Summary
Background
There are few data on the incidence of thrombosis among COVID-19 cases, with most research concentrated on hospitalised patients. We aimed to estimate the incidence of venous thromboembolism, arterial thromboembolism, and death among COVID-19 cases and to assess the impact of these events on the risks of hospitalisation and death.
Methods
We conducted a distributed network cohort study using primary care records from the Netherlands, Italy, Spain, and the UK, and outpatient specialist records from Germany. The Spanish database was linked to hospital admissions. Participants were followed up from the date of a diagnosis of COVID-19 or positive RT-PCR test for SARS-CoV-2 (index date) for 90 days. The primary study outcomes were venous thromboembolic events, arterial thromboembolic events, and death, all over the 90 days from the index date. We estimated cumulative incidences for the study outcomes. Multistate models were used to calculate adjusted hazard ratios (HRs) for the association between venous thromboembolism or arterial thromboembolism occurrence and risks of hospitalisation or COVID-19 fatality.
Findings
Overall, 909 473 COVID-19 cases and 32 329 patients hospitalised with COVID-19 on or after Sept 1, 2020, were studied. The latest index dates across the databases ranged from Jan 30, 2021, to July 31, 2021. Cumulative 90-day incidence of venous thromboembolism ranged from 0·2% to 0·8% among COVID-19 cases, and up to 4·5% for those hospitalised. For arterial thromboembolism, estimates ranged from 0·1% to 0·8% among COVID-19 cases, increasing to 3·1% among those hospitalised. Case fatality ranged from 1·1% to 2·0% among patients with COVID-19, rising to 14·6% for hospitalised patients. The occurrence of venous thromboembolism in patients with COVID-19 was associated with an increased risk of death (adjusted HRs 4·42 [3·07–6·36] for those not hospitalised and 1·63 [1·39–1·90] for those hospitalised), as was the occurrence of arterial thromboembolism (3·16 [2·65–3·75] and 1·93 [1·57–2·37]).
Interpretation
Risks of venous thromboembolism and arterial thromboembolism were up to 1% among COVID-19 cases, and increased with age, among males, and in those who were hospitalised. Their occurrence was associated with excess mortality, underlying the importance of developing effective treatment strategies that reduce their frequency.
Funding
European Medicines Agency.
Introduction
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- et al.
Numerous studies have assessed risks of venous thromboembolism among patients hospitalised with COVID-19, with recent systematic reviews and meta-analyses identifying more than 100 such studies.
- Tan BK
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- et al.
,
- Nopp S
- Moik F
- Jilma B
- Pabinger I
- Ay C
However, most of these studies were relatively small (with few including more than 1000 patients) and varied substantially in setting, design, and outcome definitions. Consequently, there has been substantial heterogeneity in results across previous studies. Across studies that did not use specific ultrasound screening, the prevalence of venous thromboembolic events among patients hospitalised with COVID-19 ranged from 0% to 37%.
- Nopp S
- Moik F
- Jilma B
- Pabinger I
- Ay C
Similar heterogeneity was also seen for arterial thromboembolism, with estimates varying from 1% to 18% for hospitalised patients.
- Tan BK
- Mainbourg S
- Friggeri A
- et al.
- Tan BK
- Mainbourg S
- Friggeri A
- et al.
,
- Nopp S
- Moik F
- Jilma B
- Pabinger I
- Ay C
the timing of these events during the disease course and their association with worse outcomes have not been fully detailed.
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- Fernandez-Bertolin S
- et al.
,
- Petrilli CM
- Jones SA
- Yang J
- et al.
,
- Reilev M
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,
,
- Docherty AB
- Harrison EM
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- et al.
,
- Gupta S
- Hayek SS
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- et al.
,
- Williamson EJ
- Walker AJ
- Bhaskaran K
- et al.
Many of these factors have also previously been shown to predispose individuals to thromboembolic events in the general population.
,
- Previtali E
- Bucciarelli P
- Passamonti SM
- Martinelli I
The associations between patient characteristics and risks of thromboembolic events among patients with COVID-19 have yet to be elucidated.
Evidence before this study
Several systematic reviews have summarised the existing evidence base on thrombosis in COVID-19, and we did further searches of PubMed, with no language restrictions, up to Feb 1, 2022, to identify additional recently published studies. Although more than 100 studies have been published, most have focused on patients hospitalised with COVID-19. Across these, the prevalence of venous thromboembolism has been estimated to be around 9%, whereas the prevalence of arterial thromboembolism was 4%, although specific estimates varied substantially across studies. To date, little research has been published on thrombosis among outpatient COVID-19 cases.
