First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland

Abstract

Reports of ChAdOx1 vaccine-associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0-27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41-13.83), with an estimated incidence of 1.13 (0.62-1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29-3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12-1.34) 0-27 d after vaccination, with an SCCS RR of 0.97 (0.93-1.02). For hemorrhagic events 0-27 d after vaccination, the aRR was 1.48 (1.12-1.96), with an SCCS RR of 0.95 (0.82-1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.

Fig. 1. Schematic presentation of the self-controlled case series study design.

Blue, the control (pre-risk) period: the 90-day period prior to 14 d before vaccination (i.e., 15–104 d before vaccine receipt). Green, a 14-day clearance period. Orange, the time period from the date of first vaccination dose to 28 d after, as the risk (exposed) period.

Extended Data Fig. 1. Vaccine uptake by type of vaccine for individuals in Scotland, up to 10th April 2020 - (a) number by vaccine type, (b) percentage of population by vaccine type, and (c) percentage uptake by age and sex.

Note: (a) and (b) ChAdOx1 (AZ) or BNT162b2 (PB) vaccines, (c) both vaccines. The percentages are based upon the population alive at 8 December 2020. This is derived from the cohort set up on 1 March 2020 by removing individuals who died. Individuals in the population who died before vaccination will count in the denominator but cannot count in the numerator and this explains the drop off in uptake percentage in the elderly.

Extended Data Fig. 2. Number of ITP events per day since September 2019.

Note: The line comes from a generalised additive Poisson model fitted to the number of cases with a simple spline term for the trend. Graph based upon data up to 22 March 2020. One of the assumptions of the standard self-controlled case series analysis is that the underlying rates of the event are constant over time. Fig. S2 shows the number of events for idiopathic thrombocytopenic purpura (ITP) since September 2019. A generalised Additive Poisson model was fitted to the daily data with a spline for the number of days since 1 September 2019 and a factor for the months. There was no evidence of any seasonal pattern associated with the months of the year (p = 0.189, using a change in deviance test) but there was evidence of a non-linear trend (p = 0.0138). Further investigation of the trend was undertaken by including binary change in level variables associated with the period post BNT162b2 (8 December 2020) and post ChAdOx1 (5 January 2021) This showed that there was no residual increasing trend (p = 0.58), nor any change in level following the introduction of BNT162b2 (p = 0.4315) but there was evidence of a change in level amounting to an 0.44 (95% CI 0.20, 0.68; p = 0.0003), additional events per day in the period after the introduction of the ChAdOx1 vaccine.

Extended Data Fig. 3. Dates of vaccination and type of vaccine for individuals with an ITP event during the study period.

Note: Figure shows when individuals with an ITP event were vaccinated. Most received the ChAdOx1 (AZ) rather than the BNT162b2 (PB) vaccine.

Extended Data Fig. 4. Data linkage diagram.

Note: Community Health Index (CHI) numbers were used to link all datasets. Details on these datasets are available in our published protocol (Simpson CR, Robertson C, Vasileiou E, et al. Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II): protocol for an observational study using linked Scottish national data. BMJ Open 2020;10:e039097. doi: 10.1136/bmjopen-2020-039097) There are two core methods of recording vaccine delivery, the national Turas Management Vaccination Tool (TMVT) system and local GP IT systems. TMVT was developed as a web application by National Education Scotland (NES). It is in general the preferred method of recording a vaccination where this is done outside the normal vaccine locations, predominantly dedicated vaccination centres and community programmes. Most vaccinations delivered in general practice settings are recorded in local IT systems; there are a few geographical areas that have however mandated the use of TMVT in every setting, including GP practices. Currently GP’s are paid per 100 vaccines administered so they are highly motivated to record information accurately. If this is not recorded to a minimum standard, they will not receive payment. All vaccines administered through vaccination centres and community programmes are accounted for on a daily basis. All vaccines recorded via TMVT are transferred to the national clinical datastore (NCDS) then to Albasoft on a daily basis. At 9 pm each night, these are loaded into a secure database and each practice “polls” the data store as part of the ESCRO data pump run between 12:00am and 5:00am each day to request the records for their specific practice. These are then loaded into a local queue at the practice for processing later in the day. As part of the same data pump run, the local GP IT system is queried and all vaccination records for the previous day are extracted (with a 10 day overlap to catch any retrospective recording) These records are then transferred back to Albasoft and collated into a single data source which is returned to the National Clinical Data Store (NCDS) at 8am each morning. As a result, all vaccinations recorded either by TMVT or GP IT systems pass through Albasoft in a 24-hour cycle. As part of the agreement to provide these data for EAVE II, vaccination records from both the TMVT and GP IT systems are transferred each day following the National Clinical Data Store processing to the EAVE II secure datastore in Public Health Scotland (PHS). This ensures that the EAVE II data are as up to date as possible. It is therefore extremely unlikely that any vaccinations will have been missed. Prescriptions: Glycoprotein IIb/IIIa inhibitors (tirofiban, abciximab, and eptifibatide), heparin, cephalosporins, linezolid, penicillins, sulphonamides, trimethoprim, vancomycin, quinine, ethambutol, rifampicin, carbamazepine, phenytoin, sodium valproate, ibuprofen, naproxen,, amiodarone, furosemide, quinidine, thiazides,, haloperidol, paracetamol, irinotecan, mirtazapine, oxaliplatin, salmeterol, tacrolimus and ciprofloxacin (prescription inducing thrombocytopenia); oral corticosteroids, intravenous immunoglobulin, azathioprine, ciclosporin, cyclophosphamide, danazol, dapsone, mycophenolate, rituximab, vinca alkaloids, eltrombopag, romiplostim (ITS related prescribing).