1 Appraisal Committee's preliminary recommendations

1.1 Ticagrelor in combination with aspirin is recommended as a treatment option in adults with acute coronary syndromes (ACS) that is, people with:

• ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or
• non-ST-segment-elevation myocardial infarction (NSTEMI) or
• unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia and one risk factor for cardiovascular disease (see section 1.2) – in hospitalised patients. After treatment is initiated it should only be continued if the diagnosis is confirmed by a cardiologist.

1.2 For the purposes of this guidance risk factors for cardiovascular disease are: age 60 years or older; previous myocardial infarction; previous coronary artery bypass grafting (CABG); coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke; previous transient ischaemic attack; previous carotid stenosis of at least 50%; previous cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60 ml per minute per 1.73 m² of body-surface area.

2 The technology

2.1 Ticagrelor (Brilique, AstraZeneca) is an oral antagonist of the P2Y12 adenosine diphosphate receptor that inhibits platelet aggregation and thrombus formation inatherosclerotic disease. The summary of product characteristics (SPC) states that ticagrelor, co-administered with aspirin, is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS), defined as STEMI, NSTEMI or unstable angina. Patients with acute coronary syndromes who receive ticagrelor and aspirin may receive drugs only or may also undergo revascularisation with PCI or CABG.

2.2 According to the SPC, treatment should be initiated with a loading dose of 180 mg ticagrelor (two tablets of 90 mg) and then continued at 90 mg twice daily for up to 12 months. Patients taking ticagrelor should also take aspirin daily, unless it is specifically contraindicated. Following an initial loading dose of aspirin, ticagrelor should be taken daily with a maintenance dose of 75–150 mg aspirin.

2.3 Ticagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or moderate-to-severe hepatic impairment. Co-administration of ticagrelor with a strong CYP3A4 inhibitor (for example, ketoconazole, clarithromycin, nefazodone, ritonavir, or atazanavir) is also contraindicated. The most commonly reported adverse effects of treatment with ticagrelor include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, and bruising. For full details of side effects and contraindications, see the SPC.

2.4 The manufacturer stated in its submission that the cost of 90 mg tablets of ticagrelor is £54.60 for a pack of 56 tablets (28 days). Costs may vary in different settings because of procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ticagrelor and a review of this submission by the Evidence Review Group (ERG; appendix B). This evidence related to the clinical and cost effectiveness of ticagrelor.

Clinical effectiveness

3.1 For the comparison of ticagrelor plus aspirin (hereafter referred to as ticagrelor) with clopidogrel plus aspirin (hereafter referred to as clopidogrel), the manufacturer identified one trial, the PLATO trial, an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study. The trial evaluated the efficacy and safety of ticagrelor compared with clopidogrel over 12 months in people with ACS whose symptoms began up to 24 hours before their admission to hospital. In the trial, 18,624 adult patients with ACS with or without ST-segment elevation from 43 countries including 18 UK centres (n = 281) were admitted to hospital, and randomised to either ticagrelor (n = 9333) or clopidogrel (n = 9291). In the ticagrelor group, patients received a loading dose of 180 mg, then 90 mg twice daily. Patients randomised to clopidogrel received loading doses of 300–600 mg, then 75 mg daily thereafter. Patients did not need loading doses of clopidogrel if they had taken clopidogrel before admission or had received clopidogrel after admission but before randomisation (median approximately 5 hours). In the time between admission and randomisation, 46% of patients in both the ticagrelor and clopidogrel groups received clopidogrel. All patients also received aspirin (in addition to ticagrelor or clopidogrel) with a loading dose of 325 mg, then 75–100 mg daily. Patients already taking aspirin did not need a loading dose of aspirin.

3.2 The primary end point was time to first event (a composite of myocardial infarction, stroke or death from vascular causes). The planned duration of treatment and follow-up was 12 months. If before this time 1780 individuals had a primary end point event, then patients who had not yet been followed for 12 months would finish the study at their 6 or 9 month visit. At the conclusion of the trial, 1878 participants had experienced events and the median duration of treatment was 9.1 months. Secondary end points for the entire study population included: myocardial infarction; stroke; death from vascular causes; death from any cause; a composite of myocardial infarction, stroke and death from any cause; and a composite of myocardial infarction, stroke, severe recurrent cardiac ischaemia, recurrent cardiac ischaemia, transient ischaemic attack, other arterial thrombotic events and death from vascular causes. In the subgroup of patients for whom PCI was planned at randomisation, the first pre-specified secondary end point was the same as the primary end point (that is, the composite of myocardial infarction, stroke and death from any cause).

3.3 The results showed that patients in the ticagrelor group were 16% less likely to experience a primary end point event compared with those in the clopidogrel group (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.77 to 0.92; p < 0.001). Of the components of the primary end point, ticagrelor reduced the incidence of myocardial infarction (MI) (HR 0.84; 95% CI 0.75–0.95; p = 0.005) and death from vascular causes (HR 0.79; 95% CI 0.69–0.91; p = 0.001), but not of stroke (HR 1.17; 95% CI 0.91–1.52). Treatment with ticagrelor reduced the absolute risk of experiencing the primary endpoint from 5.43% to 4.77% at 30 days (absolute risk reduction of 0.6%) compared with clopidogrel and reduced the absolute risk of experiencing the primary endpoint from 11.7% to 9.8% at 12 months (absolute risk reduction 1.9%) compared with clopidogrel.

3.4 An analysis of the primary end point was conducted in several pre-defined subgroups. The manufacturer’s submission stated that analyses showed statistically significant differences in treatment efficacy in three groups: geographic region; body weight above or below a gender-specific median; and use of lipid-lowering drugs at randomisation. The HRs for the major subgroups - unstable angina, NSTEMI and STEMI - were 0.96 (95% CI 0.75 to 1.22), 0.83 (95% CI 0.73 to 0.94) and 0.84 (95% CI 0.72 to 0.98) respectively. The manufacturer presented six sub studies in subgroups that included patients managed invasively and medically, those with diabetes, those with genetic polymorphisms and those undergoing CABG. The results of these six subgroup analyses were generally consistent with the primary analysis.

