Appraisal Consultation Document: Drugs for early thrombolysis in the treatment of acute myocardial infarction
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE
Appraisal consultation document
Drugs for early thrombolysis in the treatment of acute myocardial infarction
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The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of the use of available drugs suitable for early initiation of thrombolysis for acute myocardial infarction (AMI) in two settings: (i) pre-hospital and (ii) hospital, and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of available drugs suitable for early initiation of thrombolysis for acute myocardial infarction (AMI) in two settings: (i) pre-hospital and (ii) hospital. This document has been prepared for consultation with the formal
consultees. Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. The process the Institute will follow after the consultation period is summarised below. (For further details, see the Guide to the Technology Appraisal Process on the Institute's website).
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The key dates for this appraisal are: |
| Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. |
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | Patients with acute myocardial infarction (AMI) in whom thrombolysis is indicated should receive thrombolytic treatment (with alteplase, reteplase, streptokinase or tenecteplase) as soon as possible after the onset of symptoms. |
| 1.2 |
In hospital, the choice of drug should take account of:
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| 1.3 | Local circumstances (for example, population geography, accessibility of acute hospital facilities) may make pre-hospital administration of thrombolysis (by ambulance paramedics or general practitioners) desirable. If this is the case, it is recommended that drugs administered by bolus injection (reteplase or tenecteplase) should be used for pre-hospital administration of thrombolysis. |
| 2 | Clinical need and practice |
| 2.1 |
Acute myocardial infarction (AMI) is caused by blockage of a coronary artery by a thrombus or clot. This is usually the result of rupture of an atherosclerotic plaque within the artery. The heart muscle supplied by that artery is damaged or dies because of lack of oxygen (ischaemia). Patients with AMI may develop heart failure or potentially fatal cardiac arrhythmias as a result of damage to the heart muscle. These and other complications may occur early, within the first few hours of the event, or may develop over the subsequent months or years. |
| 2.2 | There are around 240,000 people who experience AMIs in England and Wales each year. Up to 50% of people who have an AMI die within 30 days of the event, and over half of these deaths occur before medical assistance arrives or the patient reaches hospital. Onset of AMI symptoms is usually sudden and the highest risk of death (usually as the result of an acute fatal arrhythmia) is within the first hour of experiencing symptoms - around one-third of all AMI deaths occur within the first hour. |
| 2.3 | Thrombolytic drugs break down the thrombus so that the blood flow to the heart muscle can be restored to prevent further damage. The sooner the blood flow can be restored, the better the chances of avoiding the death of the heart muscle. Along with clinical symptoms (typically but not exclusively chest pain), characteristic changes in the 12-lead electrocardiogram (for example, ST segment elevation) provide the most immediate proof of diagnosis of AMI for patients requiring thrombolysis for AMI. |
| 2.4 | Intravenous thrombolytic therapy is an established standard treatment for AMI. It is estimated that around 50,000 patients currently receive thrombolysis in England and Wales each year. However, evidence suggests that thrombolysis continues to be under-used. |
| 2.5 | Early primary percutaneous coronary intervention (PCI) may be an alternative to thrombolysis. Despite research evidence of the potential value of early PCI, currently few trusts have the capacity to provide it. Treatment delivering thrombolytics in combination with glycoprotein IIb/IIIa inhibitors is also being researched. However, these interventions are beyond the scope of this appraisal. |
