Acute coronary syndrome - prasugrel: appraisal consultation document
The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using prasugrel in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.
This document has been prepared for consultation with the consultees.It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation
The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).
- The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
- At that meeting, the Committee will also consider comments made by people who are not consultees.
- After considering these comments, the Committee will prepare the final appraisal determination (FAD).
- Subject to any appeal by consultees, the FAD may be used as the basis for NICE's guidance on using prasugrel in the NHS in England and Wales.
The key dates for this appraisal are:
Closing date for comments: 30 June 2009
Second Appraisal Committee meeting: 15 July 2009
Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.
1. †Appraisal Committee's preliminary recommendations
1.1 †Prasugrel in combination with aspirin, within its marketing authorisation, is recommended as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when:
- immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary, or
- stent thrombosis has occurred during clopidogrel treatment.
1.2 †People currently receiving prasugrel for treatment of acute coronary syndromes whose circumstances do not meet the criteria in 1.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
2. †The technology
2.1† Prasugrel (Efient, Eli Lilly) is an oral inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of adenosine diphosphate receptors on platelets. Because platelets are involved in starting and/or progressing the thrombotic complications of atherosclerotic disease, inhibiting platelet function can reduce the rate of cardiovascular events such as death, myocardial infarction, or stroke. The summary of product characteristics (SPC) states that prasugrel, co-administered with acetylsalicylic acid, is indicated for the prevention of atherothrombotic events in patients with acute coronary syndrome (that is, unstable angina, non-ST-segment-elevation myocardial infarction or ST-segment-elevation myocardial infarction) undergoing primary or delayed percutaneous coronary intervention.
2.2† According to the SPC, prasugrel should be started with a single 60 mg loading dose and then continued at 10 mg once a day for up to 12 months. Prasugrel should be used cautiously in patients at increased risk of bleeding, especially in patients who are 75 years or older, people with a tendency to bleed or with body weight less than 60 kg. For full details of side effects and contraindications, see the SPC.
2.3 †The manufacturer stated in its submission that the cost of both 5 mg and 10 mg tablets of prasugrel is £47.56 for a pack of 28 tablets. The cost of a loading dose of prasugrel is £10.20 and a course of treatment for 12 months is £628.47 (based on a cost of £1.70 per day for maintenance therapy). Patients would also receive aspirin daily. Costs may vary in different settings because of negotiated procurement discounts.
3. †The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of prasugrel and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 †Clinical evidence in the manufacturer's submission was taken from the trial TRITON-TIMI 38, a randomised double-blind trial that compared prasugrel with clopidogrel in 13,608 patients with moderate to high-risk acute coronary syndromes (unstable angina, ST-segment-elevation myocardial infarction [MI] or non-ST-segment-elevation MI) who were scheduled to have percutaneous coronary intervention. Patients were also given aspirin in combination with the drugs studied. Patients were randomised to receive a loading dose of 60 mg prasugrel followed by 10 mg prasugrel daily or a loading dose of 300 mg clopidogrel followed by 75 mg clopidogrel daily for up to 15 months (the median treatment period was 14.5 months). After percutaneous coronary intervention, patients received daily maintenance doses of placebo tablets matched to clopidogrel or prasugrel. Aspirin was given at a recommended daily dose of 75 to162 mg.
3.2 †The primary efficacy endpoint was a composite of the rate of non-fatal MI, non-fatal stroke or death from cardiovascular causes, during the entire follow-up period. A range of secondary composite endpoints was also included. Major safety endpoints included TIMI (thrombolysis in myocardial infarction) major bleeding not related to coronary artery bypass graft (CABG), non-CABG-related TIMI life-threatening bleeding, and TIMI major bleeding (a fall in haemoglobin of 5 g/100 ml or more) or minor bleeding (a fall in haemoglobin of 3 to less than 5 g/100 ml). The manufacturer conducted several post hoc exploratory analyses of patients at high risk of bleeding, identifying patients who had a previous stroke or transient ischaemic attack, patients weighing less than 60 kg or patients aged 75 years or older as higher-risk groups.
