CVD-COVID-UK

• CCU001: Investigating the effects of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 outcomes – project lead Jonathan Sterne, University of Bristol

  ACE inhibitors and angiotensin receptor blockers are drugs that are commonly used to lower high blood pressure. These drugs may affect the ability of the coronavirus to enter cells of the body and cause COVID-19. We plan to investigate whether use of these drugs affects people’s chance of becoming infected or unwell with COVID-19.

  We will conduct carefully planned analyses of data from millions of people’s healthcare records. These records provide information about people’s health and prescribed medications, as well as on which people became infected or unwell with COVID-19.

  People who take drugs to lower their blood pressure are more likely to have other risk factors for becoming infected or unwell with COVID-19. Our analysis methods will account for these risk factors, to work out whether any change in risk is due to the blood pressure lowering drugs themselves.

  Our results will help to inform the way that blood pressure lowering drugs are used in the future, particularly while the pandemic continues.

• CCU002: SARS-CoV-2 infection and risk of venous thromboembolism and arterial thrombotic events – project lead William Whiteley, University of Edinburgh

  Coronavirus infection (‘COVID-19’) might increase a person’s chance of having a stroke, heart attack or clot in the deep veins or lungs (‘blood vessel diseases’).

  During the COVID-19 pandemic, some doctors have looked after patients with COVID-19 who also had unusual strokes, clots or heart complaints. This suggests there could be a link between COVID-19 and blood vessel diseases. But no individual doctor will see enough patients to find out if COVID-19 really does increase the risk of blood vessel diseases.

  To understand more, we will use healthcare records to study every person alive in England, Scotland and Wales at the beginning of the pandemic in 2020. We will find out how many people had a stroke, heart attack, heart condition or other disease of the blood vessels over the following year.

  We will compare the number of people with COVID-19 infection who developed a blood vessel disease with the number of people without COVID-19 infection who developed a blood vessel disease. Different types of people might have different risks, so we will also examine people of different ages, ethnicities and medical history.

  The result of this research will be an estimate of how much COVID-19 increases the risk of different blood vessel diseases. This information is needed so that people with COVID-19 know whether they need to worry about blood vessel diseases as they recover. If this research shows there is an increased risk, then treatments might be needed to reduce this.

  Amendment to approved project made on 8th April 2021:

  There have been a number of reports of vascular complications after coronavirus vaccination. The complication that is of most concern is a very rare condition of clotting of the veins in unusual places like the brain and the gut which has been associated with low levels of platelets.

  As an extension to the project outlined above, we will find out which people in England had a disease involving blood clots in the arteries or veins, and also diagnosed with low platelet levels. We will compare the risk of developing one of these conditions among people who have had a COVID-19 vaccine versus those who have not had a vaccine. We will assess the risks for clotting events of different types, for different vaccines, for people who have had one or two vaccine doses, and for people with different characteristics. Our results will allow us to estimate whether COVID-19 vaccine is associated with an increased risk of one or more of these different types of clotting events, and if so by how much.

  This research is needed to provide reliable information to medicines regulators, the Department of Health and Social Care, health professionals and the public about any risks associated with COVID-19 vaccines. Because the clotting events that might be affected are very rare, any increase in risk is likely to be very small. It will, therefore, be important to understand not only whether or not there is an increased risk but also the size of any increased risk and whether it only applies to particular groups of people. It will also be important to understand how any risk compares with the protective benefits of the vaccine, which are known to be substantial.

• CCU003: Direct and indirect effects of the coronavirus (COVID-19) pandemic in individuals with cardiovascular disease – project lead Amitava Banerjee, UCL

  Coronavirus (COVID-19) directly impacts individuals who become infected with the virus. It can also influence people’s healthcare decisions (such as deciding not to attend medical appointments for fear of infection). In addition, hospitals have sometimes had to prioritise treatment of COVID-19 patients over routine healthcare.

  Access to data from healthcare records will help to improve our understanding of what puts certain people at an increased level of risk. This includes people with cardiovascular disease, including heart disease and stroke.

  This research project has three main priorities.