| 3 | The technology |
| 3.1 | Thrombolytic drugs |
| 3.1.1 | In the UK, four thrombolytic agents are licensed and available to treat AMI. There is a long history of use of one, streptokinase, whereas the other three, alteplase, reteplase, and tenecteplase, are newer developments. Streptokinase is derived from streptococcal bacteria. It is given by intravenous (iv) infusion. Alteplase was introduced in the late 1980s. It is essentially the same as the naturally occurring activator of plasminogen in the human body, and is produced by recombinant DNA technology. It is given by iv infusion. Reteplase and tenecteplase have been introduced more recently (1997 and 2001, respectively). They are new modified forms of plasminogen activator and can be given by rapid iv bolus injection, rather than infusion. |
| 3.1.2 | The timing of administration is a crucial factor determining the extent of benefit achieved by thrombolysis, and treatment should be given as soon as possible (normally up to 12 hours - depending on the drug used) after the onset of AMI symptoms. |
| 3.1.3 | Bleeding complications are the main risks associated with thrombolysis. The most important bleeding complication is haemorrhagic stroke, which occurs in 0.5-1.5% of patients and is associated with high mortality and long-term disability in survivors. Bleeding may occur at the injection site, in the gastrointestinal tract or elsewhere. Hypotension may also occur. The risks and benefits of giving thrombolysis need to be considered in individual patients and settings. The risk of haemorrhagic stroke following thrombolysis increases with age and increasing blood pressure. Thrombolysis is contraindicated in individuals with bleeding disorders or a history of recent haemorrhage, trauma, surgery or acute cerebrovascular event. For full details of side effects and contraindications, see the Summary of Product Characteristics for the individual agents. |
| 3.1.4 | Heparin (an anticoagulant) is given with all of the thrombolytic drugs except streptokinase. It is usually administered as an iv bolus injection before thrombolysis. When given with tenecteplase the heparin dose is weight adjusted. Aspirin (an antiplatelet agent) is also usually given with any thrombolytic drug. |
| 3.1.5 | Streptokinase (Streptase) is indicated up to 12 hours after onset of symptoms. It is administered as an iv infusion over 1 hour. It has been extensively studied and remains widely used. Streptokinase is associated with hypotension, infrequent allergic reactions and rarely anaphylaxis. Patients treated with streptokinase develop anti-streptococcal antibodies, which can inactivate the drug if subsequent treatment is needed. Consequently patients can be treated with streptokinase only once. It is estimated that around one-third of people with AMI have contraindications to streptokinase. Streptokinase has been extensively studied and remains widely used. A recent survey found that it was used for eligible patients experiencing their first AMI in 82% of hospitals in England, and other data suggest that streptokinase represents between 53% and 65% of thrombolytic drug use. Streptokinase costs £80 to £90 per patient (British National Formulary 43, March 2002). |
| 3.1.6 | Alteplase (Actilyse, recombinant human tissue plasminogen activator, rtPA) can be delivered as a standard or accelerated regimen. The accelerated regimen, which is most commonly used, is indicated up to 6 hours after symptom onset and is delivered by an initial iv bolus injection, followed by two iv infusions, the first given over 30 minutes and the second over 60 minutes. The standard regimen is indicated between 6 and 12 hours after symptom onset and requires a bolus injection followed by five infusions over 3 hours. Like the other newer drugs, alteplase does not stimulate the production of antibodies and so it can be used repeatedly. It is estimated that alteplase represents between 23% and 32% of thrombolytic drug use. It costs £600 per patient (British National Formulary 43, March 2002). |