3.3 †The results of an intention-to-treat analysis of the 13,608 patients (as reported in the main trial publication) enrolled in the TRITON-TIMI 38 trial were that the primary efficacy endpoint was reached in 9.9% of patients in the prasugrel group and 12.1% of patients in the clopidogrel group at 15 months (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73 to 0.90, p < 0.001). There were statistically significant reductions in the prasugrel group compared with the clopidogrel group for rates of MI (7.3% compared with 9.5%, p < 0.001), urgent target vessel revascularisation (2.5% compared with 3.7%, p < 0.001) and stent thrombosis (1.1% compared with 2.4%, p < 0.001). Rates of death for the prasugrel group compared with the clopidogrel group from cardiovascular causes (2.1% compared with 2.4%, p = 0.31) and non-fatal stroke (1.0% compared with 1.0%, p = 0.93) were not statistically significantly different between the groups. In the subgroup of patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared with clopidogrel (10.8% compared with 15.4%, HR 0.65; 95% CI 0.46 to 0.92, p = 0.016).
3.4 †Prasugrel statistically significantly increased the rate of TIMI non-CABG major bleeding, which was reported in 2.4% of patients in the prasugrel group compared with 1.8% of patients in the clopidogrel group (HR 1.32; 95% CI 1.03 to 1.68, p = 0.03). Life-threatening bleeding occurred at a rate of 1.4% in the prasugrel group compared with 0.9% in the clopidogrel group (HR 1.52; 95% CI 1.08 to 2.13, p = 0.01), of which 0.4% were fatal in the prasugrel group and 0.1% in the clopidogrel group (HR 4.19; 95% CI 1.58 to 11.11, p = 0.002).
3.5 †Quality of life was assessed in a substudy using the Seattle angina questionnaire, angina frequency and physical limitations scores, the London School of Hygiene dyspnea questionnaire score, and the EuroQoL utility score and visual analogue score. The study planned to recruit 3000 patients, but actually enrolled 475 patients.
3.6 †The manufacturer presented data on subpopulations of the trial, including the 'licensed' and 'target' populations. The marketing authorisation for prasugrel excludes patients with a history of stroke or transient ischaemic attack. Of the total trial population of 13,608 patients, 518 had a history of stroke or transient ischaemic attack, so the licensed population (as in the marketing authorisation) consisted of 13,090 patients. The target population was a subgroup of the licensed population and consisted of patients for whom the full 10 mg maintenance dose of prasugrel would be considered suitable, specifically patients younger than 75 years, weighing 60 kg or more, and with no history of stroke or transient ischaemic attack. The target population in TRITON-TIMI 38 included 10,941 patients (around 80% of the full trial population). In the target population, the primary efficacy endpoint was reached in 8.3% of patients in the prasugrel group and 11% of patients in the clopidogrel group at 15 months (HR 0.66; 95% CI 0.66 to 0.84, p < 0.001). Non-CABG-related TIMI major bleeding occurred in 2.0% of the prasugrel group and 1.5% of the clopidogrel group (HR 1.24; 95% CI 0.91 to 1.69, p = 0.17).
3.7 †There were 3421 patients with ST-segment-elevation MI in the licensed population. In this subgroup of patients, the primary efficacy endpoint was reached in 9.8% of patients in the prasugrel group and 12.3% of patients in the clopidogrel group at 15 months (HR 0.79; 95% CI 0.65 to 0.97, p = 0.02). The occurrence of non-CABG-related TIMI major bleeding at 15 months was not statistically significantly different between the prasugrel group and the clopidogrel group (2.4% and 2.1%, respectively).
3.8 ††There were 2947 patients with diabetes in the licensed population. In this subgroup of patients, the primary efficacy endpoint was reached in 12.2% of patients in the prasugrel group and 17.0% of patients in the clopidogrel group at 15 months (HR 0.70; 95% CI 0.58 to 0.85, p < 0.001). The occurrence of non-CABG-related TIMI major bleeding at 15 months was not statistically significantly different between the prasugrel group and the clopidogrel group (2.5% and 2.6%, respectively).
3.9 †The manufacturer conducted a systematic review of relevant economic evidence and a new economic evaluation of the use of prasugrel for patients with acute coronary syndromes having percutaneous coronary intervention. The evaluation used individual patient data from TRITON-TIMI 38.
