Association between thrombosis with thrombocytopenia syndrome (TTS) or thromboembolic events, and covid-19 vaccines

Date of Approval
Application Number
21_000641
Technical Summary

BACKGROUND
TTS are being investigated as potential adverse effects of viral vector-based COVID-19 vaccines. Evidence on this association is subject to selection bias and confounding. Insights into the magnitude of TTS risk related to COVID-19 vaccination is urgently needed. This study is part of a European Medicines Agency tender to investigate this.

OBJECTIVES
1) To study the association between the administration of a COVID-19 vaccine and the occurrence of thrombosis with thrombocytopenia syndrome/s (TTS) and thromboembolic events (TE).
2) To quantify the association between the administration of different COVID-19 vaccine brands and the occurrence of TTS and VTE events.
3) To study the association between pre-specified risk factors and the occurrence of post-vaccine TTS/TE
4) To characterize the treatments used in vaccinated patients after TTS/TE.

METHODS
Data: OMOP mapped version of CPRD GOLD and AURUM
Participants: All adults registered in CPRD GOLD/AURUM for >one year

Propensity Score (PS) matching with 1 (vaccinated): 1 (unvaccinated) ratio will be used to account for confounding in Objective 1. In the derived PS matched sample, the incidence rate of TTS/TE in unexposed will be compared to rates among exposed person-time after COVID-19 vaccine/s using Poisson models. Negative control outcomes will be used to assess residual confounding.
Objective 2. A separate PS will be estimated and used to match people vaccinated with ChAdOx1 (Vaxzevria) to those receiving BNT162b2 (Comirnaty). Rates of TTS/TE post-vaccine will be compared and Rate Ratios estimated in the PS matched cohorts using Poison modelling.
3: Logistic regression will be used to estimate unadjusted as well as age and sex-adjusted Odds Ratios for pre-specified risk factors including socio-demographics, comorbidities, and medicine/s use.
4. Sunburst plots will be used to depict treatment pathways following post-vaccination TTS/TE.

Health Outcomes to be Measured

We will use the observational medical outcomes partnership (OMOP) common data model (CDM) to harmonise data from both CPRD GOLD and AURUM. Numerous code lists and algorithms have been validated for the study of vaccines and related outcomes using the OMOP CDM through ongoing research in collaboration with international regulators and academics (1-3).
Preliminary concept lists of the outcomes are shown in Appendix.
• TE will contain the following:
o Deep vein thrombosis (DVT)
o Pulmonary embolism (PE)
o Venous thromboembolism (VTE) as a composite of DVT or PE
o Cerebral venous sinus thrombosis (CVST)
o Splanchnic and visceral vein thrombosis (SVT)
o Ischemic stroke
o Myocardial infarction
o Arterial thromboembolism (ATE) as a composite of the two above and other rare arterial thromboembolisms defined in Appendix.
VTE and ATE will be assessed separately for Objectives 2, 3, and 4.
• TTS
Our definition of TTS, the primary outcome for Objective 1a, 1b and 3, is based on the one proposed by the Brighton collaboration (4), and encompasses the occurrence of one of the TE of interest above with concurrent thrombocytopenia within 10 days before/after the thromboembolic event date after the vaccination.
Thrombocytopenia will be identified either by a diagnostic code or a measurement of <150,000 platelets per microliter of blood as proposed by the Brighton collaboration, observed over a time window post vaccination starting ten days prior to the event of interest and up to ten days afterwards. This definition has been implemented in the OMOP CDM as part of our ongoing study (5).
We will explore additional time window and threshold for thrombocytopenia according to the latest evidence and guideline.

We will explore if mortality as a competing outcome of TTS/TE in a sensitivity analysis.

Collaborators

Daniel Prieto-Alhambra - Chief Investigator - University of Oxford
Victoria Y Strauss - Corresponding Applicant - University of Oxford
Albert Prats Uribe - Collaborator - University of Oxford
Annika Jodicke - Collaborator - University of Oxford
Antonella Delmestri - Collaborator - University of Oxford
Edward Burn - Collaborator - Oxford University Hospitals
Junqing Xie - Collaborator - University of Oxford
Xintong Li - Collaborator - University of Oxford

Linkages

HES Admitted Patient Care