Ticagrelor for preventing atherothrombotic events after myocardial infarction

The committee heard from the clinical expert and patient experts that a history of a myocardial infarction causes considerable anxiety, particularly about having further myocardial infarctions or other cardiovascular events such as a stroke. People also have concerns about the risk of bleeding associated with antiplatelet therapy, particularly with extended treatment. The fear of a bleed increases over time and can have a negative impact on the quality of life of the person and their family. The committee concluded that an additional antiplatelet agent to reduce the risk of further cardiovascular events would be useful, but that any additional bleeding risk associated with extended treatment should be taken into account when deciding whether to continue a person's antiplatelet treatment.

The committee understood that ticagrelor is a therapy to prevent further atherothrombotic events after treatment of the acute coronary syndrome has stopped. It therefore briefly discussed the clinical management of acute coronary syndromes. It was aware of NICE's technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes and prasugrel with percutaneous coronary intervention for treating acute coronary syndromes, as well as the NICE guidelines on myocardial infarction with ST-segment elevation: acute management and unstable angina and NSTEMI: early management. The clinical experts explained that practice varies across the NHS and although clopidogrel plus aspirin has been the most commonly used treatment for acute coronary syndromes, the use of newer therapies such as prasugrel and ticagrelor (each as dual antiplatelet therapy with aspirin) is increasing.

The committee considered how treatment with ticagrelor would fit into the clinical pathway for preventing a myocardial infarction. The committee was aware that patients enrolled into PEGASUS‑TIMI 54, the trial which formed the basis of the company submission, had a history of myocardial infarction occurring between 12 and 36 months before entry. Patients also had at least 1 additional risk factor for subsequent atherothrombotic events, listed in the summary of product characteristics as age 65 or over, diabetes mellitus needing medication, a second prior myocardial infarction, evidence of multivessel coronary artery disease, or chronic non‑end‑stage renal dysfunction. In the trial, treatment with a previous adenosine diphosphate (ADP) receptor could have been stopped any time before randomisation to the treatment arms. The committee was also aware that 84% of patients in each treatment arm received clopidogrel plus aspirin as their previous antiplatelet therapy and, therefore, had switched from clopidogrel (as their first-line therapy) to ticagrelor. The committee heard from clinical experts that switching between treatments occurs in clinical practice and is not as much of a concern as having a gap between treatments. The clinical experts clarified that when there is a gap in therapy, the risk of an atherothrombotic event increases, particularly in people at high risk. Therefore any gap in therapy should be minimised whenever possible. The committee considered whether ticagrelor would only be used as continuation therapy, but noted from consultation comments that this would not always be possible if, for example, a person had stopped their first-line therapy because of an adverse reaction within 1 year of their myocardial infarction (that is, before ticagrelor 60 mg is indicated). Based on comments from clinical experts and those received during consultation, the committee concluded that patients and clinicians would value ticagrelor either as continuation therapy after their first year of treatment, or when first-line dual antiplatelet therapy has been used but stopped for less than 1 year.

The committee was aware that the population in the company's decision problem, and therefore the focus of the company's submission, was adults who had a myocardial infarction between 1 and 2 years ago who are at increased risk of an atherothrombotic event (referred to by the company as its base-case population). The committee noted that the company had defined a narrower population than that in NICE's scope, that is, adults who have had a myocardial infarction and are at increased risk of atherothrombotic events. The committee was aware that the company's rationale for the narrower population was that the marketing authorisation focuses on those patients for whom the adverse effect profile was most favourable in PEGASUS‑TIMI 54. The marketing authorisation allows ticagrelor to be started in patients 1 to 2 years after a myocardial infarction or within 1 year of stopping treatment with a previous antiplatelet therapy. Based on clinical practice in England, the company suggested that few patients would have stopped antiplatelet therapy within 1 year. However, the committee noted comments received during consultation that the full population covered by the marketing authorisation should be included in the committee's discussions; that is, not only people who had a myocardial infarction 1 to 2 years ago, but also people who had a myocardial infarction more than 2 years ago and stopped taking antiplatelet therapy no more than 1 year ago. The committee considered that because this latter group is covered by the marketing authorisation, and given comments that ticagrelor would be valued as an option for these people, it should include this group. The committee further concluded that although there may be only a minority of patients in this position, it was not appropriate to exclude these people in decision-making.