3.5 The manufacturer reported adverse events from the PLATO study, specifically bleeding, dyspnoea and ventricular pauses. There was no significant difference in the primary safety end point of ‘major’ bleeding between the ticagrelor and clopidogrel groups, which were analysed according to treatment received (11.6% versus 11.2% respectively; p = 0.43) or bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) scale; these findings were consistent across all major subgroups. Patients randomised to ticagrelor experienced more bleeds (major or minor) not related to CABG (HR 1.19; 95% CI 1.02 to 1.38; p = 0.03 and HR 1.11; 95% CI 1.03 to 1.20; p = 0.008 respectively). Intracranial bleeding was more common in the ticagrelor group than in the clopidogrel group, with fatal intracranial bleeding being significantly more common in the ticagrelor group (HR not reported; p = 0.02). Fatal bleeding not attributed to intracranial bleeding was significantly higher in the clopidogrel group (HR not reported; p = 0.03). Patients randomised to ticagrelor experienced dyspnoea significantly more frequency than patients taking clopidogrel (13.8% versus 7.8% respectively; p < 0.001). More patients in the ticagrelor group than in the clopidogrel group discontinued treatment because of dyspnoea (0.9% versus 0.1% respectively; p = <0.001). Holter monitoring detected more ventricular pauses of length greater than or equal to 3 seconds during the first week in the group than in the clopidogrel group, but these occurred infrequently at 30 days and were rarely associated with symptoms. Patients randomised to ticagrelor had significantly greater increases from baseline in levels of serum uric acid and serum creatinine compared with those on clopidogrel; p < 0.001 for both events throughout the study.

3.6 The manufacturer identified no direct comparisons of ticagrelor with prasugrel plus aspirin (hereafter referred to as prasugrel). Instead, the manufacturer identified two studies comparing prasugrel with clopidogrel that provided data for an indirect comparison: the PLATO trial (ticagrelor versus clopidogrel) and TRITON-TIMI 38, which compared prasugrel with clopidogrel in patients (n = 13,608) with ACS who were to be treated with primary or planned PCI. The manufacturer took the view that the trials were not comparable and, by inference, the comparison between prasugrel and ticagrelor was inappropriate and should be viewed with caution. Although the manufacturer noted that the PLATO and TRITON-TIMI 38 were similar in many ways, both including populations with ACS, both comparing the intervention to clopidogrel plus aspirin, and both trials shared the same primary end point, there were potentially important differences. TRITON-TIMI 38 enrolled patients with ACS who were managed invasively with PCI, whereas in PLATO investigators pre-specified whether patients were to receive revascularisation or medical therapy alone. The loading dose of clopidogrel in the TRITON-TIMI 38 trial was 300 mg, whereas in the PLATO trial loading doses of 300 mg or 600 mg were allowed (19.6% of patients treated with clopidogrel in PLATO received the 600 mg loading dose). In the TRITON-TIMI 38 trial, most patients received their loading dose of clopidogrel in the time interval from the insertion of the guide-wire for PCI to 1 hour after the procedure, whereas in the PLATO trial, most patients received their loading dose of clopidogrel before randomisation. Assessing whether a patient has a MI or not differed because of the different timing from hospital admission to PCI, in the two studies. In TRITON-TIMI 38, (excluding the STEMI Primary PCI cohort) there was time for at least two pre-procedure enzyme measurements, whereas in the PLATO trial, only one pre-procedure enzyme measurement was taken, which made it more difficult to detect subsequent MI because elevated enzymes could not be reliably attributed to the index event or a new MI. Therefore adjudication of MI was much more sensitive in TRITON-TIMI 38.  Although the manufacturer dismissed the indirect comparison as inappropriate, it cited a published paper based on the PLATO and TRITON TIMI 38 trials that showed no significant differences in MI, stroke, death from any cause or the composite of these outcomes. Prasugrel was associated with a significantly lower risk of any major bleeding and major bleeding associated with bypass grafting than ticagrelor. The risk of major bleeding not related to bypass surgery did not differ between the prasugrel and ticagrelor groups.

3.7 The PLATO trial included a pre-specified health economics and quality of life sub-study to evaluate the health-related quality of life for ticagrelor compared with clopidogrel. Investigators administered the EQ-5D questionnaire at discharge from the index visit, at 6 months and at the end of treatment in all countries where a version of EQ-5D in the country’s official language was available. Among 8840 patients in the sub-study, investigators found no differences between the ticagrelor plus aspirin group and the clopidogrel plus aspirin group for any of the items on the EQ-5D.

Cost effectiveness

3.8 The manufacturer did not identify any publications that evaluated the cost effectiveness of ticagrelor for the treatment of ACS. Therefore, the manufacturer developed a new economic model, informed by nine existing economic evaluations. For the health economics evaluation of ticagrelor compared with prasugrel, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.

3.9 The manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study, and a Markov model to extrapolate costs and benefits to the lifetime horizon (40 years), and to incorporate major clinical events and resource use. Patients in the model had ACS (STEMI, NSTEMI and unstable angina) including patients managed medically and those managed with PCI or CABG; the model therefore reflected the marketing authorisation for ticagrelor. The model compared ticagrelor with clopidogrel.

3.10 The 1-year decision tree contained four mutually exclusive health states: non-fatal MI, non-fatal stroke, death from any cause, and no further event. The Markov model included six states: non-fatal MI, post-MI, non-fatal stroke, post-stroke, death, and no further event. Non-fatal MI and non-fatal stroke were tunnel states, which allowed for a worse prognosis the first year after a non-fatal event compared with second and subsequent years. After the first year, these patients proceeded to one of four mutually exclusive health states: post-MI, post-stroke, death or no further event. Costs and health outcomes were discounted at 3.5%. The Markov model used a half-cycle correction to adjust for simulated costs and outcomes. The model did not permit a patient to discontinue treatment for any reason other than death.

