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NIHR Health Technology Assessment programme: Executive Summaries. Southampton (UK): NIHR Journals Library; 2003-.
Background
Coronary heart disease (CHD) is a major cause of morbidity and mortality in the UK accounting for around 125,000 deaths a year. Acute myo-cardial infarction (AMI) affects an estimated 274,000 people each year. Of these, approximately 50% (137,000) die within 30 days of AMI and over half these deaths occur prior to reaching hospital or other medical assistance.
The development and introduction of new pharmacological agents has made it necessary to review the clinical and cost-effectiveness of older and newer agents used for early thrombolysis. Those reviewed in this document include streptokinase, alteplase, reteplase and tenecteplase.
Objectives
To examine the clinical and cost-effectiveness of available drugs for early thrombolysis in the treatment of AMI in hospital and pre-hospital settings.
Methods
The search incorporated a number of strategies for clinical effectiveness and economic evaluation. The search strategy covered the period from 1980 to 2001 and included the following electronic databases: MEDLINE, EMBASE, Science Citation Index/Web of Science, Cochrane Trials Register, NHS Centre for Reviews and Dissemination Health Technology Assessment (NHS CRD HTA), Database of Abstracts of Reviews of Effectiveness (DARE) and NHS Economic Evaluation Database (NHS EED). Search terms included were myocardial infarction/heart infarction combined with specific drug terms including alteplase, reteplase, streptokinase, tenecteplase, anistreplase and urokinase. Reference lists of included studies and pharmaceutical company submissions to the National Institute for Clinical Excellence (NICE) were searched to identify other relevant studies. In addition, a number of medical journals were handsearched to identify any newly published papers that might not yet have been indexed in electronic databases.
Study selection
Randomised controlled trials (RCTs) that included comparison of the specified drugs (alteplase, reteplase, streptokinase and tenecteplase) in the early stages of AMI delivered in the pre-hospital or hospital setting were included in the review. Studies that examined the use of anistreplase or urokinase were identified but not included in the analysis. Data on the following outcome measures were included in the review: mortality, bleeding, stroke, reinfarction, allergy and anaphylaxis.
Economic evaluation included studies reporting efficacy data primarily based on drug versus drug randomised controlled clinical evidence, explicit synthesis of costs and outcomes in a cost-effectiveness ratio, full economic evaluation.
Quality assessment
The methodological quality of studies for clinical effectiveness was assessed using the criteria based on the NHS CRD Report No. 4 (University of York, 1996).
The quality of cost-effectiveness was assessed using a checklist updated from that produced by Drummond and colleagues.*
Results
Clinical effectiveness
Hospital
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. These included 14 comparative studies involving a total study population of 142,907 pa{ients. Data from two studies were combined in the study reports and this combination of data is maintained in the review.
Definitive conclusions on efficacy (30-35-day mortality) are that streptokinase is as effective as non-accelerated alteplase, that tenecteplase is as effective as accelerated alteplase, and that reteplase is at least as effective as streptokinase.
Some conclusions require interpretation of data, i.e. whether streptokinase is as effective as, or inferior to accelerated alteplase; and whether reteplase is as effective as accelerated alteplase or not.
Depending on these, two further conclusions on indirect comparisons arise, whether tenecteplase is superior to streptokinase or not, and whether reteplase is as effective as tenecteplase or not.
That these questions remain to be resolved illustrates that any differences in mortality between drugs is small.
There seem to be significant differences between drugs in incidence of stroke, with streptokinase having the lowest rate.
Streptokinase causes more allergic reactions than other drugs.
Pre-hospital
The search failed to identify any studies conducted in the pre-hospital setting that compared the effectiveness of different drugs. There is no reason to believe that the effectiveness of a drug will be altered by administration in the pre-hospital setting.
Nine RCTs that examined the efficacy and safety of pre-hospital thrombolysis were identified and are discussed. The required use of heparin with either of the bolus products does not seem to provide any practical barrier to their widespread use.
Cost-effectiveness and modelling
A detailed review of the economic literature was undertaken. Of the 107 articles assessed, only eight met the quality criteria that led them to be evaluated in detail. The general quality of economic analyses undertaken in this area was disappointing and largely focused on evaluating cost-effectiveness in healthcare environments outside the NHS.
A critique and re-analysis were also undertaken of the two detailed economic models contained in the industry submissions to NICE. Both models were rerun using the assumptions contained in the competitor model. In addition, they were re-analysed using a preferred set of coefficients that reflected, as far as possible, the weight of the available evidence.
Variations in quality-adjusted life-years (QALYs) gained between the individual drugs were small. Supposed advantages presented in the industry submissions to NICE largely related to comparatively minor variations in efficacy or minor improvements in aspects of the side-effect profile associated with each individual drug. Streptokinase was clearly the most cost-effective drug and other drugs were compared to it. Costs per QALY for newer drugs compared to streptokinase ranged up to £17,000. Given the similarity in outcome, cost-effectiveness becomes largely determined by the acquisition costs of the drug. This conclusion was robust to a range of variations in assumptions. In contrast to this robust conclusion, differences between alteplase, tenecteplase and reteplase were small and their relative ranking in cost-effectiveness changed according to the assumptions used.
