI. The goal is to increase the percentage of patients who receive timely primary PCI, with an emphasis on having at least 75% of patients treated within 90 minutes of presentation at the hospital, with a recommendation for the use of evidence-based strategies to reduce needless delays (30). The 75% goal was set in recognition that some patients have clinically relevant non–system-based delays that do not represent quality-of-care issues. In hospitals without PCI capability, immediate transfer for primary PCI is a treatment option when the expected door-to-balloon time is within 90 minutes of first medical contact (31,32).
It is important to note that the door-to-balloon goal is a systems goal that may not be possible to achieve for an individual patient because of patient variables (uncertainty about diagnosis, evaluation and treatment of other life-threatening conditions, obtaining informed consent, etc.) that delay the patient’s arrival in the interventional cardiology laboratory or anatomical challenges (issues of arterial, coronary, or lesion access) that prolong the PCI procedure. In the absence of such circumstances, however, reperfusion should be achieved as soon as possible within this time, and many hospitals with refined systems are approaching median door-to-balloon times of 60 to 70 minutes. Discussions about measurement, particularly with respect to inclusion criteria and the appropriate time to end measurement, are beyond the scope of this document and are being considered by groups that are focusing on how to improve the alignment between what is measured and patient outcomes. The focus on measurement should not displace the emphasis on improving processes that will facilitate more rapid treatment that is delivered safely and appropriately. This committee continues to endorse the concept that faster times to reperfusion and better systems of care are associated with important reductions in morbidity and mortality rates in patients with STEMI. An underutilized but effective strategy for improving systems of care for STEMI patients is to expand the use of prehospital 12-lead electrocardiography programs by emergency medical systems (EMS) that provide advanced life support (33,34).
The emphasis on primary PCI should not obscure the importance of fibrinolytic therapy. Many hospital systems in North America do not have the capability of meeting the time goal for primary PCI (35). Therefore, because of the critical importance of time to treatment from onset of symptoms of STEMI in reducing morbidity and mortality, fibrinolytic therapy is preferred. In these settings, transfer protocols need to be in place for arranging rescue PCI when clinically indicated (36).
For fibrinolytic therapy, the system goal is to deliver the drug within 30 minutes of the time that the patient presents to the hospital (Table 4). The focus for primary PCI is from first medical contact because in regionalization strategies, extra time may be taken to transport patients to a center that performs the procedure. Consequently, it is important to consider the time from first medical contact. The writing group does believe that every effort should be made to reduce the time from first medical contact to fibrinolytic therapy when that is considered the appropriate reperfusion strategy.
5 Facilitated PCI
Facilitated PCI refers to a strategy of planned immediate PCI after administration of an initial pharmacological regimen intended to improve coronary patency before the procedure. These regimens have included high-dose heparin, platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduced-dose fibrinolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent (e.g., fibrinolytic dose typically reduced 50%). Facilitated PCI should be differentiated from primary PCI without fibrinolytic therapy, from primary PCI with a GP IIb/IIIa inhibitor started at the time of PCI, from early or delayed PCI after successful fibrinolytic therapy, and from rescue PCI after unsuccessful fibrinolytic therapy. Potential advantages of facilitated PCI include earlier time to reperfusion, smaller infarct size, improved patient stability, lower infarct artery thrombus burden, greater procedural success rates, higher TIMI (Thrombolysis in Myocardial Infarction trial) flow rates, and improved survival rates. Potential risks include increased bleeding complications, especially in older patients. Potential limitations include additional cost (37).
Despite the potential advantages, clinical trials of facilitated PCI have not demonstrated any benefit in reducing infarct size or improving outcomes. The largest of these was the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention) trial (5), in which 1667 patients were randomized to receive full-dose tenecteplase and PCI versus primary PCI. The trial was terminated prematurely because of a higher in-hospital mortality rate in the facilitated PCI group (6% vs. 3%; p=0.01). The primary end point, a composite of death, shock, and congestive heart failure within 90 days, was significantly higher with facilitated PCI than with primary PCI (18.6% vs. 13.4%; p=0.0045), and there was a trend toward a higher 90-day mortality rate (6.7% vs. 4.9%; p=0.14). Defenders of the facilitated PCI strategy point out that the absence of an infusion of heparin after bolus administration and the absence of a loading dose of clopidogrel, plus prohibition of GP IIb/IIIa inhibitors except in bail-out situations, made adjunctive antithrombotic therapy suboptimal for the facilitated PCI group. Moreover, the median treatment delay between administration of tenecteplase and PCI was only 104 minutes, and mortality rates were higher in PCI centers. The evidence on whether earlier (prehospital) administration of fibrinolytic therapy, better antithrombotic therapy, longer delays to PCI, or selective use of PCI as a rescue strategy would make the facilitated PCI strategy beneficial is unclear. These issues require further study. On the basis of these data, however, facilitated PCI offered no clinical benefit.
Keeley and coworkers performed a quantitative review of 17 trials that compared facilitated PCI with primary PCI (38) (Figure 2). Nine trials involved GP IIb/IIIa inhibitors alone (n=1148), 6 trials with fibrinolytic therapy (including ASSENT-4 PCI) (n=2953), and 2 trials with a fibrinolytic agent plus a GP IIb/IIIa inhibitor (n=399). Facilitated PCI with fibrinolytic therapy had significantly higher rates of mortality, nonfatal reinfarction, urgent target-vessel revascularization, total and hemorrhagic stroke, and major bleeding compared with primary PCI. There were no differences in efficacy or safety when facilitated PCI with a GP IIb/IIIa inhibitor was compared with primary PCI.
A planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI may be harmful (Table 5). Nevertheless, selective use of the facilitated strategy with regimens other than full-dose fibrinolytic therapy in subgroups of patients at high risk (large MI or hemodynamic or electrical instability) with low risk of bleeding who present to hospitals without PCI capability might be performed when transfer delays for primary PCI are anticipated. Although quantitative analysis showed no advantage for pretreatment with a GP IIb/IIIa inhibitor, it did not document any major disadvantage either. The use of GP IIb/IIIa inhibitors, particularly abciximab, during primary PCI is well established (55). Further trials of reduced-dose fibrinolytic therapy, with or without GP IIb/IIIa inhibitors, are in progress and may yield different efficacy and/or safety results.
6 Immediate or Emergency Invasive Strategy and Rescue PCI
Pharmacological reperfusion with full-dose fibrinolysis is not uniformly successful in restoring antegrade flow in the infarct artery. In such situations, a strategy of prompt coronary angiography with intent to perform PCI is frequently contemplated. In certain patients, such as those with cardiogenic shock (especially those less than 75 years of age), severe congestive heart failure/pulmonary edema, or hemodynamically compromising ventricular arrhythmias (regardless of age), a strategy of coronary angiography with intent to perform PCI is a useful approach regardless of the time since initiation of fibrinolytic therapy, provided further invasive management is not considered futile or unsuitable given the clinical circumstances (Table 6). Further discussion of the management of such patients may be found in the 2004 STEMI Guidelines (see Section 188.8.131.52.4.6, as well as Sections 7.6.3 through 7.6.6) (15). These sections have not been updated in this document.
In other patients who do not exhibit the clinical instability noted above, PCI may also be reasonable if there is clinical suspicion of failure of fibrinolysis. This is referred to as rescue PCI. Critical to the success of rescue PCI is the initial clinical identification of patients who are suspected of having failed reperfusion with full-dose fibrinolysis. Because the presence or absence of ischemic discomfort may be unreliable for identifying failed reperfusion, clinicians should search for evidence of inadequate ST-segment resolution on the 12-lead electrocardiogram (ECG). Operationally, the 12-lead ECG should be scrutinized after adequate time has elapsed before it is decided that fibrinolytic therapy has not been effective. Although earlier times have been used in some studies, the writing committee believed that 90 minutes after initiation of fibrinolysis was the best time point for evaluating the need for rescue PCI; hence, if there is less than 50% ST resolution in the lead showing the greatest degree of ST-segment elevation at presentation, fibrinolytic therapy has likely failed to produce reperfusion.
The 2004 STEMI Guidelines recommendations for rescue PCI were based on observational data and the results of 2 small randomized clinical trials (n=179) from the early 1990s (56,57). More recently, MERLIN (Middlesbrough Early Revascularization to Limit INfarction) (n=307), REACT (Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis) (n=427), and 3 meta-analyses have refocused attention on rescue PCI (58–62). This subject has been studied with fewer than 1000 patients enrolled in randomized trials.
In the period between trials studying rescue PCI, there was a transition between angiographic and electrocardiographic diagnosis to detect failed reperfusion. Importantly, in the earlier studies, rescue PCI was performed in infarct arteries with TIMI 0/1 flow, often after a protocol-mandated 90-minute angiogram. In MERLIN and REACT, however, patients were randomized if they had less than 50% ST-segment elevation resolution at 60 or 90 minutes, respectively. Many patients had patent infarct arteries on angiography; only 54% of patients in MERLIN and 74% of patients in REACT (which required less than TIMI grade 3 flow for PCI) actually underwent PCI. From a procedural standpoint, stents have replaced balloon angioplasty, antiplatelet therapy has improved with the addition of a thienopyridine agent and often a GP IIb/IIIa receptor antagonist, and procedural success rates are higher.
Despite these historical differences, recent data support the initial observation that rescue PCI decreases adverse clinical events compared with medical therapy. In the Wijeysundera meta-analysis (62) (Figure 3), there was a trend toward reduced mortality rates with rescue PCI from 10.4% to 7.3% (RR 0.69 [95% confidence interval (CI) 0.46 to 1.05]; p=0.09), reduced reinfarction rates from 10.7% to 6.1% (RR 0.58 [95% CI 0.35 to 0.97]; p=0.04), and reduced heart failure rates from 17.8% to 12.7% (RR 0.73 [95% CI 0.54 to 1.00]; p=0.05). These event rates suggest that high-risk patients were selected for enrollment, so these data do not inform the clinical community about the role of rescue PCI in lower-risk patients. Also, the benefits of rescue PCI need to be balanced against the risk. There was an excess occurrence of stroke in 2 trials (10 events vs. 2 events), but the majority of the strokes were thromboembolic rather than hemorrhagic, and the sample size was small, so more data are needed to define this risk. There also was an increase in absolute risk of bleeding of 13%, suggesting that adjustments in antithrombotic medication dosing are needed to improve safety. It should be noted that the majority of patients who underwent rescue PCI received fibrinolytic therapy with streptokinase.
Given the association between bleeding events and subsequent ischemic events (63), it might be reasonable to select moderate- and high-risk patients for PCI after fibrinolysis and to treat low-risk patients with medical therapy. As noted above, patients with cardiogenic shock, severe heart failure, or hemodynamically compromising ventricular arrhythmias are excellent candidates. An ECG estimate of potential infarct size in patients with persistent ST-segment elevation (less than 50% resolution at 90 minutes following initiation of fibrinolytic therapy in the lead showing the worst initial evaluation) and ongoing ischemic pain is useful for selecting other patients for rescue PCI. Anterior MI or inferior MI with right ventricular involvement or precordial ST-segment depression usually predicts increased risk (64). Conversely, patients with symptom resolution, improving ST-segment elevation (less than 50% resolution), or inferior MI localized to 3 ECG leads probably should not be referred for angiography. Likewise, it is doubtful that PCI of a branch artery (diagonal or obtuse marginal branch) will change prognosis in the absence of high-risk criteria noted above.