3.11 In the model, costs, life years, and quality-adjusted life years (QALYs), accrue beyond the 1 year of treatment with ticagrelor or clopidogrel; however, the model assumed that the beneficial effect of ticagrelor does not persist beyond 1 year. This means that the transition probabilities between states in the Markov model were the same for both treatments; the only difference was the number of patients who started the Markov model in each state, which is based on the output of the 1-year decision tree. Adverse events (notably bleeding) were not included in the structure of the model. The increased costs and decreased health-related quality of life associated with adverse events were recorded in PLATO (as part of PLATO-HECON) and are included in the first year (decision tree) of the model reflecting the trial. The manufacturer assumed that adverse events including bleeding and dyspnoea have no effect beyond the 12-month duration of the trial. For cardiovascular complications beyond 1 year (in the Markov component of the model), the manufacturer assumed a constant probability of having an event at 3.15% per year for non-fatal MI and 1.02% per year for non-fatal stroke. The risk of death from MI after the index event (STEMI, NSTEMI or unstable angina) was assumed to be the same as that of death at least 1 year after the index ACS event. .

3.12 For the 1-year decision tree, the manufacturer used a parametric time-to-event survival model with a Weibull distribution to determine the baseline risk (that is, the risk of events in the clopidogrel group), and applied HRs reflective of the effectiveness of ticagrelor to the baseline risk. Using data in the 1-year decision tree derived from the PLATO study, the manufacturer estimated age-adjusted event rates (MI, stroke, death from any cause and death from vascular causes) for a UK population with ACS from the clopidogrel group (mean age of PLATO patients = 62.2 years; reported age of UK patients with ACS in 2009–10 = 69.7 years). In the Markov model, the transition probabilities from the no event health state to each of the non-fatal MI or non-fatal stroke health states were estimated from a study the manufacturer commissioned from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. The probabilities of transitioning between all other health states were taken from standard UK life tables.

3.13 The manufacturer used the 12-month cohort in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period. Investigators in PLATO-HECON elicited utility values from patients using the EQ-5D UK tariff. The manufacturer reviewed utility scores via a literature search to assess the relationship between utility values in the PLATO study and in the literature. The lower values from the literature were used in sensitivity analyses. The utility scores from both the PLATO-HECON sub-study and the literature were adjusted downwards by 0.0328 to reflect the UK population. In addition, because utility decreases with age, the manufacturer applied a utility decrement of 0.004 to each cycle beyond the first year to account for the ageing population in the Markov model.

3.14 The costs for the generic drugs clopidogrel and aspirin, were taken from the NHS Drug Tariff, November 2010. The key drug costs used in the economic evaluation were: aspirin 28-pack = £0.82; clopidogrel 30-pack = £3.40; ticagrelor 28-pack = £54.60. The PLATO-HECON sub-study measured resource use and determined costs for all patients participating in the PLATO study by recording admissions to hospital, interventions, investigations, blood products, re-operations due to bleeding and use of concomitant or study drugs, to estimate total healthcare costs associated with ticagrelor and clopidogrel. Resource use included costs from randomisation to the time of discharge from hospital, as well as after discharge from hospital to the end of the PLATO study. The manufacturer also included in sensitivity analyses the costs of a visit to the GP and of a blood test to check renal function, as stipulated in the SPC for ticagrelor.

3.15 In its deterministic base case (40-year time horizon), the manufacturer’s model estimated that ticagrelor provides an incremental health gain of 0.108 QALYs compared with clopidogrel, at an incremental cost of £379, resulting in an incremental cost-effectiveness ratio (ICER) of £3521 per QALY gained. Results using time horizons of 1 year, 5 years, 10 years and 20 years were also presented: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained. The manufacturer also presented base-case ICERs for the subgroups of ACS specified in the scope, which were £2551 per QALY for STEMI, £5217 per QALY for NSTEMI and £5310 per QALY for unstable angina.

3.16 The manufacturer carried out deterministic sensitivity analyses to the base case and showed the effects of changing 43 model parameters. Only the change to the costs of the no further event health state impacted substantially on the results. When the cost of the ‘no further event’ health state for ticagrelor was set to its lowest, ticagrelor dominated clopidogrel (that is, ticagrelor was more effective and less expensive than clopidogrel), whereas when the cost of the clopidogrel ‘no further  event’ health state was set to its lowest, the ICER was £21,000 per QALY gained. Changes in all other parameters did not increase the ICER beyond £7620.

3.17 Scenario analyses were run for 0% and 6% discount rates, using published utility values, removing baseline utility adjustment and removing the age-related decrease in utility per cycle. The results of the scenario analyses showed that the ICER for ticagrelor compared with clopidogrel ranged from £2358–£4699 per QALY gained.

3.18 The cost-effectiveness acceptability curve showed that at £5000 per QALY gained, the probability of ticagrelor being cost effective compared with clopidogrel was 76.6%. At £20,000 per QALY gained, the probability of ticagrelor being cost effective compared with clopidogrel was 99.9%.

3.19 The manufacturer’s submission also provided results for ticagrelor versus prasugrel for the subgroup receiving PCI, based on the results of a published indirect comparison of the PLATO and TRITON 38 trials. Because of the small number of patients who participated in the TRITON 38 sub-study of quality of life, the model incorporated utility information from the literature, rather than from the sub-study. If costs from the PLATO-HECON sub-study were not available, the manufacturer used NHS reference costs in the analysis for prasugrel. The manufacturer obtained the cost of prasugrel from MIMS, October 2010. The analysis of ticagrelor compared with prasugrel resulted in an incremental cost of £227, incremental QALYs of 0.065 and an ICER of £3482 per QALY, with a 40-year time horizon. The manufacturer stated that the results of the indirect comparison should be viewed with caution because of the problems associated with the indirect comparison of ticagrelor with prasugrel discussed in section 3.6.