Added value of this study
In this study we bring together data from five European countries to study venous thromboembolism, arterial thromboembolism, and death among COVID-19 cases. Over 900 000 COVID-19 cases were included in the study, allowing for a detailed summary of the occurrence of these events of interest. For one data source, which had patient-level linkage to hospitalisation data, the risks in patients hospitalised with COVID-19 were also characterised.
Implications of all the available evidence
Risks of venous and arterial thromboembolism were close to 1% for COVID-19 cases and 4% in hospitalised patients. The occurrence of these events was associated with worse outcomes for those affected. These findings underline the widespread negative consequences associated with COVID-19 and emphasise the importance of developing effective treatment strategies that reduce the frequency of thromboembolism in patients with COVID-19.
Study cohorts derived from routinely collected health-care data can be used to further describe thromboembolism in COVID-19, particularly when the breadth of data capture is large enough to include both outpatient and inpatient COVID-19 cases and to have sufficient sample sizes to describe the associations between patient factors and outcomes. In this study, we bring together data from across Europe to summarise the incidence of venous and arterial thromboembolism and death among people with COVID-19, describe the association between patient factors and risks of such events, and assess the association between venous thromboembolism and arterial thromboembolism and worse health outcomes for the patients affected.
Methods
Study design and participants
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- Overhage JM
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The Clinical Practice Research Datalink (CPRD) Aurum database contains data contributed by general practitioners from the UK.
- Herrett E
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- et al.
The Information System for Research in Primary Care (SIDIAP) is a primary care records database that covers approximately 80% of the population of Catalonia, Spain. SIDIAP was linked to Conjunto Mínimo de Datos Básicos al Alta Hospitalaria (CMBD-AH), which includes diagnosis and procedures registered during hospital admissions.
- Recalde M
- Rodríguez C
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- et al.
- Jouaville SL
- Miotti H
- Coffin G
- Sarfati B
- Meihoc A
At the time of assessing feasibility, this database did not capture death and had only partial capture of arterial thromboembolism and venous thromboembolism and therefore this database was omitted.
Two cohorts were defined for the primary analyses. First, a cohort of people who were diagnosed with COVID-19 or had a positive RT-PCR test result for SARS-CoV-2 were identified. The first occurrence of either was used as the index date for a given person. The second cohort was people hospitalised with COVID-19, available only in SIDIAP CMBD-AH data. These individuals had a hospitalisation with a COVID-19 diagnosis or PCR-positive test between 21 days before or up to 3 days after their hospital admission. For this cohort, date of hospital admission was taken as the index date. For the primary analyses, individuals were also required to have at least 1 year of observation time available before their index date. Cohorts were also identified for sensitivity analysis: (1) solely based on clinical diagnoses; (2) solely based on clinical diagnoses and with a broader algorithm, including less specific codes for identifying COVID-19 diagnoses; (3) solely based on RT-PCR testing; and (4) solely based on SARS-CoV-2 testing, but with antigen tests included as well as RT-PCR tests. All the aforementioned cohorts were also identified without the requirement for having a 1 year observation time before study enrolment.
Study outcomes and covariates
- Burn E
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- Kostka K
- et al.
The demographics of study participants are summarised, along with previous health conditions and medication use. Health conditions and medications of interest were prespecified based on discussions with key stakeholders and after reviewing the literature, and approved at protocol stage by the study funders. Comorbidities were identified on the basis of prespecified Systemized Nomenclature of Medicine codes in all available history before the index date, and consisted of autoimmune disease, antiphospholipid syndrome, thrombophilia, asthma, atrial fibrillation, malignant neoplastic disease, diabetes, obesity, heart disease, hypertensive disorder, renal impairment, chronic obstructive pulmonary disease, and dementia. Previous medication use was characterised using RxNorm codes and based on prescriptions or dispensations in the 4–183 days before the index date. Medications extracted were antithrombotic and anticoagulant therapies, non-specific non-steroidal anti-inflammatory drugs, Cox-2 inhibitors, systemic corticosteroids, lipid modifying agents, antineoplastic and immune-modulating agents, hormonal contraceptives for systemic use, tamoxifen, and sex hormones and modulators of the genital system. Smoking (ever vs never) was also assessed based on diagnostic codes and observations recorded any time before the index date.
Statistical analysis
The 90-day cumulative incidence of study outcomes was estimated, overall and stratified by age and sex. Cumulative incidence was estimated using the Kaplan-Meier approach for IQVIA DA Germany, where deaths were not reliably captured. To account for the competing risk of death, we used cumulative incidence functions for the other four databases.