7 PCI After Fibrinolysis or for Patients Not Undergoing Primary Reperfusion
As described in the 2004 STEMI Guidelines, PCI has been performed immediately after successful fibrinolytic therapy, hours to days after successful fibrinolytic therapy, and days to weeks after successful fibrinolytic therapy (15). With the increase in use of an invasive strategy, consideration is now also given to PCI in patients who did not undergo fibrinolysis, and this concept is reflected in the decision of the writing committee to rename this section to reflect considerations for PCI both after fibrinolytic therapy and in STEMI patients who do not undergo primary reperfusion. See the 2004 STEMI Guidelines, Section 184.108.40.206, and updates herein to Sections 220.127.116.11.4.4 and 18.104.22.168.4.5 for additional discussions bearing on PCI after fibrinolysis.
7.1 The Late Open Artery Hypothesis: Clinical Outcomes
The open artery hypothesis suggested that late patency of an infarct artery is associated with improved LV function, increased electrical stability, and provision of collateral vessels to other coronary beds for protection against future events. The OAT (Occluded Artery Trial) (12,13) tested the hypothesis that routine PCI for total occlusion 3 to 28 days after MI would reduce the composite of death, reinfarction, or Class IV heart failure. Stable patients (n=2166) with an occluded infarct artery after MI (about 20% of whom received fibrinolytic therapy for the index event) were randomized to optimal medical therapy and PCI with stenting or optimal medical therapy alone. The qualifying period of 3 to 28 days was based on calendar days; thus, the minimal time from symptom onset to angiography was just over 24 hours. Inclusion criteria included total occlusion of the infarct-related artery with TIMI grade 0 or 1 antegrade flow and left ventricular ejection fraction (LVEF) less than 50% or proximal occlusion of a major epicardial artery with a large risk region. Exclusion criteria included NYHA Class III or IV heart failure, rest angina, serum creatinine greater than 2.5 mg per dL, left main or 3-vessel disease, clinical instability, or severe inducible ischemia on stress testing if the infarct zone was not akinetic or dyskinetic (12). The 4-year cumulative end point was 17.2% in the PCI group and 15.6% in the medical therapy group (HR 1.16 [95% CI 0.92 to 1.45]; p=0.2) (13). Reinfarction rates tended to be higher in the PCI group, which may have attenuated any benefit in LV remodeling. There was no interaction between treatment effect and any subgroup variable.
7.2 The Late Open Artery Hypothesis: Angiographic Outcomes
Preclinical studies have suggested that late opening of an occluded infarct artery may reduce adverse LV remodeling and preserve LV volumes. However, 5 previous clinical studies in 363 patients have demonstrated inconsistent improvement in LVEF or LV end-systolic and end-diastolic volumes after PCI. The largest of these, the DECOPI (DEsobstruction COronaire en Post-Infarctus) trial, found a higher LVEF at 6 months with PCI (65). TOSCA-2 (Total Occlusion Study of Canada) (14) enrolled 381 stable patients in a mechanistic ancillary study of OAT and had the same eligibility criteria (12,13). The PCI procedure success rate was 92% and the complication rate was 3%, although 9% had periprocedural MI as measured by cardiac biomarkers. At 1 year, patency rates (n=332) were higher with PCI (83% vs. 25%; p less than 0.0001), but each group (n=286) had equivalent improvement in LVEF (4.2% vs. 3.5%; p=0.47). There was modest benefit of PCI in preventing LV dilation over 1 year in a multivariate model, but only 42% had paired volume determinations, so it is unclear whether this finding extends to the whole cohort. The potential benefit of PCI in attenuating remodeling may have been decreased by periprocedural MI and the high rate of beta blocker and angiotensin-converting enzyme (ACE) inhibitor use. There was no significant interaction between treatment effect and time, infarct artery, or infarct size.
These studies demonstrate that elective PCI of an occluded infarct artery 1 to 28 days after MI in stable patients had no incremental benefit beyond optimal medical therapy with aspirin, beta blockers, ACE inhibitors, and statins in preserving LV function and preventing subsequent cardiovascular events (Table 7).
8 Ancillary Therapy
2004 STEMI Guidelines—Section 22.214.171.124.8.1. Anticoagulants as Ancillary Therapy to Reperfusion Therapy
Since publication of the 2004 STEMI Guidelines (15), a number of studies have provided data that inform the recommendations on ancillary therapy to support reperfusion therapy for STEMI. In recognition that many agents capable of inhibiting the coagulation cascade may inhibit proteins other than thrombin, the writing group decided to change the nomenclature for this section. Therefore, the term anticoagulants is used in place of the prior term antithrombins. Also, although the material discussed below crosses several subsections in the 2004 STEMI Guidelines (Sections 126.96.36.199.8.1.1 and 188.8.131.52.8.1.2), because of a number of common issues, the writing group has elected to describe the updates on anticoagulant therapy collectively in this section.
