This is the current release of the guideline.

This guideline updates a previous version: Ohman EM, Harrington RA, Cannon CP, Agnelli G, Cairns JA, Kennedy JW. Intravenous thrombolysis in acute myocardial infarction. Chest 2001 Jan;119(1 Suppl):253S-277S.

Acute myocardial infarction (MI)

Treatment

Cardiology
Critical Care
Emergency Medicine
Family Practice
Internal Medicine

Physicians

• To provide an evidence-based set of recommendations for the use of fibrinolytic therapy in acute myocardial infarction (MI)
• To focus on approved agents and the randomized trials that have led to their widespread utilization
• To discuss the utility of adjunctive antithrombotic therapies, such as aspirin, clopidogrel, intravenous (IV) unfractionated heparin (UFH), low molecular weight heparin (LMWH), glycoprotein (GP) IIb/IIIa inhibitors, and direct thrombin inhibitors (DTIs)
• To detail limitations and complications associated with fibrinolytic therapy
• To compare outcomes with thrombolysis and primary angioplasty (although a complete review of the two different reperfusion strategies is beyond the scope of this document)

Patients with acute myocardial infarction (MI)

Treatment

1. Intravenous (IV) fibrinolytic therapy
   • Streptokinase
   • Anistreplase
   • Alteplase
   • Reteplase
   • Tenecteplase

   Note: Urokinase, single-chain urokinase-type plasminogen activator, lanoteplase, and staphylokinase were considered but not recommended.

2. Aspirin in combination with fibrinolytic therapy
3. Clopidogrel in combination with fibrinolytic therapy
4. Unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in combination with fibrinolytic therapy
5. Direct thrombin inhibitors (DTIs) in combination with fibrinolytic therapy (recommended only as an alternative to heparin in patients with suspected heparin-induced thrombocytopenia)
   • Hirudin with tissue plasminogen activator (tPA)
   • Bivalirudin with streptokinase

   Note: Adjunctive therapy with other direct thrombin inhibitors, such as desirudin, and lepirudin were considered but not recommended. In addition, adjunctive therapy with glycoprotein (GP) IIb/IIIa receptor blockers (abciximab) was considered but not recommended.

Evaluation of Therapeutic Efficacy

1. Angiographic assessment of epicardial coronary flow
2. Electrocardiogram (ECG) evaluation
3. Activated partial thromboplastin time (aPTT)

• Effectiveness and safety of fibrinolytic therapy for acute myocardial infarction as defined by the following:
  • Rates of mortality
  • Rates of intracranial hemorrhage or other major bleeding
  • Patency of infarct-related artery
  • Incidence of recurrent ischemia
  • Recurrence of myocardial infarction
• Cost-effectiveness

Hand-searches of Published Literature (Primary Sources)
Searches of Electronic Databases

Not stated

Weighting According to a Rating Scheme (Scheme Given)

The rating scheme framework captures the trade-off between benefits and risks (1 or 2) (and the methodological quality of the underlying evidence (A, B, C+, or C). See "Rating Scheme for the Strength of the Recommendations."

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Summarizing Evidence

The electronic searches also included searching for systematic reviews. If authors were satisfied with a recent high-quality systematic review, evidence from that review provided a foundation for the relevant recommendation.

Pooled analyses from high-quality systematic reviews formed, wherever possible, the evidence base of the recommendations. Pooling offers the advantage of obtaining more precise estimates of treatment effects and allows for a greater generalizability of results. However, pooling also bears the risk of spurious generalization. In general, the summary estimates of interest were the different types of outcomes conveying benefit and downsides (i.e., risk, burden, and cost).

Expert Consensus (Consensus Development Conference)

The strength of any recommendation depends on the following two factors: the trade-off between the benefits and the risks, burdens, and costs; and the strength of the methodology that leads to the treatment effect. The guideline developers grade the trade-off between benefits and risks in the two categories: 1, in which the trade-off is clear enough that most patients, despite differences in values, would make the same choice; and 2, in which the trade-off is less clear, and individual patients’ values will likely lead to different choices.