3.10 †The model had a Markov model structure with two phases. The first phase spanned the duration of the TRITON-TIMI 38 trial and the second phase modelled long-term events. Rather than using data from the trial directly in the model, separate risk equations for primary endpoint events were derived from individual patient data from the TRITON-TIMI 38 trial. These risk equations were then used to model events and hospitalisation. Mortality was modelled based on adjustment of population life tables, to reflect the impact on mortality in the long term of the events modelled over the short term. Patients entered the model at the point of the index acute coronary syndrome event immediately before having percutaneous coronary intervention.
3.11 †Key efficacy and safety outcomes associated with the drugs were included in the manufacturer's economic evaluation. However, the adverse reactions (other than bleeding) reported in TRITON-TIMI 38 were not included in the model as they were considered unlikely to affect results.
3.12 †The manufacturer considered that health-related quality of life (HRQoL) data associated with the clinical trial did not provide robust estimates, so it conducted a systematic review to identify HRQoL data relevant to the modelled trial populations. Utility decrements for acute coronary syndromes (0.0409) and stroke/MI (0.0524) were taken directly from a US study, with background UK population norms (free of disease) used to determine utility weights for use in the model. The manufacturer's submission assumed that for a major bleed, a decrement of 25% of the population norm was applied for a 14 day period.
3.13 †The key categories of costs estimated in the submission were related to hospitalisation and drug costs. The total cost of treatment for 12 months would be £628.47 (based on £1.70 per day) for prasugrel and £464.05 (based on £1.26 per day) for clopidogrel. Aspirin (75-325 mg daily, cost £0.01 per day) for each intervention was modelled over 15 months. The unit cost per hospitalisation for prasugrel was assumed to be the same as for clopidogrel (£2619), rather than using the lower weighted average from data collected in the trial (£2530).
3.14 †The manufacturer identified two errors in its model after the ERG had concluded its critique of the manufacturer's submission. Unless stated otherwise, the results presented below are based on updated analyses from the manufacturer.
3.15 †For the licensed population, the manufacturer reported an ICER of £159,358 per quality-adjusted life year (QALY) gained for a time horizon of 1 year and an ICER of £3435 per QALY gained for prasugrel compared with clopidogrel for a time horizon of 40 years. For subgroups of the licensed population, for prasugrel compared with clopidogrel at 40 years, the manufacturer reported ICERs of £3461 per QALY gained for the target population, £1441 for patients with diabetes and £2167 per QALY gained for patients with ST-segment-elevation MI (£4494 per QALY gained for unstable angina and non-ST-segment-elevation MI). The ICERs in the original submission were not substantially different from these revised ICERs from the corrected model.. For example, the ICERs for a time horizon of 40 years reported in the original submission for the licensed population were £3220 and £3250 per QALY gained for the target population respectively.
3.16 †In addition to the results for the populations above, ICERs at 40 years were presented for selected subgroups and for sensitivity analyses. Halving the relative risk for all-cause mortality for the median unstable angina and non-ST-segment-elevation MI profile increased 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 effect of preloading clopidogrel) resulted in a maximum ICER of £22,727 per QALY gained.
3.17 †The ERG stated that the TRITON-TIMI 38 trial used in the manufacturer's submission had followed robust methods and was suitably powered to show a clinically significant difference in the primary efficacy endpoint between the treatment groups. Appropriate specified subgroup analyses and justifiable post hoc exploratory analyses were carried out. However, the ERG noted that there was only one relevant randomised controlled trial (TRITON-TIMI 38) which compared prasugrel with clopidogrel in patients treated with percutaneous coronary intervention. It also considered that the composite endpoint for primary efficacy required further justification. The ERG questioned whether the results of the trial could be generalised to clinical practice in England and Wales. Differences in the efficacy of prasugrel and clopidogrel in the TRITON-TIMI 38 trial were largely because of statistically significant differences in non-fatal MI, which included both clinical MI (which is symptom driven) and non-clinical MI (based on biomarkers and ECG readings). The ERG commented that if only clinical MIs were compared between treatment arms, the differences between prasugrel and clopidogrel may not remain. The ERG commented that the loading dose of clopidogrel (the quantity administered and the timing of the dose) used in the trial did not reflect current clinical practice in England and Wales. It also noted that the bleeding risk associated with prasugrel in the TRITON-TIMI 38 trial may have been higher than that experienced in clinical practice, because there was a growing trend in England and Wales for percutaneous coronary intervention to be performed by radial artery access.
