NICE 发布替卡格雷治疗ACS指南2011

Copyright © NICE 2011 NHS Evidence has accredited the process used by the Centre for Health Technology Evaluation at NICE to produce technology appraisals guidance. Accreditation is valid for 3 years from September 2009 and applies to guidance produced since June 2008 using the processes described in NICE's 'The guide to the methods of technology appraisal' (2008). More information on accreditation can be viewed at www.evidence.nhs.uk Ticagrelor for the treatment of acute coronary syndromes Issued: October 2011 NICE technology appraisal guidance 236 www.nice.org.uk/ta236 Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 2 of 45 Contents 1 Guidance .............................................................................................................................. 3 2 The technology ..................................................................................................................... 4 3 The manufacturer's submission ............................................................................................ 5 Clinical effectiveness .............................................................................................................. 5 Cost effectiveness ................................................................................................................... 8 ERG comments ..................................................................................................................... 12 4 Consideration of the evidence ............................................................................................ 17 Clinical effectiveness ............................................................................................................ 17 Cost effectiveness ................................................................................................................. 21 Summary of Appraisal Committee's key conclusions ............................................................ 23 5 Implementation ................................................................................................................... 34 6 Recommendations for further research .............................................................................. 35 7 Related NICE guidance ...................................................................................................... 36 8 Review of guidance ............................................................................................................ 37 Appendix A: Appraisal Committee members and NICE project team ........................................ 38 A Appraisal Committee members ......................................................................................... 38 B NICE project team ............................................................................................................. 40 Appendix B: Sources of evidence considered by the Committee ............................................... 41 About this guidance ................................................................................................................... 44 Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 3 of 45 1 Guidance 1.1 Ticagrelor in combination with low-dose aspirin is recommended for up to 12 months 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 with non-ST-segment-elevation myocardial infarction (NSTEMI) or admitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist. 1.2 For the purposes of this guidance, characteristics to be used in defining treatment with ticagrelor for unstable angina are: age 60 years or older; previous myocardial infarction or 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, 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. Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 4 of 45 2 The technology 2.1 Ticagrelor (Brilique, AstraZeneca) is an oral antagonist at the P2Y12 adenosine diphosphate receptor, which inhibits platelet aggregation and thrombus formation in atherosclerotic disease. The summary of product characteristics (SPC) states that ticagrelor, co-administered with low-dose aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, defined as STEMI, NSTEMI or unstable angina. Patients with ACS who receive ticagrelor and aspirin may receive drugs only (medical management) 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 a day for up to 12 months. Patients taking ticagrelor should also take low-dose aspirin daily, unless specifically contraindicated. Following an initial loading dose of aspirin, the maintenance dose is 75–150 mg per day. 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 reactions to treatment with ticagrelor include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, and bruising. For full details of adverse 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. Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 5 of 45 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 plus aspirin. Clinical effectiveness 3.1 For the comparison of ticagrelor plus aspirin with clopidogrel plus aspirin, 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 plus aspirin compared with clopidogrel plus aspirin 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 on electrocardiogram from 43 countries including 18 UK centres (n = 281) were admitted to hospital, and randomised to either ticagrelor plus aspirin (n = 9333) or clopidogrel plus aspirin (n = 9291). In the ticagrelor group, patients received a loading dose of 180 mg of ticagrelor, then 90 mg twice a day. Patients randomised to clopidogrel received loading doses of 300–600 mg of clopidogrel, then 75 mg every day 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 end of the trial, 1878 participants had experienced events and the median duration of treatment was 9.1 months. Secondary end points 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, Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 6 of 45 recurrent cardiac ischaemia, transient ischaemic attack, other arterial thrombotic events and death from vascular causes. 3.3 The results showed that the relative risk of experiencing a primary end point event was 16% lower in the ticagrelor group compared with 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, randomisation to ticagrelor plus aspirin reduced the incidence of myocardial infarction (HR 0.84; 95% CI 0.75 to 0.95; p = 0.005) and death from vascular causes (HR 0.79; 95% CI 0.69 to 0.91; p = 0.001), but not of stroke (HR 1.17; 95% CI 0.91 to 1.52). Randomisation to ticagrelor plus aspirin reduced the absolute risk of experiencing the primary end point from 11.7% to 9.8% at 12 months (absolute risk reduction 1.9%) compared with clopidogrel plus aspirin. 