ERG comments

3.20 The ERG conducted a literature search and agreed that the PLATO trial was the only trial relevant to the decision problem. The ERG considered that the PLATO trial was well designed with robust processes for randomisation and blinding. It noted that compliance and deviations in protocol were similar across treatment arms. Although only 281 patients in the PLATO trial were from centres in the UK, the ERG considered that they were not dissimilar to other European participants. The ERG also noted that participants in the PLATO trial were younger than patients with ACS in England and Wales, but that the manufacturer’s model accounted for this difference.

3.21 The ERG noted that for patients with STEMI not undergoing stenting, NICE recommends dual antiplatelet therapy (aspirin plus clopidogrel) for at least 4 weeks (‘MI: secondary prevention’ [NICE clinical guideline 48]). From statements in the ‘clinical need and practice’ and ‘evidence and interpretation’ sections of ‘Drug-eluting stents for the treatment of coronary artery disease’ (NICE technology appraisal guidance 152), the ERG concluded that standard practice for STEMI should include dual antiplatelet therapy for 3 months for patients undergoing revascularisation with bare-metal stents and 12 months for patients undergoing revascularisation with drug-eluting stents.

3.22 The ERG considered that the PLATO trial reflects current clinical practice and that all patients received antiplatelet treatment at a clinically meaningful dose. The ERG was satisfied with the manufacturer’s means of categorising adverse events from bleeding. The ERG expressed concerns about the components of the primary efficacy end point in the PLATO trial. First, the primary endpoint was inconsistent with the concept that all components of an end point should be of similar importance to patients. For example, the average utility values from the 12-month cohort in the PLATO-HECON study used in the manufacturer’s model differed by endpoint and were 0.246 for death from a vascular cause, 0.812 for MI and 0.736 for stroke. Second, the primary endpoint was inconsistent with the concept that all components of an end point occur with similar frequencies. For example, in 18,624 participants there were 795 vascular deaths, 1097 MIs and 231 strokes. Third, the primary endpoint was inconsistent with the concept that the effect of a treatment should have an effect of similar magnitude and direction on all components of a primary end point. In the PLATO study, the HR for stroke differed from those of MI and death from vascular causes. The ERG concluded that the results of the overall composite end point should be interpreted cautiously. The ERG also noted that the manufacturer excluded ‘silent’ MIs (defined as new or presumed pathological Q waves on electrocardiogram in the absence of symptoms). The ERG considered that the secondary end points and their components reflected those used in other cardiovascular trials.

3.23 The ERG noted that the manufacturer tested whether the effectiveness and safety of ticagrelor compared with clopidogrel differed across 25 pre-specified and eight post-hoc subgroups, without adjustment for multiple comparisons. The ERG expressed concern about the large number of subgroups and potential overemphasis of any significant results from these analyses, which might have occurred by chance alone. With these caveats noted, the ERG observed that the regional analysis showed that in the USA, patients randomised to clopidogrel did better than those randomised to ticagrelor.

3.24 For patients with STEMI who receive bare-metal stents, the ERG highlighted concerns about the comparator treatment included in the economic evaluation. It interpreted NICE technology appraisal guidance 152 as stating that dual antiplatelet therapy for 3 months was standard practice for patients undergoing revascularisation with bare-metal stents, whereas for patients undergoing revascularisation with drug-eluting stents, NICE clinical guideline 48 recommends dual antiplatelet therapy for 12 months. Another concern of the ERG was that the manufacturer treated the STEMI group as a homogenous population and estimated a single ICER. By contrast, the ERG believed that STEMI has four distinct populations differing by treatment: STEMI with medical management, STEMI with drug-eluting stent, STEMI with bare-metal stent and STEMI with other intervention (for example CABG).

3.25 The ERG considered that if the trial was designed to test the efficacy of 12 months of treatment, then all patients should have been followed for 12 months. The ERG noted that the PLATO trial design did not involve uniform follow-up for all participants, with patients receiving treatment for 6, 9 or 12 months. Approximately 44% of patients were followed-up for 12 months in the trial. This increased the uncertainty in the estimates of effectiveness at the conclusion of the trial, which in turn was the prime driver of the Markov model and, therefore, the long-term benefits for patients.

3.26 The ERG noted that the model featured two separate paths. In one path, after first presentation with ACS, patients may have a non-fatal MI at any time during the decision-tree part of the model and remain in the non-fatal MI health state to the end of the cycle in which the MI occurs, then progress to the ‘post-MI’ state for all succeeding cycles until death (whether from cardiovascular or non-cardiovascular causes). In parallel, patients may have a non-fatal stroke as their first event (after the initial presentation with ACS) during a period, and then progress to the post-stroke state until death. The ERG considered that this structure does not represent reality, because it does not allow patients to have more than one MI, more than one stroke, or a combination of MIs and strokes in their lifetime following their initial presentation with ACS. Consequently, future costs and benefits would be biased. The ERG also noted that the model simplified the natural history of treated cardiovascular disease by keeping constant the transition probability of previously event-free patients (since initial treatment for ACS) experiencing a non-fatal MI or stroke throughout the long-term Markov model. The modelling ignored the increase in risk associated with other factors, notably, increasing age. The ERG considered that this omission may have led to the manufacturer’s model inaccurately estimating future events, costs and progressive changes in the outcomes and quality of life of patients.

3.27 The ERG was concerned that the model applied an average utility score for the first year, whereas clinical experience showed that ACS patients experience an initial decline in utility which steadily improves. Therefore, the ERG noted that the ICER at 12 months may be an underestimate.

3.28 The ERG noted that the subgroups of interest in the economic evaluation did not reflect the subgroups of interest in the clinical section of the manufacturer’s submission. The ERG could not verify the estimates of clinical effectiveness used in the model ascribed to ticagrelor in patients with NSTEMI or unstable angina. The ERG also noted that the manufacturer considered the subgroup with unstable angina as a homogeneous group whereas, in clinical practice in England and Wales, physicians typically categorise patients into low, medium and high risk groups using the Global Registry of Acute Coronary Events (GRACE) classification and treat them accordingly.

