Acute coronary syndrome (ACS) is a major cause of morbidity and mortality, and imposes significant costs on healthcare systems.1 ACS is a pathophysiologic continuum ranging from unstable angina (UA) to non-ST-segment elevation myocardial infarction (NSTEMI) to ST-segment elevation myocardial infarction (STEMI). Current guidelines recommend early diagnostic cardiac catheterisation and percutaneous coronary intervention (PCI) within 2 hours for STEMI patients2,3, and within 72 hours for moderate to high risk NSTEMI patients.4,5

Platelets play a key role in the pathogenesis of atherothrombotic complications that may occur due to plaque rupture in ACS and PCI. Therefore, dual antiplatelet therapy with aspirin and clopidogrel has been recommended in practice guidelines for ACS patients undergoing PCI to prevent ischemic events.3-6

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that prasugrel, significantly reduced, compared to standard-dose clopidogrel, the composite endpoint of cardiovascular death, non fatal myocardial infarction or non-fatal stroke in ACS patients undergoing PCI treated with aspirin for up to 15 months. Prasugrel was associated with a significant increase in the rate of bleeding.7 Analysis of net clinical benefit (defined as the rate of death from any cause, nonfatal myocardial infarction, non-fatal stroke, or non-CABG-related non-fatal TIMI major bleeding), however, favoured prasugrel over clopidogrel in the overall patient population.7 There were three subgroups of patients, however, among whom prasugrel did not have a favourable net clinical benefit: patients who had prior history of stroke or transient ischemic attack had net harm from prasugrel, while net clinical benefit among patients aged &75 years and patients weighing less than 60 kg was neutral.7 The European Medicines Agency (EMA) approved prasugrel to be given as a loading dose of 60 mg and followed with 12 months of treatment with a daily 10 mg dose in ACS patients undergoing PCI, with prasugrel contraindicated in patients with previous stroke or TIA. The label also reflects the higher rates of bleeding in patients a:75 years old and patients weighing < 60 kg in recommending a reduced maintenance dose (5 mg) for these patients.8 In patients a 75 years old, the use of prasugrel was generally not recommended and a careful benefit/risk evaluation needs to be performed and prasugrel used when the benefits of ischemic events prevention outweighs bleeding risks (Efient® SPC).8

Given the increasing pressures on health care budgets, it is necessary to assess health interventions not only in terms of their safety and efficacy but also in terms of their cost-effectiveness. Economic evaluation of competing healthcare interventions compares these in terms of their incremental costs and benefits, such as quality adjusted life years (QALYs), expressing cost-effectiveness in terms of incremental cost per QALY. Cost-effectiveness analyses have shown prasugrel to be cost-saving in a US setting, based on substantial reductions in re-hospitalisation costs.9 The present study evaluates the long-term cost-effectiveness, in terms of both cost per life year and cost per QALY gained, from the perspective of the Spanish health care system, of treating ACS patients undergoing PCI, with prasugrel compared to clopidogrel for a period of time of 12 months. The base case analysis considers the overall licensed population in TRITON-TIMI 38 (defined as all patients other than those with prior stroke or TIA and including patients who are now recommended to be treated with a 5 mg maintenance dose). The analysis is based on a model the main elements of which are briefly described below. Further details of the model, including the risk equations based on TRITON TIMI-38 that it employs, have been reported elsewhere.10

This cost-effectiveness analysis compares 12 months treatment with prasugrel (60 mg loading dose and 10 mg daily maintenance dose) to 12 months treatment with clopidogrel (a 300 mg loading dose and a 75 mg daily maintenance dose) using a lifetime horizon. Detailed model methods have previously been described elsewhere.10

Briefly, a Markov state transition model was developed to estimate health outcomes, life years (LYs), quality adjusted life years (QALYs), and costs over the patients’ lifetimes. Life years and QALYs were modelled as a function of index ACS type and events occurring during 12 months of treatment. Individual patient data from TRITON-TIMI 38 were used to construct a series of risk equations to estimate the risks of clinical events. The equations predict the risk of the primary endpoint in the trial of cardiovascular death, non-fatal MI or stroke, and its key safety endpoint, TIMI major or minor bleeding (including CABG bleeds) over the 12 month period of treatment conditional on patients’ clinical characteristics at baseline and treatment allocation. Following the 12 month treatment period, risks for all-cause mortality are increased by non-fatal myocardial infarctions and strokes that are predicted to have occurred during the treatment period. The Markov state transition model approximated a lifetime horizon for the analysis (maximum survival of 40 years following the index ACS event).

Costs and outcomes were discounted at an annual rate of 3% according to current Spanish recommendations.11Table 1 presents a summary of the inputs used in the model.

Markov model

Figure 1 shows the model pathways (rectangles represent model states and arrows between ovals represent transitions between those states), for the Markov model. The model consists of two phases: one representing 12 months of treatment following PCI for ACS and the second representing remaining potential life expectancy. Patients enter the model and face risks for cardiovascular death, non-fatal MI, or non-fatal stroke, and bleeding (fatal, major or minor), during the 12 months antiplatelet treatment phase. Patients’ longer term mortality is then predicted based on the occurrence of events over the first 12 months. Though further events will occur over patients’ remaining lifetimes, an average effect of these further (unobserved) events on long term mortality is reflected in the relative risks for all-cause mortality employed in the model.12,13

Figura 1.

