Table 1

Examples/wider context of the two main challenges encountered during the PASS programme

Challenge encounteredExample/wider context
Finalising country-tailored study designs before the extent of rivaroxaban uptake was knownUncertainty in the level of future rivaroxaban uptake in different European countries meant that finalising country-specific designs for each database study was challenging. This was particularly pertinent when evaluating the safety of rivaroxaban in the context of the ACS indication. Here, it transpired that rivaroxaban uptake remained low, and in hindsight, it would have been more pragmatic to have undertaken a drug utilisation study as a precursor to a rivaroxaban safety study.
New research questions that arose during the programmeBecause the database studies included in the PASS programme were truly observational, they provided an opportunity to learn not only about safety/effectiveness of rivaroxaban but also about physicians’ prescribing patterns regarding indications and dosing over a long period. As we had communicated to the EMA that access to the data sources was still possible (post addressing the original research questions), we received several comprehensible and relevant requests that were not included in the original protocol:

  • Rivaroxaban use in certain patients with VTE and cancer with low risk of bleeding (as DOAC use in these patients was introduced, and observational studies had indicated that DOACs could be an alternative treatment option to LMWH).

  • Use of rivaroxaban in patients with prosthetic valves (although rivaroxaban was not recommended for use in these patients, it was a relevant issue and in the regulator’s interest to see how well physicians were following guidelines).

  • Use of rivaroxaban in patients with severe kidney function (<15 mL/min/1.73 m2), which rarely or never happens in practice, yet is a measure of how physicians comply with treatment guidelines.

  • Use of rivaroxaban in certain subgroups of patients for whom there is missing information in the patient risk management plan, which we had overlooked in the original study report.

  • Consideration of VKA no longer being the standard of care as treatment practices changed over the length of the programme (ie, VKA was the clear standard of care at the beginning of the study period but was significantly less prescribed at the end).

  • ACS, acute coronary syndrome; DOAC, direct oral anticoagulant; EMA, European Medicines Agency; LMWH, low-molecular-weight heparin; PASS, postauthorisation safety study; VKA, vitamin K antagonist; VTE, venous thromboembolism.