Risk of thrombosis with thrombocytopaenia syndrome (TTS) after vaccination with AZD1222: a European VAC4EU...

A post-authorisation safety study was conducted for the AZD1222 COVID-19 vaccine. This paper presents one study outcome, thrombosis with thrombocytopenia syndrome (TTS), and estimates TTS risk in subjects administered ≥1 AZD1222 dose versus concurrent unvaccinated, pre-pandemic historical, or mRNA-vaccinated subjects. The cohort study used data from CPRD Aurum (UK), VID (Spain), SIDIAP (Spain) and PHARMO-GP database (PHARMO) (the Netherlands). AZD1222-vaccinated subjects were matched on age, sex, region, prior COVID-19, and special population status. Incident venous TTS was defined as a thromboembolic event and thrombocytopaenia within ±10 days and no TTS within the prior year. 5,321,930 subjects were matched with concurrent unvaccinated comparators, 4,831,010 with historical comparators, and 4,028,091 with mRNA active comparators (CPRD only). In CPRD, 83% of subjects were vaccinated in Q1 2021; 64% were < 60 years. In VID, SIDIAP, and PHARMO, >59% were vaccinated after Q1 2021; most subjects were ≥ 60 years. Propensity score-weighted incidence rate ratios (IRRs) (95% confidence intervals) for TTS were CPRD, 1.14 (0.60-2.17); VID, 0.34 (0.10-1.18); SIDIAP, 0.66 (0.33-1.34); and zero events in PHARMO. Incidence rates (IRs) and IRRs for TTS, where available, were higher in AZD1222-vaccinated versus concurrent unvaccinated subjects <60 years or during shorter risk windows. After case validation, positive predictive value-adjusted IRRs were < 1. For historical comparators, meta-analysis resulted in an IRR of 1.78 (95% CI,1.12-2.82; I² = 0%). For mRNA active comparators, the IRR was 1.12 (95% CI,0.61-2.05). Considering the magnitude, precision, and potential biases-such as selection bias due to informative censoring and potential outcome misclassification-the totality of evidence suggests a possible increased risk of TTS with post-AZD1222 vaccination that may be higher among subjects <60 years and 1-42 days after first AZD1222 dose, in line with the literature. Differential age distributions resulting from country-level differences in the risk minimisation measures may explain IRR disparities across data sources.