Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes

The assessment group found 1 new study (GUSTO IV), in addition to 4 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, 2 at tirofiban and 1 at abciximab; all these studies compared treatment with placebo or no treatment. On the whole, the studies were well conducted. Outcome measures included death, myocardial infarction (MI), need for revascularisation and adverse events associated with use of the trial drugs. Differences between trials precluded pooling results in the assessment report.

In nearly all studies involving the small-molecule glycoprotein (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.

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.

The assessment group concluded that the effects of GP IIb/IIIa inhibitors were small compared with those of other interventions in acute coronary syndrome (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 percutaneous coronary intervention (PCI), the rate of cardiac complications is reduced following the administration of GP IIb/IIIa inhibitors.

The submissions for this appraisal from consultees (manufacturers or sponsors, professional, and patient or 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.

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.

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.

The assessment group found 5 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, 10 of which involved abciximab, 3 involved eptifibatide and 1 involved tirofiban. There were 2 head-to-head trials, 1 of abciximab and eptifibatide and 1 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 1,000 participants). Outcomes measured included death, non-fatal MI, the need for PCI or coronary artery bypass grafting (CABG) after the current procedure, and adverse events.

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 1 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 1 trial only.

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.

The only new data submitted on the use of GP IIb/IIIa inhibitors during PCI were longer-term data from 2 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).

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.

The assessment group found no additional cost-effectiveness studies beyond the 7 included in the previous appraisal of GP IIb/IIIa inhibitors. None of these studies were 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.

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 £8,179 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.

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.

A further 6 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.

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 £6,941 to £9,053 based on the EPILOG trial and from £3,949 to £5,151 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.

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 1 of 3 factors: age over 70 years, diabetes, ST-depression). Initially, baseline event rates were calculated based on PRAIS-UK and 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 £4,605 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 £3,966. 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.

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.