When randomized trials provide precise estimates suggesting large treatment effects, and the risks and costs of therapy are small, treatment for average patients with compatible values and preferences can be confidently recommended.

If the balance between benefits and risks is in doubt, methodologically rigorous studies providing Grade A evidence and recommendations may still be weak (Grade 2). Uncertainty may come from less precise estimates of benefit, harm, or costs, or from small effect sizes.

There is an independent impact of validity and consistency, and the balance of positive and negative impacts of treatment on the strength of recommendations. In situations in which there is doubt about the value of the trade-off, any recommendation will be weaker, moving from Grade 1 to Grade 2.

Grade 1 recommendations can only be made when there is a relatively clear picture of both the benefits and the risks, burdens, and costs, and when the balance between the two clearly favors recommending or not recommending the intervention for the typical patient with compatible values and preferences. A number of factors can reduce the strength of a recommendation, moving it from Grade 1 to Grade 2. Uncertainty about a recommendation to treat may be introduced if the following conditions apply: (1) the target event that is trying to be prevented is less important (confident recommendations are more likely to be made to prevent death or stroke than asymptomatic deep vein thrombosis); (2) the magnitude of risk reduction in the overall group is small; (3) the probability of the target event is low in a particular subgroup of patients; (4) the estimate of the treatment effect is imprecise, as reflected in a wide confidence interval (CI) around the effect; (5) there is substantial potential harm associated with therapy; or (6) there is an expectation for a wide divergence in values even among average or typical patients. Higher costs would also lead to weaker recommendations to treat.

The more balanced the trade-off between benefits and risks, the greater the influence of individual patient values in decision making. Virtually all patients, if they understand the benefits and risks, will take aspirin after experiencing a myocardial infarction (MI) or will comply with prophylaxis to reduce the risk of thromboembolism after undergoing hip replacement. Thus, one way of thinking about a Grade 1 recommendation is that variability in patient values is unlikely to influence treatment choice in average or typical patients.

When the trade-off between benefits and risks is less clear, individual patient values may influence treatment decisions even among patients with average or typical preferences.

Grade 2 recommendations are those in which variation in patient values or individual physician values will often mandate different treatment choices, even among average or typical patients. An alternative, but similar, interpretation is that a Grade 2 recommendation suggests that clinicians conduct detailed conversations with patients to ensure that their ultimate recommendation is consistent with the patient's values.

*These situations include RCTs with both lack of blinding and subjective outcomes, where the risk of bias in measurement of outcomes is high, or RCTs with large loss to follow-up.

While conference participants agreed that recommendations should reflect economic considerations, incorporating costs is fraught with difficult challenges. For most recommendations, formal economic analyses are unavailable. Even when analyses are available, they may be methodologically weak or biased. Furthermore, costs differ radically across jurisdictions, and even sometimes across hospitals within jurisdictions.

Because of these challenges, the guideline developers consider economic factors only when the costs of one therapeutic option over another are substantially different within major jurisdictions in which clinicians make use of these recommendations. As a result, in jurisdictions in which resource constraints are severe, alternative allocations may serve the health of the public far better than some of the interventions that are designated as Grade 1A. This will likely be true for all less industrialized countries and, with the increasing promotion of expensive drugs with marginal benefits, may be increasingly true for wealthier nations. Furthermore, recommendations change (either in direction or with respect to grade) only when the guideline developers believe that costs are high in relation to benefits. Instances in which costs have influenced recommendations are labeled in the "values and preferences" statements associated with the recommendation.

Cost-effectiveness of Alteplase in Comparison to Streptokinase

A formal cost-effectiveness analysis was incorporated into the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-I) protocol as a substudy in the United States and Canada. At 1 year, alteplase-treated patients had both higher costs ($2,845) and higher survival (an absolute 1.1% higher rate, or 11 more patients surviving per 1,000 patients treated) compared with streptokinase-treated patients. The incremental cost-effectiveness ratio was $32,678 per year of life saved. The cost-effectiveness of alteplase was more favorable in patients with anterior myocardial infarction (MI) but less favorable in those with inferior myocardial infarction and of young age.