The committee noted that the final scope specified clopidogrel plus aspirin and aspirin alone as comparators and that the company considered aspirin alone to be the appropriate comparator. The committee understood that the company did not consider clopidogrel plus aspirin to be an appropriate comparator because it does not have a marketing authorisation for use more than 12 months after a myocardial infarction and is not considered established clinical practice at that point in the treatment pathway. The committee recognised that although the company did not consider clopidogrel plus aspirin to be an appropriate comparator, it had considered doing an indirect comparison of ticagrelor with clopidogrel plus aspirin because there were no trials directly comparing the 2 treatments. But the company considered this inappropriate (as did the evidence review group; ERG) because of differences in the design of the trials and the patient populations included in the indirect comparison. The committee understood from the clinical experts that clopidogrel plus aspirin was commonly used as an initial antiplatelet agent for up to 12 months after a myocardial infarction. However it is not used in clinical practice when continued treatment is needed for patients with a history of myocardial infarction and a high risk of an atherothrombotic event, that is, at the same point in the treatment pathway where the summary of product characteristics recommends ticagrelor (see section 4.3). The committee concluded that clopidogrel plus aspirin was not an appropriate comparator and that the most appropriate comparison for its decision-making was ticagrelor compared with aspirin alone.

The committee considered the cost effectiveness of ticagrelor for preventing atherothrombotic events after myocardial infarction. It noted that the company's economic model was based on data for secondary efficacy outcomes in PEGASUS‑TIMI 54, including first and subsequent events, hospitalisations, dyspnoea, bleeds, EQ‑5D responses and treatment discontinuations. The committee considered whether PEGASUS‑TIMI 54 was underpowered to analyse these data. It was persuaded by the clinical and health economic experts that using these outcomes was acceptable because the population was large, so the numbers of patients on whom the secondary outcomes were based were likely to generate reasonable estimates. In addition, the committee understood that the model used equations to calculate the risk of an event occurring and that the company had used the intention-to-treat population for calculating these. The ERG confirmed the company's view that the risk equations were likely to be conservative and would, therefore, be unfavourable to ticagrelor. The committee concluded that the company's incremental cost-effectiveness ratios (ICERs) were likely to be overestimates because the parameters used to derive them were for the intention-to-treat population and therefore likely to underestimate the effect of ticagrelor.

The committee considered the most plausible ICER on which to base its decision. It considered the company's deterministic base-case estimate of £20,636, which incorporated some minor amendments suggested by the ERG. It also considered the ERG's exploratory preferred base case of £24,711, which incorporated small changes to parameters including the cost and disutility associated with gout, adjusted health care costs, uncertainty around NHS reference costs and disutility for major bleeds. The committee was further reassured that when the ERG conducted scenario analysis, only one scenario resulted in an ICER above £30,000 per quality-adjusted life year (QALY) gained. This scenario was considered to be implausible because it held treatment efficacy constant while assuming that all patients who did not die or have a non-fatal event incurred 3‑year treatment costs, whereas the actual time on treatment for patients in the study who did not die or have a non-fatal event was less than 3 years. The committee concluded that all the estimates were within a range considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) and that it could recommend treatment with ticagrelor in line with its marketing authorisation. The committee agreed that, although the ICERs presented did not include the people at high risk who had a myocardial infarction more than 2 years ago and whose antiplatelet therapy had been stopped less than 1 year ago, the recommendation should cover this group.

The committee recognised that all the cost-effectiveness evidence assumed a maximum treatment length of 3 years. It understood that some clinicians and patients may want to continue treatment indefinitely, but that the costs and clinical benefits of doing so had not been presented. The committee therefore concluded that the positive recommendation should only be for the length of time for which evidence had been presented, specifically 3 years.

The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.