Unfractionated heparin (UFH) is commonly administered to patients receiving fibrinolytic therapy. With limited evidence supporting the benefits of prolonged infusions of UFH and because of the progressive increase in the risk of heparin-induced thrombocytopenia (both rapid- and delayed-onset presentations) (66,67), the 2004 STEMI Guidelines recommended that infusions of UFH be given routinely for 48 hours but be given for a longer period only in patients with an ongoing indication for anticoagulation (15,68,69). Although no new trials specifically focusing on UFH in STEMI were reported, a number of studies have compared alternative anticoagulant regimens with UFH or placebo. Importantly, each study tested a strategy that involved administering the new regimen (reviparin, fondaparinux, or enoxaparin) for the duration of the index hospitalization; that is, longer than current practice and longer than recommended in the 2004 STEMI Guidelines. In addition, some of the new anticoagulant regimens used dosing schemes that were based on patient weight, age, or both. With the exception of reviparin, the details of the dosing schemes are noted in the recommendations above; the text below refers simply to the name of the anticoagulant regimen. Major efficacy and safety observations from the main trial and important subgroups reported to date are shown in Table 9.
The CREATE (Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin beta) trial was a randomized, double-blind comparison of a strategy of low-molecular-weight heparin (LMWH) reviparin versus placebo in 15 570 patients with STEMI enrolled in China and India (70). Although reviparin is not available for clinical use in North America, the writing group felt that the data from the CREATE trial were informative to clinicians and supported the data from the trials discussed subsequently. The dosing regimen for reviparin was as follows: for patients weighing less than 50 kg, subcutaneous injections of 3436 IU Ph Eur anti-Xa units every 12 hours; for patients weighing 50 to 75 kg, subcutaneous injections of 5153 IU Ph Eur anti-Xa units every 12 hours; and for patients weighing more than 75 kg, subcutaneous injections of 6871 IU Ph Eur anti-Xa units every 12 hours. Reviparin was continued for the duration of the index hospitalization, up to 1 week. Fibrinolytic therapy (predominantly non–fibrin-specific agents) was administered to 73% of the CREATE trial population, and it was recommended that the study drugs be started within 15 minutes of initiation of fibrinolysis. A total of 76% of the trial population received blinded study therapy for 7 days (see Table 9).
The OASIS-6 (Organization for the Assessment of Strategies for Ischemic Syndromes) trial was an international, randomized, double-blind comparison of fondaparinux, a synthetic factor Xa inhibitor, versus control therapy (either placebo or UFH) in 12 092 patients enrolled in 41 countries (7). Patients for whom the treating physician thought UFH was not indicated (e.g., non–fibrin-specific fibrinolytic administered) were enrolled in stratum I and received placebo in the control arm; patients for whom the treating physician thought UFH was indicated (e.g., fibrin-specific fibrinolytic administered or primary PCI performed) were enrolled in stratum II and received UFH in the control arm. The median duration of fondaparinux therapy was 8 days in stratum I and 7 days in stratum II (compared with 45 hours of UFH). Within the trial population, 2867 patients (23.7%) did not receive any reperfusion therapy and, depending on physician preference, were enrolled in either stratum I or II (see Table 9).
The ExTRACT-TIMI 25 trial was an international, double-blind comparison of a strategy of enoxaparin versus UFH in 20 506 patients enrolled in 48 countries who presented within 6 hours after the onset of STEMI and for whom fibrinolytic therapy was planned (6). Because prior trials reported that bleeding with enoxaparin was increased in elderly patients, a novel dosing regimen was devised for patients 75 years of age or older, and strict attention was paid to dose reduction in patients with significantly impaired renal function to minimize the accumulation of anti-Xa activity (71,72). The median duration of treatment was 7 days with enoxaparin and 2 days for UFH (see Table 9).
Some patients who receive pharmacological reperfusion with a fibrinolytic are referred for PCI. Consideration must be given to the anticoagulant regimen to support PCI in the face of preceding (upstream) anticoagulant therapy. The CREATE, OASIS-6, and ExTRACT-TIMI 25 trials took different approaches to the selection of anticoagulants to support PCI. Both CREATE and OASIS-6 included subsets of patients undergoing primary PCI; ExTRACT-TIMI 25 did not study patients undergoing primary PCI. In CREATE, patients in both the reviparin and placebo groups received open-label UFH at the time of PCI. In OASIS-6, the protocol recommended an IV bolus of fondaparinux (2.5 to 5.0 mg, depending on whether the patient received open-label UFH and/or GP IIb/IIIa inhibitors before randomization) (see Table 9). The number of patients in whom catheter thrombosis was observed was 0 in the UFH group and 22 in the fondaparinux group (p less than 0.001) (7). When the subset of patients who received both open-label UFH and fondaparinux was analyzed, the number of catheter thromboses was 0 in the UFH group and 2 in the fondaparinux group.
In ExTRACT-TIMI 25, patients were maintained on the allocated anticoagulant as they moved from the medical to PCI phase of treatment (n=2178) or received open-label anticoagulant at the treating physician’s discretion if performed after 8 days (n=2498). Among the patients allocated to enoxaparin, a dose of 0.3 mg per kg was administered intravenously if the last subcutaneous dose was 8 to 12 hours earlier, whereas no additional enoxaparin was administered if the last subcutaneous dose was administered within the prior 8 hours. UFH was dosed according to the activated clotting time (ACT), using a target of 200 seconds for patients receiving a GP IIb/IIIa inhibitor and 250 seconds for those not receiving a GP IIb/IIIa inhibitor (73). The main observations (Table 9) were the same whether the results were analyzed by intention to treat or by the actual anticoagulant received during the procedure (blinded study or open-label anticoagulant if PCI was performed after Day 8) (73).
