• National Institute for Clinical Excellence (NICE). Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction. London (UK): National Institute for Clinical Excellence (NICE); 2002 Oct. 25 p. (Technology appraisal guidance; no. 52).

Acute myocardial infarction

Assessment of Therapeutic Effectiveness
Treatment

Cardiology
Emergency Medicine
Family Practice
Internal Medicine

Advanced Practice Nurses
Nurses
Patients
Physician Assistants
Physicians

To examine the clinical and cost-effectiveness of available drugs for early thrombolysis in the treatment of acute myocardial infarction (AMI) in hospital and pre-hospital settings

Patients with acute myocardial infarction (AMI)

Thrombolytic agents (alteplase, reteplase, streptokinase, or tenecteplase)

• Clinical effectiveness
  • Mortality
  • Patency of coronary arteries
  • Left ventricular function
  • Stroke
  • Reinfarction
  • Bleeding
  • Allergy
  • Anaphylaxis
  • Adverse effects
• Cost-effectiveness

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Searches of Unpublished Data

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the Liverpool Reviews and Implementation Group (See the "Availability of Companion Documents" field.)

Clinical Effectiveness

Search Strategy

The search incorporated a number of strategies. Search terms for electronic databases included were myocardial infarction/heart infarction and thrombolysis combined with specific drug terms (e.g., alteplase [t-PA], reteplase, streptokinase, tenecteplase, anistreplase, and urokinase.

Electronic searches included the following databases:

• MEDLINE (1980-2001)
• EMBASE (1980-2001)
• Science Citation Index/Web of Science (1988-2001)
• Cochrane Trials Register (2001, 4)
• Health Technology Assessment (HTA) (1992-2001)
• Database of Abstracts of Reviews of effectiveness (DARE) (1998-2001)

Specific search strategies and the number of references retrieved for each search is provided in Appendices III, IV and V of the Assessment Report (see the "Availability of Companion Documents" field).

Searching was limited to English language reports.

Reference lists of included studies and pharmaceutical company submissions were searched to identify other relevant studies. In addition, hand searching of American Heart Journal, Circulation, American Journal of Cardiology, British Medical Journal, European Heart Journal, Heart, Emergency Medicine Journal, International Journal of Cardiology, Journal of the American College of Cardiology, Journal of the American Medical Association, Lancet, New England Journal of Medicine, and Stroke was carried out for the period of January 2001 to January 2002 to identify any newly published papers that might not yet have been indexed in electronic databases.

All the references were exported to Endnote reference database, ISI Research Soft, Cal., USA, version 5.

Inclusion and Exclusion Criteria

The identified citations were assessed for inclusion through two stages and disagreements were settled by discussion at each stage. Two reviewers independently scanned all the titles and abstracts and identified the potentially relevant articles to be retrieved. Full text copies of the selected papers were obtained and assessed independently by two reviewers for inclusion. Studies were considered eligible for inclusion if they met the following criteria:

Study Design

Randomised controlled trials (RCTs) that include comparison of included drugs and any or all of the listed outcomes.

Interventions

Comparison of currently available intravenous thrombolytic therapies administered in the early stages of acute myocardial infarction (AMI) in the hospital or pre-hospital setting. Drugs included in the review were: tissue plasminogen activator (t-PA), reteplase, streptokinase, and tenecteplase. Studies that examine the use of anistreplase (not currently available) or urokinase (not currently licensed for use in thrombolysis in the United Kingdom) were also identified and used to inform the background of the review but not included in the analysis.

Participants

Patients with recent on-set AMI without contraindications to thrombolytic therapy. Diagnosis of AMI to be made through clinical assessment or electrocardiogram (ECG).

Outcomes

Data on the following outcome measures were included:

• Mortality
• Patency of coronary arteries
• Left ventricular function
• Stroke
• Reinfarction
• Bleeding
• Allergy
• Anaphylaxis

Cost-Effectiveness

Search Strategy

The following databases were searched for English language papers.

• MEDLINE
• EMBASE
• NHS Economic Evaluation Database (NHSEED)
• Database of Abstracts of Reviews of Effectiveness (DARE)
• Science Citation Index/Web of Science
• Cochrane Trials Register
• Health Technology Assessment (HTA)

Search strategies and results of the searches undertaken are presented in Appendix VI of the Assessment Report (see the "Availability of Companion Documents" field).

Inclusion and Exclusion Criteria

Using explicit, predetermined criteria, two reviewers independently identified studies for inclusion in the cost-effectiveness review process. Decisions were compared.

Where there was disagreement, both reviewers discussed the paper together and a final decision was made. The inclusion and exclusion criteria used in the review are presented below.