3.18 †In summary, the ERG considered prasugrel and clopidogrel to be broadly equivalent in terms of clinical effectiveness at 15 months for patients with acute coronary syndromes having percutaneous coronary intervention.
3.19 †The ERG identified six key areas where corrections and/or adjustments to the economic model were required. These included life table calculations, discounting, treatment costs, utility values, long-term relative risk of mortality and incidence of non-fatal recurrent MIs. The ERG stated that, taken together, these corrections and/or adjustments would increase the ICER for all patient populations. The ERG was unable to generate model results based on the full model logic (of more than 13,000 cases) due processing time associated with the original model. Therefore the ERGs exploratory analyses are based the prespecified 'typical' or 'median' patient profiles selected by the manufacturer to represent each of the patient populations. The corrected manufacturer cost-effectiveness estimates were received just before the EGR had concluded its report. All results reported by the ERG were based on the manufacturer's original model. The ERG exploratory analyses reported that at a time horizon of 1 year, clopidogrel dominated prasugrel (prasugrel offered no additional benefit and was more expensive) for all 'typical patient' populations, except those patients with diabetes. At 40 years, for a 'typical patient' population the original manufacturer's model estimated an ICER of £5751 per QALY gained. Revision of treatment costs reduced the ICER for prasugrel compared with clopidogrel to £4015 per QALY gained. Using alternative utility data resulted in an increased ICER of £6648 per QALY gained. Amending the relative long term risk of mortality increased the ICER to £12,288 per QALY gained and reducing the incidence of non-fatal recurrent MI resulted in an ICER of £11,515 per QALY gained (all ICERs are for prasugrel compared with clopidogrel). Combining the adjustments in the ERG analysis resulted in an estimated ICER of £20,475 per QALY gained for the licensed population and £20,247 per QALY gained for the target population.
3.20 †The ERG advised that interpretation of the ICERs presented in the manufacturer's submission was dependent on the full acceptance of the manufacturer's assumptions about long-term mortality projections.
3.21 †The ERG stated that the following key uncertainties in the underlying clinical evidence had not been addressed by their exploratory analyses:
- The extent to which patients in the trial would have benefited clinically (through reduced MIs) from a higher loading dose and pre-treatment with clopidogrel was uncertain.
- Practice in the TRITON-TIMI 38 trial did not reflect the growing trend in England and Wales for percutaneous coronary intervention to be performed by radial artery access. The ERG referred to evidence that major bleeding rates are reduced when percutaneous coronary intervention is performed by this route.
- As incremental health gains for prasugrel compared with clopidogrel were small, the resulting ICERs were highly sensitive to changes in the relative benefits of prasugrel and clopidogrel.
3.22 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx
4. †Consideration of the evidence
4.1 †The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of prasugrel, having considered evidence on the nature of acute coronary syndromes and the value placed on the benefits of prasugrel by people with this condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
4.2 †The Committee considered the evidence presented by the manufacturer on the clinical effects of prasugrel compared with clopidogrel for the treatment of patients having percutaneous coronary intervention. The Committee noted that the submission was based on the results of a single large trial, TRITON-TIMI 38, which reported statistically significant reductions in a composite endpoint, non-fatal MI and stent thrombosis, but an increased rate of major bleeds (including fatal bleeds) in patients allocated to prasugrel compared with clopidogrel. Overall, all-cause mortality, cardiovascular death and non-fatal stroke did not differ statistically significantly between groups.
4.3 †The Committee noted the evidence submitted and presented at the meeting by the patient experts and clinical specialists. It heard that overall, prasugrel is a potentially useful addition to the options available. It has a key advantage over clopidogrel in some circumstances because of its greater speed of antiplatelet action. However, the Committee also heard that the evidence base in the manufacturer's submission did not reflect the current clinical use of clopidogrel in England and Wales. Firstly, it understood from the clinical specialists' submitted statements, the ERG report and the manufacturer's submission that a preloading dose of 600 mg clopidogrel was administered to patients several hours before percutaneous coronary intervention in most procedures carried out in England and Wales. This dose and timing of clopidogrel differed from that used in TRITON-TIMI 38. Therefore the clinical specialists considered that more cardiovascular events could have been associated with the clopidogrel group in the trial than might be experienced in a similar cohort of patients having percutaneous coronary intervention in routine clinical practice in England and Wales. As a result, the advantages of prasugrel over clopidogrel in preventing cardiovascular events may have been overstated in the manufacturer's submission, especially for non-ST-segment-elevation MI patients for whom there would be adequate time to give a preloading dose of clopidogrel.
