Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention

Article history

The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 08/78/01. The assessment report began editorial review in May 2009 and was accepted for publication in August 2009. See the HTA programme website for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Michael Fisher has received remuneration from Bristol Myers Squibb/Sanofi for consultancy, symposium attendance, organising education, speaking and staffing.

Copyright statement

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2010 Queen’s Printer and Controller of HMSO

Description of the underlying health problem

Acute coronary syndromes (ACS) are life threatening conditions comprising clinical symptoms associated with acute myocardial ischaemia with or without infarction. 3 ACS represent manifestations of atherosclerosis, which is usually precipitated by acute thrombosis, induced by a ruptured or eroded atherosclerotic plaque, with or without concomitant vasoconstriction, causing a sudden and critical reduction in coronary blood flow. 4

The leading symptom that initiates the diagnostic and therapeutic cascade is chest pain, but the classification of patients is based on the presentation electrocardiogram. 4 The presence of acute chest pain and persistent ST-segment elevation indicates total occlusion of an affected coronary artery. Most of these patients will ultimately develop ST-segment elevated myocardial infarction (STEMI), resulting in necrosis of the tissue supplied by that artery. ACS with acute pain without ST-segment elevation is classified as either unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI). 4

Options for the initial management of ACS patients include: (1) drug therapy (heparin, antiplatelet agents, beta blockers, nitrates, calcium channel blockers, thrombolytic agents and statins) or (2) drug therapy in combination with an early invasive strategy with percutaneous coronary intervention (PCI) (with or without coronary stenting) or coronary artery bypass grafting (CABG). PCI with coronary stenting is endorsed as an early invasive treatment for intermediate to high risk patients with ACS. 4,5

Approximately 15% of the UK ACS population is treated with PCI. In 2007, within the 250,000 patients diagnosed with ACS, 77,373 PCIs were performed. Of these, 40.48% were patients with UA/NSTEMI and 13.24% were patients with STEMI. Most of the remaining patients (45.10%) had stable disease. 6

Scope of the evidence review group report

Prasugrel is licensed in Europe to be co-administered with aspirin for the prevention of atherothrombotic events in patients with ACS undergoing primary or delayed PCI. The use of prasugrel in patients with a history of stroke or transitory ischaemic attack (TIA) is contraindicated in the Special Product Characteristics, whilst use of prasugrel in lighter (less than 60 kg) and older (75 years or more) patients is generally not recommended.

The ERG report presents the results of the evaluation of the manufacturer (Eli Lilly) evidence submission regarding the use of prasugrel with patients with ACS who are to be managed with PCI. The report includes an assessment of both the clinical effectiveness and cost-effectiveness evidence submitted by the manufacturer. The manufacturer submission described the use of prasugrel in combination with aspirin compared with clopidogrel in combination with aspirin.

The primary clinical outcome measure was a composite end point of death from cardiovascular causes, non-fatal myocardial infarction (MI) or non-fatal stroke at 15 months. Secondary outcomes included the primary end point at 30 days and 90 days; a composite end point of death from cardiovascular causes, non-fatal MI or urgent target vessel revascularisation; a composite end point of death from cardiovascular causes, non-fatal MI, non-fatal stroke or rehospitalisation due to a cardiac ischaemic event; and stent thrombosis. Safety end points included non-CABG-related thrombolysis in MI (TIMI) major bleeding, TIMI life threatening and TIMI minor bleeding. Health-related quality of life (HRQoL) was also measured.

An additional outcome measure of net clinical benefit comprising a composite end point of death from any cause, non-fatal MI, non-fatal stroke, or non-CABG-related non-fatal TIMI major bleeding was calculated.

Cost-effectiveness was measured in terms of incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained.

Data for a number of different patient populations were presented:

• overall trial cohort including stroke or TIA (n = 13,608)

• all the ACS licensed population excluding prior stroke or TIA (n = 13,090)

• ACS 10-mg licensed population excluding prior stroke or TIA (target population) (n = 10,941)

• UA/NSTEMI licensed population excluding prior stroke or TIA (n = 9669)

• STEMI licensed population excluding prior stroke or TIA (n = 3421)

• ACS licensed population excluding prior stroke or TIA with diabetes (n = 2947)

• ACS licensed population excluding prior stroke or TIA without diabetes (n = 10,143).

Summary of submitted clinical evidence

The clinical effectiveness evidence was derived from a phase III double-blind, double-dummy randomised controlled trial (RCT) which compared the use of prasugrel with clopidogrel. The TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel(TRITON)–TIMI 38 was conducted in 30 countries and included 13,608 patients. For the overall trial cohort during the 15 month follow-up period, the results of the TRITON–TIMI 38 trial demonstrated a statistically significant benefit of prasugrel compared with clopidogrel on the primary outcome (a composite end point of death from cardiovascular causes, non-fatal MI or non-fatal stroke). The efficacy difference between treatment groups was, in the main, due to a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group. No statistically significant differences were found for death from cardiovascular causes or non-fatal stroke. The trial results reported a benefit for prasugrel in the overall trial cohort for the majority of secondary end points with the exception of death from any cause, where no statistical difference was identified. The results are summarised in Table 1. In the trial, HRQoL data were limited as this substudy comprised responses from too few patients. In the overall trial cohort, statistically significantly more bleeding events occurred in patients in the prasugrel arm than in those in the clopidogrel arm. The analysis of the pre-specified net clinical benefit outcome (death from any cause, non-fatal MI, non-fatal stroke, or non-CABG-related non-fatal TIMI major bleeding) favoured the use of prasugrel in the overall trial cohort. For the fully licensed and target populations, there was a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group; there was no statistically significant difference in bleeding rates.

