4 Evidence and interpretation
The Appraisal Committee considered evidence from a number of sources (see Appendix B). Each indication was considered separately.
22.214.171.124 The Assessment Group found one new study (GUSTO IV), in addition to four studies from the previous appraisal that are relevant to this review. All were classified as randomised controlled trials (RCTs) that included patients with unstable angina or NSTEMI, but the definitions of the participants varied between trials. Two studies looked at eptifibatide, two at tirofiban and one at abciximab; all these studies compared treatment with placebo or no treatment. On the whole, the studies were well conducted. Outcome measures included death, MI, need for revascularisation and adverse events associated with use of the trial drugs. Differences between trials precluded pooling results in the Assessment Report.
126.96.36.199 In nearly all studies involving the small-molecule GP IIb/IIIa inhibitors (eptifibatide and tirofiban), the rates of death and MI were reduced in the treatment groups compared with the comparator group; however, the difference was not always statistically significant. In all of the trials, the risk of bleeding was greater in the groups receiving a GP IIb/IIIa inhibitor than in the comparator group, but the difference was not always statistically significant.
188.8.131.52 In the GUSTO-IV trial of abciximab, the results demonstrated neither benefit nor trends of benefit in the primary outcomes of death and MI at 30 days.
184.108.40.206 The Assessment Group concluded that the effects of GP IIb/IIIa inhibitors were small compared with those of other interventions in ACS, for example aspirin. Subgroup analyses showed that GP IIb/IIIa inhibitors may be particularly effective in troponin-positive patients. A recently published meta-analysis seen by the Committee (the Boersma study) analysed the data for various subgroups and suggested that, in those not routinely scheduled for early PCI, the rate of cardiac complications is reduced following the administration of GP IIb/IIIa inhibitors.
220.127.116.11 The submissions for this appraisal from consultees (manufacturers/sponsors and professional and patient/carer groups) contained no clinical evidence on the use of GP IIb/IIIa inhibitors for the medical management of ACS that had not already been included in the Assessment Report.
18.104.22.168 The clinical experts were asked about the evidence for medical management in those not going on to have a PCI during GP IIb/IIIa inhibitor administration, which is frequently the scenario in current UK practice. They stated that current evidence-based good practice is to investigate, by means of coronary angiography, with a view to early revascularisation, all of those patients presenting with ACS deemed to be at high enough risk to merit a GP IIb/IIIa inhibitor.
22.214.171.124 They were also asked to comment on the importance of various risk factors used to identify high-risk ACS patients. They considered that an elevated troponin result often confirms the high-risk status of an individual, but that increased troponin should not be thought of as the only indicator of high risk and that other clinical factors have to be taken into account.
126.96.36.199 The Assessment Group found five new trials (PRICE, ADMIRAL, TACTICS-TIMI, TARGET and ESPRIT), in addition to 12 studies from the previous appraisal that are relevant to this review. Fourteen trials compared treatment with placebo or no treatment – ten of these involved abciximab, three involved eptifibatide and one involved tirofiban. There were two head-to-head trials, one of abciximab and eptifibatide and one of abciximab and tirofiban. One further trial compared invasive and conservative treatment, with all participants receiving tirofiban. The definition of participants both within and between trials was broad, from patients undergoing elective PCI to those who had acute PCI after MI. All trials were classified as RCTs, and many of them were large (with at least 1000 participants). Outcomes measured included death, non-fatal MI, the need for PCI or CABG after the current procedure, and adverse events.
188.8.131.52 Again the results of the trials were not pooled for the Assessment Report because of heterogeneity, which included differences between studies in the inclusion criteria for patients undergoing the procedure. Only one trial showed the use of a GP IIb/IIIa inhibitor to be associated with a significant reduction in the mortality rate at 30 days; another trial showed significant reduction in the mortality rate at 6 months. The use of a GP IIb/IIIa inhibitor was associated with a reduction in the rate of revascularisation at 30 days and at 6 months in studies in which this was measured, but the difference was statistically significant in one trial only.