External Peer Review
Internal Peer Review

The guideline authors formulated draft recommendations prior to the conference that served as the foundation for authors to work together and critique the recommendations. Drafts of all articles including draft recommendations were available for review during the conference. A representative of each article presented potentially controversial issues in their recommendations at plenary meetings. Article authors met to integrate feedback, to consider related recommendations in other articles, and to revise their own guidelines accordingly. Authors continued this process after the conference until they reached agreement within their groups and with other author groups who had provided critical feedback. Finally, the editors of this supplement harmonized the articles and resolved remaining disagreements through facilitated discussion.

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Appropriate use of fibrinolytic therapy in acute myocardial infarction (MI) has been demonstrated to have a statistically significant mortality benefit over placebo

• The main complication of fibrinolytic therapy is bleeding, with the most dreaded complication being intracranial hemorrhage (ICH).
• The excess stroke risk associated with fibrinolytic therapy largely is attributable to the excess risk of ICH.

Subgroups Most Likely to be Harmed

• Several patient characteristics are associated with a higher risk of ICH. Table 9 in the original guideline document summarizes predictors of ICH after fibrinolysis for acute myocardial infarction (MI), the highest predictor being advanced age.
• Several patient characteristics (age, Killip class, and infarct location) are associated with higher 30-day mortality.

The guideline developers recommend against administration of fibrinolytic therapy in patients with any history of intracranial hemorrhage (ICH), closed head trauma, or ischemic stroke within past 3 months.

Interpreting the Recommendations

Clinicians, third-party payers, institutional review committees, or the courts should not construe these guidelines in any way as absolute dictates. In general, anything other than a Grade 1A recommendation indicates that the article authors acknowledge that other interpretations of the evidence, and other clinical policies, may be reasonable and appropriate. Even Grade 1A recommendations will not apply to all circumstances and all patients. For instance, the guideline developers have been conservative in their considerations of cost and have seldom downgraded recommendations from Grade 1 to Grade 2 on the basis of expense. As a result, in jurisdictions in which resource constraints are severe, alternative allocations may serve the health of the public far better than some of the interventions that we designate Grade 1A. This will likely be true for all less industrialized countries and, with the increasing promotion of expensive drugs with marginal benefits, may be increasingly true for wealthier nations.

Similarly, following Grade 1A recommendations will at times not serve the best interests of patients with atypical values or preferences or of those whose risks differ markedly from those of the usual patient. For instance, consider patients who find anticoagulant therapy extremely aversive, either because it interferes with their lifestyle (e.g., prevents participation in contact sports) or because of the need for monitoring. Clinicians may reasonably conclude that following some Grade 1A recommendations for anticoagulation therapy for either group of patients will be a mistake. The same may be true for patients with particular comorbidities (e.g., a recent gastrointestinal bleed or a balance disorder with repeated falls) or other special circumstances (e.g., very advanced age) that put them at unusual risk.

The guideline developers trust that these observations convey their acknowledgment that no recommendations or clinical practice guidelines can take into account the often compelling and unique features of individual clinical circumstances. No clinician, and no body charged with evaluating a clinician’s actions, should attempt to apply our recommendations in a rote or blanket fashion.

Limitations of Guideline Development Methods

The limitations of these guidelines include the possibility that some authors followed this methodology more closely than others, although the development process was centralized and supervised by the editors. Second, it is possible that the guideline developers missed relevant studies despite the comprehensive searching process. Third, the guideline developers did not centralize the methodological evaluation of all studies to facilitate uniformity in the validity assessments of the research incorporated into these guidelines. Fourth, if high-quality meta-analyses were unavailable, the guideline developers did not statistically pool primary study results using meta-analysis. Finally, sparse data on patient preferences and values, resources, and other costs represent additional limitations that are inherent to most guideline development methods.