  1. For people with cardiovascular disease, we will estimate by how much becoming infected or unwell with COVID-19 increases their risk of dying within one year of infection. This will involve analysing routine healthcare data from multiple sources, including from general practices, hospitals and national death registers.
  2. We will study how the treatment of patients with cardiovascular disease has been affected during the pandemic.
  3. We will develop and improve models that predict the risk of dying at one year among people with cardiovascular disease who have and who have not contracted COVID-19.

  Our research will help to shape health policy, help patients and clinicians to make more informed decisions, and improve health outcomes.

• CCU004: COVID and cardiovascular disease risk prediction – project lead Angela Wood, University of Cambridge

  Cardiovascular disease (CVD), comprising mostly heart attacks and strokes, is one of the UK’s leading causes of death and disability. It is far better and cheaper to prevent CVD than to treat patients after they get sick. Consequently, doctors aim to identify patients at high risk of future CVD and offer healthy lifestyle advice and medication, such as statins.

  However, studies have found that such advice is poorly communicated to patients. This has resulted in low numbers of patients choosing to make healthy lifestyle changes and take medication, especially amongst patients living in more deprived areas. It is important to improve the way CVD risk is communicated to patients across the whole of society so that more people benefit from advice and medication, and also to reduce inequalities in CVD.

  Currently, doctors use risk prediction calculators to help decide whether a patient is at high risk of future CVD. The most commonly used risk prediction calculators in England were developed using data from 2004-2016 from 2.3 million patients in England. More current data is now available from over 56 million patients in England, as well as 10 million patients from Wales, Scotland and Northern Ireland. These datasets also include information about whether a patient has had COVID-19 and any related complications. Patients with COVID-19 complications may be at higher risk of future CVD than patients without COVID-19 complications. Therefore, COVID-19 information may be useful information for doctors in helping to identify the right patients at high risk of CVD.

  We plan to develop new risk prediction tools to assess and help communicate a patients’ future risk of CVD. Our aims are (i) to better identify patients at high risk of CVD in the UK and (ii) to improve communication of CVD risk to patients across the whole of society. Ultimately, this should reduce CVD in the UK.

• CCU005: Data management and analysis methods – project lead Angela Wood, University of Cambridge

  Since the COVID-19 pandemic, there has been rapid progress made towards the availability and accessibility of national healthcare data for research. Consequently, for the first time we are analysing data from over 65 million patients across the UK to help us understand more about COVID-19. Our analyses have the advantages of being able to study individuals with and without different health-related problems across all age groups, ethnicities, geographies and socioeconomic settings. Our results will be directly relevant to everyone living in the UK.

  However, there are a number of challenges and limitations to using routinely collected healthcare data for research. The problems mainly arise because electronic health records are designed for clinical purposes, and do not necessary provide an accurate picture of the true health status on all patients at all times. If we do not address these problems properly in the analysis, then we will get biased results and make incorrect conclusions.

  We aim to identify and provide solutions to address the challenges and limitations in the analysis of population-wide healthcare data. Ultimately, we want to ensure results arising from population-data healthcare data are accurately reported.

  BMJ publication 08/04/21 can be viewed here.

  BMJ editorial 08/04/21 can be viewed here and public contributor opinion piece here.

  MedRxiv pre-print 26/02/21 can be viewed here.

  Code is now also available on the Github repository which can be found here.

• CCU007: Impact of COVID-19 pandemic on Congenital Heart Disease (CHD) patients undergoing cardiac surgery - project lead Massimo Caputo, University of Bristol

  13 babies in the UK are born with congenital heart disease (CHD) every day, and most of these children will need several high-risk operations and treatments during their lives. There is currently very limited information available regarding how delays to treatment caused by the COVID-19 pandemic has affected children and young adults with CHD undergoing these very high-risk interventions.

  We will be using healthcare records from England, Wales and Scotland to better understand  the risks between delaying surgery because of the pandemic or not, and if so what length of delay remains safe for children with CHD. We will also evaluate whether the COVID-19 pandemic has affected the future health and wellbeing of these children and young adults with CHD. This will include seeing if there is impact on their schooling and education, and whether there are any differences in the impact of the pandemic on young patients with CHD based on race and ethnicity.

  The information obtained from this research will allow for better planning of operations and treatments, aiming to improve health outcomes for children and young adults with CHD. The findings of this project will help patients and clinicians to make more informed decisions during these challenging pandemic times.