3.29 The ERG noted that the manufacturer adjusted the age of the modelled patients to reflect the UK population with ACS. The ERG noted potential problems with the methods chosen by the manufacturer, which may have led to inaccuracies. The ERG established that these inaccuracies represented an 8% underestimate of benefits associated with ticagrelor relative to clopidogrel and suggests that the ICER presented by the manufacturer may be an overestimate.

3.30 The ERG acknowledged that use of healthcare resources was estimated in the model using data from an imbedded health economic study, which collected details of hospital care received by patients during the PLATO trial. However, it noted that these data were collected for only 57.4% of the trial population, and the manufacturer provided no information about how this subset was selected. The ERG also noted that for each patient category in the model the resources used by each patient were calculated separately for each treatment arm, and these were multiplied by a corresponding unit cost and totalled for an estimated hospital-care cost per patient for the first 12-month period. The ERG had some concerns relating to this type of resource analysis, and conducted a combined analysis of resource use (taking all patient groups together), making some adjustments for double-counting. Results suggested that the difference in resource cost associated with clopidogrel and ticagrelor is £100 per patient rather than the £371 shown in the manufacturer’s base-case results, which would have the effect of doubling the estimated ICER at the 1- year time horizon.

3.31 The ERG noted that the manufacturer’s base-case analysis estimated costs for the study drugs assuming 100% use in the trial period, despite clear evidence of deaths before the end of follow-up, treatment withdrawals, and poor compliance in some participants. The ERG instead incorporated data on drug use from the PLATO trial and noted that this reduced the average cost of both ticagrelor and clopidogrel substantially, and the difference in drug costs of ticagrelor compared with clopidogrel reduced from £651 to £507 per patient. Applying the ERG’s amended age adjustment, resource use, and costs of study drugs to the manufacturer’s model resulted in a 42% increase in the manufacturer’s ICER for the 1-year time horizon from £36,177 to £51,204 per QALY gained. However, the ERG emphasised that both the incremental costs and additional benefits associated with ticagrelor compared with clopidogrel were very small at longer time horizons, and subject to considerable uncertainty.

3.32 The ERG conducted a wide-ranging sensitivity analysis, calculating overall deterministic cost-effectiveness estimates for all combinations of four long-term variables – survival gain at 12 months, life expectancy at 12 months, the mean long-term utility value and the mean long-term discounted cost per patient year. The most favourable ICERs for ticagrelor are £3407 per QALY for all patients, £3551 per QALY for the STEMI group, £3350 per QALY for the NSTEMI group and £3405 per QALY for the group with unstable angina. Incorporating the least favourable combination of assumptions resulted in an estimated ICER for ticagrelor plus aspirin below £20,000 per QALY gained for each of the specified populations compared with 12 months’ clopidogrel plus aspirin treatment. The central estimates from these sensitivity analyses were £7897 per QALY for all patients, £8872 per QALY for the STEMI group, £7215 per QALY for the NSTEMI group and £9131 for the subgroup with unstable angina.

3.33  The ERG noted that there are no head-to-head trial data comparing ticagrelor with prasugrel. With regard to the indirect comparison of ticagrelor and prasugrel, the ERG considered that any comparison of the PLATO and TRITON-TIMI 38 trials posed problems. The ERG agreed with the manufacturer that sufficient clinical evidence is not yet available for a credible indirect comparison of ticagrelor versus prasugrel for patients with ACS. It concluded that the comparative effectiveness and safety of ticagrelor compared with prasugrel remains unknown.

3.34 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ticagrelor, having considered evidence on the nature of acute coronary syndromes (ACS) and the value placed on the benefits of ticagrelor by people with these conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee discussed the clinical management of ACS. It heard from the clinical specialists that, in the UK, treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent. The Committee heard that the dose of clopidogrel does not vary whether a bare-metal or drug-eluting stent is used, because all people with ACS undergoing PCI are treated with clopidogrel for 12 months. The Committee heard that in UK clinical practice people with NSTEMI are offered treatments depending on their GRACE or TIMI score: medical management is an option for people at low risk of future adverse cardiovascular events, whereas people at high risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin. The Committee heard from the clinical specialists that in the UK most people with NSTEMI will undergo PCI. The Committee understood that in the UK people with unstable angina, are generally not offered revascularisation, but receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it was unusual for a patient with ACS to undergo primary CABG.

Clinical effectiveness

4.3 The Committee considered the evidence for the clinical effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the manufacturer based its submission on a large trial, PLATO, which compared ticagrelor with clopidogrel. The Committee noted that ticagrelor reduced the relative risk of MI, stroke and death from vascular causes by 16% (95% CI 0.77 to 0.92; p < 0.001) compared with clopidogrel. The Committee also noted that if the components of the primary endpoint were considered individually, the reductions in MI and death from vascular causes were statistically significant (16% and 21% respectively) for patients randomised to the ticagrelor group. The Committee also noted the non-significant increase in the incidence of stroke, in particular haemorrhagic stroke, in patients randomised to the ticagrelor group. The Committee considered the clinical evidence for ticagrelor compared with clopidogrel in the subgroups of patients that were specified in the scope (STEMI, NSTEMI and unstable angina) and noted that the test for interaction showed no statistical difference between the groups. The Committee noted that the manufacturer had performed a large quality of life sub-study based on EQ-5D scores, which indicated no difference in the quality of life for people taking ticagrelor versus clopidogrel.

4.4 The Committee heard from the clinical specialists that overall the trial was representative of the population in the UK, although it was noted that the population in the trial was younger and had a higher proportion of men than the population with ACS in the UK. The Committee understood that the manufacturer had taken account of this in its analysis. With respect to how representative managing ACS in the PLATO trial was relative to management in the UK, the Committee heard from the clinical specialists that the standard loading dose of clopidogrel in the UK was 600 mg but noted that only a fifth of patients in the trial had received this dose. The Committee concluded that the trial was broadly reflective of clinical practice in the UK.