4.4 †A second issue concerning the clinical data in the manufacturer's submission was the use of composite endpoints. The Committee noted that, although common in cardiovascular clinical research, they were difficult to interpret. It noted that non-clinical MIs were included in non-fatal MIs and that this would have increased composite endpoint event rates reported in the trial. The Committee considered that it was not clear if any statistically significant differences would remain between prasugrel and clopidogrel without including non-clinical MI. In addition, the Committee took account of the concern expressed in the clinical specialists' statement about the inclusion of non-clinical MI in the TRITON-TIMI 38, and noted that without non-clinical MI it was possible that few statistically significant differences would remain between prasugrel and clopidogrel.
4.5 †A third issue discussed by Committee was the long-term extrapolation of the effects reported in the clinical trial. The Committee was mindful of the long-term extrapolation of the effects reported in the clinical trial and the ERG critique which stated that the methods for projecting future survival involved evidence from different sources that lacked relevance to current clinical practice and that the model may have overestimated the number of long-term deaths prevented. This possible overestimation may have resulted from the manufacturer applying historical data from people with clinical MIs (alone) to the risks of death from the combination of both clinical and non-clinical MIs in the clinical trial. The Committee agreed that projecting mortality benefits based on short-term prognostic factors and the use of older, less relevant data resulted in considerable uncertainty.
4.6 †The Committee concluded that the TRITON-TIMI 38 study, though well conducted, was not totally applicable to current clinical practice in England and Wales. The Committee noted that the use of a radial artery for percutaneous coronary intervention access was associated with reduced bleeding complications and was increasingly used in England and Wales. It agreed that using the femoral artery in the trial rather than the radial artery may have disadvantaged prasugrel, but in most aspects the design of the trial favoured the prasugrel. When also considering the absence of preloading with clopidogrel, the limitations of the endpoints used and uncertainty about the projection of benefits in the long term, the Committee agreed that there was considerable uncertainty about whether prasugrel was clinically superior to clopidogrel for the licensed or the target population as proposed in the manufacturer's submission.
4.7 †The Committee therefore considered whether there were any identifiable subgroups of patients in the target population for whom prasugrel might show clear superiority over clopidogrel. Three subgroups were considered: patients with clopidogrel 'resistance' may not achieve as much inhibition of platelet function as the majority of patients who are not resistant to clopidogrel; patients with ST-segment-elevation MI who required urgent primary percutaneous coronary intervention and patients with diabetes. Clopidogrel resistant patients may therefore be at risk of further cardiovascular events if their treatment is not adjusted. The clinical specialists described various procedures for testing platelet response and potentially adjusting treatment. The Committee noted these issues, but was mindful that testing of clopidogrel response and adjusting treatment lacked evidence and was not part of routine clinical practice. The Committee agreed that prasugrel may be beneficial for patients in whom clopidogrel may not prevent cardiovascular events, but identifying these patients could be difficult. The Committee heard from the clinical specialists that a clear exception to this concerned patients where a stent thrombosis occurred despite clopidogrel treatment. These patients could reasonably be considered as relatively clopidogrel resistant and could therefore potentially benefit from being treated with an alternative such as prasugrel.
4.8 †The Committee then considered the clinical evidence for prasugrel in patients with ST-segment-elevation MI. In these patients having primary percutaneous coronary intervention, the time window for starting antiplatelet treatment is usually very short. The Committee considered the subgroup results presented in the manufacturer's submission. These indicated a trend towards benefit in ST-segment-elevation MI patients across endpoints even though the primary composite endpoint for ST-segment-elevation MI patients having primary percutaneous coronary intervention was not statistically significant in the clinical trial results. The Committee heard from the clinical specialists that the onset of antiplatelet activity was more rapid and consistent with prasugrel than with clopidogrel. The delayed onset of antiplatelet activity with clopidogrel was of particular concern when urgent percutaneous coronary intervention was required because there would be little or no time to give a preloading dose of clopidogrel. The Committee, taking all the above factors into consideration, agreed that prasugrel could have a clear advantage for ST-segment-elevation MI patients having primary percutaneous intervention.