184.108.40.206 However, with composite outcomes (usually a combination of death, subsequent MI and revascularisation), the great majority of trials showed a statistically significant benefit of treatment with a GP IIb/IIIa inhibitor. There were more minor and major bleeds in the treatment groups in all studies, but the increased rates were not always statistically significant. There was little evidence of benefit for subgroups.
220.127.116.11 The only new data submitted on the use of GP IIb/IIIa inhibitors during PCI were longer-term data from two trials (ESPRIT and EPIC), some re-analysis of the existing data, and data from a recent UK audit presented by the British Cardiac Society and Royal College of Physicians (London).
18.104.22.168 The clinical experts were asked to comment on the use of GP IIb/IIIa inhibitors as an adjunct during elective PCI. Their view was that elective single-vessel PCI in a low-risk patient carries a very small absolute risk of complications. Consequently, the use of GP IIb/IIIa inhibitors in such low-risk patients was generally considered unlikely to confer any clinically significant additional benefit; GP IIb/IIIa inhibitors should only be used in these circumstances if unexpected complications occur. Conversely, the use of GP IIb/IIIa inhibitors as an adjunct to PCI was considered beneficial in patients with evidence of recent ACS, in patients with diabetes and in patients undergoing potentially complex PCI, which might include multivessel disease, the use of multiple stents, PCI of a vein graft or PCI of bifurcation lesions.
22.214.171.124 The Assessment Group found no additional cost-effectiveness studies beyond the seven included in the previous appraisal of GP IIb/IIIa inhibitors. None of these studies was UK-based. Since management of ACS in the UK differs from that in other developed countries, particularly in regard to the rate of PCI, the results were not considered to be applicable to the UK. Economic models for tirofiban and eptifibatide were submitted by the manufacturers for the original appraisal.
126.96.36.199 The eptifibatide manufacturer's model was based on a prospective economic evaluation conducted as part of the PURSUIT trial. Based on the subgroup of patients from Western Europe (12% of the total patients), the cost per life-year gained for eptifibatide was estimated as £8179 to £11,079. Although lifetime survival duration was modelled, no extrapolation of costs over the patients' lifetime was attempted and it is not clear how this would impact on the results.
188.8.131.52 The tirofiban manufacturer's model reported that 22% of the cost of tirofiban is offset by savings due to the reduction in events. The lack of a standardised outcome measure makes it difficult to interpret these results in relation to other treatments. The absolute reduction in event rates associated with tirofiban was not adjusted for UK-specific baseline-event rates.
184.108.40.206 A further six economic studies in the literature were identified in addition to the 17 studies included in the original appraisal, but none of these fully reflects current UK practice and the long-term costs and consequences. The original appraisal also considered the manufacturer's submission for abciximab.
220.127.116.11 In the manufacturer's model for abciximab, for patients undergoing urgent and elective PCIs in a UK setting, estimates of cost per quality-adjusted life year (QALY) ranged from £6941 to £9053 based on the EPILOG trial and from £3949 to £5151 based on the EPISTENT trial. These estimates must be interpreted with caution for the following reasons: the baseline risk of events is different in the UK from that in the trials; the assumption that patients surviving the first year will live for a further 15 years ignores variability of prognosis; and it may not be valid to assume that costs do not differ between treatment options over a period of 2 to 15 years.
18.104.22.168 The Assessment Group developed a UK-specific model to look at the optimal use and timing of use of GP IIb/IIIa inhibitors in ACS patients. The model estimated health outcomes in terms of QALYs and had a lifetime time horizon. Four treatment strategies for GP IIb/IIIa inhibitors were compared:
a GP IIb/IIIa inhibitor used as part of initial management, with treatment begun immediately in all ACS patients at the time they were identified
a GP IIb/IIIa inhibitor started only after making a decision to carry out PCI
a GP IIb/IIIa inhibitor used as an adjunct to PCI, started up to 1 hour before the procedure
no use of GP IIb/IIIa inhibitors.