4.5 The Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation. However, the Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated to 1 year and, therefore, concluded that the difference in loading doses of clopidogrel was unlikely to have significantly biased the results. The Committee noted that not all patients in the PLATO trial received treatment for 12 months and that the median duration of treatment was 9 months. The Committee heard that the results presented were for all patients including those censored before 12 months. The Committee therefore concluded that the analysis conducted was sufficiently robust.

4.6 The Committee understood that ticagrelor was dosed twice daily whereas clopidogrel was once daily and heard from the patient experts that, in practice, people would be less likely to take drugs twice daily. The Committee noted that no clear differences had been established on adherence between once daily and twice daily medication. It also heard from the clinical specialists that people taking clopidogrel or ticagrelor would usually receive information to ensure that they understand why compliance is important and why stopping treatment early might increase the risk of recurrent cardiovascular disease. The Committee concluded that decreased compliance would be unlikely to significantly reduce the effectiveness of ticagrelor plus aspirin relative to clopidogrel plus aspirin in the ‘real world’ setting.

4.7 The Committee then discussed the safety concerns and adverse effects associated with ticagrelor. The Committee heard that dyspnoea, ventricular pauses, increase in serum uric acid and increase in serum creatinine from baseline were significantly more common in the ticagrelor group compared with the clopidogrel group, and noted that patients randomised to ticagrelor were more likely to discontinue the study drug. The Committee heard from the patient experts that shortness of breath (dyspnoea) frustrated patients with ACS and the clinical specialists stated that a patient randomised to ticagrelor was nine times as likely to discontinue the study because of dyspnoea relative to patients randomised to clopidogrel, but that the absolute risk was small. The Committee heard from the manufacturer that the effects of dyspnoea were limited mainly to mild episodes. The Committee noted that there was no significant difference in the primary safety end point of ‘major’ bleeding between ticagrelor and clopidogrel. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.

4.8 The Committee discussed whether ticagrelor plus aspirin would be more or less effective in any other specific subgroups including in patients with STEMI, NSTEMI or unstable angina. The Committee noted that several additional subgroups were presented in the trial but agreed that the numbers of patients were small and were unlikely to be powered to find a difference in effectiveness. The Committee also heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. Because there had been no evidence of statistical or biological plausibility presented to allow the Committee to reach any conclusions regarding these other subgroups, the Committee concluded that providing specific recommendations for groups other than those with STEMI, NSTEMI and unstable angina would be highly speculative.

4.9 The Committee noted the concerns around the indirect comparison of ticagrelor and prasugrel highlighted in the manufacturer’s submission and reiterated by the ERG. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor and prasugrel was unknown. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.

Cost effectiveness

4.10 The Committee considered the estimates of cost-effectiveness presented in the manufacturer’s submission for the licensed population as a whole and the subgroups and noted that all ICERs were below £5400. The Committee was mindful of the concerns raised by the ERG around the model structure adopted in the manufacturer’s submission, and agreed that the assumption that patients could not have multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event and an increased risk of further events associated with a first or subsequent event, then the ICERs for ticagrelor compared with clopidogrel would be lower than in the manufacturer’s base case. The Committee was mindful of the ERG’s concerns over the method used to adjust for age but agreed that this would not result in major changes to the ICERs. The Committee also noted that it would have been more appropriate to incorporate a utility value reflective of clinical practice rather than modelling the average utility score but acknowledged that this too was unlikely to have a large impact on the ICERs.

4.11 The Committee was mindful of the ERG’s concerns about the manufacturer’s method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms. The Committee accepted the ERG’s adjustments to the manufacturer’s model and noted the resulting estimates of cost effectiveness. The Committee agreed that the central ICERs from the ERG’s sensitivity analysis (£7897 per QALY for all ACS, £8872 per QALY for STEMI, £7215 per QALY for NSTEMI and £9131 per QALY for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the ICERs produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources.

4.12 The Committee heard from the Primary Care Trust expert that although treatment with ticagrelor relative to clopidogrel appeared cost effective within the range considered to represent good value for money by NICE, the high incidence of ACS in England and Wales means that ticagrelor would have a large impact on budgets and opportunity costs if it was approved for use. The Primary Care Trust expert noted that this would invariably lead to reduced spending elsewhere for health, which would include cardiology services. However, the Committee noted that the guide to the methods of technology appraisal states that budget impact and affordability do not form part of its decision making.

4.13 The Committee noted that the STEMI patients in the PLATO trial were a specific group of STEMI patients. The Committee agreed that only patients with STEMI, defined as ST elevation or new left bundle branch block on electrocardiogram, that cardiologists intend to treat with primary PCI should be treated with ticagrelor. The Committee heard that there is a spectrum of severity with respect to unstable angina. The Committee was mindful that in clinical practice in the UK a diagnosis of unstable angina could be made using less stringent criteria than those defined in the PLATO trial. The Committee agreed that only patients with unstable angina aligned with the definition in the PLATO trial should be treated with ticagrelor. The Committee noted that the definition of unstable angina in the PLATO trial was that patients had to have ST-segment changes on electrocardiography, indicating ischemia;  and one of several risk factors: age 60 years or older; previous MI or CABG; coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke, transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60 ml per minute per 1.73 m² of body-surface area.

4.14 The Committee therefore concluded that ticagrelor plus aspirin could be considered a cost-effective use of NHS resources and should be recommended as a treatment option in adults with ACS that is, people with: STEMI – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary PCI; NSTEMI; or unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia and one risk factor for cardiovascular disease – in hospitalised patients. After treatment is initiated in people with unstable angina, it should only be continued if the diagnosis is confirmed by a cardiologist.  