Summary of submitted cost-effectiveness evidence

In the absence of UK-based economic evaluations of prasugrel for patients with ACS undergoing PCI, the manufacturer conducted a de novo economic evaluation. The analysis described in the manufacturer submission used a Markov model structure with cohorts of patients modelled to experience events over the course of the TRITON–TIMI 38 study period with long-term mortality based on adjustment of population life tables to reflect prognostic implications of the events modelled over the short term. The model also permitted in-hospital costs to accumulate after the end of the trial follow-up period. The model can be separated into two distinct phases: (1) the trial-based period of 15 months and (2) extrapolation beyond the trial to a lifetime horizon (40 years). The economic evaluation adopts a lifetime horizon for the consideration of in-hospital costs and benefits and the perspective is that of the UK NHS and Personal Social Services.

For the fully licensed population (i.e. excluding patients with prior stroke or TIA), the manufacturer reported an ICER of £159,358 per QALY gained at 12 months and an ICER of £3,220 per QALY gained at 40 years; the incremental QALY gain for prasugrel patients is very small (0.001 QALYs and 0.05 QALYs at 12 months and 40 years respectively). In addition to the main results, ICERs for selected subgroups were also presented at 40 years. Univariate sensitivity analysis was undertaken using a range of parameters. At 40 years, using the median UA/NSTEMI profile and halving the relative risks for all-cause mortality increases the ICER to £10,070 per QALY gained; varying the relative risk for prasugrel compared with clopidogrel in the first 3 days in an attempt to explore the preloading of clopidogrel on cost-effectiveness yielded a maximum ICER for this median patient profile of £22,727 per QALY gained.

Probabilistic sensitivity analysis was also conducted by the manufacturer using median patient profiles. At 40 years, the probabilistic sensitivity analyses illustrate that prasugrel is likely to be cost-effective compared with clopidogrel (around 75%) for what would usually be considered low levels of willingness to pay (£20,000) for an additional QALY; the ICERs were within the cost-effectiveness threshold range used by NICE.

Commentary on the robustness of submitted evidence

The manufacturer cited evidence from a large trial (TRITON–TIMI 38) to support the superior clinical effectiveness of prasugrel compared with clopidogrel for the treatment of patients with ACS managed with PCI. The trial used robust randomisation techniques and was suitably powered to show a clinical difference in the primary efficacy composite end point between the treatment groups. Appropriate pre-specified subgroup analyses and post hoc exploratory analyses were carried out.

There is only one relevant RCT (TRITON–TIMI 38) that compares prasugrel versus clopidogrel with PCI. The clinical superiority of prasugrel over clopidogrel on the primary efficacy endpoint is driven largely by a reduction in non-fatal MI, an event recorded clinically (symptomatic) and non-clinically (by biomarkers/electrocardiogram readings). If the non-clinical MIs were considered less important to patients, the resultant clinical difference in non-fatal MIs alone may not be statistically significant.

The primary efficacy composite end point used in the trial may not be appropriate as it fails to meet published recommendations. In addition, there is limited generalisability of the trial protocol to NHS patients in England and Wales due to differences in the use of clopidogrel and its current use in UK clinical practice. Moreover, the growing trend in England and Wales for PCI to be performed via radial artery access is not reflected in the trial; there is evidence that when PCI is performed radially, major bleeding rates are reduced. The HRQoL trial data were limited as the quality of life substudy recruited too few patients to allow meaningful analysis of responses.

The economic model described in the manufacturer submission made use of a large quantity of individual patient data allowing the heterogeneity of different patient groups to be assessed. The manufacturer asked a clearly defined question and attempted to identify, measure and value relevant costs and benefits in the economic evaluation.

The ERG identified six key areas where corrections and/or adjustments to the economic model were required: life table calculations to allow for competing risks; conventional approach to discounting; revised treatment costs reflecting actual usage and pack wastage; alternate utility values; amended long-term relative risks of mortality; and reduced incidence of non-fatal recurrent MIs. Taken together, these corrections and/or adjustments have increased the size of the ICER for all patient populations (Table 2).

The methods used to project outcomes and costs after the trial period are crucial to the acceptance or rejection of the manufacturer’s ICER. The ERG advises caution in view of the various problems that are apparent with this part of the submitted model. If the ERG had been able to modify some of the model’s underlying assumptions, then it is likely that the magnitude of the re-estimated ICER would be increased further.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.