The Risk of Venous Thromboembolism in Systemic Inflammatory Disorders: a UK Matched Cohort Study
Conditions: Venous Thromboses, Venous Thromboembolism, Deep Vein Thrombosis, Pulmonary Embolism, Rheumatoid Arthritis, Inflammatory Bowel Diseases, Ulcerative Colitis, Crohn Disease, Psoriatic Arthritis
Sponsor: Momentum Data

The risk of venous thromboembolism in 
systemic inflammatory disorders: a UK 
matched cohort study 
 
NCT number: Not available at submission 
Document date: 6th Dec 2018 
Academic contributors 
James Galloway1, Kevin Barrett2, Peter Irving3, Kaivan Khavandi4, Simon de Lusignan5,6 
 
1 Academic Rheumatology, King’s College London, London, United Kingdom 
(RCGP) Research and Surveillance Centre (RSC), London, United Kingdom 
2 New Road Surgery, Croxley Green, Hertfordshire, United Kingdom 
3 Department of Gastroenterology, Guy's & St Thomas' Hospital, London, UK. New Road 
Surgery, Croxley Green, Hertfordshire, United Kingdom 
4 Pfizer Innovative Health, Walton Oaks, Walton on the Hill, Tadworth, Surrey, United 
Kingdom 
5 Department of Clinical and Experimental Medicine, University of Surrey, Guildford, United 
Kingdom 
6 Royal College of General Practitioners, Royal College of General Practitioners, United 
Kingdom 
 
The research is supported by Momentum Data Ltd 
 
 
 
 
 
 

Abstract 
Background 
Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein 
thrombosis (DVT), are common and associated with significant morbidity and mortality. VTE 
risk is higher in chronic inflammatory conditions including inflammatory bowel disease (IBD) 
and rheumatoid arthritis (RA) compared to the general population. Evidence for differential 
VTE risk in other inflammatory diseases, notably psoriatic arthritis (PsA) and vasculitis, is more 
limited. Risk factors for VTE have been described in the general population, but there has 
been little interrogation of VTE risk factors for individuals with chronic inflammatory 
conditions and their association with subsequent VTE.  
 
Objective 
We aim to describe the prevalence of VTE risk and risk factors in individuals with systemic 
inflammatory disorders in a contemporary real-world population, by disease type (IBD, RA, 
and PsA) and relative to a control population without systemic inflammatory disease. In the 
same cohorts we will further compare the influence of VTE risk factors on risk of VTE events 
in individuals with systemic inflammatory disorders. 
 
Method 
We will perform a retrospective cohort study to compare VTE risk and VTE risk factors in 
adults with IBD, RA, and PsA and matched controls between January 1, 1998 and January 1, 
2018, within the RCGP RSC network. In the cohorts with and without inflammatory conditions 
we will estimate the risk of VTE overall, and for PE and DVT separately, using unadjusted Cox 
proportional hazards models, stratified by matched set (exposed cohort versus unexposed 
cohort), to provide overall hazard ratios for the association with each outcome. Models will 
be subsequently adjusted for sociodemographic and clinical and VTE risk factors in 
multivariable analysis to explore potentially important associations with VTE. We will then 
repeat the same analyses for each autoimmune condition separately. We will perform 
prespecified sensitivity analyses to explore the robustness of any potential associations. 
 
 
 

Lay summary 
Blood clots occurring in the legs and in the lungs are relatively common; they occur in around 
3 in a 1000 people per year. They can cause disability and are also potentially life threatening. 
When a clot occurs in the legs it is called a deep vein thrombosis or DVT. When they occur in 
the lungs they are called a pulmonary embolism or PE. The risk for DVT and PE is higher in 
people with conditions which cause inflammation. The most common of these are 
inflammatory bowel disease (ulcerative colitis and Crohn’s disease), rheumatoid arthritis, and 
psoriatic arthritis (a condition comprised of psoriasis and joint inflammation). 
 
What is not known is how much higher the risk of DVT and PE is in these groups compared 
with people without inflammatory disease, and what causes the excess risk in these people. 
This study aims to assess the measure the exact increase in risk for DVT and PE in people with 
these inflammatory conditions and to identify which risk factors are most strongly associated 
with the increased risk. These data should help us understand the causes of blood clot risk in 
these inflammatory conditions and identify targets for reducing risk. 
 
 

Introduction 
Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein 
thrombosis (DVT), is relatively common, with an incidence in the general population of around 
3 cases per 1000 patient years.1 It is associated with significant morbidity and mortality. 
 