| 3.1.7 | Reteplase (Rapilysin) is indicated up to 12 hours after symptom onset. It is given as two iv bolus injections 30 minutes apart. It is estimated that reteplase represents between 12% and 15% of thrombolytic drug use. Reteplase costs £716 per patient (British National Formulary 43, March 2002). |
| 3.1.8 | Tenecteplase (Metalyse) is indicated up to 6 hours after symptom onset. It is administered as a single (weight-adjusted) iv bolus injection. It is estimated that tenecteplase currently accounts for around 1% of thrombolytic drug use, though given its relatively recent launch the proportion may be increasing. Tenecteplase costs £700 to £770 per patient (British National Formulary 43, March 2002). |
| 3.2 | Delivering thrombolytic drugs |
| 3.2.1 | The National Service Framework (NSF) for coronary heart disease (CHD) in England and Tackling CHD in Wales specify that eligible patients with AMI should be given thrombolysis within 60 minutes of calling for professional help ('call to needle time') and should receive thrombolysis within 20 minutes of arriving at hospital ('door to needle time'). It is also suggested that it may be appropriate to provide pre-hospital thrombolysis where local 'call to hospital' times are likely to be over 30 minutes. The NHS Plan in England gave a commitment to train and equip ambulance paramedics to provide thrombolysis. |
| 3.2.2 | Direct admission to a coronary care unit (CCU) is often not possible, and accident and emergency (A&E) departments are being encouraged to administer thrombolysis to reduce delays in door to needle times. The potential for specialist nursing input in the delivery of thrombolysis is also beginning to be explored. |
| 3.2.3 | Given the benefits of early administration of thrombolysis on reducing damage to heart muscle and consequently on long-term outcomes, pre-hospital administration of thrombolysis by ambulance paramedics is being gradually implemented in the NHS. |
| 3.2.4 | Currently, pre-hospital thrombolysis is administered in fewer than five ambulance services and a small number of remote community hospitals in England and Wales. Substantial investment in infrastructure and training will be required to implement the requirements of the CHD NSF, Tackling CHD in Wales and the NHS Plan to allow more widespread delivery in pre-hospital settings. |
| 3.2.5 | Currently streptokinase is the only thrombolytic that paramedics are authorised to administer under the Prescription Only Medicines (Human Use) Order 1997. However, paramedics can administer other thrombolytic drugs under local Patient Group Directions, and guidelines on their use by paramedics have been developed by the Joint Royal Colleges Ambulance Liaison Committee (JRCALC). |
| 3.2.6 | There are practical difficulties in giving controlled-rate infusions in pre-hospital settings, including drug preparation requirements, the practicalities of giving an infusion in an ambulance, and for streptokinase concerns about higher rates of allergic reactions and hypotension, which are more difficult to manage away from hospital. Therefore, only the newer drugs delivered by bolus injection (reteplase and tenecteplase) are considered appropriate for pre-hospital settings. |
| 3.2.7 |
Although they are not within the scope of this appraisal, a number of organisational models of service delivery are relevant when considering the feasibility of administering different thrombolytic agents and their effectiveness in particular settings. These involve organisational, practical and operator issues. In-hospital thrombolysis models include:
Pre-hospital models include:
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| 4 | Evidence and interpretation |
| The Appraisal Committee considered evidence from a number of sources (see Appendix B). | |
| 4.1 | Clinical effectiveness |
| 4.1.1 | In-hospital thrombolysis |