4.9 †The Committee then considered the use of prasugrel compared with clopidogrel in patients with diabetes who were having percutaneous coronary intervention. It noted that the manufacturer's submission indicated that in diabetes patients, prasugrel reduced primary endpoints compared with clopidogrel to a greater extent than for the licensed population. The Committee, mindful of the views expressed by the clinical specialists, considered that lack of a preloading dose, combined with the dose of clopidogrel used in the trial, may have disadvantaged clopidogrel in the diabetes population. It agreed that the evidence presented on the efficacy of prasugrel in diabetes patients was highly uncertain and did not show a clear advantage over clopidogrel as used in current practice in England and Wales.
4.10 †The Committee also discussed the patients not included in the manufacturer's 'target' population. These were patients aged 75 years or older and patients whose weight was below 60 kg. The Committee noted that the recommended maintenance dose was lower for these patients, but it heard from the clinical specialists that the evidence for treating these patients with prasugrel in preference to clopidogrel in any circumstances was limited. The Committee agreed that evidence was weak but was not persuaded that the recommendations should differentiate between those included or not included in the target population.
4.11 †The Committee considered the estimates of cost effectiveness presented in the manufacturer's submission for the licensed population and for subpopulations at a range of time horizons from 1-40 years. It noted that QALY gains for prasugrel were small (in the region of 0.05 QALYs gained) and that the increase in cost from clopidogrel to prasugrel was comparatively small over a lifetime analysis. As a result, the cost effectiveness of prasugrel was highly susceptible to changes in key model assumptions. The Committee was particularly mindful of the concerns identified in considering the clinical evidence and considered that as a result, there was considerable uncertainty about the assumptions used in the manufacturer's model. These included uncertainty about whether people who have had a non-fatal MI (as defined in the clinical trial) would have the same rates of recurrent non-fatal MIs and mortality as the population from which data were sourced for use in the model, all of whom had clinical MIs. The Committee also agreed that the lack of correction for clopidogrel used at a lower dose and started later than in clinical practice was a further key source of uncertainty. The Committee concluded that the most plausible cost per QALY gained of prasugrel compared with clopidogrel would be higher than presented in the manufacturer's submission.
4.12 †The Committee then considered the results of the exploratory analysis conducted by the ERG using the 'typical patient' profile as defined by the manufacturer for the licensed population. The ERG analysis reported an ICER of £5800 per QALY gained rising to £20,500 per QALY gained in combined scenario analyses. The Committee agreed that while the ERG exploratory analysis addressed some elements of the model which needed adjustment, but these did not deal with key uncertainties in the underlying clinical evidence. The Committee therefore agreed that the most plausible ICER was likely to be higher than the ICER for the combined scenario analysis. The Committee specifically noted that the manufacturer's sensitivity analyses, which removed the first 3 days' effect of prasugrel on cardiovascular outcomes to compensate for the absence of clopidogrel preloading in the model, multiplied the cost per QALY gained by several fold compared with the manufacturer's base case. It concluded that the cost effectiveness of prasugrel compared with clopidogrel had not been demonstrated for the prasugrel licensed or target population.
4.13 †The Committee considered possible patient groups where the overall evidence and strong clinical specialist opinion would support prasugrel as an option for people in whom the drug would be clinically and cost effective. The Committee was mindful of the evidence for ST-segment-elevation MI patients and the potential advantage of the rapid and consistent onset of action of prasugrel and agreed that, for these patients, no correction for the lack of clopidogrel preloading was necessary thereby removing one aspect of uncertainty around the ICER. Additionally, the Committee also considered that in patients who were identified as relatively clopidogrel resistant, experiencing a stent thrombosis during treatment with clopidogrel, the benefits of continuing with clopidogrel were likely to be poor. The relative efficacy and therefore the relative cost effectiveness of prasugrel would be greater in these patients. Therefore, the Committee concluded that the use of prasugrel for patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention and for patients experiencing a stent thrombosis during treatment with clopidogrel would be an appropriate use of NHS resources and could be recommended as an option for these groups of people.