Inclusion Criteria for Economic Evaluation Papers

• Active comparator (streptokinase, alteplase, reteplase, or tenecteplase)
• Efficacy data primarily based on published drug versus drug randomised controlled clinical trial evidence
• Explicit synthesis of costs and outcomes in a cost effectiveness ratio
• Full economic evaluation
• Primary paper

Exclusion Criteria for Economic Evaluation Papers

• Non-drug comparator (e.g., placebo or conservative therapy) or aspirin, urokinase, anistreplase
• Source of clinical efficacy data from non-randomised clinical trial or not explicitly stated
• No attempt to synthesise costs and benefits
• Letters, editorials, reviews, commentaries or methodological papers

All the references were exported to Endnote reference database, ISI Research Soft, Cal., USA, version 5.

Clinical Effectiveness

A total of 162 references were identified to which the inclusion criteria were applied. Of these, 20 studies reported in 50 articles fulfilled the inclusion criteria.

Cost-Effectiveness

Of the 107 articles assessed, only eight met the quality criteria that led them to be evaluated in detail.

Expert Consensus

Not applicable

Meta-Analysis
Systematic Review with Evidence Tables

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the Liverpool Reviews and Implementation Group (See the "Availability of Companion Documents" field.)

Clinical Effectiveness

Data Extraction

Hospital

Data extraction was carried out by three reviewers. Data were independently extracted by one reviewer and checked by a second into a pre-designed data extraction form.

Data from multiple reports of single trials were extracted onto a single data extraction form.

Pre-hospital

Data for information tables were extracted by one reviewer and checked by a second.

Quality Assessment

Hospital

Three reviewers independently evaluated the included primary studies for methodological quality. This involved methodological assessment for clinical effectiveness based on Centre for Reviews and Dissemination, York, Report 4 (see Appendix VI of the Assessment Report [see the "Availability of Companion Documents" field]). Any discrepancies were resolved through consensus.

Pre-hospital

Since no studies comparing drugs used in the pre-hospital setting were identified, there were no studies to be assessed. Descriptive comment is provided regarding trials that evaluated pre-hospital care.

Cost-Effectiveness

Data Extraction

All cost-effectiveness data was abstracted by a single reviewer and then checked by a second reviewer. Both reviewers are health economists with expertise in economic evaluation. Given that several of the cost-effectiveness papers included in the review incorporated the use of modelling techniques, it was appropriate to extract additional data from these papers.

The data extracted from the published cost-effectiveness analyses were presented in four sections.

Firstly, there is a section on study design where the following information is stated:

• Type of economic evaluation and measure of synthesis
• Intervention
• Study population
• Time period of analysis and extrapolation details

The second section summarises the key cost and cost data sources used in the studies:

• Cost items
• Cost data sources
• Country, currency and year

The third section summarises the range of outcomes and efficacy data sources used in the studies:

• Range of outcomes
• Efficacy data sources
• Utility values and data sources
• Modelling method and data sources

Finally, the fourth section explores the results of the cost-effectiveness studies:

• Cost-effectiveness ratio
• Subgroup analysis and results
• Sensitivity analysis and results
• Authors conclusions

Quality Assessment

The quality assessment of cost-effectiveness analyses was based on the Drummond 10-point checklist. All studies were scored according to the checklist detailed in Appendix VIII of the Assessment Report (see the "Availability of Companion Documents" field).

Expert Consensus

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

In-Hospital Thrombolysis

The Assessment Group's literature review found eight published articles on the cost-effectiveness of thrombolytic agents that met the inclusion criteria for the review of cost effectiveness. All compared streptokinase and alteplase (standard and accelerated) in a hospital setting. Three of the articles reported different aspects of the same cost-effectiveness model. Most studies reported incremental costs per life-year gained, and three also reported incremental cost per quality-adjusted life year (QALY). Most of the studies were based on the effectiveness results of GUSTO-I, in which data on resource use were collected only for USA centres. Consequently the analyses undertaken in Canada, Ireland, and France had to attempt to translate these to settings in other countries.

Pre-Hospital Thrombolysis

No published articles examining the cost effectiveness of different thrombolytic drugs in pre-hospital settings were found.

See Section 4.2 of the original guideline document for a detailed discussion of the cost-effectiveness analysis.

External Peer Review

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

This guidance provides recommendations on the selection of thrombolytic drugs in patients with acute myocardial infarction (AMI). Recommendations are made in relation to the use of the drugs in hospital and pre-hospital settings. The guidance does not compare hospital and pre-hospital models of delivering thrombolysis.