| 4.1.1.1 | The Assessment Group found 14 randomised controlled trials (RCTs) comparing thrombolytic drugs that met the inclusion criteria for the review. Overall the studies were considered to be of excellent quality. In total, the trials involved over 142,000 patients, and five of the trials included over 10,000 patients. The trials had similar inclusion criteria in terms of age (usually <70 or <75 years), ECG changes, duration of symptoms, and presentation within 6 hours of symptom onset. Five of the trials included between 12% and 26% of patients aged over 70-75 years. Women were under-represented in all of the studies. Primary endpoints included 30-day mortality, 90-minute artery patency/flow rates and left ventricular function. Secondary endpoints included bleeding, stroke, congestive heart failure, reinfarction, allergy and anaphylaxis. The results of the trials were also pooled in a meta-analysis. |
| 4.1.1.2 | No direct trial comparisons between tenecteplase and streptokinase or between tenecteplase and reteplase have been undertaken. The Assessment Group recommend that only cautious conclusions can be drawn from the indirect comparisons that can be deduced from other studies. |
| Streptokinase | |
| 4.1.1.3 | Two very large placebo-controlled trials established the efficacy of streptokinase in reducing mortality. The GISSI trial (published in 1986) included 11,712 patients, and the ISIS-2 trial (published in 1988) included 17,187 patients. In the GISSI study, the 21-day overall hospital mortality was 10.7% in patients treated with streptokinase compared with 13% in the control group, an 18% relative reduction in risk. In the ISIS-2 study there was a significantly lower incidence of vascular death at 5 weeks in patients treated with streptokinase (9.2% compared with 12.0% in the placebo group, a 23% reduction in relative risk). These benefits were in addition to those of early aspirin treatment. |
| 4.1.1.4 | Streptokinase has subsequently been
an active comparator in 10 randomised trials of alteplase and one of reteplase. Alteplase |
| 4.1.1.5 | A meta-analysis of eight comparisons of standard alteplase with streptokinase found no significant difference between the two drugs in terms of mortality up to 35 days (odds ratio 1.0; 95% confidence interval [CI] 0.94 to 1.06). A statistically significant difference in reinfarction rates in favour of alteplase was found (odds ratio 0.86; 95% CI 0.77 to 0.95). However, alteplase was associated with a statistically significant higher risk of stroke (odds ratio 1.37; 95% CI 1.16 to 1.62), due to a doubling in the risk of haemorrhagic stroke (odds ratio 2.13; 95% CI 1.04 to 4.36). However, streptokinase was associated with a statistically significant higher risk of major bleeds (other than stroke) than alteplase (odds ratio 0.81; 95% CI 0.68 to 0.97). The categorisation and reporting of bleeding events varied between the trials, so it is difficult to judge the clinical significance of this. |
| 4.1.1.6 | The majority of studies included in this meta-analysis used the standard alteplase administration regimen, whereas the GUSTO-I trial also used the accelerated regimen. GUSTO-I is the only trial to have demonstrated superiority between different thrombolytic agents. The trial found an odds ratio of 0.85 (95% CI 0.78 to 0.94) for 30-day mortality for accelerated alteplase compared with streptokinase, and an absolute reduction in mortality at 30 days of 1.0% (6.3% versus 7.3%; 95% CI 0.4% to 1.6%) in favour of accelerated alteplase. However, this benefit was balanced by a statistically significantly higher incidence of haemorrhagic stroke (odds ratio 1.42; 95% CI 1.05 to 1.91). Using a combined outcome measure of mortality and disabling stroke the absolute advantage of accelerated alteplase over streptokinase was lower (0.9%; p = 0.006). Rates of bleeds (moderate or worse), allergic reaction, anaphylaxis, congestive heart failure, and sustained hypotension were statistically significantly lower in the group treated with accelerated alteplase. |
| 4.1.1.7 |
Some argue that the finding of superiority of accelerated alteplase over streptokinase in the GUSTO-I trial has been over-emphasised, and that it should not be considered in isolation from other trials. Furthermore, when considering the combination of mortality and stroke endpoints, it may be argued that the differences in overall benefit are less clear, particularly for subgroups at higher risk of developing haemorrhagic stroke. Some of the criticisms of GUSTO-I are as follows.