• CCU008: Evaluating impact of COVID-19 pandemic on management of blood pressure and lipids in patients with and at high risk of cardiovascular disease - project lead Julian Halcox, Swansea University

  Although cardiovascular disease (CVD), including heart attacks and strokes, is still the leading cause of death in the UK, the risk of clinical CVD events and death can be reduced by the identification and effective treatment of major risk factors such as high blood pressure (BP) and lipids (e.g. cholesterol). Access to routine clinical care was dramatically disrupted during 2020 due to the COVID-19 pandemic. Patterns of attendance in primary care changed from March 2020 onwards as a consequence of this and we have recently found that patterns of drug prescribing and dispensing, including cardiovascular drugs, changed significantly in 2020.

  Although these changes in practice are likely to have had an influence on the nature of testing, treatment and control of major risk factors for CVD, the extent and potential impact of these changes is unknown. We therefore propose to use routine healthcare records to examine patterns of BP and lipid testing in the general population and evidence for control of these risk factors (according to expert clinical guideline recommendations) in patients with CVD and at high risk of developing CVD. We will also examine whether differences in the quality of testing, diagnosis and control of risk factors are related to any particular patient characteristics (e.g. sex, socioeconomic status, common chronic conditions).

  This work will be undertaken in close alignment with another recently approved CVD-COVID-UK project, examining changes in CVD drug prescribing during the same period. Considered together, these analyses will provide important insights into the potential impact of the COVID-19 pandemic on the detection and control of key modifiable CVD risk factors in the UK population. Outputs from these analyses will be used to model the potential consequences for future CVD events in the UK and help to identify where efforts could potentially be focused most effectively to address emerging gaps in the provision of preventive care.

• CCU010: In people with CVD and COVID-19, what is the influence of multi-morbidity on risk of poorer outcomes? - project lead Claire Lawson, University of Leicester

  Since the first case of COVID-19 in the UK in January 2020, there have been nearly 4 million cases reported. Whilst most people have recovered with only mild to moderate symptoms, others have more severe symptoms requiring admission to hospital. There have been over 120,000 COVID-19 related deaths reported in the UK.

  We know that certain groups of people are more susceptible to severe COVID-19 disease and to dying from their infection. People with long term conditions (LTCs), particularly cardiovascular disease, have been found to be particularly vulnerable to complications related to COVID-19. We also know that the risk of complications after contracting COVID-19 in people with cardiovascular disease increases for those who have multiple LTCs, and in those with certain ‘characteristics’ including being older, male, or from non-Caucasian ethnic groups.

  However, because people with COVID-19 often have a combination of different high risk characteristics, it can be difficult to know which are the most likely cause of complications. For example, we don’t know whether some or all of the higher risk of COVID-19 complications in people with cardiovascular disease who are older, male or non-Caucasian is explained by their multiple LTCs.

  This 12 month study will investigate people with different types of cardiovascular disease to understand what role multiple LTCs and other characteristics play in increasing the risk of COVID-19 complications. This will help us to identify those patients who may be at greater risk from COVID-19 complications, so that we can provide tailored interventions to improve their outcomes.

• CCU013: High-throughput electronic health record phenotyping approaches - project lead Spiros Denaxas, UCL

  When a patient visits their GP or is admitted into hospital, information about their symptoms, diagnosis, lab test results and prescriptions is inputted and stored in ‘Electronic Health Records’ (‘EHRs’). These EHR’s are a valuable resource for researchers and clinicians to be able to analyse the health data of large numbers of patients, with the aim of using this information to improve patient health and care.

  However, as information in these EHRs is inputted by different health workers around the UK, there can be variations in the amount of detail that has been included and the records can contain many inconsistencies. This means that researchers need to initially spend a considerable amount of time and effort to be able to obtain the most relevant information from these EHRs, before they can then start to effectively analyse them. Examples include trying to identify which patients may or may not have a particular disease, or to extract individual measurements – such as high blood pressure or whether they are a smoker – from billions of rows of data.

  To improve this, this project will create and evaluate different ways of being able to extract this valuable information from complex EHRs, so that the records can be most effectively analysed by the CVD-COVID-UK consortium. As our understanding of COVID-19 is developing rapidly, being able to access accurate information for research more quickly is especially important. This includes being able to accurately understand the impact that COVID-19 infection has in patients in the longer term – known as ‘long COVID’ – which affects multiple organs in the body.

