No increased risk of venous thrombosis and pulmonary embolism after SARS-CoV-2 vaccination in Germany

The Covid-19 pandemic has had a dramatic impact on social life and economic development worldwide (1-5). The use of recently developed vaccines has proven effective in combating the spread of severe acute respiratory syndrome SARS-CoV-2 and preventing severe Covid-19 (6). However, vaccine hesitancy is reported in many countries for various reasons (7). Although vaccine distribution and administration has increased over time, some vaccine hesitancy remains a problem (7, 8). In addition to the obvious differences in vaccination rates between developed and developing countries, a similar trend in vaccine hesitancy emerged, with factors such as higher levels of education, higher income, residence outside of rural areas or the provision of free vaccinations as key factors in acceptance of vaccinations have been identified (7, 8). Some research has found that general trust in authorities and the government is strongly correlated with willingness to be vaccinated (7). However, possible side effects of the vaccine were identified as the most common reason for hesitancy about the Covid-19 vaccination and were cited by more than 90% of anti-vaccination respondents (8, 9).

>> Common immediate side effects after vaccination such as local reactions, fever, fatigue, headache or joint pain are of minor importance and not threatening (10). On the other hand, some events such as autoimmune-inflammatory neurological or vascular and hematological disorders including myocardial infarction, thrombosis, cerebral vein thrombosis or thrombocytopenia have been described in the literature, which could potentially be caused by vaccination (11-15). However, reports of this type of serious adverse event are rare in the literature, and their association with Covid-19 vaccination remains controversial (16). Given vaccine hesitancy and a global Covid-19 pandemic, it is important to examine the risk of such events using robust data, for example data from large-scale surveys. Reliable evidence on the safety of Covid-19 vaccines can help increase confidence in these recently released vaccines and improve their acceptance among the population.
For these reasons, this study examined the frequency of thrombosis and non-fatal pulmonary embolism in patients who were vaccinated against SARS-CoV-2 and determined the corresponding risk by calculating the incidence rate ratio using data from general practitioners in Germany from a large database .
methods
This study is based on data from the Disease Analyzer Database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data obtained directly and in anonymized form from the computer systems used in the practices of general practitioners and specialists (17) . The database covers around 3% of all outpatient practices in Germany. It has already been shown that the practices included in the Disease Analyzer database are representative of general and specialist practices in Germany (17). Additionally, this database has been used in previous studies focused on Covid-19 ( 18 , 19 ) as well as cardiovascular outcomes ( 20 , 21 ).
This retrospective cohort study included people aged ≥18 years who received a first vaccination against Covid-19 between April 2021 and June 2021 (index date) in one of 1,134 general practitioner practices in Germany. Individuals who were diagnosed with thrombosis (ICD-10: I80-I82) or pulmonary embolism (ICD-10: I26) within 12 months before the index date were excluded, as were those who had Covid-19 either before the index date or was diagnosed during the follow-up period.
Vaccinated patients were matched with unvaccinated individuals 1:1 using the propensity scores method. Age, gender, index month (April, May, June) and diagnoses that may be associated with an increased risk of thrombosis and were documented within 12 months before the index date were taken into account, including obesity (CD-10: E66), atrial fibrillation (ICD-10: I48. 0, I481, I48.2, I48.9), heart failure (ICD-10: I50), ischemic heart disease (ICD-10: I20-I25), cancer (ICD-10; C00-C97 ), coagulation disorders (ICD-10: D65-D69), convulsions
veins (ICD-10: I83-I85), injuries (ICD-10: S00-T12, within 6 months) and status after surgery (ICD-10: Z98, within 6 months). Since vaccination data was only available from general practitioners and not from vaccination centers, unvaccinated individuals (matched cohort) were selected based on a randomly selected visit date between April and June 2020, as no Covid-19 vaccinations were available during this period.
The main outcome of the study was the incidence of thrombosis (ICD-10: I80-I82) and non-fatal pulmonary embolism diagnoses (ICD-10: I26) depending on Covid-19 vaccination. Each subject was followed for up to 122 days after the index date. Poisson regression models were applied to obtain incidence rate ratios. P values <0.05 were considered statistically significant. Analyzes were performed using SAS version 9.4 (SAS Institute, Cary, USA).
Results
The present study included 326,833 people who received a Covid-19 vaccination between April and June 2021 and 326,833 people without vaccination who visited a general practitioner between April and June 2020. The basic characteristics of the study patients are presented in Table 1. The average age in both groups was 55.7 years; 49.3% were women. On average, people with a Covid-19 vaccination were followed for 38 days and people without a Covid-19 vaccination for 34 days after the index date.