Modelpathways for the Markov model.

(0.1MB).

Treatment with prasugrel was cost effective compared with clopidogrel among patients with an ACS undergoing PCI from the perspective of the Spanish healthcare system. Drug costs for prasugrel were higher than clopidogrel by €538 but this higher cost was partially offset by savings from reduced re-hospitalisations over one year. Prasugrel was associated with a non-significant reduction in the rate of cardiovascular death in TRITON-TIMI 38, however, life year gains will also accrue over the longer term principally due to the significantly lower rate of non-fatal MI. The model recognises, through the long term application of the rehospitalisation equation’s baseline admission rate, that surviving patients will continue to require a certain level of health care due to their underlying coronary disease irrespective of potential further events. Though the admission rates associated with modelled events could also have been applied over the long term, this would clearly have favoured prasugrel without evidence to support this. The approach taken may to this extent, therefore, be conservative with respect to prasugrel’s expected cost-effectiveness; although greater numbers of prasugrel patients remain alive and therefore at risk of further events, a greater proportion of surviving clopidogrel patients carry the added risk due to re-infarctions seen in the trial. Additional life-years and QALYs over the longer term result in incremental cost-effectiveness ratios below the Spanish threshold considered for cost-effectiveness (€30,000 per QALY).28 Sensitivity analysis showed prasugrel’s cost-effectiveness was robust to different assumptions within the model.

Though prasugrel is cost-effective in all sub-groups, it’s ICER is lower in those groups at higher risk of ischemic events - the STEMI and diabetic populations. The model reported here, however, is designed to assess prasugrel’s cost-effectiveness based on the licensed population in the trial, and accounts for prasugrel’s greater effectiveness in patients without prior TIA/stroke. Wiviott et al. have emphasised the greater effectiveness of prasugrel seen in patients with what they term a ‘core clinical cohort’, which includes not only those patients within TRITON TIMI-38 without prior TIA/stroke, but also those patients aged under 75 years with body weight a 60 kg. The model does not account for differences in treatment effects by age and weight, and the results reported for the core clinical cohort may therefore reflect conservative estimates of prasugrel’s likely QALY gains in these patients.

The results and sensitivity analyses presented in tables 3 (main results) and 4 (deterministic sensitivity analysis), are based on aggregating analyses for individual patient profiles, reflecting diversity in patients’ baseline characteristics in TRITON. To conduct probabilistic analyses on this basis, however, would be impractical as this would require several million iterations of the model. We therefore report a limited probabilistic analysis in Figure 2 that shows the probabilities of prasugrel being cost-effective at given thresholds for cost per QALY based on the patient profile in the overall licensed population with median cost-effectiveness.

Fatal bleeding is accounted for in the model, and the higher bleeding risk associated with prasugrel treatment can be expected to cease once patients stop treatment, in this case at a maximum of 12 months following PCI. This assumption is consistent with prior cost-effectiveness analyses of anti-thrombotic agents known to be associated with differences in bleeding rates.29 While bleeding has been associated with increased mortality over a long time period,30 Hochholzer et al., estimated the impact of serious bleeding on mortality in TRITON-TIMI 38.31 A declining HR over time following a non-fatal serious bleed stabilised after 40 days at approximately 1.38 (0.72-2.66).31 We explored our assumptions around bleeding in our analyses, and an eight-fold increase in the disutility associated with bleeds had little on the cost-effectiveness.

A potential limitation of the analysis concerns the utility estimates which are drawn from the US Medical Expenditure Panel Survey.21 Though these were based on the EQ-5D, the tariff used was that of the USA and so may not be representative of the Spanish population. However, the impact of the utility data assumptions were tested in the sensitivity analysis by varying the weights (utilities) attached to modelled events; reducing the impact of these events’ utility decrements by 50%, and increasing them by 100%, varied prasugrel’s cost per QALY by only ± €50.

In Spain, clopidogrel’s cost-effectiveness has been demonstrated by Badia et al.32 in a short-term trial based, and longer-term modelled analysis. The short-term incremental cost per event avoided of adding clopidogrel to standard therapy was €17,190; long-term incremental cost per life-year gained was €8,132.32 In an analysis by Latour-Perez et al.33 clopidogrel cost-effectiveness in NSTEMI patients, was shown to vary between €5,000 per QALY for high risk 40 year old patients and €30,000 for low risk 80 year olds.

In conclusion this analysis shows that treatment with prasugrel compared to clopidogrel in patients with ACS undergoing PCI in Spain represents a cost-effective use of health care resources.

TRITON-TIMI 38 was funded by Daiichi Sankyo Company, Limited and Eli Lilly and Company. Economic analyses were funded by Eli Lilly and Company and undertaken by Oxford Outcomes. A. Barrett, JA Sacristán, T Huete and T Dilla are employees of Eli Lilly and Company.