Ticagrelor for Secondary Prevention of Atherothrombotic Events After Myocardial Infarction: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Xavier G. L. V. Pouwels, Robert Wolff, Bram L. T. Ramaekers, Anoukh Van Giessen, Shona Lang, Steve Ryder, Gill Worthy, Steven Duffy, Nigel Armstrong, Jos Kleijnen, Manuela A. Joore

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique®), to submit evidence on the clinical and cost effectiveness of ticagrelor 60 mg twice daily (BID) in combination with low-dose aspirin [acetylsalicylic acid (ASA)] compared with ASA only for secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (MI) and who are at increased risk of atherothrombotic events. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Centre+, was commissioned as the evidence review group (ERG). This paper summarises the company submission (CS), the ERG report and the NICE guidance produced by the appraisal committee (AC) for the use of ticagrelor in England and Wales. The ERG critically reviewed the clinical- and cost-effectiveness evidence in the CS. The systematic review conducted as part of the CS identified one randomised controlled trial (RCT), PEGASUS-TIMI 54. This trial reported the time to first occurrence of any event from the composite of cardiovascular death, MI and stroke as the primary outcome (hazard ratio 0.84 ticagrelor 60 mg BID vs. placebo, 95% confidence interval 0.74-0.95). The population addressed in the CS was a subgroup of the PEGASUS-TIMI 54 trial population, i.e. the 'base-case' population, which comprised patients who had experienced an MI between 1 and 2 years ago, whereas the full trial population included patients who had experienced an MI between 1 and 3 years ago. While the ERG believed the findings of this RCT to be robust, doubts concerning the applicability of the trial to UK patients were raised. The company submitted an individual patient simulation model to estimate the cost-effectiveness of ticagrelor 60 mg BID + ASA versus ASA only. Parametric time-to-event models were used to estimate the time to first and subsequent (cardiovascular) events, time to treatment discontinuation and time to adverse events. The company's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £20,098 per quality-adjusted life-year (QALY) gained. The main issues surrounding the cost effectiveness of ticagrelor 60 mg BID + ASA were the use of parametric time-to-event models estimated based on the full trial population instead of being fitted to the 'label' population (the 'label' population comprised the 'base-case' population and patients who started ticagrelor 60 mg BID within 1 year of previous adenosine diphosphate inhibitor treatment), the incorrect implementation of the probabilistic sensitivity analysis (PSA) of the individual patient simulation, and simplifications of the model structure that may have biased the health benefits and costs estimations of the intervention and comparator. The ERG believed the use of the full trial population to inform the parametric time-to-event models was not appropriate because the 'label' population was the main focus of the scope and CS. The ERG could not investigate the magnitude of the bias introduced by this assumption. The PSA of the individual patient simulation provided unreliable probabilistic results and underestimated the uncertainty surrounding the results because it was based on a single patient. The ERG used the cohort simulation presented in the cost-effectiveness model to perform its base-case and additional analyses and to obtain probabilistic results. The ERG amended the company cost-effectiveness model, which resulted in an ERG base-case ICER of £24,711 per QALY gained. In its final guidance, the AC recommended treatment with ticagrelor 60 mg BID + low-dose ASA for secondary prevention of atherothrombotic events in adults who have had an MI and are at increased risk of atherothrombotic events.