During the follow-up period, 406 of the vaccinated and 342 of the unvaccinated patients in the 2020 cohort were diagnosed with one of the selected diagnoses for the first time. This resulted in an incidence rate of 11.9 or 11.3 cases per 1,000 patient-years and a non-significant incidence rate ratio (IRR: 1.06; 95% CI: 0.93-1.22). The highest IRR was observed in the 41-60 age group (IRR: 1.30, 95% CI: 0.98-1.73) and the lowest in the 18-40 age group (IRR: 0.6, 95% CI: 0 .0-1.05); however, none of the individual age group IRs were significant.
discussion
Using a large-scale database, no significant difference was found between the incidence rates of thrombosis or non-fatal pulmonary embolism in people who had received a Covid-19 vaccination and in the unvaccinated comparison group.
Clinical studies testing vaccines against SARS-CoV-2 have clearly shown that the vaccines are highly effective in preventing severe cases of Covid-19 (22-25). Regarding safety analyses, very few serious adverse events associated with the use of the vaccine have been reported (22-25). Of the few serious events reported, most notable are several cases of peripheral facial nerve paralysis and several cases of tinnitus (22-25). However, since the reports of these unusual and unexpected serious adverse events are anecdotal and the total number is approximately two dozen across all studies, the authors have critically discussed their possible association with the vaccine administered (22-25). Of 19,630 people who received a single dose of the Ad26.COV2.S vaccine (Janssen vaccine), 15 cases of thromboembolic events were reported (24). This number corresponded to the rates in the placebo group (n=10), making a causal connection with the vaccination unlikely (24). However, with increasing vaccination rates, increasing cases of thrombotic and embolic events have been reported worldwide (11-15). In November 2021, Bilotta et al. 58 cases of hemostatic complications after Covid-19 vaccination, showing that both the arterial and venous systems can be affected and reporting cerebral vein thrombosis as the most common event (12). In a recently (December 2021) published systematic review including 98 studies, Al-Ali et al. 460 thrombotic events as a possible complication after Covid-19 vaccination and reported 159 (34.6%) cases of cerebral vein thrombosis, followed by 67 venous thrombosis (14.6%) and 63 cases (13.7%) of pulmonary embolism (11). Thrombocytopenia was frequently observed in affected patients, suggesting that this phenomenon may be related to the still unclear pathomechanism of this adverse effect (11-15). However, the available data on thrombotic and thromboembolic events after Covid-19 vaccination, such as thrombosis or pulmonary embolism, are limited to individual reports or case series. There is currently a lack of data on the frequency of these events in vaccinated people compared to unvaccinated people to estimate the risk.
Venous thrombosis and pulmonary embolism often occur in patients with predisposing risk factors. In addition, the use of certain medications influences the occurrence of these events (25,26). The overall crude incidence rate of thrombotic and thromboembolic events in unselected adults is much lower, approximately one in 1,000 per year (27). Our study participants (vaccinated and paired unvaccinated individuals) may be at low to moderate risk of thrombotic and thromboembolic events due to selection bias in prioritizing sick or at-risk individuals for vaccination. However, we found almost the same incidence rate in the vaccinated and unvaccinated groups, which is the main finding of the present study. The incidence of thrombotic and thromboembolic events in the vaccination group observed in our study corresponds to the expected intrinsic rate in a low-to-intermediate risk population and is not due to the use of the Covid-19 vaccine. Although our results clearly indicate that vaccination against Covid-19 is not a factor promoting thrombotic and thromboembolic events, they need to be verified in further large-scale studies.
The two greatest strengths of this study are the number of patients available for analysis and the detailed analyzes performed on real data. However, this study also has some limitations that should be mentioned here. First, our data on thrombosis and pulmonary embolism diagnosis relied solely on ICD-10 codes, and no data on diagnostic procedure or disease severity/activity were available. Second, because there was no information about behavioral factors (e.g., alcohol consumption, smoking, contraceptive use, and physical inactivity), the role of these factors could not be examined. Third, hospital data were not available and only outpatients were analyzed, even though severe cases of both Covid-19 and thrombosis are treated in hospitals. Fourth, we did not conduct analyzes stratified by vaccine manufacturer. However, more than 90% of patients in this BNT162b2 study received a Covid-19 mRNA vaccine.
conclusion
In this large-scale study of the occurrence of thrombosis and pulmonary embolism, no differences were found between vaccinated and non-vaccinated people. It is therefore very likely that these illnesses, if they occur after vaccination against SARS-CoV-2, are an unavoidable part of the patient's medical history rather than a consequence of vaccination. <<