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Background There is considerable interindividual variation in drug response and the risk of adverse drug reactions. This variation may be due to several factors, including genetic predisposition and clinical characteristics.

Aim To use pharmacogenomic and pharmacoepidemiological approaches to identify risk factors for the adverse reactions thrombosis and bleeding during treatment with direct oral anticoagulants (DOACs), and venous thromboembolism (VTE) following Covid-19 vaccination.

Methods Study I examined how genetic variation influences the pharmacokinetics of apixaban by analysing data from a pivotal clinical trial using both a genome-wide association study (GWAS) and candidate gene analyses. Study II evaluated a methodology for identifying clinical risk factors for DOAC-induced bleeding using a pharmacovigilance database. In Study III, a GWAS was conducted in patients who experienced bleeding during DOAC therapy to identify genetic risk factors. Study IV combined a GWAS with pharmacoepidemiological analyses to identify risk factors for developing VTE after Covid-19 vaccination.

Results In Study I, genetic variation in the drug transporter gene ABCG2 was associated with the pharmacokinetics of apixaban. However, the effect of ABCG2 on drug exposure was modest and not associated with bleeding or thromboembolic events. The methodology evaluated in Study II identified several established and some novel potential risk factors for bleeding during DOAC treatment. Study III revealed that genetic variation in the genes BAIAP2L2, CYP3A5, ABCG2, and VWF may be associated with bleeding in DOAC-treated patients. In Study IV, individuals with well-characterised genetic variants in coagulation factor V (Leiden, rs6025) or factor II (prothrombin, rs1799963) exhibited higher risk of VTE within 42 days following Covid-19 vaccination. A large population-based health register study further showed that people diagnosed with these congenital thrombophilias had five times higher risk of VTE within 42 days after vaccination.

Conclusion This thesis highlights the complementary roles of pharmacogenomics and pharmacoepidemiology in post-marketing drug safety surveillance. Although further studies are required, the results contribute important knowledge towards the prevention of adverse drug reactions.

Aim: We aimed to investigate whether genetic variation is associated with venous thromboembolism after immunization with SARS-CoV-2 vaccines.

Methods: We conducted a genome-wide association study (GWAS) on cases of venous thromboembolism within 42 days after SARS-CoV-2 vaccination, recruited from reports of adverse drug reactions sent to the Swedish Medical Products Agency. Two hundred one cases (43% women, 91% Swedish) were compared with 4891 Swedish population controls. Analyses were performed on two candidate variants in coagulation factor II (rs1799963) and coagulation factor V (rs6025), on 14 prespecified candidate genes and across the whole genome. To support the findings, we conducted an observational register study of the Swedish general population with/without a diagnosis of thrombophilia and the risks of venous thromboembolism after SARS-CoV-2 vaccination.

Results: In the GWAS, the main findings were that the candidate variants of coagulation factors II rs1799963 and V rs6025 were significantly associated with venous thromboembolism (odds ratio [OR] 2.4 [95% confidence interval (CI) 1.2–4.8], p = .015 and OR 1.8 [95% CI 1.3–2.6], p = .0022). No genetic marker passed the significance threshold in the candidate gene analysis or the full genome-wide analysis. In the register study, people with a thrombophilia diagnosis had a five-fold elevated risk of venous thromboembolism within 42 days after vaccination, adjusted for potential confounders, OR 5.06 [95% CI 3.98–6.44].

Conclusion: Well-characterized genetic variants in the genes of coagulation factors II and V were associated with thromboembolism after SARS-CoV-2 immunization. Further research is recommended to elucidate their potential role in vaccine-related thromboembolic events.

Purpose

Direct oral anticoagulants (DOACs) are used to prevent and treat thromboembolic events in adults. We aimed to investigate whether pharmacogenomic variation contributes to the risk of bleeding during DOAC treatment.

Methods

Cases were recruited from reports of bleeding sent to the Swedish Medical Products Agency (n = 129, 60% men, 93% Swedish, 89% on factor Xa inhibitors) and compared with population controls (n = 4891) and a subset matched for exposure to DOACs (n = 353). We performed a genome-wide association study, with analyses of candidate single nucleotide polymorphisms (SNPs) and candidate gene set analyses.

Results

Forty-four cases had major, 37 minor, and 48 clinically relevant non-major (CRNM) bleeding. When cases were compared with matched controls, BAIAP2L2 rs142001534 was significantly associated with any bleeding and major/CRNM bleeding (P = 4.66 × 10⁻⁸ and P = 3.28 × 10⁻⁸, respectively). The candidate SNP CYP3A5 rs776746 was significantly associated with major and major/CRNM bleeding (P = 0.00020 and P = 0.00025, respectively), and ABCG2 rs2231142 was nominally associated with any bleeding (P = 0.01499). Rare coding variants in the candidate gene VWF were significantly associated with any bleeding (P = 0.00296).

Conclusion

BAIAP2L2, CYP3A5, ABCG2, and VWF may be associated with bleeding in DOAC-treated patients. The risk estimates of the candidate variants in CYP3A5 and ABCG2 were in the same direction as in previous studies. The Von Willebrand Factor gene (VWF) is linked to hereditary bleeding disorders, while there is no previous evidence of bleeding associated with BAIAP2L2.