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| Reteplase | |
| 4.1.1.8 | Reteplase has also been compared with streptokinase in a study in 5986 patients (the INJECT study). This study found an absolute difference of 0.5% in 35-day mortality in favour of reteplase (not statistically significant). The 95% confidence interval of -1.98% to 0.96% implies that reteplase is unlikely to have a more than a 1.98% absolute risk reduction in mortality over streptokinase and that streptokinase is unlikely to have more than a 0.96% absolute risk reduction in mortality over reteplase. If the confidence limits are interpreted as an indication of equivalence, and a 1% absolute difference is considered appropriate tolerance (as suggested by the American College of Chest Physicians), one interpretation is that reteplase is not inferior to streptokinase and the study was not able to rule out the possibility that it could be superior. An alternative interpretation is that in terms of overall effects on mortality and disabling stroke reteplase may be inferior to streptokinase, as the trial also found a statistically significantly lower risk of haemorrhagic stroke (odds ratio 2.1; 95% CI 1.02 to 4.31) in the streptokinase group. |
| 4.1.1.9 | Reteplase has also been compared with accelerated alteplase in one relatively small (n = 324) study that examined intermediate angiographic endpoints of coronary vessel patency (RAPID-2), and one larger study that examined patient-focused endpoints (GUSTO?III, n = 15,059). GUSTO-III was designed to test the clinical superiority of reteplase over accelerated alteplase, following the findings in RAPID-2 of better coronary artery patency with reteplase. However, GUSTO-III found no statistically significant difference between the two drugs. The mortality rate at 30 days was 7.5% in the reteplase group and 7.2% in the accelerated alteplase group: an absolute risk reduction of 0.23% in favour of accelerated alteplase (95% CI -1.10% to 0.66%). That is, the confidence limits indicate that reteplase is unlikely to have more than a 0.66% absolute risk reduction in mortality over accelerated alteplase, and accelerated alteplase is unlikely to have more than a 1.10% absolute risk reduction in mortality over reteplase. The results show that there is no statistically significant difference in 30-day mortality. However, if the limits of equivalence are set at a 1% absolute difference, then the results of the trial cannot be used to say that reteplase is as effective as accelerated alteplase. |
| Tenecteplase | |
| 4.1.1.10 | The ASSENT?2 equivalence trial found that 35-day mortality was almost the same in the tenecteplase group (6.2%) and the accelerated alteplase (6.1%) group. The absolute difference was 0.03% in favour of accelerated alteplase (95% CI -0.55% to 0.61%). The CI was within the limit of a less than 1% absolute difference that had been pre-specified to signify equivalence. However, there was a small but statistically significant reduction in the incidence of bleeding with tenecteplase (26.4% compared with 28.9% in the alteplase group), resulting in fewer blood transfusions in the tenecteplase group (4.3% of patients compared with 5.5% in the accelerated alteplase group). |
| Adverse events/outcomes | |
| 4.1.1.11 | Evidence suggests that there are important differences in major adverse events between the drugs. It appears that major bleeds (leading to transfusions) and allergic reactions are more common with streptokinase than with the other drugs. There is also some evidence that tenecteplase causes less major bleeding than accelerated alteplase. However, the newer drugs are associated with a higher risk of haemorrhagic stroke compared with streptokinase. There were no apparent differences in the frequency of haemorrhagic stroke between accelerated alteplase and reteplase (GUSTO-III), and between accelerated alteplase and tenecteplase (ASSENT-2). Evidence also suggests that the newer drugs may also be associated with a lower incidence of congestive heart failure. |
| Sub-groups | |
| 4.1.1.12 | None of the trials discussed was designed to investigate clinical sub-groups, such as by age or site of infarct (anterior, inferior). The Assessment Group concluded that there was no convincing evidence of relative differences in the effectiveness of the available drugs in sub-groups. The greater absolute benefit found in patients with anterior infarcts in GUSTO-I may simply be a reflection of the higher baseline risk in this group. The greater relative benefit in patients aged under 75 years was not reflected in their level of absolute risk reduction. None of the differences between the sub-groups appeared to be statistically significant by interaction. |
| Summary | |
| 4.1.1.13 |
In summary, given the evidence on clinical effectiveness in the hospital setting it can be concluded that:
However, given the uncertainties over the interpretation of GUSTO-I, less firm conclusions can be drawn regarding the effectiveness of accelerated alteplase compared with streptokinase. If accelerated alteplase is believed to be superior to streptokinase, then indirectly tenecteplase would also be considered to be superior to streptokinase. Conclusions regarding the equivalence of reteplase compared with accelerated
alteplase depend on the interpretation of GUSTO-III. Important differences between the agents in the frequency of adverse events and their long-term outcomes (that is, disabling stroke and congestive heart failure) are also apparent and must be taken into account. That is, major bleeds and allergic reactions are more common with streptokinase than with the newer drugs whereas haemorrhagic stroke is more common with the newer drugs than with streptokinase. |
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| 4.1.2 | Pre-hospital thrombolysis |
| 4.1.2.1 | The Assessment Group did not find any trials comparing the different thrombolytic drugs in pre-hospital settings. |
| 4.1.2.2 | However, nine RCTs and a systematic review investigating the feasibility, safety and efficacy of pre-hospital administration of thrombolysis compared with hospital administration were considered in the context of the appraisal. A number of other papers reporting non-randomised studies and audits of pre-hospital thrombolysis were also considered in relation to practical and implementation issues. |
| 4.1.2.3 | The RCTs were small, except for one that included over 5000 patients (EMIP). They were undertaken in a mixture of urban and/or rural settings in Israel, continental Europe, Canada, the USA, Northern Ireland, and Scotland. A variety of thrombolytic drugs were studied - four studies used alteplase, four used streptokinase-type drugs, and one used urokinase (which is not available in the UK). Only the USA study (MITI) involved paramedics administering the thrombolytic (after remote consultation with a physician). In all but one of the other studies, a hospital physician attended the patient and administered the drug. In the rural Scottish trial (GREAT) a general practitioner undertook assessment and treatment. |
| 4.1.2.4 | The RCTs found that, on average, pre-hospital thrombolysis was administered 58 minutes earlier than hospital thrombolysis. The difference ranged from a 33-minute reduction in the MITI study to a 130-minute reduction in the GREAT study. Individually, the trials failed to show statistically significant reductions in in-hospital mortality, although findings in all of the studies favoured pre-hospital administration. However, a meta-analysis of six of the trials found a statistically significant absolute reduction in mortality of 1.6% (95% CI 0.2% to 3%), and a relative risk reduction of 17% (95% CI 2% to 30%, p = 0.03) favouring pre-hospital administration of thrombolysis. This analysis is heavily influenced by the results of the GREAT study (in which thrombolysis was administered by general practitioners in rural Scotland) and therefore does not directly reflect on the potential for pre-hospital thrombolysis administered by paramedics in England and Wales. |
| 4.1.2.5 | A number of observational studies examining pre-hospital thrombolysis were considered briefly in the assessment report, although these generally only provide further insight into feasibility. They include studies of administration of anistreplase (a streptokinase-like drug that is no longer available in the UK) by paramedics or general practitioners in a Dutch city, reteplase administered by ambulance-based nurses in Sweden, and anistreplase administered in a rural Italian emergency room, and two reports of a small number of cases of reteplase administered by paramedics with hospital telemetry support in England. |
| 4.2 | Cost effectiveness |
| 4.2.1 | In-hospital |
| 4.2.1.1 | 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. All considered 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. |
| 4.2.1.2 | In general the studies had the following limitations: costs and benefits were not measured in the same populations; comparator treatments were often inadequately described; and the derivation of utility values was inadequately explained. None of the studies undertook costing at patient level, and while in general similar cost categories were included, only some of the studies included the longer-term costs of stroke and heart failure. Some of the studies included consideration of adverse events, including stroke, reinfarction, major bleeds, anaphylaxis, and congestive heart failure. |
| 4.2.1.3 | The analyses undertaken following GUSTO-I, which found a survival advantage for accelerated alteplase at 30 days, showed the drug to be cost effective compared with streptokinase within the context of the clinical trial in the US healthcare system. In all of the studies, sensitivity analyses found that assumptions regarding mortality differences and costs were important, and so any conclusions drawn are heavily dependent on the interpretation of the effectiveness findings of GUSTO-I. |
