PO:12:178 | Don't count your chickens before they hatch! Analysis of cardiovascular definitions in studies on rheumatic diseases: a systematic literature review

Laura Pezzoni¹, Silvia Sirotti^1|2, Georgios Filippou^1|2, Piercarlo Sarzi Puttini^1|2, Greta Pellegrino^1|2. | ¹Università degli Studi di Milano, Milano; ²IRCCS Ospedale Galeazzi Sant'Ambrogio, Milano, Italy.

Background. Interest in defining the cardiovascular (CV) burden of rheumatologic diseases has progressively increased. The focus has been on rheumatoid arthritis (RA), but an increased CV risk has also been recognized in connective tissue diseases (CTD). FDA provided a definition of major cardiac adverse event (MACE), and WHO states a definition of cardiovascular diseases (CVD). Nonetheless, there is a considerable variability regarding the denotation of CV outcomes and exposures among both observational studies and clinical trials (RCT). This leads to a lack of reproducibility that hinders future research and possible interventions. The primary aim of this review is to investigate the variability of CV definitions in the scientific literature on CTD and RA. Secondary aims are to compare the use of FDA MACE definition according to study design, pharmacological intervention, and diseases evaluated.

Methods. A systematic search from PubMed, Embase and Cochrane Central Library was performed from January 2008 to 22 May 2025. Literature screening and data extraction were independently performed by two researchers. The research included papers on Systemic Lupus Erythematosus, primary Antiphospholipid Syndrome, Systemic Sclerosis, Sjogren Syndrome and RA. We divided CV definitions into categories: “MACE”, “CVD”, “other MACE definition” or “other CVD definition” if the authors referred to the composite endpoint as MACE or CVD without it matching the original standard definitions. When CV definitions did not fit into the above categories, they were referred to as “other CV events”. We reported studies where an instrumental tool was employed as CV outcome, or the CV definition was not provided.

Results. From an initial pool of 7644 articles, 549 were included in the final evaluation (Fig. 1). FDA MACE and WHO CVD definitions were employed respectively in 49 and 27 articles (Table 1). 38 articles fell under the “other MACE definition” category, 31 studies under “other CVD definition” and 170 papers reported “other CV events”. In 204 articles an instrumental technique was used to assess CV outcome, while in 31 cases CV definition was not otherwise specified. FDA MACE definition was used in 55.5% of RCT and in 6.5% of observational studies (p<0.001). MACE was more frequently used as endpoint in observational studies if they concerned a pharmacological intervention (2.7% vs 0.56%, p<0.001). A MACE definition not in accordance with that of FDA appeared in 14.8% of RCTs and in 6.7% of observational studies. There was a significant underemployment of MACE in papers on CTD compared to papers on RA (1.7% vs 13.2%, p<0.001).

Conclusions. Standard definitions of MACE and CVD are rarely applied and frequently misused, especially in real world studies. There is a need for standardization among the rheumatologic community to increase reproducibility and ensure useful results.