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Introduction: Large administrative healthcare databases can be used for near real-time sequential safety surveillance of drugs as an alternative approach to traditional reporting-based pharmacovigilance. The study aims to build and empirically test a prospective drug safety monitoring setup and perform a sequential safety monitoring of rofecoxib use and risk of cardiovascular outcomes., Methods: We used Danish population-based health registers and performed sequential analysis of rofecoxib use and cardiovascular outcomes using case-time-control and cohort study designs from January 2000 to September 2004. Each monitoring period added 6 months of data until the end of the study period. In the case-time-control study, incident cases of myocardial infarction (MI) and ischemic stroke were identified and matched with up to five time controls on age, sex, and calendar time. Exposure status on the date of diagnosis was assessed using a 60-day focal window, with reference windows 120, 180, and 240 days prior to the diagnoses. In the cohort study, incident users of rofecoxib were matched up to 1:4 with ibuprofen users (active comparators) using high-dimensional disease risk scores and were followed for 60 days., Results: The earliest association between rofecoxib use and the risk of MI was seen in study period 2 for case-time-control design (OR 1.42, 95% CI 1.04-1.93) and in study period 7 for the cohort study design (RR 1.22; 95% CI 1.02-1.47)., Conclusions: Our prospective drug safety monitoring setup showed that the risk of MI could have been detected 3.5 years before the ultimate market withdrawal of rofecoxib. However, further research is needed to validate this approach., Competing Interests: Declarations. Funding: Open access funding provided by University of Southern Denmark. The project was funded by the Independent Research Fund Denmark – Sapere Aude (grant no. 1052-00035B). Conflicts of Interest: The authors have no conflicts of interest to declare. Authors’ Contributions: Saad Hanif Abbasi and Anton Pottegård were responsible for the initial concept and planning of the study. Saad Hanif Abbasi and Lars Christian Lund were responsible for managing and analyzing the data. All authors provided significant contributions in the planning and subsequent reporting of the work described in this paper. The manuscript was primarily drafted by Saad Hanif Abbasi. All authors have revised the manuscript for important intellectual content and approved the final version. Data and Code Availability: Due to Danish data protection regulations, individual-level data cannot be shared directly by the authors. Deidentified data from Danish healthcare registries are accessible for researchers after application to the Danish Health Data Authority. The source code can be shared by the authors upon request. A protocol was registered and made publicly available prior to the commencement of any statistical analysis ( https://osf.io/va3yj ). Ethics Approval: Not applicable. Consent to participate/consent for publication: Not applicable., (© 2025. The Author(s).)