• It is recommended that, in hospital, the choice of thrombolytic drug (alteplase, reteplase, streptokinase, or tenecteplase) should take account of:
  • The likely balance of benefit and harm (for example, stroke) to which each of the thrombolytic agents would expose the individual patient
  • Current United Kingdom clinical practice, in which it is accepted that patients who have previously received streptokinase should not be treated with it again
  • The hospital's arrangements for reducing delays in the administration of thrombolysis
• Where pre-hospital delivery of thrombolytic drugs is considered a beneficial approach as part of an emergency-care pathway for AMI (for example, because of population geography or the accessibility of acute hospital facilities), the practicalities of administering thrombolytic drugs in pre-hospital settings mean that the bolus drugs (reteplase or tenecteplase) are recommended as the preferred option.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate use of thrombolytic drugs in acute myocardial infarction (MI)

This guidance represents the view of the Institute, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. The guidance does not, however, override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

Getting Better

Effectiveness
Patient-centeredness

• National Institute for Clinical Excellence (NICE). Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction. London (UK): National Institute for Clinical Excellence (NICE); 2002 Oct. 25 p. (Technology appraisal guidance; no. 52).

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

2002 Oct (reviewed 2005)

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Dr Jane Adam, Radiologist, St. George's Hospital, London; Professor RL Akehurst, Dean, School of Health Related Research, Sheffield University; Dr Sunil Angris, General Practitioner, Waterhouses, Medical Practice; Professor David Barnett (Chairman) Professor of Clinical Pharmacology, University of Leicester; Dr Sheila Bird, MRC Biostatistics Unit, Cambridge; Professor Carol Black, Consultant Physician, Royal Free Hospital & UCL, London; Professor John Brazier, Health Economist, University of Sheffield; Professor Martin Buxton, Director of Health Economics Research Group, Brunel University; Professor Mike Campbell, Statistician, Institute of General Practice & Primary Care, Sheffield; Dr Karl Claxton, Health Economist, University of York; Professor Sarah Cowley, Professor of Community Practice Development, Kings College, London; Professor Jack Dowie, Health Economist, London School of Hygiene & Tropical Medicine, London; Mr Chris Evennett, Chief Executive, Mid-Hampshire, Primary Care Group; Dr Paul Ewings, Statistician, Taunton & Somerset NHS Trust; Professor Terry Feest, Clinical Director and Consultant Nephrologist, Richard Bright Renal Unit, and Chairman of the UK Renal Registry; Professor Gary A Ford, Professor of Pharmacology of Old Age/Consultant Physician, Newcastle upon Tyne Hospitals NHS Trust; Mrs Sue Gallagher, Chief Executive, Merton, Sutton and Wandsworth Health Authority; Dr Trevor Gibbs, Head, Global Clinical Safety & Pharmacovigilance, GlaxoSmithKline; Sally Gooch, Director of Nursing, Mid-Essex Hospital Services Trust; Mr John Goulston, Director of Finance, The Royal Free Hampstead NHS Trust; Professor Trisha Greenhalgh, Professor of Primary Health Care, University College London; Miss Linda Hands, Consultant Vascular Surgeon, John, Radcliffe Hospital, Oxford; Professor Philip Home, Professor of Diabetes Medicine, University of Newcastle; Dr Terry John, General Practitioner, The Firs, London; Dr Diane Ketley, Research into Practice Programme, Leader, NHS Modernisation Agency; Dr Mayur Lakhani, General Practitioner, Highgate Surgery, Leicester, and Lecturer, University of Leicester; Ruth Lesirge, Lay Representative; Director, Mental Health Foundation; Dr George Levvy, Lay Representative; Chief Executive, Motor Neurone Disease Association; Dr Gill Morgan, CEO, North & East Devon Health Authority; Professor Miranda Mugford, Health Economist, University of East Anglia; Mr M Mughal, Consultant Surgeon, Chorley and South Ribble NHS Trust; Mr James Partridge, Lay Representative; Chief Executive, Changing Faces; Siân Richards, General Manager, Cardiff Local Health Group; Professor Philip Routledge, Professor of Clinical Pharmacology, University of Wales College of Medicine; Dr Rhiannon Rowsell, Pharmaceutical Physician, AstraZeneca UK Ltd; Dr Stephen Saltissi, Consultant Cardiologist, Royal Liverpool University Hospital; Professor Andrew Stevens (Vice-chairman) Professor of Public Health, University of Birmingham; Professor Ray Tallis, Consultant Physician, Hope Hospital, Salford; Dr Cathryn Thomas, General Practitioner, and Senior Lecturer, Department of Primary Care and General Practice, University of Birmingham; Professor Mary Watkins, Head of Institute of Health Studies, University of Plymouth; Dr Norman Waugh, Public Health Consultant, University of Southampton

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

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