  The approaches developed in this project will benefit all of the research being undertaken by the CVD-COVID-UK consortium, and shared with the wider scientific and medical community by publishing the results openly. This will maximise the benefits of using information from EHRs, and ensure research can be reproduced effectively. Most importantly, this will speed up the ability to effectively analyse health information in EHRs, and directly improve benefits to patients and healthcare.

• CCU014: Assessing cardiovascular disease impact through medicines - project lead Reecha Sofat, UCL

  Cardiovascular disease (CVD, including heart attacks and strokes) remains one of the leading causes of death in the UK. There are a number of conditions that commonly increase an individual’s risk of developing CVD. Some of these conditions, such as diabetes and having high circulating levels of cholesterol in the blood, can be controlled by using medicines.

  However, these conditions need to be diagnosed before an individual can be prescribed the medicines to control them. Because of disruption from the COVID-19 pandemic resulting in changes in health care services and fewer face-to-face medical appointments, it is likely that the number of conditions being diagnosed has fallen. Therefore some individuals are not being prescribed the medicines to control the condition.

  One way to investigate this problem is to look at what changes there have been in the prescriptions for these conditions. This involves looking at new and repeat prescriptions that have been issued by the GP, and also the amount of prescriptions dispensed by the pharmacy.

  We already know that the COVID-19 pandemic caused a disruption to the usual pattern of prescribing of medicines for these conditions. For example, there was a significant increase in the number of repeat prescriptions issued in March 2020, presumably as doctors and patients ensured they had sufficient medication for the first lockdown. Subsequent patterns in the prescribing of medicines for these conditions during 2020 have not yet been adequately studied.

  The number of GP appointments also fell during Spring-Summer 2020, presumably resulting in a reduced number of individuals being diagnosed with CVD. It is also presumed that there would be a reduction in the diagnosis in new patients of conditions that can increase their risk of developing CVD, and therefore a decrease in the amount of prescriptions for medicines to control these conditions.

  For this project, we therefore propose to examine patterns in the prescription of medicines for these conditions. This will enable us to understand how the COVID-19 pandemic has had an impact on the control of CVD and its related conditions in the UK population. We will use this information to understand how many people are likely to be affected by cardiovascular disease in the future. It is hoped that this will enable more accurate planning for better patient care.

• CCU016: Cardiovascular and cerebrovascular diseases related to antipsychotic prescribing in patients with dementia during the COVID-19 pandemic - project lead Tim Wilkinson, University of Edinburgh

  People living with dementia have been amongst the hardest hit during the COVID-19 pandemic. A group of drugs called ‘antipsychotics’ are sometimes used to treat distress and agitation in people living with dementia. However, there is evidence to suggest that these medicines may increase the risk of stroke and heart attacks when given to people with dementia. They should therefore only be used as a last resort, when other treatments have failed.

  Since March 2020, the prescribing of these drugs for people with dementia has increased. We think this may be because social distancing restrictions have caused more people to need treatment for distress or agitation as they do not have access to their normal support structures. This increase in antipsychotic prescribing during the COVID-19 pandemic is concerning, as it may have led to an increase in heart attacks and strokes in these patients.

  We will investigate whether this increase in antipsychotic prescribing has led to an increase in strokes or heart attacks. To do this, we will use information that is collected routinely by health services, such as GP records, prescriptions and diagnoses recorded in hospital. We hope that the results of this study will help inform decision making between doctors, patients and carers, by enabling them to weigh up the risks and benefits of prescribing an antipsychotic.

• CCU018: COVID infection during pregnancy on cardiovascular disease and related risk factors - project lead Elena Raffetti, University of Cambridge

  COVID-19 infection during pregnancy may increase the risk of cardiovascular health problems related to pregnancy and giving birth. Small hospital-based studies have suggested a relationship between COVID-19 infections during pregnancy and severe complications for mothers and their babies. However, since some complications are rare, detailed analyses from large population-based studies are required.