Cause-specific Cox models were used to describe the association between prespecified explanatory variables of interest and risks of venous thromboembolism, arterial thromboembolism, and death. The association between age and outcomes was studied stratified by sex and using restricted cubic splines to account for non-linearity where their use led to a lower Akaike information criterion compared with a linear fit. The association with sex was estimated with models adjusted for age. Finally, the association between comorbidities or medications and outcomes was estimated from unadjusted and age-adjusted and sex-adjusted models. Models were fit only where at least 40 outcomes were observed.
- Putter H
- Fiocco M
- Geskus RB
and we previously developed such a model to describe patient outcomes during the first wave of COVID-19 in Catalonia, Spain.
- Burn E
- Tebé C
- Fernandez-Bertolin S
- et al.
We used a similar framework, where individuals start in a general population and COVID-19-free state and then can progress to states of outpatient COVID-19 diagnosis or PCR test positive, hospitalised with COVID-19, and death. The model was informed using data from SIDIAP CMBD-HA as this dataset was the only one to capture information on all of the states. The starting population was people in the SIDIAP CMBD-AH who, as of Sept 1, 2020, had at least 1 year of previous history captured in the database, had no previous history of COVID-19 or positive test for SARS-CoV-2, and no history of venous thromboembolism or arterial thromboembolism in the 1 year before. Venous thromboembolism and arterial thromboembolism were then assessed, separately, as time-dependent exposures for the following transitions: (1) from outpatient COVID-19 diagnosis or PCR test positive to hospitalised with COVID-19, (2) from outpatient COVID-19 diagnosis or PCR test positive to death (without a COVID-19 hospitalisation in between), and (3) from being hospitalised with COVID-19 to death. As above, models were adjusted for age and sex. The framework used for the multistate modelling is depicted in the appendix (p 1). All analytical code is available at GitHub.
This study is registered with the EU Electronic Register of Post-Authorisation Studies (EUPAS40414).
Role of the funding source
The funder provided feedback on the study protocol (study design, data collection, and data analysis) but had no role in the data interpretation or the decision to submit the manuscript for publication.
Results
Table 1Patient characteristics
Data are n (%) or median (IQR). CPRD Aurum=Clinical Practice Research Datalink Aurum database. IPCI=Integrated Primary Care Information database. IQVIA DA Germany=IQVIA Disease Analyzer Germany database. IQVIA LPD Italy=IQVIA Longitudinal Patient Database Italy. SIDIAP CMBD-AH=Information System for Research in Primary Care Conjunto Mínimo de Datos Básicos al Alta Hospitalaria data.
Table 290-day cumulative incidence of venous thromboembolism, arterial thromboembolism, and fatality in COVID-19 cases
Data are n or % (95% CI). CPRD Aurum=Clinical Practice Research Datalink Aurum database. IPCI=Integrated Primary Care Information database. IQVIA DA Germany=IQVIA Disease Analyzer Germany database. IQVIA LPD Italy=IQVIA Longitudinal Patient Database Italy. SIDIAP CMBD-AH=Information System for Research in Primary Care Conjunto Mínimo de Datos Básicos al Alta Hospitalaria data.
Figure 1Cumulative incidence of venous thromboembolism, arterial thromboembolism, and death in COVID-19 cases
Data are stratified by age and sex. Estimates (solid lines) are presented with 95% CIs (dashed lines). Index date refers to the date of first COVID-19 diagnosis or positive RT-PCR test result. CPRD Aurum=Clinical Practice Research Datalink Aurum database. IPCI=Integrated Primary Care Information database. IQVIA DA Germany=IQVIA Disease Analyzer Germany database. IQVIA LPD Italy=IQVIA Longitudinal Patient Database Italy. SIDIAP CMBD-AH=Information System for Research in Primary Care Conjunto Mínimo de Datos Básicos al Alta Hospitalaria data.
Figure 2Association of age with risks of venous thromboembolism, arterial thromboembolism, and death in COVID-19 cases, stratified by sex
Data are estimates (solid lines) with 95% CIs (dashed lines), relative to age 65 years. Too few outcomes were observed to fit models for arterial thromboembolism for IPCI and IQVIA LPD Italy. CPRD Aurum=Clinical Practice Research Datalink Aurum database. IPCI=Integrated Primary Care Information database. IQVIA DA Germany=IQVIA Disease Analyzer Germany database. IQVIA LPD Italy=IQVIA Longitudinal Patient Database Italy. SIDIAP CMBD-AH=Information System for Research in Primary Care Conjunto Mínimo de Datos Básicos al Alta Hospitalaria data.