Implementation
There are substantial opportunities for refining hospital thrombolysis procedures to meet National Service Framework (NSF) targets. Changing drugs is a very minor element in achieving improved door-to-needle time.
Pre-hospital thrombolysis will be necessary in some areas to allow NSF targets to be met. The choice of drug for pre-hospital thrombolysis is determined by acquisition cost and by convenience. Our experts did not wish to consider the use of infusion products (e.g. alteplase or streptokinase) but preferred bolus administration (reteplase and tenecteplase).
The cost-impact of switching to the more expensive bolus drugs could be as much as £50 million per year, over and above existing costs of approximately £30-40 million for the NHS in England and Wales.
Conclusions
Clinical effectiveness
The decision regarding which agent to use is therefore a balance of the risks and benefits related to mortality and stroke. No clear conclusion, based on statistical comparison, can be drawn.
Economic evaluation
Given the similarity in outcome, cost-effectiveness becomes largely determined by the acquisition costs of the drug. This conclusion was robust to a range of variations in assumptions. Streptokinase was therefore the most cost-effective drug.
Publication
- Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation. Health Technol Assess 2003;7(15). [PubMed: 12773258]
NHS R&D HTA Programme
The NHS R&D Health Technology Assessment (HTA) Programme was set up in 1993 to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS.
The research reported in this monograph was commissioned by the HTA Programme on behalf of the National Institute for Clinical Excellence (NICE). Technology assessment reports are completed in a limited time to inform the appraisal and guidance development processes managed by NICE. The review brings together evidence on key aspects of the use of the technology concerned. However, appraisals and guidance produced by NICE are informed by a wide range of sources.
The research reported in this monograph was funded as project number 01/27/01.
The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme, NICE or the Department of Health. The editors wish to emphasize that funding and publication of this research by the NHS should not be taken as implicit support for any recommendations made by the authors.
Criteria for inclusion in the HTA monograph series
Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.
Reviews in Health Technology Assessment are termed 'systematic' when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.
HTA Programme Director: Professor Kent Woods
Series Editors: Professor Andrew Stevens, Dr Ken Stein, Professor John Gabbay, Dr Ruairidh Milne and Dr Chris Hyde
Managing Editors: Sally Bailey and Sarah Llewellyn Lloyd
The editors and publisher have tried to ensure the accuracy of this report but do not accept liability for damages or losses arising from material published in this report.
Footnotes
- *
Drummond M, Stoddart GL, Torrance GW. Methods for the economic evaluation of health care programmes. Oxford: Oxford Medical Publications; 1987.
- PubMedLinks to PubMed
- Pitfalls in the economic evaluation of thrombolysis in myocardial infarction. The impact of national differences in the cost of thrombolytics and of differences in the efficacy across patient subgroups.[Eur Heart J. 1998]Pitfalls in the economic evaluation of thrombolysis in myocardial infarction. The impact of national differences in the cost of thrombolytics and of differences in the efficacy across patient subgroups.Lorenzoni R, Pagano D, Mazzotta G, Rosen SD, Fattore G, De Caterina R, Gensini G. Eur Heart J. 1998 Oct; 19(10):1518-24.
- Economic and cost-effectiveness in evaluating the value of cardiovascular therapies. The impact of the cost-effectiveness study of GUSTO-1 on decision making with regard to fibrinolytic therapy.[Am Heart J. 1999]Economic and cost-effectiveness in evaluating the value of cardiovascular therapies. The impact of the cost-effectiveness study of GUSTO-1 on decision making with regard to fibrinolytic therapy.Califf RM, Stump D, Topol EJ, Mark DB. Am Heart J. 1999 May; 137(5):S90-3.
- Streptokinase and enoxaparin as an alternative to fibrin-specific lytic-based regimens: an ExTRACT-TIMI 25 analysis.[Drugs. 2009]Streptokinase and enoxaparin as an alternative to fibrin-specific lytic-based regimens: an ExTRACT-TIMI 25 analysis.Giraldez RR, Wiviott SD, Nicolau JC, Mohanavelu S, Morrow DA, Antman EM, Giugliano RP. Drugs. 2009 Jul 30; 69(11):1433-43.
- Review Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review.[QJM. 2003]Review Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review.Dundar Y, Hill R, Dickson R, Walley T. QJM. 2003 Feb; 96(2):103-13.
- Review Clinical and economic lessons from studies of coronary thrombolysis.[J Vasc Interv Radiol. 1995]Review Clinical and economic lessons from studies of coronary thrombolysis.Mark DB. J Vasc Interv Radiol. 1995 Nov-Dec; 6(6 Pt 2 Suppl):94S-101S.
- Early thrombolysis for the treatment of acute myocardial infarction: a systemati...Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation - NIHR Health Technology Assessment programme: Executive Summaries
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