Guideline Implementation Strategies

A full review of implementation strategies for practice guidelines is provided in the companion document titled "Antithrombotic and Antithrombolytic Therapy: From Evidence to Application." The review suggests that there are few implementation strategies that are of unequivocal, consistent benefit, and that are clearly and consistently worth resource investment. The following is a summary of the recommendations (see "Major Recommendations" for a definition of the recommendation grades).

To encourage uptake of guidelines, the guideline developers recommend that appreciable resources be devoted to distribution of educational material (Grade 2B).

They also suggest that:

• Few resources be devoted to educational meetings (Grade 2B)
• Few resources be devoted to educational outreach visits (Grade 2A)
• Appreciable resources be devoted to computer reminders (Grade 2A)
• Appreciable resources be devoted to patient-mediated interventions to encourage uptake of the guidelines (Grade 2B)
• Few resources be devoted to audit and feedback (Grade 2B)

Getting Better

Effectiveness

Not applicable: The guideline was not adapted from another source.

2001 Jan (revised 2004 Sep)

American College of Chest Physicians - Medical Specialty Society

Funding was provided through an unrestricted educational grant by AstraZeneca LP, Aventis Pharmaceuticals, GlaxoSmithKline, Bristol-Myer Squibb/Sanofi-Synthelabo Partnership, and Organon Sanofi-Synthelabo LLC.

American College of Chest Physicians Consensus Panel on Antithrombotic and Thrombolytic Therapy

Primary Authors: Venu Menon, MD; Robert A. Harrington, MD; Judith S. Hochman, MD; Christopher P. Cannon, MD; Shaun D. Goodman, MD; Robert G. Wilcox, MD; Holger J. Schünemann, MD, PhD, FCCP; E. Magnus Ohman, MD, FCCP

Committee Co-Chairs: Jack Hirsh, MD, FCCP (Chair); Gregory W. Albers, MD; Gordon H. Guyatt, MD, MSc; Holger J. Schünemann, MD, MSc, PhD, FCCP

Participants: Giancarlo Agnelli, MD; Amin Al-Ahmad, MD; Pierre Amarenco, MD; Jack E. Ansell, MD; Shannon M. Bates, MD; Richard C. Becker, MD; Peter B. Berger, MD; David Bergqvist, MD, PhD, FRCS; Rebecca J. Beyth, MD, MSc; Stewart Brower, MLIS; Harry R. Buller, MD; Henry I. Bussey, PharmD, FCCP; Christopher P. Cannon, MD, FACC; Elizabeth A. Chalmers, MB, ChB, MD, MRCP(UK). FRCPath; Anthony K.C. Chan, MD; G. Patrick Clagett, MD; Barry Coller, MD; Clifford W. Colwell, MD; Deborah Cook, MD, MSc; James E. Dalen, MD, MPH, FCCP; J. Donald Easton, MD; Michael Ezekowitz, MD; Garret A. Fitzgerald, MD; William H. Geerts, MD, FCCP; Jeffrey S. Ginsberg, MD, FCCP; Alan S. Go, MD; Shaun D. Goodman, MD, FACC; Ian A. Greer, MD, FRCP, FRCOG; Andreas Greinacher, MD; Jeremy Grimshaw, MD, PhD; Cindy Grines, MD; Jonathan L. Halperin, MD; Robert A. Harrington, MD; John Heffner, MD, MPH; John A. Heit, MD; Judith S. Hochman, MD, FACC; Dieter Horstkotte, MD, FESC; Russell D. Hull, MBBS, MSc, FCCP; Elaine Hylek, MD; Thomas M. Hyers, MD, FCCP; Mark R. Jackson, MD; Alan Jacobson, MD; Roman Jaeschke, MD, MSc; Ajay Kakkar BSc, PhD; Clive Kearon, MD, PhD, FCCP; Matthew Kraay; Michael R. Lassen, MD; Mark N. Levine, MD, MSc; Alessandro Liberati, MD; Gregory YH Lip, MD, FESC, FACC; Warren J. Manning, MD; M. Patricia Massicotte, MD, MSc, FRCPC, MSc; Thomas W. Meade, MD; Venu Menon, MD, FACC; Alan D. Michelson, MD; Nancy Miller, RN; Paul Monagle, MBBS, MSc, MD, FRACP, FRCPA, FCCP; Heather Munger, MLS; Christopher M. O’Connor, MD; Martin O’Donnell, MD; E. Magnus Ohman, MD, FCCP; Carlo Patrono, MD; Stephen G. Pauker, MD; Graham F. Pineo, MD; Leon Poller, MD; Jeffrey J. Popma, MD; Martin H. Prins, MD; Robert Raschke, MD, MS; Gary Raskob, PhD; Joel G. Ray, MD, MSc; Gerald Roth, MD; Ralph L. Sacco, MD; Deeb N. Salem, MD, FCCP; Meyer M. Samama, MD; Andrew Schafer; Sam Schulman, MD, PhD; Daniel Singer, MD; Michael Sobel, MD; Paul D. Stein, MD, FCCP; Marco Tangelder, MD; Victor F. Tapson, MD, FCCP; Philip Teal, MD; Raymond Verhaeghe, MD; David A. Vorchheimer, MD; Theodore E. Warkentin, MD; Jeffrey Weitz, MD; Robert G. Wilcox, MD