An additional analysis looked at initial management in high-risk ACS patients only (defined as those with at least one of three factors: age > 70 years, diabetes, ST-depression). Initially, baseline event rates were calculated based on PRAIS-UK/Leeds audit data. Since PCI rates here may be lower than in current practice, an alternative analysis using the Boersma meta-analysis was performed. The model applied relative risks from all available trials and from the Boersma data. All analyses showed that use of GP IIb/IIIa inhibitors in initial management was the preferred strategy. Depending on the assumptions used, estimates of cost per QALY ranged from £4605 to £11,671. However, the most cost-effective option was initial medical management in the subgroup of high-risk patients only, with cost per QALY estimated at £3966. The additional benefit of use in all patients compared to use in high-risk patients alone was gained at a cost per QALY of £91,000. When using GP IIb/IIIa inhibitors as an adjunct to PCI was compared with not using them, the base-case cost per QALY was £25,811; this was reduced to £11,160 if baseline event rates based on Boersma data were applied.
22.214.171.124 In summary, the Assessment Report model, which is the closest representation of current UK practice available, indicates that the most cost-effective strategy is for GP IIb/IIIa inhibitors to be used as part of the initial medical management of high-risk ACS patients, irrespective of whether angiography with a view to PCI is performed. Although early angiography with a view to PCI is considered to be of benefit in the initial management of high-risk ACS patients, this was not assessed in the model and is not within the scope of the present guidance. The model suggests that the cost effectiveness of GP IIb/IIIa inhibitors is not dependent on whether a PCI is performed; therefore their administration does not need to be delayed until a decision is made to carry out PCI. The use of GP IIb/IIIa inhibitors as an adjunct during PCI only is also less cost effective than their use in initial medical management.
4.3.1 The Committee considered the evidence available and the viewpoints expressed by the experts on the current management of ACS patients in the UK. It was emphasised that this appraisal related solely to the use of the GP IIb/IIIa inhibitors in the management of ACS, and that it did not extend to the role of PCI or the management of ACS in general.
4.3.2 Historically, PCI rates have been lower in the UK than in the countries where the majority of the published trials of the GP IIb/IIIa inhibitors in ACS have been carried out. The Committee took this into account when considering the validity of these trials in relation to current UK practice, together with evidence from the experts suggesting that PCI rates in the UK are now rising by approximately 20% per annum.
4.3.3 The Committee considered that the Assessment Group model provided the best estimates of cost effectiveness for the UK and, on the balance of clinical and cost effectiveness, the Committee concluded that use of GP IIb/IIIa inhibitors for initial medical management in high-risk patients was the preferred treatment strategy.
4.3.4 The current licensed indications for the GP IIb/IIIa inhibitors are for use with aspirin and unfractionated heparin. However, the Committee recognised that LMWH is used widely in the management of ACS in place of unfractionated heparin, and was aware of the ongoing trials using GP IIb/IIIa inhibitors in conjunction with LMWH.
4.3.5 If GP IIb/IIIa inhibitors are to be used as part of medical management in high-risk patients, the Committee thought that it was important that treatment should be initiated as soon as possible. This proves problematic if raised troponin alone is used to identify high-risk status, as the earliest that raised troponin levels can be accurately detected is 6 to 12 hours after the onset of chest pain. The Committee considered that, in the presence of sufficient high-risk factors (described in 1.4), GP IIb/IIIa inhibitor treatment should be initiated without delaying to confirm high-risk status with a positive cardiac troponin test.
4.3.6 The Committee considered that those ACS patients undergoing PCI should be treated with a GP IIb/IIIa inhibitor. In situations where this is not covered by initial medical management, the Committee thought that the administration of a GP IIb/IIIa inhibitor would still be appropriate. No clinical trial evidence is available on a strategy that involves a second administration of a GP IIb/IIIa inhibitor (that is, after initial medical management) for a delayed PCI.
4.3.7 At the same time, the Committee considered that, for clinically stable patients without diabetes who are undergoing procedurally uncomplicated, routine, elective single-vessel PCI, GP IIb/IIIa inhibitors may not be necessary and therefore should not be recommended for routine use unless unexpected immediate complications occur. The low risk of adverse events during such PCI procedures is demonstrated by UK audit data submitted by the British Cardiac Society and Royal College of Physicians (London).