Evaluating the Risk of Cardiovascular Adverse Events and Appendicitis After COVID-19 Diagnosis in Adults in the United States: Implications of the Start of Follow-Up

Purpose This study evaluated the association between coronavirus disease 2019 (COVID-19) diagnosis and adverse events (AEs), including cardiovascular AEs and appendicitis, in US adults before the introduction of COVID-19 vaccines. Real-world studies of AEs after COVID-19 suggest that diagnoses of AEs and COVID-19 frequently occur on the same day and may be a source of bias. Methods Cohort and self-controlled risk interval (SCRI) designs were used in 2 US administrative claims data sources—Merative™ MarketScan® (ages 18-64 years) and Medicare (ages ≥ 65 years). AEs included stroke (nonhemorrhagic and hemorrhagic), acute myocardial infarction, myocarditis/pericarditis, deep vein thrombosis, pulmonary embolism (PE), disseminated intravascular coagulation (DIC), unusual-site and common-site thrombosis with thrombocytopenia syndrome, and appendicitis. In cohort analyses, weighted hazard ratios (HRs) and 95% confidence intervals (CIs) compared adults with a COVID-19 diagnosis and matched comparators. In SCRI analysis, relative incidences (RIs) and 95% CIs compared risk and reference windows within individuals. Analyses were performed starting follow-up on Time 0 and Day 1. Results For cardiovascular AEs, all estimates starting follow-up on Day 1 were above 1.0 in both data sources. For cohort analyses, the strongest associations were for inpatient PE in both databases: MarketScan, HR=8.65 (95% CI, 6.06-12.35), Medicare HR=3.06 (95% CI, 2.88-3.26). For SCRI analyses, the strongest association in MarketScan was for DIC: RI=32.28 (95% CI, 17.06-61.09) and in Medicare was for myocarditis/pericarditis: RI=4.53 (95% CI, 3.89-5.27). AEs diagnosed concurrently with COVID-19 (ie, on Time 0) were common; including Time 0 in follow-up/risk windows resulted in higher RIs, as well as higher HRs for some AEs. However, some AEs (eg, stroke) were more common on Time 0 in the comparator group resulting in lower HRs. Conclusion COVID-19 diagnoses had moderate to strong associations with cardiovascular AEs and weak or inconsistent associations with appendicitis, although estimates varied by design and methodology.