Figure 3Association of male sex (compared with female sex) with risks of venous thromboembolism, arterial thromboembolism, and death in COVID-19 cases, adjusted for age
Horizontal lines represent 95% CIs. Too few outcomes were observed to fit models for arterial thromboembolism for IPCI and IQVIA LPD Italy. CPRD Aurum=Clinical Practice Research Datalink Aurum database. IPCI=Integrated Primary Care Information database. IQVIA DA Germany=IQVIA Disease Analyzer Germany database. IQVIA LPD Italy=IQVIA Longitudinal Patient Database Italy. SIDIAP CMBD-AH=Information System for Research in Primary Care Conjunto Mínimo de Datos Básicos al Alta Hospitalaria data.
Figure 4Unadjusted and age-sex-adjusted hazard ratios for association of selected medications and comorbidities with venous thromboembolism, arterial thromboembolism, and death
Horizontal lines represent 95% CIs. Too few outcomes were observed to fit models forarterial thromboembolism for IPCI and IQVIA LPD Italy. CPRD Aurum=Clinical Practice Research Datalink Aurum database. IPCI=Integrated Primary Care Information database. IQVIA DA Germany=IQVIA Disease Analyzer Germany database. IQVIA LPD Italy=IQVIA Longitudinal Patient Database Italy. SIDIAP CMBD-AH=Information System for Research in Primary Care Conjunto Mínimo de Datos Básicos al Alta Hospitalaria data.
Discussion
In this study we have estimated the incidence of venous thromboembolism and arterial thromboembolism among people with COVID-19. For people with a positive PCR test or a diagnosis of COVID-19, 90-day cumulative incidence ranged from 0·2% to 0·8% for venous thromboembolism and 0·1% to 0·8% for arterial thromboembolism. The highest estimates came from a database with patient-level linkage to hospital records. Incidence of these events increased to 4·5% for venous thromboembolism and 3·1% for arterial thromboembolism in those hospitalised with COVID-19. 90-day fatality was between 1·1% and 2·0% among COVID-19 cases and increased to 14·6% for those hospitalised.
Although fatality was much higher for those people at oldest ages, the increase in risks of arterial thromboembolism for higher ages was less pronounced and risks of venous thromboembolism appeared to peak at around age 70 years in some databases. After adjusting for age, men were generally at an increased risk of venous thromboembolism, arterial thromboembolism, and death. In addition, various comorbidities and previous medications were associated with an increased risk of venous thromboembolism, arterial thromboembolism, and death in unadjusted models, but estimates were generally attenuated after age and sex adjustment.
The occurrence of venous thromboembolism and arterial thromboembolism were both associated with worse COVID-19-related health outcomes for patients. The occurrence of venous thromboembolism before hospitalisation with COVID-19 was associated with increased risks of hospital admission and death (without an intermediate hospitalisation) following a COVID-19 diagnosis, and venous thromboembolism and arterial thromboembolism occurring after hospitalisation with COVID-19 were also associated with increased inpatient fatality.
- Clayton TC
- Thompson M
- Meade TW
,
- Clayton TC
- Gaskin M
- Meade TW
Numerous studies have been undertaken to describe the prevalence of these events in COVID-19; however, these have predominantly focused on patients hospitalised with COVID-19, and even for this population estimates have varied substantially.
- Tan BK
- Mainbourg S
- Friggeri A
- et al.
,
- Nopp S
- Moik F
- Jilma B
- Pabinger I
- Ay C
Overall, across studies that did not only include patients in the ICU, the prevalence of venous thromboembolism during admission was around 9% and the prevalence of arterial thromboembolism was 4%.
- Tan BK
- Mainbourg S
- Friggeri A
- et al.
In our study, among people hospitalised with COVID-19, the 90-day cumulative incidence of venous thromboembolism was estimated to be 4·5% and of arterial thromboembolism was estimated to be 3·1%. Data on the incidence of these events among COVID-19 cases in general are scarce. As would be expected, in our study we found rates among all COVID-19 patients to be lower than among those hospitalised. Considering the vast numbers of people who have been infected with SARS-CoV-2, these relatively small risks translate into large numbers of people being affected. Estimates were higher for the dataset with hospital linkage (SIDIAP CMBD-AH), probably indicating underreporting in datasets based solely on primary care records. It should also be noted that people with COVID-19 but who did not have an interaction with the health system were not captured.