| 4.2.14 | In particular, the economic analysis undertaken in the USA alongside GUSTO-I modelled lifetime costs and benefits, and reported an incremental cost per life-year gained of $32,678 and an incremental cost per QALY of $36,402 for accelerated alteplase compared with streptokinase. The sub-group analyses found that accelerated alteplase became more cost effective in patients with higher absolute mortality risk - for example, $13,410 per life-year gained in patients older than 75 years with anterior myocardial infarction. However, the analysis requires extremely cautious interpretation, given a number of issues, including uncertainties over the interpretation of GUSTO-I (in general and in sub-groups), application of US data on resource use, and the assumption that costs did not differ significantly between treatment groups. |
| 4.1.2.5 | Overall, there is little relevant published evidence on the economics of thrombolytics in a UK setting, and none examining the currently available bolus drugs. However, two cost-effectiveness models were submitted by manufacturers. |
| 4.1.2.6 | There is uncertainty over the benefits of very early administration of thrombolysis. However, it is logical to assume that the earlier the administration the greater the reduction in damage to the heart. While assumptions about the survival/time-to-treatment curve affect the benefit results in any modelling, it is unlikely that any one drug has advantage over any other with regard to timing of administration. |
| 4.1.2.7 | The two manufacturers' models are similar in structure and scope, although they differ in terms of method and level of detail. Roche's model examines costs up to 30 days, assumes all four drugs have equivalent efficacy, and has less detailed costing. In contrast the Boehringer Ingelheim (BI) model includes costing up to 10 years, includes long-term costing for individual complications (such as congestive heart failure and stroke), and incorporates differential survival and complication outcomes for the drugs and more detailed estimation of utilities. Both models incorporate a range of different assumptions regarding adverse events. The models also incorporate adjustment for the timing of administration, including time savings in pre-hospital settings, in which only bolus drugs are compared. |
| 4.1.2.8 | The Roche model essentially represents a cost-minimisation analysis, and finds reteplase slightly less costly than accelerated alteplase or tenecteplase in hospital. The BI model assumes better survival and a lower incidence of post-infarct congestive heart failure (streptokinase 15.4%, accelerated alteplase 13.5%, reteplase 13.5%, tenecteplase 11.8%) for tenecteplase. These assumptions, together with 10-year discounted costs, lead to a finding that tenecteplase dominates accelerated alteplase and reteplase in hospital (that is, it is of lower cost and greater effectiveness). |
| 4.1.2.9 | The Assessment Group adjusted key parameters, tested sensitivities and presented revised results using the manufacturers' models. Any assumed additional efficacy advantage from the potentially earlier administration of drugs in hospital was not included as a factor in the adapted model, given that the impact of this would already be accounted for in terms of outcome, and was thought unlikely to differ substantially between the drugs. |
| 4.1.2.10 | The Assessment Group used the adjusted models to compare the three newer drugs with streptokinase. For each comparison, the additional benefit (using QALYs) of the newer thrombolytic was small, while the additional cost was substantial. The cost differences between the newer drugs are relatively small. The most reliable finding is that streptokinase is by far the cheapest drug and although it is a little less effective (in terms of discounted QALYs), it is the most cost effective. |
| 4.1.2.11 | Using the adjusted manufacturers' models, the incremental costs per QALY reported for the three drugs compared with streptokinase were: accelerated alteplase, £7219 (adjusted BI model) and £7,878 (adjusted Roche model); reteplase, £7893 and £10,247; and tenecteplase, £8321 and £9509. However, these relative cost-utility rankings are sensitive to changes in assumptions in the models, and so are not conclusive. |
| 4.1.2.12 | These results show all three drugs to be cost effective compared with streptokinase. However, the incremental costs per QALY are very sensitive to a range of assumptions, including the extent of survival gain attributed to the newer drugs compared with streptokinase and the cost and utility adjustments applied to adverse outcomes, particularly stroke and congestive heart failure. Therefore they could be much higher than the values calculated using the Assessment Group's preferred assumptions. |
| 4.2.2 | Pre-hospital |