Background and Objectives: Reports of suspected adverse drug reactions are of a great importance for the safety monitoring of new vaccines to identify potential safety risks promptly and to ensure necessary measures for risk mitigation. We reviewed the reports of fatal adverse drug reactions after coronavirus disease 2019 (COVID-19) vaccination with Comirnaty (R), Spikevax (R), and Vaxzevria (R) during the national vaccination campaign in Sweden.

Methods: Swedish reports of suspected adverse drug reactions with fatal outcomes after COVID-19 vaccines were retrieved from the EudraVigilance database. Vaccination data were obtained from the National vaccination register. Reporting rates were calculated by dividing the number of adverse drug reaction reports with fatal outcomes by the number of people exposed to at least one dose of the COVID-19 vaccines or by the number of vaccine doses given. A causality assessment of adverse drug reaction reports was performed by clinically qualified reviewers.

Results: More than 26 million doses of COVID-19 vaccines were administered and 456 reports of suspected adverse drug reactions with fatal outcomes were reported during 27 December, 2020-31 May, 2023. The reporting rate was 5.7 fatal outcomes per 100,000 persons vaccinated with at least one dose of any COVID-19 vaccine or 1.7 per 100,000 vaccine doses given. Most of the fatalities were related to patients' pre-existing conditions, predominantly among people aged 70 years or older. Only ten of the reported fatalities (0.1 per 100,000 persons vaccinated) were assessed as consistent with a causal association to COVID-19 vaccination.

Conclusions: Adverse drug reactions with fatal outcomes after COVID-19 vaccines in Sweden were very rare. No new safety concerns were observed in this study.

Background: During the COVID-19 vaccination campaign in Sweden, pulmonary embolism (PE) was a frequently reported suspected serious adverse drug reaction. The aim was to estimate risk of PE following vaccination for COVID-19 in the Swedish population aged 18 to 84 years.

Methods: Population-based cohort study using the CoVacSafe-SE established platform including national registers. PE-case definition: Individuals discharged from inpatient-care or visiting specialized outpatient-care with a main diagnosis of PE occurring between 27-Dec-2020 and 31-Dec-2022 without simultaneous diagnosis of COVID-19 infection. Time-to-event analysis was performed using multi-variable Cox' proportional hazard's models. Hazard Ratios (HR) adjusted for age, sex and co-morbidities were modelled. The vaccines were BNT162b2/Comirnaty (R), mRNA1273/Spikevax (R) and ChAdOx1 nCoV-19/Vaxzevria (R) without regard to variants. Doses number one to five were studied.

Results: Eighty percent of the study-population (approximate to 6.1 million people) received at least two doses of COVID-19 vaccine. A total of 12,456 cases of PE were identified. Twenty-eight days after vaccinations we observed 99 cases after 701,455 1st doses of ChAdOx1 nCoV-19, HRadj, 1.29 (95%-CI, 1.05-1.59). Corresponding for BNT162b2 was 361 cases after 4,708,284 1st doses of BNT162b2 HR adj of 1.19 (95%-CI, 1.06-1.34) driven by age group 65-84; HR adj, 1.24 (95%-CI, 1.07-1.44). No increased risks were observed for mRNA1273.

Conclusion: In this nation-wide study, no strong associations were found between COVID-19 vaccinations and pulmonary embolism. Small increases in relative risk for the earliest doses of vaccines may be associated with prioritizing the frailest groups of people in the vaccination campaign, thus selection bias or unmeasured residual confounding is possible.

Introduction

In addition to identifying new safety signals, pharmacovigilance databases could be used to identify potential risk factors for adverse drug reactions (ADRs).

Objective

To evaluate whether data mining in a pharmacovigilance database can be used to identify known and possible novel risk factors for ADRs, for use in pharmacovigilance practice.

Method

Exploratory data mining was performed within the Swedish national database of spontaneously reported ADRs. Bleeding associated with direct oral anticoagulants (DOACs)-rivaroxaban, apixaban, edoxaban, and dabigatran-was used as a test model. We compared demographics, drug treatment, and clinical features between cases with bleeding (N = 965) and controls who had experienced other serious ADRs to DOACs (N = 511). Statistical analysis was performed by unadjusted and age adjusted logistic regression models, and the random forest based machine-learning method Boruta.

Results

In the logistic regression, 13 factors were significantly more common among cases of bleeding compared with controls. Eleven were labelled or previously proposed risk factors. Cardiac arrhythmia (e.g., atrial fibrillation), hypertension, mental impairment disorders (e.g., dementia), renal and urinary tract procedures, gastrointestinal ulceration and perforation, and interacting drugs remained significant after adjustment for age. In the Boruta analysis, high age, arrhythmia, hypertension, cardiac failure, thromboembolism, and pharmacodynamically interacting drugs had a larger than random association with the outcome. High age, cardiac arrhythmia, hypertension, cardiac failure, and pharmacodynamically interacting drugs had odds ratios for bleeding above one, while thromboembolism had an odds ratio below one.

Conclusions

We demonstrated that data mining within a pharmacovigilance database identifies known risk factors for DOAC bleeding, and potential risk factors such as dementia and atrial fibrillation. We propose that the method could be used in pharmacovigilance for identification of potential ADR risk factors that merit further evaluation.