Ticagrelor for the treatment of acute coronary syndromes

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 plus aspirin with clopidogrel plus aspirin. The Committee noted that ticagrelor plus aspirin reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel plus aspirin. The Committee also noted that if the components of the primary end point were considered individually, the reductions in myocardial infarction and death from vascular causes were statistically significant (16% and 21% respectively) for patients randomised to the ticagrelor plus aspirin group. The Committee also noted the non-statistically 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 plus aspirin compared with clopidogrel plus aspirin 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 (p = 0.41), interpreting this as no difference in the effectiveness between treatments by clinical presentation of ACS. The Committee noted that the manufacturer had performed a large substudy of quality of life based on EQ-5D scores, which indicated no difference in the quality of life between people taking ticagrelor plus aspirin and those taking clopidogrel plus aspirin.

4.4 The Committee heard from the clinical specialists that in general the trial was representative of the population in the UK, although the trial had a younger population and a higher proportion of men than the population with ACS in the UK. The Committee understood that the manufacturer had accounted for age in its analysis. The Committee noted comments from consultees and commentators questioning the generalisability of the PLATO trial to UK clinical practice because most of the patients presenting with ACS in the UK would receive medical therapy only whereas 21% of patients in the PLATO trial received medical therapy only. However, the Committee noted the clinical specialists' testimonies that most STEMI and NSTEMI patients would receive PCI. The Committee was also aware that results of the PLATO study showed no statistically significant difference in effectiveness between the patients whose condition was managed medically or otherwise. 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, and that of those randomised to clopidogrel, only approximately one fifth received a loading dose in the range (600–675 mg) recommended in the UK (600 mg). The Committee also 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 included those censored before 12 months. The Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated as early as 1 month and up to 1 year and, therefore, concluded that neither the difference in loading doses of clopidogrel nor censoring was likely to have substantially biased the results.

4.6 The Committee understood that ticagrelor is administered twice a day compared with once a day with clopidogrel and heard from the patient experts that, in practice, people may be less likely to take drugs twice a day. The Committee noted that no clear differences had been established on adherence between once-a-day clopidogrel and twice-a-day ticagrelor. The Committee noted comments from consultees and commentators that, particularly with a gastrointestinal bleed, the fast offset (time taken for ticagrelor to become inactive after it is stopped) could put a patient at increased risk of myocardial infarction and stroke more quickly than had the patient been taking clopidogrel, and with insufficient time to consult a cardiologist. However, the Committee heard from the manufacturer that missing a dose of ticagrelor would not result in a lower level of platelet activation than if the patient were treated with clopidogrel without missing a dose. The Committee heard that when a CABG is planned, the marketing authorisation recommends stopping ticagrelor 7 days before the procedure, suggesting that the offset is not as fast as had been suggested in the consultation comments. The Committee also noted comments from consultees and commentators that treatment with ticagrelor should be limited to people who clinicians have counselled on the importance of adherence. The Committee heard from the clinical specialists that people taking clopidogrel or ticagrelor would usually receive information to ensure that they understand why adherence is important and why stopping treatment early might increase the risk of recurrent cardiovascular disease. Therefore, the Committee agreed that advice on adherence should not explicitly be factored into the recommendations. Lastly, the Committee noted that most patients with cardiovascular disease take drugs twice a day, including statins in the evening. The Committee concluded that in the 'real world' setting, the need to take medication twice a day rather than once a day would be unlikely to substantially reduce the effectiveness of ticagrelor plus aspirin relative to clopidogrel plus aspirin.