The writing group felt that several important messages emerged from the CREATE, OASIS-6, and ExTRACT-TIMI 25 trials, and these are reflected in the updated recommendations (Table 8) and summarized in Table 10. Anticoagulant therapy is beneficial in patients with STEMI, and there is benefit in more prolonged anticoagulant therapy (duration of index hospitalization) in patients receiving fibrinolytics, as seen in the comparisons of reviparin versus placebo (CREATE), fondaparinux versus placebo (stratum I in OASIS-6), and enoxaparin versus UFH (ExTRACT-TIMI 25). The mechanism of benefit from a more prolonged anticoagulant regimen is probably multifactorial and includes a longer exposure to anticoagulants to prevent rethrombosis of the infarct artery and prevention of the rebound increase in events seen after abrupt discontinuation of UFH infusions. Concern was raised about a rebound increase in events after abrupt discontinuation of UFH infusions in patients with UA/NSTEMI (74), but this also appears to occur in patients with STEMI (6). The optimum method of terminating treatment with UFH has not been rigorously established for patients with either UA/NSTEMI or STEMI, but it is common clinical practice to simply discontinue UFH infusions. Finally, when the new anticoagulant regimens are compared with UFH as an active control, the greater degree of inhibition of the proximal portion of the coagulation cascade may lead to a greater reduction in thrombin generation.
Of note, reviparin, enoxaparin, and fondaparinux all involve, at least in part, clearance via the renal route. Hence, the potential exists for accumulation of anti-Xa activity with increasing degrees of renal failure. On the basis of available data, recommendations have been formulated for baseline creatinine cut points when a patient is considered for one of the new regimens. Also, estimation of creatinine clearance should be calculated via the Cockcroft-Gault formula rather than the Modification of Diet and Renal Disease (MDRD) equation, because the former has been used to modify dosing in clinical trials (75). The writing group endorses further research into the optimum anticoagulant regimen in patients with moderate degrees of renal dysfunction. This group has not been studied extensively and may be at an increased risk of bleeding, which has been seen in contemporary dosing regimens. The group also recommends head-to-head comparative studies to evaluate newer anticoagulant drugs (e.g., fondaparinux, enoxaparin, bivalirudin) to assess optimal anticoagulant therapy in patients with STEMI; such studies could provide more clinically useful information than comparisons against UFH or no anticoagulant.
When added to previous data, the benefits of anticoagulation therapy started concurrently with non–fibrin-specific fibrinolytic agents (e.g., streptokinase) seen with all 3 of the new anticoagulation regimens led the writing group to recommend the use of an anticoagulant across the spectrum of fibrinolytic agents in common clinical use (6,7,70,76,77).
When moving to PCI after fibrinolytic therapy, those patients who received upstream UFH or enoxaparin can continue to receive those anticoagulants in a seamless fashion (i.e., without crossover to another agent) using the dosing regimens listed in the recommendations (73). On the basis of the reports of catheter thrombosis with fondaparinux alone during primary PCI in OASIS-6 and the experience with fondaparinux in the OASIS-5 trial (78), the writing group thought fondaparinux should not be used as the sole anticoagulant during PCI but should be coupled with an additional agent that has anti-IIa activity to ameliorate the risk of catheter complications. Although bivalirudin and UFH are potential options for supplemental anticoagulation with fondaparinux, the available experience, albeit limited, is largely with UFH. The only available data from the CREATE trial that bear on this point are with UFH.
Given the complexities of the characteristics of the individual agents and their actions on the coagulation cascade, clinicians are cautioned about extrapolating any of the observations with agents discussed in this update to other anticoagulant regimens. In particular, as noted by the FDA, LMWHs are sufficiently distinct that they should be evaluated individually rather than considered as a class of interchangeable agents (79).
The writing group also advises clinicians against drawing comparisons between the new anticoagulant regimens across trials because of the nonrandomized nature of such comparisons and the inability to ensure comparability of baseline characteristics for the populations in the trials. Finally, the writing group strongly cautions clinicians against overinterpretation of subgroup analyses in the trials listed in Table 9 (e.g., reperfusion with either fibrinolytics or PCI versus no reperfusion; reperfusion with various categories of fibrinolytics; and comparison of the new anticoagulant strategy versus placebo or UFH). Subgroup comparisons are less statistically robust than the main trial results because of their nonrandomized nature, the lack of statistical power to discern true differences in treatment effects, and the need to account for multiple comparisons. Nonsignificant interaction tests should not be used to definitively assert a lack of heterogeneity of treatment effects across subgroups, as such analyses are relatively weak statistical tests, especially in the case of small sample sizes in subgroups (80–83). In the case of the data in Table 9, an additional layer of complexity—a mixture of comparisons between placebo and an active comparator (UFH)—was introduced. The approach taken in Table 9 was to provide the point estimate and 95% CI of the treatment effect in various subgroups to allow readers to see the range of possible treatment effects (82).
The writing group encourages randomization of additional patients in future trials to clarify a number of questions, such as 1) the benefits of reviparin compared with UFH in patients receiving fibrin-specific fibrinolytics or undergoing PCI, 2) the relative benefits of fondaparinux compared with UFH in patients receiving non–fibrin-specific and fibrin-specific fibrinolytics, as well as those patients not undergoing reperfusion, and 3) the relative benefits of enoxaparin compared with UFH in patients undergoing primary PCI and those not receiving reperfusion therapy.
The 2004 STEMI Guidelines made no specific recommendation related to dual antiplatelet therapy with clopidogrel plus low-dose aspirin for a broad population of patients at high risk for atherothrombotic events. Clopidogrel has previously been shown to benefit patients with documented atherosclerosis (recent MI, recent stroke, established peripheral arterial disease, PCI, and NSTEMI). Since publication of the 2004 STEMI Guidelines, 2 trials have been reported that provide data supporting expansion of the use of clopidogrel to the STEMI end of the acute coronary syndrome spectrum (84).