Dr. Menon has received honoraria from Roche Inc.

Dr. Cannon, through the Department of Medicine of Brigham and Women’s Hospital, currently receives research grant support from Bristol-Myers Squibb, Merck, and Sanofi-Synthelabo. He is a consultant to Asahi Chemical Company, Bayer, Pfizer Limited, Vertex, Medicines Company, Ortho-Clinical Diagnostics, AstraZeneca, GlaxoSmithKline. Dr. Cannon is on the speaker bureau of Aventis, Bristol-Myers Squibb, Centocor, Eli Lilly, Genentech, Merck, Millennium, Sanofi-Synthelabo. He has received honoraria for preparation of educational materials from Best Med, Discovery East, Excerpta Medica, Medical Decision Point, and NCME.

Dr. Robert Harrington has received research grants through the Duke Clinical Research Institute from Aventis, AstraZeneca, Millennium, Schering, Merck, Lilly, Centocor, Roche, The Medicines Company, BMS, Sanofi, Glaxo, Daiichi.

Dr. Goodman has received research funding and has received honoraria for his participation on advisory boards and/or as a speaker at educational events from AstraZeneca, Aventis Pharma, Bayer, Biovail, Boehringer Ingelheim, BrystolMyers Squibb, CanAm, Centocor, Daiichi, Eli Lilly, Fournier Pharma, Hoffman-La Roche, Key Schering/Schering Plough, Millenium, Merck, Novartis, Sanofi Synthelabo, Servier, and Solvay.

Dr. Wilcox has received research funding from AstraZeneca, Aventis and Bristol-Myers Squibb.

Dr. Ohman has received research grants from the following organizations: BMS, Sanofi, Millennium, Schering-Plough, Aventis, and Berlex.

Dr. Schünemann has received research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, and Amgen Inc. He has received honoraria and consultant fees from AstraZeneca, Boehringer Ingelheim, and Amgen that were deposited into research accounts at the University of Buffalo and McMaster University.

This is the current release of the guideline.

This guideline updates a previous version: Ohman EM, Harrington RA, Cannon CP, Agnelli G, Cairns JA, Kennedy JW. Intravenous thrombolysis in acute myocardial infarction. Chest 2001 Jan;119(1 Suppl):253S-277S.

This summary was completed by ECRI on July 30, 2001. The information was verified by the guideline developer on October 17, 2001. This NGC summary was updated by ECRI on December 9, 2004. The updated information was verified by the guideline developer on January 12, 2005. This summary was updated by ECRI Institute on June 22, 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on March 14, 2008 following the updated FDA advisory on heparin sodium injection.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.