4.7 The Committee discussed the concerns about safety and adverse effects associated with ticagrelor. The Committee heard that dyspnoea (shortness of breath), ventricular pauses, increases in serum uric acid and increases in serum creatinine from baseline were statistically 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 because of adverse reactions. The Committee heard from the patient experts that 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 as a patient randomised to clopidogrel, but that the absolute risk, at less than 1%, was small. The Committee heard from the manufacturer that the effects of dyspnoea were limited mainly to mild episodes. The Committee noted no statistically significant difference in the primary safety end point of major bleeding between ticagrelor plus aspirin and clopidogrel plus aspirin but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. 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 subgroups including patients with STEMI, NSTEMI or unstable angina. The Committee noted that several additional subgroups were presented in the trial. The Committee noted that among those defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared with clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted the comment from a consultee saying that patients with unstable angina are unlikely to benefit from ticagrelor because subgroup analysis shows benefit only for patients whose blood tests following the index event were positive for troponin. The Committee noted, however, that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for interaction 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease. Therefore, the Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter the statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.

4.9 The Committee was aware of comments from consultees and commentators that the estimate of total mortality remained 'exploratory'. This was because the analysis plan for PLATO stated that secondary end points should be tested individually in a pre-specified order, so mortality should not have been included because it followed the non-statistically significant result for stroke. The Committee was aware that the result for the association between ticagrelor and total mortality, while exploratory, had a HR of 0.78 and a 95% CI of 0.69 to 0.89, so was likely to reflect a real decrease in total mortality associated with ticagrelor plus aspirin.

4.10 The Committee noted the concerns around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin 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 plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.

Cost effectiveness

4.11 The Committee considered the estimates of cost effectiveness presented in the manufacturer's submission and noted that all ICERs for ticagrelor were below £5400 for the whole population in which ticagrelor is licensed and the subgroups. The Committee was aware of the concerns raised by the ERG around the structure of the model adopted in the manufacturer's submission, and agreed that the assumption that patients could not experience 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 after the index event, and had accounted for the increased risk of a cardiovascular event associated with having had prior events, then the ICERs for ticagrelor compared with clopidogrel would be lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event. The Committee was aware 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 that reflected 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 noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.

4.12 The Committee was aware 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 gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained 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 and therefore ticagrelor plus low-dose aspirin should be recommended as a treatment option for up to 12 months in adults with ACS. However the Committee agreed that the patient populations for STEMI and unstable angina needed to be further specified.

4.13 The Committee noted that the inclusion criteria in the PLATO trial for patients with STEMI, defined as ST elevation or new left bundle branch block on electrocardiogram, included the 'intention to perform primary PCI'. The Committee therefore agreed that only patients with STEMI 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 aware 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 were hospitalised and had to have ST-segment changes on electrocardiography indicating ischemia, and that patients had at least one of the following characteristics: age 60 years or older; previous myocardial infarction 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. The Committee was aware that it may be necessary to start treatment with ticagrelor immediately when a patient presents with symptoms. However, the Committee was concerned that a wrong diagnosis of unstable angina could result in the patient unnecessarily taking ticagrelor. The Committee therefore agreed that it would be appropriate to specify that before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.

4.14 The Committee noted the comments from consultees and commentators about whether 'lowest risk' patients (that is, patients who have a 6-month mortality of 1.5% or less as defined by the GRACE scoring system) should receive ticagrelor, given that Unstable angina and NSTEMI (NICE clinical guideline 94) stipulates that these patients would not receive clopidogrel because the harms potentially outweigh the benefits. The Committee concluded that, because patients potentially suitable for treatment with ticagrelor with unstable angina must have at least one specific risk factor for myocardial infarction as well as ST-segment changes on electrocardiography, these patients would therefore not be classed as 'lowest risk'.

4.15 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 substantially impact budgets were it 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. The Committee noted further comments received from consultees that affordability was an issue that NHS commissioners needed to consider 'very seriously'. Although the Committee agreed that that budget impact would be substantial, it was possible that any services displaced might be less cost effective than ticagrelor relative to clopidogrel. Moreover, the Committee noted that NICE's current guide to the methods of technology appraisal states that budget impact and affordability are not relevant to its decision making.

Summary of Appraisal Committee's key conclusions