Summary of Appraisal Committee’s key conclusions  

TAXXX (STA)	Appraisal title: Ticagrelor for the treatment of acute coronary syndromes	ACD section
Key conclusion
Ticagrelor in combination with aspirin is recommended as a treatment option in adults with acute coronary syndromes (ACS) that is, people with: ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or non-ST-segment-elevation myocardial infarction (NSTEMI) or unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia and one risk factor for cardiovascular disease – in hospitalised patients. After treatment is initiated it should only be continued if the diagnosis is confirmed by a cardiologist.  The Committee noted that the ICERs produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources.		1.1, 4.14
Current practice
Clinical need of patients, including the availability of alternative treatments	The Committee heard from the clinical specialists that, in the UK, treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent. The Committee heard that in UK clinical practice people with NSTEMI are offered treatments depending on their GRACE or TIMI score: medical management is an option for people at low risk of future adverse cardiovascular events, whereas people at high risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin. The Committee understood that in the UK people with unstable angina, are generally not offered revascularisation, but receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it was unusual for a patient with ACS to undergo primary CABG.	4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?	Ticagrelor is an oral antagonist of the P2Y12 adenosine diphosphate receptor that inhibits platelet aggregation and thrombus formation in atherosclerotic disease. No specific claim of innovation was made.	2.1
What is the position of the treatment in the pathway of care for the condition?	Ticagrelor, co-administered with aspirin, is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS), defined as STEMI, NSTEMI or unstable angina. Patients with acute coronary syndromes who receive ticagrelor and aspirin may receive drugs only or may also undergo revascularisation with PCI or coronary artery bypass grafting (CABG).	2.1
Adverse events	The Committee heard that dyspnoea, ventricular pauses, increase in serum uric acid and increase in serum creatinine from baseline were significantly more common in the ticagrelor group compared with the clopidogrel group, and noted that patients randomised to ticagrelor were more likely to discontinue the study drug. The Committee heard from the patient experts that shortness of breath (dyspnoea) frustrated patients with ACS. The Committee heard from the manufacturer that the effects of dyspnoea were limited mainly to mild episodes. The Committee noted that there was no significant difference in the primary safety end point of ‘major’ bleeding between ticagrelor and clopidogrel. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.	3.5, 4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The manufacturer based its submission on a large trial, PLATO, which compared ticagrelor with clopidogrel. The PLATO trial was an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study. The Committee also noted that the manufacturer had performed a large quality of life sub-study based on EQ-5D scores which indicated no difference in the quality of life for people taking ticagrelor versus clopidogrel. The Committee concluded that the trial was broadly reflective of clinical practice in the UK and that the analysis conducted was sufficiently robust. There was no direct comparison of ticagrelor and prasugrel and the Committee noted the concerns of the manufacturer and ERG around the indirect comparison of ticagrelor and prasugrel. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor and prasugrel was unknown. The Committee also concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.	3.1, 4.3,  4.4, 4.5 4.9
Relevance to general clinical practice in the NHS	The Committee heard from the clinical specialists that overall the trial was representative of the population in the UK, although it was noted that the population in the trial was younger and had a higher proportion of men than the population with ACS in the UK. The Committee understood that the manufacturer had taken account of this in its analysis. With respect to how representative managing ACS in the PLATO trial was relative to management in the UK, the Committee heard from the clinical specialists that the standard loading dose of clopidogrel in the UK was 600 mg but noted that only a fifth of patients in the trial had received this dose. The Committee concluded that the trial was broadly reflective of clinical practice in the UK.	4.4
Uncertainties generated by the evidence	The population in the trial was younger and had a higher proportion of men than people with ACS in the UK. The Committee understood that the manufacturer had taken account of this in its economic modelling. With respect to how representative managing ACS in the PLATO trial was relative to management in the UK, the Committee heard from the clinical specialists that the standard loading dose of clopidogrel in the UK was 600 mg but noted that only a fifth of patients in the trial had received this dose. The Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation. However, the Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated to 1 year and, therefore, concluded that the difference in loading doses of clopidogrel was unlikely to have significantly biased the results. There was no direct comparison of ticagrelor and prasugrel and the Committee noted the concerns of the manufacturer and ERG around the indirect comparison of ticagrelor and prasugrel. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor and prasugrel was unknown. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.	4.4, 4.5 4.9
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	Several additional subgroups were presented in the trial but the Committee agreed that the numbers of patients were small and were unlikely to be powered to find a difference in effectiveness. The Committee also heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. Because there had been no evidence of statistical or biological plausibility presented to allow the Committee to reach any conclusions regarding these other subgroups, the Committee concluded that providing recommendations for groups other than those with STEMI, NSTEMI and unstable angina would be highly speculative.	4.8
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee noted that ticagrelor reduced the relative risk of MI, stroke and death from vascular causes by 16% (95% CI 0.77 to 0.92; p < 0.001) compared with clopidogrel. The Committee also noted that if the components of the primary endpoint were considered individually, the reductions in MI and death from vascular causes were statistically significant (16% and 21% respectively) for patients randomised to the ticagrelor group. Treatment with ticagrelor reduced the absolute risk of experiencing the primary endpoint from 5.43% to 4.77% at 30 days (absolute risk reduction of 0.6%) compared with clopidogrel and reduced the absolute risk of experiencing the primary endpoint from 11.7% to 9.8% at 12 months (absolute risk reduction 1.9%) compared with clopidogrel.	3.3, 4.3
Evidence for cost effectiveness
Availability and nature of evidence	The manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study (ticagrelor versus clopidogrel), and a Markov model to extrapolate costs and benefits to the lifetime horizon (40 years), and to incorporate major clinical events and resource use. For the health economics evaluation of ticagrelor compared with prasugrel, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.	3.8, 3.9
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee agreed that the assumption that patients could not have multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event and an increased risk of further events associated with a first or subsequent event, then the ICERs for ticagrelor compared with clopidogrel would have been lower than in the manufacturer’s base case. The Committee was mindful of the ERG’s concerns over the method used to adjust for age but agreed that this would not result in major changes to the ICERs. The Committee also noted that it would have been more appropriate to incorporate a utility value reflective of clinical practice rather than modelling the average utility score but acknowledged that this too was unlikely to have a large impact on the ICERs. The Committee was mindful of the ERG’s concerns about the manufacturer’s method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms. The Committee accepted the ERG’s adjustments to the manufacturer’s model and noted the resulting estimates of cost effectiveness and noted that the ICERs produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources.	4.10, 4.11
Incorporation of health-related quality of life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?	The manufacturer used the 12-month cohort in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period. The Committee noted that it would have been more appropriate to incorporate a utility value reflective of clinical practice rather than modelling the average utility score but acknowledged that this was unlikely to have a large impact on the ICERs. The manufacturer reviewed utility scores via a literature search to assess the relationship between utility values in the PLATO study and in the literature. The lower values from the literature were used in sensitivity analyses. The utility scores from both the PLATO-HECON sub-study and the literature were adjusted downwards by 0.0328 to reflect the UK population. In addition, because utility decreases with age, the manufacturer applied a utility decrement of 0.004 to each cycle beyond the first year to account for the ageing population in the Markov model. For the comparison of ticagrelor versus prasugrel, because of the small number of patients who participated in the TRITON 38 sub-study of quality of life, the model incorporated utility information from the literature, rather than from the sub-study.	3.13, 4.10 3.19
Are there specific groups of people for whom the technology is particularly cost effective?	See section on subgroups above.	4.8
What are the key drivers of cost effectiveness?	Only the change to the costs of the health state in which a patient does not experience an additional cardiovascular event impacted substantially on the results. When the cost of the ‘no further event’ health state for ticagrelor was set to its lowest, ticagrelor dominated clopidogrel (that is, ticagrelor was more effective and less expensive than clopidogrel), whereas when the cost of the clopidogrel ‘no further event’ health state was set to its lowest, the ICER was £21,000 per QALY gained. Changes in all other parameters did not increase the ICER beyond £7620 per QALY gained. Results using time horizons of 1 year, 5 years, 10 years and 20 years were also presented: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained.	3.16 3.15
Most likely cost-effectiveness estimate (given as an ICER)	The Committee accepted the ERG’s adjustments to the manufacturer’s model and agreed that the central ICERs from the ERG’s sensitivity analysis (£7897 per QALY for all ACS, £8872 per QALY for STEMI, £7215 per QALY for NSTEMI and £9131 per QALY for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel.	4.11
Additional factors taken into account
Patient access scheme	Not applicable	-
End-of-life considerations	Not applicable	-
Equalities considerations, Social value judgements	No equality issues were identified during the scoping process or the appraisal.	-

