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J Am Coll Cardiol, 2008; 51:210-247, doi:10.1016/j.jacc.2007.10.001
(Published online 10 December 2007). © 2008 by the American College of Cardiology Foundation |
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,
* Chair of 2004 Writing Committee
Recused from voting on Section 8: Anticoagulants as Ancillary Therapy and Section 10: Anticoagulants
Recused from voting on Section 5: Facilitated PCI
Canadian Cardiovascular Society Representative
|| American Academy of Family Physicians Representative
¶ American College of Physicians Representative
** Recused from voting on Section 7: PCI After Fibrinolysis or for Patients Not Undergoing Primary Reperfusion
Performance Measures Liaison
Former Task Force member during this writing effort
Recused from voting on Section 13: Antiplatelet Therapy
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2004 Writing Committee Members |
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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
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Task Force Members |
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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
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Table of Contents |
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Preamble |
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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:
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.
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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.
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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
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1. Introduction |
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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).
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2. Analgesia |
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3. Beta Blockers |
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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.
3.2 Conclusion. 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 6.3.1.5, 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.
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4. Reperfusion |
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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.
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5. Facilitated PCI |
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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.
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6. Immediate or Emergency Invasive Strategy and Rescue PCI |
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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.
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7. PCI After Fibrinolysis or for Patients Not Undergoing Primary Reperfusion |
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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.
7.3 Conclusion. 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).
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8. Ancillary Therapy |
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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 6.3.1.6.8.1.1 and 6.3.1.6.8.1.2), 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 (
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2004 Writing Committee Members
Task Force Members
There is a contraindication to fibrinolysis.
Transport to non–PCI-capable hospital