The COMMIT-CCS-2 study randomized 45 852 patients within 24 hours of suspected MI at 1250 hospitals in China to 75 mg of clopidogrel daily (without a loading dose) or placebo in addition to 162 mg of aspirin daily (3). In the trial population, 93% had ST-segment elevation or bundle-branch block, 7% had ST-segment depression, and 54% were treated with fibrinolysis (predominantly urokinase). There was no upper age limit. The mean age was 61 years; 26% of patients were 70 years of age or older. Twenty-eight percent were women. The study drug treatment was to continue until hospital discharge or up to 4 weeks; mean treatment duration was 14.9 days (25th, 50th, and 75th percentiles: 9, 14, and 21 days, respectively). The composite primary end point of death, reinfarction, or stroke was reduced from 10.1% in the placebo group to 9.2% in the clopidogrel group (OR 0.91 [95% CI 0.86 to 0.97]; p=0.002). Benefit with clopidogrel tended to be seen in the subgroups of patients who did and did not receive fibrinolytic therapy. The co-primary end point of all-cause mortality was reduced from 8.1% in the placebo group to 7.5% in the clopidogrel group (OR 0.93 [95% CI 0.87 to 0.99]; p=0.03; NNT=167). The rate of cerebral and major noncerebral bleeding was 0.55% in the placebo group and 0.58% in the clopidogrel group (p=0.59).
The CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28) study randomized 3491 patients (18 to 75 years of age) receiving fibrinolytic therapy within 12 hours of STEMI to clopidogrel (300 mg oral loading dose; 75 mg oral daily maintenance dose) or placebo (9). The primary composite efficacy end point of an occluded infarct artery on angiography or death or recurrent MI before angiography (between 48 and 192 hours after the start of study medication) occurred in 21.7% of the placebo group and 15.0% of the clopidogrel group (OR 0.64 [95% CI 0.53 to 0.76]; p less than 0.001). The benefit of clopidogrel was driven largely by the reduction in rate of an occluded infarct artery, which appears to have been accomplished by preventing infarct-related reocclusion rather than by facilitating early reperfusion (85). The rate of TIMI major bleeding through 30 days was 1.7% in the placebo group and 1.9% in the clopidogrel group (p=0.80). When interpreting the safety of clopidogrel, especially in the face of a loading dose of 300 mg, it is important to note that subjects were excluded from CLARITY-TIMI 28 if they had received more than 4000 U of UFH before randomization.
The patients in the clopidogrel arm of CLARITY-TIMI 28 who underwent PCI constitute a group who were pretreated with clopidogrel and provide a comparison with those in the placebo arm who underwent PCI without pretreatment (86). The composite end point of cardiovascular death, recurrent MI, or stroke from PCI to 30 days after enrollment was 6.2% in the non-pretreatment group and 3.6% in the pretreatment group (OR 0.54 [95% CI 0.35 to 0.85]; p=0.008) (86). There was no significant difference in the rates of the composite of TIMI major or minor bleeding in the pretreatment versus non-pretreatment groups (2.0% vs. 1.9%; p greater than 0.99).
The writing group felt that the COMMIT-CCS-2 and CLARITY-TIMI 28 trials provided evidence for benefit of adding clopidogrel to aspirin in patients undergoing fibrinolytic therapy (Table 11). The COMMIT-CCS-2 trial also supported the use of clopidogrel in patients who were not receiving reperfusion therapy. Although the available data suggest that the oral maintenance dose should be 75 mg daily, uncertainty exists about the efficacy and safety of adding a loading dose to elderly patients (more than 75 years of age), especially when they receive a fibrinolytic. Thus, the writing group does not recommend a loading dose in the elderly who receive a fibrinolytic and endorses further research to define the optimum clopidogrel regimen in the elderly. On the basis of the CLARITY-TIMI 28 study, it appears that the administration of clopidogrel at the time of initial fibrinolytic therapy is of benefit when PCI is performed subsequently. No data are available from clinical trials regarding long-term clopidogrel treatment in STEMI patients. Extrapolating from experience in patients with UA/NSTEMI, as well as those patients undergoing coronary stenting, the writing committee felt that long-term therapy with clopidogrel (e.g., 1 year) can be useful in patients with STEMI (Class IIa; Level of Evidence: C) (Table 11). Clinicians should consult Figure 37 in Section 7.12.11 of the 2004 STEMI Guidelines for guidance when the patient has concurrent indications for oral anticoagulation (15).
In August 2006, the FDA approved the use of clopidogrel for the treatment of patients with STEMI to reduce the rate of death from any cause and the rate of the combined end point of death, reinfarction, or stroke (87).
In the 2004 STEMI Guidelines, anticoagulant therapy with UFH was recommended for patients not receiving reperfusion with the goal of reducing mortality and reinfarction rates. In patients with UA/NSTEMI, treatment with LMWH is recommended with a similar goal, as well as for prevention of episodes of recurrent ischemia. Since publication of the 2004 STEMI Guidelines, 2 trials (CREATE and OASIS-6) have extended the database on which such recommendations were formulated by providing evidence of the benefit of anticoagulant therapy in STEMI patients who do not receive reperfusion therapy (see Tables 9 and 10).
Although 2 contemporary trials provided internally consistent findings of benefit of prolonged anticoagulant therapy (duration of the index hospitalization) in patients not receiving reperfusion therapy, the nonreperfusion groups were subgroups that represented only about 22% of the trial populations. Also, the patients were enrolled largely at sites that may have had different practice patterns than in North America, and there is uncertainty about the exact magnitude of the treatment effect of anticoagulants in the absence of more widespread use of clopidogrel. Because of these issues, the writing group concluded that a Class IIa, Level of Evidence: B recommendation should be assigned (Table 12). Convenient strategies that may be used include those with LMWH (Level of Evidence: C) or fondaparinux (Level of Evidence: B) using the same dosing regimens as those for patients who receive fibrinolytic therapy (Table 12). See the 2004 STEMI Guidelines, Section 8 (updates to Section 184.108.40.206.8.1) (15).