Systemic inflammation is a risk factor for VTE,2 and risk of VTE has been shown to be increased 
amongst individuals with chronic inflammatory conditions including inflammatory bowel 
disease (IBD) and rheumatoid arthritis (RA) compared to the general population.3-6 Evidence 
for differential VTE risk in other inflammatory diseases, notably psoriatic arthritis (PsA) and 
vasculitis, is more limited.4 Risk factors for VTE have been described in the general population, 
and include C-reactive protein (CRP), obesity, fractures, surgery and use of oral 
corticosteroids and hormone therapy,7, 8 but there has been little interrogation of patterns of 
VTE risk factors for individuals with chronic inflammatory conditions and their association 
with subsequent VTE.9  
 
In this context we will set out to describe the prevalence of VTE risk factors in individuals with 
systemic inflammatory disorders in a contemporary real-world population, by disease type 
(IBD, RA, and PsA) and relative to a control population without systemic inflammatory 
disease. In the same cohorts we will further compare the influence of VTE risk factors on risk 
of VTE events in individuals with systemic inflammatory disorders. 
Methods 
Study design 
We will perform a retrospective cohort study to compare VTE risk and VTE risk factors in 
adults with IBD, RA, and PsA and matched controls between January 1, 1998 and January 1, 
2018, using a large UK primary care database. 
 
Data source 
The Royal College of General Practitioners Research (RCGP) and Surveillance Centre (RSC) 
database will be used for this study. The RCGP RSC cohort derives from a  large network of GP 

practices distributed across England and provides representative sample of the UK 
population.10 
 
The RCGP RSC database contains information on clinical diagnoses, anthropometric 
measurements (e.g., body mass index; BMI), laboratory tests results, and prescriptions, coded 
with the Read coding system (a thesaurus of clinical terms).11 UK general practice lends itself 
to this type of study because it is a registration-based system (each patient can only be 
registered with a single GP), it has been computerised since the 1990s, and pay-for-
performance targets introduced in 2004 have resulted in consistent high-quality clinical data 
entry about chronic disease.12 All RCGP RSC registered practices have electronic laboratory 
links; meaning all test results are automatically coded and uploaded to the GP computer 
system. Studies using RCGP RSC data have been published across a range of chronic 
diseases.13-15 
 
Study population 
Adult patients (aged ≥18) contributing to RCGP RCS primary care database between January 
1, 1998 and January 1, 2018, will be eligible for inclusion.  
 
Definition of the exposed cohort with systemic inflammatory disease 
The exposed cohort will include all individuals with an existing or incident diagnosis of IBD, 
RA or PsA (systemic inflammatory diseases) in the RCGP RCS over the study period. IBD, RA or 
PsA will be identified using Read diagnostic codes previously validated in UK primary care 
studies.16-18 Follow-up for exposed individuals will begin on the latest of the date of diagnosis 
indicated by first diagnostic code, January 1 1998 or 180 days after practice registration.  
 
Definition of the matched unexposed cohort 
The matched unexposed cohort will be defined by matching individuals in the exposed cohort 
with individuals who were never diagnosed with a systemic inflammatory disease either prior 
to or during the study period by age and sex at GP practice level. Unexposed individuals will 
require at least one year of follow-up when matched to minimise the risk they had a non-

recorded existing diagnosis of a systemic inflammatory disease of interest. Follow-up for each 
matched individual will begin at the start of follow-up of their exposed counterpart. 
 
Follow-up will end at the earliest of the study end-date (January 1, 2018), the date of patient 
transfer from an included practice, date of death, or the date an individual developed an 
outcome of interest. 
 
Outcomes 
The pre-specified outcomes include the time to incident VTE (either PE or DVT), time to PE, 
and time to DVT. These outcomes will be defined using Read codes that have been previously 
validated in a similar UK primary care database.19 Time to each outcome will be compared 
between individuals with a systemic inflammatory disorder and the matched control 
population, and across IBD, RA and PsA subgroups. 
 