3.4 The manufacturer explored the consistency of effects and safety end points in 25 pre- specified subgroups and eight post-hoc subgroups. An analysis was conducted of the primary end point in several predefined 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 by type of ACS at presentation – 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 with a non-statistically significant test for interaction (p = 0.41). The manufacturer presented six analyses in subgroups that included patients whose condition was managed invasively, managed medically, patients with STEMI, patients with diabetes, patients with genetic polymorphisms, and patients 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 statistically significant difference in the primary safety end point of 'major' bleeding between the ticagrelor plus aspirin and clopidogrel plus aspirin groups (11.6% versus 11.2% respectively; p = 0.43), or in the end point of bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) scale. Both were analysed according to which treatment a patient took, rather than to which a patient had been randomised; these findings were consistent across all major subgroups. Patients randomised to ticagrelor experienced more overall major and minor bleeding (HR 1.11; 95% CI 1.03 to 1.20; p = 0.008) as well as more major bleeding not related to CABG (HR 1.19; 95% CI 1.02 to 1.38; Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 7 of 45 p = 0.03). Intracranial bleeding was more common in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, with fatal intracranial bleeding statistically significantly more common in the ticagrelor plus aspirin group (HR not reported; p = 0.02). Fatal bleeding excluding intracranial bleeding was statistically significantly more common in the clopidogrel plus aspirin group (HR not reported; p = 0.03). There was no difference between the two groups in relation to overall fatal bleeding (0.3% in each group). Patients randomised to ticagrelor experienced dyspnoea statistically significantly more often than patients taking clopidogrel (13.8% versus 7.8% respectively; p < 0.001). More patients taking ticagrelor plus aspirin discontinued treatment because of dyspnoea than patients taking clopidogrel plus aspirin (0.9% versus 0.1% respectively; p < 0.001). Holter monitoring detected more ventricular pauses of 3 seconds or longer during the first week in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, but these occurred infrequently at 30 days of treatment and were rarely associated with symptoms. Patients treated with ticagrelor had statistically 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 trials directly comparing ticagrelor plus aspirin with prasugrel plus aspirin. Instead, the manufacturer identified two trials comparing prasugrel plus aspirin with clopidogrel plus aspirin that provided data for an indirect comparison: the PLATO trial (ticagrelor plus aspirin compared with clopidogrel plus aspirin) and TRITON-TIMI 38, which compared prasugrel plus aspirin with clopidogrel plus aspirin in patients (n = 13,608) with ACS and scheduled PCI. The manufacturer took the view that the trials were not comparable and, by inference, a comparison between prasugrel and ticagrelor based on these trials was inappropriate and should be viewed with caution. The manufacturer noted that the PLATO and TRITON-TIMI 38 trials were similar in many ways, both including populations with ACS, both comparing the intervention plus aspirin to clopidogrel plus aspirin, and both sharing the same primary end point. However, there were important differences in the use of PCI and medical management, in the size and timing of the loading dose of clopidogrel, and in assessing myocardial infarction. Although the manufacturer considered the indirect comparison inappropriate, it cited a published paper based on the PLATO and TRITON-TIMI 38 trials that showed no statistically significant differences in the occurrence of myocardial infarction, stroke, death from any cause or the composite of these outcomes between the two drugs. Ticagrelor plus aspirin was associated with a statistically significantly lower risk of major bleeding and Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 8 of 45 major bleeding specifically associated with bypass grafting than prasugrel plus aspirin. The risk of major bleeding not related to CABG did not differ between patients taking prasugrel and those taking ticagrelor. 3.7 The PLATO trial included a pre-specified sub-study of health economics and quality of life that evaluated the health-related quality of life for ticagrelor plus aspirin compared with clopidogrel plus aspirin. Investigators administered the EuroQual 5D (EQ-5D) questionnaire to 8840 patients at discharge from hospital for the index ACS event, again 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. No differences in any of the items on the EQ-5D were found between the ticagrelor plus aspirin group and the clopidogrel plus aspirin group. Cost effectiveness 3.8 The manufacturer did not identify any publications that evaluated the cost effectiveness of ticagrelor for the treatment of ACS. The manufacturer developed a new economic model, informed by nine existing economic evaluations. For the health economics evaluation of ticagrelor plus aspirin compared with prasugrel plus aspirin, 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 a lifetime horizon (40 years), and to incorporate major clinical events. Patients in the model had ACS (STEMI, NSTEMI or unstable angina) and included patients whose condition was managed medically or with PCI or CABG; the model therefore reflected the marketing authorisation for ticagrelor. The model compared ticagrelor plus aspirin with clopidogrel plus aspirin. 3.10 The 1-year decision tree contained four mutually exclusive health states: non-fatal myocardial infarction, non-fatal stroke, death from any cause, and no further event. The Markov model included six states: non-fatal myocardial infarction, post-myocardial infarction, non-fatal stroke, post-stroke, death, and no further event. Non-fatal myocardial infarction 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 following a non-fatal Copyright © NICE 2011. All rights reserved. Last modified October 2011 Ticagrelor for the treatment of acute coronary syndromes NICE technology appraisal guidance 236 Page 9 of 45 event, patients proceeded to one of four mutually exclusive health states: post-myocardial infarction, 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) accrued beyond the first 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 treatment arms; the only difference between treatment arms was the number of patients who started the Markov model in each state, which was based on the output of the 1-year decision tree. Adverse events (notably