BACKGROUND: Several HTA agencies around the world have published comprehensive HTA guidelines to help authors adhere to the principles and methods of HTA. Many have also embraced recent methodological developments in comparative effectiveness research, such as indirect and mixed treatment comparisons, and recommend their use when head-to-head evidence is not available. Differences exist, however, between these guidelines and how these are interpreted especially in terms of evidential and methodological requirements. OBJECTIVES: A case study was conducted to evaluate the impact of different evidence synthesis methods, as recommended by HTA agencies, on the effectiveness and cost-effectiveness of new medicines in the UK. METHODS: Using a reconstructed economic model based on the NICE technology appraisal for ticagrelor (TA236), different evidence base and meta-analysis methods were used, in accordance with country-specific HTA guidelines and existing assessment reports (i.e. CADTH (Canada), CVZ (The Netherlands), PBAC (Australia)), to estimate the relative effectiveness and ICER of ticagrelor compared to clopidogrel and prasugrel for the treatment of acute coronary syndromes. Differences in evidence identification and study selection, evidence synthesis, and clinical effectiveness model inputs were evaluated. PRELIMINARY RESULTS: Whilst CADTH and CVZ included a published indirect comparison between ticagrelor and prasugrel in their evidence review; NICE regarded the use of indirect evidence as inappropriate and PBAC did not consider prasugrel as a relevant comparator. Such differences in clinical evidence considerations, and methods used call into question recent efforts to promote international HTA harmonisation. In addition, the uncertainty in the results estimated in our model demonstrated the importance of appropriately defining and measuring (relative) efficacy inputs in HTA to ensure optimal health policies are implemented. CONCLUSIONS: Since 2011, ticagrelor is recommended for use in the United Kingdom; however, the Canadian Expert Drug Advisory Committee recommended that ticagrelor not be listed in publicly funded drug plans in Canada.