However, among COVID-19 patients we see, at least in some databases, risks of venous thromboembolism to peak around age 70 years. This is probably largely explained by the substantial competing risk of death for those with COVID-19, which is much increased with older age. Men have previously been associated with an increased risk of venous thromboembolism.
- Roach REJ
- Lijfering WM
- Rosendaal FR
- Cannegieter SC
- le Cessie S
Similarly, men have also been seen to have an increased risk of arterial thromboembolism.
- Millett ERC
- Peters SAE
- Woodward M
,
- Appelros P
- Stegmayr B
- Terént A
In our study we similarly found men to be at an increased risk of both arterial thromboembolism and, in most databases, venous thromboembolism. Men were also associated with an increased risk of death among those with COVID-19 in our study, consistent with previous research.
- Petrilli CM
- Jones SA
- Yang J
- et al.
,
- Docherty AB
- Harrison EM
- Green CA
- et al.
,
- Gupta S
- Hayek SS
- Wang W
- et al.
,
- Docherty AB
- Harrison EM
- Green CA
- et al.
,
- Gupta S
- Hayek SS
- Wang W
- et al.
,
- Williamson EJ
- Walker AJ
- Bhaskaran K
- et al.
For venous thromboembolism and arterial thromboembolism, age-adjusted and sex-adjusted estimates were somewhat mixed. For arterial thromboembolism, heart disease and hypertension were associated with an increased risk in people with COVID-19 in almost all analyses, consistent with their associations in the general population.
However, only a few of these factors appeared associated with increased risks of venous thromboembolism among those with COVID-19.
This study relies on routinely collected health-care data, predominantly from outpatient records. While this has allowed for large study populations to be identified and included, the absence of linkage to hospital data is a limitation for all databases other than SIDIAP CMBD-AH. Absence of hospital linkage can be expected to lead to some degree of incompleteness for the overall study populations and has meant that outcomes for those hospitalised could be described only for SIDIAP CMBD-AH. With over 30 000 hospitalised patients included, this has allowed for a detailed analysis of risks of venous thromboembolism and arterial thromboembolism among people in such a setting.
- Griffith GJ
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- et al.
Meanwhile, modelling approaches that involve the mutual adjustment for various factors of interest in the absence of a causal framework can lead to the so called table 2 fallacy, as seen, for example, in interpretations around smoking and mortality in COVID-19.
- Williamson EJ
- Walker AJ
- Bhaskaran K
- et al.
,
- Westreich D
- Edwards JK
- van Smeden M
Finally, unresolved confounding by indication precludes the causal interpretation around the observed associations between medicine use and risks of study outcomes. In our study, COVID-19 cases were identified based on clinical diagnoses or positive PCR tests. There is a risk of collider bias if, for example, PCR testing is focused on specific at-risk populations. Although this was the case during the first wave of the pandemic when the availability of testing was scarce, we report results here from Sept 1, 2020, onwards, at which point testing for SARS-CoV-2 was far more widely available. In addition, in our study, in which the research questions were descriptive in nature, we have used a modelling that at most adjusted for age and sex.
Drawing on routinely collected data from across Europe, in this study we have further described the epidemiology of venous thromboembolism and arterial thromboembolism in COVID-19. Although risks are relatively low overall, they increase with age, among men, and in those with certain risk factors. When they occur, venous thromboembolism and arterial thromboembolism are associated with worse outcomes, including hospitalisation and fatality. The absolute burden of thrombosis is high given the vast numbers of people who have been infected, and the consequences of these events to their health. The prevention of venous thromboembolism and arterial thromboembolism remains, therefore, at the forefront in the management of severe COVID-19. More data are needed on the risk–benefit of anticoagulation among patients with less severe disease and younger patients who are often treated in outpatient settings.
EB led the data analysis and wrote the initial draft of the manuscript with DP-A. EB, TD-S, CR, and SF-B had access to and verified the Information System for Research in Primary Care (SIDIAP) data; EB, AD, and DP-A had access to and verified the Clinical Practice Research Datalink (CPRD) data; PR had access to and verified the Integrated Primary Care Information (IPCI) data; and KK had access to and verified the data from IQVIA Longitudinal Patient Database (LPD) France, IQVIA LPD Italy, and IQVIA Disease Analyzer (DA) Germany. EB and DP-A were responsible for the decision to submit for publication. All authors were involved in the study conception and design, interpretation of the results, and the preparation of the manuscript.
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