| 4.2.2.1 | The Assessment Group's literature review found no published articles examining the cost effectiveness of different thrombolytic drugs in pre-hospital settings. |
| 4.2.2.2 | There is a published economic analysis of the GREAT (Scotland) study comparing cost effectiveness of pre-hospital and hospital thrombolysis (that is, the cost effectiveness of the different drugs), which found that pre-hospital delivery had an incremental cost per life saved of £3890. However, the findings of this analysis should be interpreted with caution. The sensitivity analysis found that the cost per life saved could increase to £88,000. It should also be borne in mind that the benefits found in the GREAT trial were larger than those found in other studies, and that the model of rural Scottish general practitioner care is unlikely to be applicable throughout the NHS. |
| 4.2.2.3 | In the pre-hospital setting Roche's model assumes that reteplase and tenecteplase have equivalent efficacy and that reteplase is slightly cheaper. The BI model finds that tenecteplase dominates reteplase in pre-hospital settings (that is, it has a lower cost and greater effectiveness). |
| 4.2.2.4 | Building on the conclusions about in-hospital cost effectiveness, the Assessment Group suggest that since the general pre-hospital delivery costs for the two suitable bolus drugs (reteplase and tenecteplase) would be the same, the relative cost effectiveness of the drugs in pre-hospital settings is likely to be similar to that in hospital (assuming equal effectiveness of both drugs in each setting). On this basis, the Assessment Group concluded that it was not possible to distinguish between reteplase and tenecteplase on grounds of cost effectiveness in pre-hospital settings. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | In hospital |
| 4.3.1.1 | The Committee was aware of the well-documented differences in the interpretation of the GUSTO-I trial and the higher rates of stroke associated with the newer thrombolytics. The Committee also carefully considered the views of clinical experts on these issues. On balance, the Committee concluded that it was likely that the newer thrombolytic agents are marginally more effective than streptokinase for the main outcome measure of 30-day mortality. The Committee noted that it was generally accepted that the use of streptokinase is cost effective. However, the Committee concluded that, although the acquisition cost of each of the newer drugs is substantially higher than that of streptokinase, the available economic evidence, taking account of the longer-term costs and outcomes (that is, disabling stroke and congestive heart failure), demonstrates that the newer drugs are likely to be cost effective compared with streptokinase. |
| 4.3.1.2 | The Committee also recognised that these cost-effectiveness findings were highly sensitive to the survival gains attributed to accelerated alteplase over streptokinase (from the GUSTO-I trial), and the frequencies of important adverse outcomes (disabling stroke and congestive heart failure) and the utilities attributed to these outcomes. Consequently, the costs per QALY could be markedly higher than those calculated as the baseline case in the economic models. In view of this, and that streptokinase is associated with a lower risk of stroke and is a highly cost-effective drug, the Committee also considered it appropriate that all of the available thrombolytic drugs should be considered as options for use in care pathways for AMI. Local organisational and clinical policy considerations, such as proximity of CCU facilities and A&E staffing, will also have an impact on decisions regarding the appropriate use of the available drugs in hospital. |
| 4.3.1.3 | Because the drugs will have different risk-benefit profiles for individual patients, the Committee concluded that the decision about which of the available drugs to use for individual patients should be made after balancing the likelihood of the benefits and risks (for example, stroke) to which the different drugs would expose them. |
| 4.3.2 | Pre-hospital |
| 4.3.2.1 | While there is evidence to support pre-hospital thrombolysis, applying the results to the current NHS context is difficult, in that none of the trials used currently available bolus drugs, only one was paramedic based, and none was reliably generalisable to England and Wales. |
| 4.3.2.2 | In the absence of comparative evidence on thrombolytics in pre-hospital settings, the findings of trials comparing different thrombolytic drugs in hospital can be applied to pre-hospital settings, with consideration of the additional relevant factors including safety and applicability examined in the pre-hospital studies outlined above. |
| 4.3.2.3 | On the basis of advice from experts that only
the bolus drugs were appropriate for pre-hospital administration, and given
that no high-quality evidence was available to differentiate reteplase and
tenecteplase in terms of clinical effectiveness or
This page was last updated: 30 March 2010 |