Baseline characteristics and VTE risk factors 
Baseline measures will comprise sociodemographic characteristics, clinical features and 
biomarkers, selected based on clinical expertise and existing literature demonstrating an 
established association with VTE or evidence to support an association with VTE among 
individuals with systemic inflammatory disorders.4, 7 Socioeconomic status will be defined 
using the official national measure; the index of multiple deprivation (IMD).20 This will be 
calculated at the point of data extraction, using patient postcode, with the resultant scores 
stratified by deprivation quintile. Ethnicity will be extracted from the primary care record and 
grouped into the major UK ethnic groups; white, black, Asian, mixed, and others.21 BMI will 
be defined as the most recently recorded measurement prior to the study start date. Smoking 
status and alcohol use will be defined using the most recently recorded data prior to the study 
start date. Diagnostic codes will be used to define the presence of comorbidities at baseline: 
hypertension, hyperlipidaemia, diabetes, peripheral vascular disease, cardiovascular disease 
(Atrial fibrillation, angina, myocardial infarction, congestive heart failure), cerebrovascular 
disease, cancer, chronic obstructive pulmonary disease, chronic kidney disease (stages 3–5), 
liver disease, recent hospitalisation, joint replacement, and fractures. Diabetes and diabetes 
type will be identified using an algorithm developed for use within the RCGP RSC database.22  

The Read codes used to describe cardiovascular disease within the RCGP RSC database have 
been previously reported.23, 24 We will also extract records of pregnancy and reduced 
mobility. Biomarkers and laboratory tests including cholesterol and blood pressure will be 
derived by taking the most recent value in the year before cohort entry. 
 
We will examine the following medications commonly used for the management of systemic 
inflammatory disorders: non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids, 
disease modifying anti-rheumatic drugs (DMARDs), other non-biologic immunosuppressant 
medications, and biologic therapies (where recorded). We will also include hormone therapy 
(hormonal contraceptives, hormone replacement therapy). We will also extract information 
on prescribing of antiplatelet agents (aspirin or adenosine diphosphate receptor inhibitors) 
and lipid lowering therapy (statins, fibrates, or ezetimibe). Prescribing at the study start date 
will be defined as the presence of an issued prescription in the three months preceding or 
one month after the date of diagnosis. 
 
Statistical Analyses 
We will describe the characteristics at baseline for individuals with IBD, RA and PsA separately 
in comparison to the matched unexposed cohort. We will evaluate differences in 
characteristics at entry between those with and without systemic inflammatory disease using 
the χ2 test for categorical variables and the unpaired t-test for continuous data. All reported 
P-values will be two-sided. 
 
Event rates for the primary and secondary outcomes will be compared in individuals with and 
without systemic inflammatory disease, calculated as the number of events divided by the 
total person-years of follow-up, and expressed as the number per 1000 person-years. 
 
Risk of VTE 
We will estimate the risk of VTE overall, and for PE and DVT separately, using unadjusted Cox 
proportional hazards models, stratified by matched set (exposed cohort versus unexposed 
cohort), to provide overall hazard ratios for the association with each outcome. Models will 
be subsequently adjusted for sociodemographic and clinical and VTE risk factors in 

multivariable analysis. We will then repeat the same analyses for each autoimmune condition 
separately.  
 
Predictors of VTE 
Subsequently, we will run multivariable Cox models to examine the relative influence of 
individual VTE risk factors in the cohort with systemic inflammatory disease and control 
cohort. We will then explore the impact of changing platelet count over the study follow-up 
on VTE risk by including platelet count as a time varying exposure in survival models.  
 
Sensitivity analysis 
To check the sensitivity of findings to the date of introduction of the quality and outcomes 
framework (QOF), we will repeat the main analyses with the study follow-up for exposed 
individuals beginning on the latest of the date of diagnosis indicated by first diagnostic 
code, January 1 2004 or 180 days after practice registration. 
 
All statistical analyses will be performed in R statistical package. 
 
Ethics approval 
Study approval will be requested from the Research Committee of the RCGP RSC. The study 
does not meet the requirements for formal ethics board review as defined using the NHS 
Health 
Research 
Authority 
research 
decision 
tool 
(http://www.hra-
decisiontools.org.uk/research/). 
Contributors 
Research support for this project in several areas including data analysis, literature searching, 
and medication writing will be provided by Momentum Data. John Dennis and Andrew 
McGovern of Momentum Data have contributed to the writing of this protocol and to the 
study design. Funding for these studies has been provided by Pfizer UK. 

Scientific rigor and study registration 
The team ethos at Momentum Data is to support the highest quality research, for patient 
benefit, with rigorous scientific standards. Publication bias remains an issue in observational 
studies. Therefore, if approval is granted the protocol will be registered as an observational 
study with ClinicalTrials.gov and made publicly available prior to the commencement of data 
analysis. Any protocol amendments will be published alongside this public record of the study 
and will be noted in any final publication with the rationale for the modification. Any changes 
will be assessed for the need for ethics approval and further RCGP RSC study approval; these 
will be sought if required. 
 
 
 

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