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 implement this guidance (listed below). These are available on our website (www.nice.org.uk/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 which support this locally.
- A costing statement explaining the resource impact of this guidance.
- Audit support for monitoring local practice.
6. †Related NICE guidance
- 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/CG48
- Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. NICE technology appraisal guidance 80 (2004). Available from www.nice.org.uk/TA80
- Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. NICE technology appraisal guidance 47 (2002). Available from www.nice.org.uk/TA47
NICE is developing the following guidance (details available from www.nice.org.uk):
- Clopidogrel and dipyridamole for the prevention of occlusive vascular events. NICE technology appraisal guidance. Publication expected September 2010.
- Acute coronary syndromes: the management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline. Publication expected February 2010.
7. †Proposed date for review of guidance
7.1 †NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in June 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Chair, Appraisal Committee
Appendix A: Appraisal Committee members and NICE project team
A. †Appraisal Committee members
The Appraisal Committee is a standing advisory committee of the Institute. 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 Kathryn Abel (Chair)
Reader and Consultant Psychiatrist, University of Manchester
Professor David Barnett
Professor of Clinical Pharmacology, University of Leicester
Dr David W Black
Director of Public Health, Derbyshire County Primary Care Trust
Dr Brian Buckley
Professor Mike Campbell
Professor of Medical Statistics, University of Sheffield
Mr David Chandler
Dr Peter Clark
Consultant Medical Oncologist, Clatterbridge Centre for Oncology
Dr Christine Davey
Senior Researcher, North Yorkshire Alliance R&D Unit
Dr Mike Davies
Consultant Physician, Royal Infirmary, Manchester
Professor Rachel Elliot
Lord Trent Professor of Medicines and Health, University of Nottingham
Dr Dyfrig Hughes
Senior Research Fellow, University of Wales Bangor
Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield
Professor Peter Jones
Pro Vice Chancellor for Research & Enterprise, Keele University Professor of Statistics, Keele University
Mr Henry Marsh
Consultant Neurosurgeon, St George's Hospital London
Professor Jonathan Michaels (Vice Chair)
Professor of Vascular Surgery, University of Sheffield
Professor Simon Mitchell
Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester
Dr Richard Alexander Nakielny
Consultant Radiologist, Royal Hallamshire Hospital, Sheffield
Mrs Ruth Oliver-Williams
Head of Nursing, Quality Improvement Lead Surgical Services, Royal Derby Hospital, Derby
Dr Danielle Preedy
Professor Andrew Stevens
Chair of Appraisal Committee C
Dr Matt Stevenson
Technical Director, School of Health and Related Research Technical Assessment Group, University of Sheffield
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.
Dr Ruaraidh Hill, Jo„o Vieira
Dr Helen Chung
Appendix B: Sources of evidence considered by the Committee
A †The Evidence Review Group (ERG) report for this appraisal was prepared by Liverpool Reviews and Implementation Group, University of Liverpool:
- Greenhalgh J, Bagust A, Boland A, et al. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention: a single technology appraisal, April 2009.
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.
- Eli Lilly and Company (prasugrel)
II †Professional/specialist and patient/carer groups:
- British Cardiovascular Society
- British Geriatrics Society
- British Heart Foundation
- British Institute of Radiology
- Royal College of Nursing
- Royal College of Physicians
- Action Heart
III †Commentator organisations (did not provide written evidence and without the right of appeal)
- Department of Health
- Dorset PCT
- Welsh Assembly Government
- Sandwell PCT
IV †Commentator organisations (did not provide written evidence and without the right of appeal)
- Department of Health,†Social Services and Public Safety for Northern Ireland
- NHS Quality Improvement Scotland
- Sanofi-Aventis (clopidogrel)
- Bristol-Myers Squibb Pharmaceuticals (clopidogrel)
- Daiichi-Sankyo (prasugrel)
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 prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.
- David Geldard, Immediate Past President, Heart Care Partnership (UK), nominated by Heart Care Partnership - patient expert
- Dr Nick Curzen, nominated by The British Cardiovascular Society and The Royal College of Physicians - clinical specialist
- Dr Tony Gershlick, consultant cardiologist, nominated by British Cardiovascular Society and The Royal College of Physicians - clinical specialist
This page was last updated: 30 March 2010