11 Invasive Evaluation
The committee has revised the recommendations for invasive evaluation (Table 13).
12 Secondary Prevention
Table 14 contains revised recommendations adapted from the 2006 AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease (11). This table replaces Table 32 from the 2004 STEMI Guidelines (15). Classes of recommendation and a corresponding level of evidence have been added for all recommendations. New recommendations for clopidogrel have been added to the section on antiplatelet agents/anticoagulants: clopidogrel 75 mg per day should be added to aspirin in patients with STEMI for at least 14 days whether patients undergo reperfusion with fibrinolysis or do not receive reperfusion therapy (i.e., all post-PCI nonstented STEMI patients). The benefits of clopidogrel are likely to continue with longer duration of treatment, although there are no data from randomized controlled trials beyond 30 days. This section has also been modified slightly to reflect the recent evidence on aspirin dosage for patients who have undergone PCI with stent placement.
Other changes since the 2001 AHA/ACC Secondary Prevention Guidelines (88) include the addition of recommended daily physical activity, a recommendation for lowered low-density lipoprotein cholesterol, and a new recommendation for an annual influenza vaccination.
13 Antiplatelet Therapy
The selective COX-2 inhibitors and other nonselective NSAIDs have been associated with increased cardiovascular risk. The risk appears to be amplified in patients with established cardiovascular disease (15,18,19).
Gislason et al. analyzed the risk of rehospitalization for MI and death related to the use of NSAIDs, including selective COX-2 inhibitors, in patients with prior MI (17). All patients with first-time MI between 1995 and 2002 and all prescription claims for NSAIDs after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was studied with the use of multivariable proportional hazards models and case-crossover analysis. A total of 58 432 patients were discharged alive and included in the study; 9773 were rehospitalized for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib; 4.3%, celecoxib; 17.5%, ibuprofen; 10.6%, diclofenac; and 12.7%, other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs, the HR and 95% CI for death were 2.80 (2.41 to 3.25), 2.57 (2.15 to 3.08), 1.50 (1.36 to 1.67), 2.40 (2.09 to 2.80), and 1.29 (1.16 to 1.43), respectively. There were dose-related increases in risk of death for all the drugs and non–dose-dependent trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and nonselective NSAIDs (17).
An AHA scientific statement on the use of NSAIDs concluded that the risk of cardiovascular events is proportional to COX-2 selectivity and the underlying risk in the patient (20). Nonpharmacological approaches were recommended as the first line of treatment, followed by the stepped-care approach to pharmacological therapy shown in Figure 4 (Table 15). Although not preferred, analgesic doses of aspirin may be a reasonable option for some patients. This approach provides an antiplatelet effect but confers a higher risk of bleeding than low-dose aspirin plus another analgesic (89).
American College of Cardiology Foundation
John C. Lewin, MD, Chief Executive Officer
Charlene May, Director, Clinical Policy and Documents
Lisa Bradfield, Associate Director, Practice Guidelines
Allison B. McDougall, Specialist, Practice Guidelines
Mark D. Stewart, MPH, Associate Director, Evidence-Based Medicine
Sue Keller, BSN, MPH, Senior Specialist, Evidence-Based Medicine
Erin A. Barrett, Senior Specialist, Clinical Policy and Documents
American Heart Association
M. Cass Wheeler, Chief Executive Officer
Rose Marie Robertson, MD, FACC, FAHA, Chief Science Officer
Judy Bezanson, DSN, CNS, RN, Science and Medicine Advisor
↵‡‡ Former Task Force member during this writing effort
This document is a limited update to the 2004 guidelines update and is based on a review of certain evidence, not a full literature review.
This document was approved by the American College of Cardiology Board of Trustees in October 2007 and by the American Heart Association Science Advisory and Coordinating Committee October 2007.
The American College of Cardiology Foundation and the American Heart Association request that this document be cited as follows: Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC Jr. 2007 focused update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2008;51:210–47.
This article has been copublished in the January 15, 2008, issue of Circulation.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org) and the American Heart Association (www.americanheart.org). For copies of this document, please contact Elsevier Inc, Reprint Department, fax 212-633-3820, or e-mail .
Permissions: Modification, alteration, enhancement and/or distribution of this document are not permitted without the express permission of the American College of Cardiology and the American Heart Association. Please contact 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.
- American College of Cardiology Foundation and the American Heart Association, Inc.
- Gibbons R.J.,
- Smith S.,
- Antman E.
- 2.↵Antman EM. Manual for ACC/AHA Guideline Writing Committees: Methodologies and Policies from the ACC/AHA Task Force on Practice Guidelines. 2004. Available at: http://www.acc.org/qualityandscience/clinical/manual/pdfs/methodology.pdf Accessed September 24, 2007.
- Bennett J.S.,
- Daugherty A.,
- Herrington D.,
- Greenland P.,
- Roberts H.,
- Taubert K.A.
- Smith S.C. Jr..,
- Allen J.,
- Blair S.N.,
- et al.
- Dzavik V.,
- Buller C.E.,
- Lamas G.A.,
- et al.
- Antman E.M.,
- Anbe D.T.,
- Armstrong P.W.,
- et al.
- Gislason G.H.,
- Jacobsen S.,
- Rasmussen J.N.,
- et al.
- Kearney P.M.,
- Baigent C.,
- Godwin J.,
- Halls H.,
- Emberson J.R.,
- Patrono C.
