# Early Identification of Cardiovascular Adverse Events Associated With Rofecoxib Using Real‐World Data From the UK: A Nested Case–Control and Case‐Crossover Study

## TL;DR

Using UK real-world data, researchers found that rofecoxib's heart risks could have been detected two years after it was sold, much faster than traditional methods.

## Contribution

This study shows real-world data can detect drug risks faster than traditional methods, using novel nested case–control and case–crossover designs.

## Key findings

- Rofecoxib's cardiovascular risks were detectable 2 years after market entry using real-world data.
- Case-crossover design detected the risk earlier than nested case–control design.
- Real-world data analysis can improve drug safety monitoring and detect adverse events sooner.

## Abstract

Traditional pharmacovigilance systems have limitations in detecting common adverse drug reactions. We investigated whether real‐world data (RWD) could have detected rofecoxib's cardiovascular adverse effects earlier using nested case–control (NCC) and case‐crossover (CCO) designs.

We included adult rofecoxib users from the UK CPRD GOLD (1999–2004). In NCC design, cases of a first major adverse cardiovascular event (MACE) were matched with four controls on age, sex, practice and calendar time. Rofecoxib exposure was categorised as current (≤ 3 months), recent (3–6), or past use (> 6) in NCC, and assessed at the start of each 3‐month interval in CCO design. Exposure odds in CCO were compared between a 3‐month risk with four reference windows. Conditional logistic regression models estimated adjusted intensity ratio (aIR). To identify the shortest time necessary to detect the association, analyses were conducted in 1‐, 2‐, 3‐, 4‐ and 5‐years after the drug's market uptake.

Three thousand two hundred and eighteen cases were matched to 10 745 controls (mean age 73.8 years, 66% female). In NCC, current rofecoxib use (42% of cases) was associated with an 18% higher risk of MACE (aIR 1.18, 95% CI 1.08–1.29) versus past use. The CCO (3210 risk and 12 737 reference windows) showed an 83% increased risk of MACE (aIR 1.83, 95% CI 1.53–2.18). First signal emerged after 2 years with CCO (aIR 3.94, 95% CI 1.88–8.25), and after 3 years with NCC design (aIR 1.46, 95% CI 1.18–1.81).

Using RWD, cardiovascular adverse effects of rofecoxib could have been detected within 2 years of the market entry in the UK, well before traditional pharmacovigilance methods. This supports incorporating RWD analysis into routine drug safety monitoring.

Using real‐world data from the UK, rofecoxib's cardiovascular adverse events were detected 2 years after market uptake, well before traditional pharmacovigilance methods.Both nested case–control (NCC) and case‐crossover (CCO) identified the increased cardiovascular risks of rofecoxib, showcasing their applicability for signal detection.NCC is computationally light, needs few cases, and when restricted to ever‐users, can minimise confounding by indication.CCO self‐matches cases, cancels all time‐fixed patient factors, and is ideal when exposure is transient and outcome is acute.Real‐world data and pharmacoepidemiologic methods can be integrated into routine drug safety monitoring in detecting adverse events associated with new drugs.

Using real‐world data from the UK, rofecoxib's cardiovascular adverse events were detected 2 years after market uptake, well before traditional pharmacovigilance methods.

Both nested case–control (NCC) and case‐crossover (CCO) identified the increased cardiovascular risks of rofecoxib, showcasing their applicability for signal detection.

NCC is computationally light, needs few cases, and when restricted to ever‐users, can minimise confounding by indication.

CCO self‐matches cases, cancels all time‐fixed patient factors, and is ideal when exposure is transient and outcome is acute.

Real‐world data and pharmacoepidemiologic methods can be integrated into routine drug safety monitoring in detecting adverse events associated with new drugs.

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are common painkillers that ease pain and inflammation but may cause stomach ulcers. A newer group, COX‐2 inhibitors, were developed with fewer stomach side effects. However, rofecoxib, as a COX‐2 inhibitor, later showed a higher risk of heart attack than naproxen (an older NSAID). It took the manufacturer 5 years to withdraw rofecoxib from the market due to higher risks of heart attacks and strokes. Historically, detecting adverse drug reactions (ADRs) of a new medication relies on spontaneous reporting systems (SRSs). However, this has limitations such as difficulty in detecting a common event. In the case of rofecoxib, SRS could not detect cardiovascular events earlier, and the drug was withdrawn after findings from post‐authorisation clinical trials. Nowadays, with increasing access to real‐world data (RWD), various studies can be conducted to investigate the safety profile of medications. Using RWD, we showed that rofecoxib's increased risk of heart attack, stroke, and heart failure could have been detected only 2 years after the drug's market uptake in the UK, 3 years sooner than its official withdrawal. The improved signal detection methodologies based on RWD can benefit patient care and policy making for swifter detection of ADRs in real patient groups.