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Proposed recommendations for further research

6.1 Clinical trials should be conducted comparing ticagrelor with prasugrel in people with ACS.

6.2 Further research into whether ticagrelor is particularly beneficial in any clinical or biological subgroups would be useful.

7 Related NICE guidance

Published

• Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline 94 (2010). Available from www.nice.org.uk/guidance/CG94
• Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. NICE technology appraisal guidance 182 (2008). Available from www.nice.org.uk/guidance/TA182
• Drug-eluting stents for the treatment of coronary artery disease. NICE technology appraisal guidance 152 (2008). Available from www.nice.org.uk/guidance/TA152
• MI – secondary prevention: secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE clinical guideline 48 (2007). Available from www.nice.org.uk/guidance/CG48

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Bivalirudin for the treatment of ST-segment elevation myocardial infarction. NICE technology appraisal guidance. Publication date to be confirmed.

8 Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is incorporated into the forthcoming NICE clinical guideline on ‘The management of myocardial infarction with ST-segment elevation’ (cg167). NICE welcomes comments on this proposal.

Amanda Adler
Chair, Appraisal Committee
June 2011

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Chakravarty
External Relations Director - Pharmaceuticals & Personal Health, Oral Care Europe

Professor Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Mrs Eleanor Grey
Lay member

Dr Neil Iosson
General Practitioner

Mr Terence Lewis
Lay Member

Professor Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the NIHR Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Dr Sanjeev Patel
Consultant Physician & Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Casey Quinn
Lecturer in Health Economics, Division of Primary Care, University of Nottingham

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay Member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Professor Rod Taylor
Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Mr Tom Wilson
Director of Contracting & Performance, NHS Tameside & Glossop

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Raisa Sidhu
Technical Lead

Joanna Richardson
Technical Adviser

Jeremy Powell
Project Manager

 Appendix B: Sources of evidence considered by the Committee

A  The Evidence Review Group (ERG) report for this appraisal was prepared by the Liverpool Reviews and Implementation Group (LRiG):

• Bagust A, Boland A, Blundell M et al. Ticagrelor for the treatment of acute coronary syndromes, February 2011

B  The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I and II also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• AstraZeneca

II Professional/specialist and patient/carer groups:

• Action Heart
• British Cardiovascular Intervention Society (BCIS)
• British Cardiovascular Society
• British Heart Foundation
• Heart Care Partnership (UK)
• HEART UK
• Royal College of Nursing
• Royal College of Physicians
• South Asian Health Foundation

III Other consultees:

• Department of Health
• NHS Bradford and Airedale
• Oxfordshire PCT
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Bristol-Myers Squibb
• British National Formulary
• British Society for Cardiovascular Research
• Commissioning Support Appraisals Service
• Daiichi Sankyo
• Department of Health, Social Services and Public Safety for Northern Ireland
• Eli Lilly
• Healthcare Improvement Scotland
• Medicines and Healthcare products Regulatory Agency (MHRA)
• Sanofi-Aventis

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on ticagrelor by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Nick Curzen, nominated by the Royal College of Physicians - clinical specialist
• Professor Anthony Gershlick, Consultant Cardiologist, University Hospitals of Leicester, nominated by the Royal College of Physicians, Consultant Cardiologist,Southampton University Hospitals - clinical specialist
• Liz Clark, nominated by the Heart Care Partnership - patient expert
• John Miller, nominated by the Heart Care Partnership - patient expert

D The following individuals were nominated as NHS Commissioning experts by the selected PCT allocated to this appraisal. They gave their expert/NHS commissioning personal view on ticagrelor by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Greg Fell, Consultant in Public Health, NHS Bradford and Airedale selected by NHS Bradford and Airedale – NHS Commissioning expert

E Representatives from the following manufacturer/sponsor attended Committee Meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• AstraZeneca