- Antman E.M.,
- Bennett J.S.,
- Daugherty A.,
- Furberg C.,
- Roberts H.,
- Taubert K.A.
- Timmers L.,
- Sluijter J.P.,
- Verlaan C.W.,
- et al.
- Gibson C.M.,
- Murphy S.A.,
- McCabe C.H.,
- Morrow D.A.,
- Antman E.,
- Braunwald E.,
- Association of treatment with non-steroidal anti-inflammatory agents (NSAIDS) on study entry with 30 day adverse outcomes among ST elevation MI (STEMI) patients treated with a fibrinolytic agent
- Roberts R.,
- Rogers W.J.,
- Mueller H.S.,
- et al.
- van de Werf F.,
- Janssens L.,
- Brzostek T.,
- et al.
- Pfisterer M.,
- Cox J.L.,
- Granger C.B.,
- et al.
- Freemantle N.,
- Cleland J.,
- Young P.,
- Mason J.,
- Harrison J.
- Lopez-Sendon J.,
- Swedberg K.,
- McMurray J.,
- et al.
- Nallamothu B.K.,
- Wang Y.,
- Magid D.J.,
- et al.
- Jacobs A.K.,
- Antman E.M.,
- Faxon D.P.,
- Gregory T.,
- Solis P.
- Dalby M.,
- Bouzamondo A.,
- Lechat P.,
- Montalescot G.
- Garvey J.L.,
- MacLeod B.A.,
- Sopko G.,
- Hand M.M.
- Nallamothu B.K.,
- Bates E.R.,
- Herrin J.,
- Wang Y.,
- Bradley E.H.,
- Krumholz H.M.
- Pinto D.S.,
- Kirtane A.J.,
- Nallamothu B.K.,
- et al.
- Sinno M.C.,
- Khanal S.,
- Al-Mallah M.H.,
- Arida M.,
- Weaver W.D.
- van’t Hof A.W.,
- Ernst N.,
- de Boer M.J.,
- et al.
- Lee D.P.,
- Herity N.A.,
- Hiatt B.L.,
- et al.
- Gabriel H.M.,
- Oliviera J.A.,
- da Silva P.C.,
- et al.
- Arntz H.R.,
- Schroeder J.,
- Pels K.,
- Schwimmbeck P.,
- Witzenbichler B.,
- Schultheiss H.
- Gyongyosi M.,
- Domanovits H.,
- Benzer W.,
- et al.
- Zeymer U.,
- Zahn R.,
- Schiele R.,
- et al.
- O’Neill W.W.,
- Weintraub R.,
- Grines C.L.,
- et al.
- Widimsky P.,
- Groch L.,
- Zelizko M.,
- Aschermann M.,
- Bednar F.,
- Suryapranata H.
- Vermeer F.,
- Oude Ophuis A.J.,
- vd Berg E.J.,
- et al.
- Ross A.M.,
- Coyne K.S.,
- Reiner J.S.,
- et al.
- Fernandez-Aviles F.,
- Alonso J.,
- Castor-Beiras A.,
- et al.
- ADVANCE MI Investigators
- Montalescot G.,
- Antoniucci D.,
- Kastrati A.,
- et al.
- Ellis S.G.,
- da Silva E.R.,
- Heyndrickx G.,
- et al.
- Sutton A.G.,
- Campbell P.G.,
- Graham R.,
- et al.
- Collet J.P.,
- Montalescot G.,
- Le M.M.,
- Borentain M.,
- Gershlick A.
- Wijeysundera H.C.,
- Vijayaraghavan R.,
- Nallamothu B.K.,
- et al.
- Bates E.R.
- Steg P.G.,
- Thuaire C.,
- Himbert D.,
- et al.
- 66.↵(2004) Heparin Sodium Injection, USP (Baxter Healthcare Corp, Deerfield, Ill) [Package Insert].
- Thompson P.L.,
- Aylward P.E.,
- Federman J.,
- et al.
- Wallentin L.,
- Goldstein P.,
- Armstrong P.W.,
- et al.
- Antman E.M.,
- Morrow D.A.,
- McCabe C.H.,
- et al.
- Gibson C.M.,
- Murphy S.A.,
- Montalescot G.,
- et al.
- White H.
- Peters R.J.,
- Joyner C.,
- Bassand J.-P.,
- et al.
- Wallentin L.C.,
- Mehta S.R.,
- Afzal R.,
- et al.
- Giraldez R.R.,
- Nicolau J.C.,
- Corbalan R.,
- et al.
- White H.D.,
- Braunwald E.,
- Murphy S.A.,
- et al.
- Weiner R.B.,
- O’Donoghue M.
- Scirica B.M.,
- Sabatine M.S.,
- Morrow D.A.,
- et al.
- Bridgewater N.
- Chobanian A.V.,
- Bakris G.L.,
- Black H.R.,
- et al.,
- National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National High Blood Pressure Education Program Coordinating Committee
- Smith S.C. Jr..,
- Blair S.N.,
- Bonow R.O.,
- et al.
- Antithrombotic Trialists’ Collaboration
- Armstrong P.W.,
- Collen D.,
- Antman E.
- 2004 Writing Committee Members
- Task Force Members
- Table of Contents
- 1 Introduction
- 2 Analgesia
- 3 Beta Blockers
- 4 Reperfusion
- 5 Facilitated PCI
- 6 Immediate or Emergency Invasive Strategy and Rescue PCI
- 7 PCI After Fibrinolysis or for Patients Not Undergoing Primary Reperfusion
- 8 Ancillary Therapy
- 9 Thienopyridines
- 10 Anticoagulants
- 11 Invasive Evaluation
- 12 Secondary Prevention
- 13 Antiplatelet Therapy