  We will assess and quantify the role of COVID-19 infection during pregnancy on cardiovascular-related maternal health outcomes (for example, pre-eclampsia, gestational hypertension, gestational diabetes, miscarriage, preterm birth, stillbirth, peripartum cardiomyopathy), and on longer-term cardiovascular related diseases for the mother and child. Results from our study will help to inform women on potential risks related to COVID-19 infection during pregnancy, identify women with greatest risks, and help evaluate if any preventative interventions are needed.

• CCU019: Identification and personalised risk prediction for severe COVID19 in patients with rare disorders impacting cardiovascular health - project lead Honghan Wu, UCL

  We know individuals with underlying health conditions have greater risk of developing severe COVID-19 and ending up with poorer outcomes. That is why governments and public health services have been providing dedicated and prioritised protections for these more clinically vulnerable people – for example, via recommending shielding or being prioritised to have COVID-19 vaccinations.

  However, the majority of those living with rare diseases – around 5.8% of the UK population, or 3.7 million people – are often overlooked. Rare diseases are often poorly recorded in clinical data leading to a challenge in identifying patients whose rare condition makes them clinically vulnerable. We don’t know the most effective way to personalise and manage treatments for patients with rare diseases who contracted COVID-19.

  In this project, we aim to tackle these challenges by bringing together a comprehensive set of knowledge about rare diseases, and applying the most up to date data science technologies to use such knowledge and resources on CVD-COVID-UK datasets. In this way, we hope to develop a more accurate identification system for people living with rare diseases who are clinically vulnerable. We will also provide the much needed information on the risk of severe COVID-19 in people with rare diseases, hopefully leading to an improvement in their care by providing evidence on treatments that may work better for them.

• CCU020: Evaluation of antithrombotic use and COVID-19 outcomes - project lead Alex Handy, UCL

  Antithrombotics are blood thinning medications that are used to treat a range of cardiovascular diseases. Atrial fibrillation (AF) is one such disease, and is the most common disturbance of heart rhythm and a common cause of stroke. In individuals who have AF, antithrombotics are used to lower stroke risk. However, around a third of those with AF are not on the most effective type of antithrombotic or take no medication at all.

  New evidence is emerging that individuals already taking antithrombotic medication (whether for AF or for another disease) may have improved outcomes if they become infected with COVID-19. However, the evidence for a protective association between antithrombotics and COVID-19 remains inconclusive.

  This project will, therefore, explore three questions:

  1.       How many individuals in the UK with AF are not currently on antithrombotic medication?

  2.       Do individuals with AF taking antithrombotic medication prior to COVID-19 infection have better outcomes (e.g. hospitalisation, mortality) than those that don’t?

  3.       What factors (e.g. location, age) are associated with a lack of antithrombotic medication in individuals with AF?

  In addressing these questions, this project will create the software to automatically evaluate antithrombotic use in near real-time across the whole UK population. This will provide the information to help ensure individuals with AF are given the most effective treatments and confirm whether antithrombotics offer some protection against COVID-19.

• CCU022: Genomics of multimorbidity and CVD associated with susceptibility to COVID-19 infection and complications - project lead Michael Inouye & Howard Tang, University of Cambridge

  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new virus responsible for the COVID-19 pandemic, which has caused many deaths worldwide. We are worried that some long-term (“chronic”) diseases, such as heart disease and diabetes, can worsen COVID-19 infection and lead to increased risk of death. Also, these diseases often occur together in groups, and a person can have multiple diseases. When this happens, we call this “multimorbidity”. However we do not fully understand why this happens, nor how they may be linked to COVID-19.

  We therefore wish to study electronic health records (EHR) from hospitals and doctor’s clinics, as well as large-scale electronic databases of genetic and biological data, that cover people from a broad range of social and ethnic backgrounds from across the UK. Our team has expertise in using advanced computer-assisted techniques that can effectively make sense of such complex data, to find patterns and results beyond what is possible with traditional methods.

  Ultimately, we aim to identify groups of individuals with cardiovascular-related multimorbidities and assess their response to COVID-19 infection, and explore how genetic, biological, and social factors interact to change this response. Our results may help us better identify people who are at greatest risk of disease, and find new possibilities to treat or prevent the disease.

• CCU023: Repurposing medicines used to treat CVD risk to prevent COVID-19 - project leads Reecha Sofat, UCL & John Overington, Medicines Discovery Catapult

  COVID-19 vaccine rollout in the UK has been very successful. However, how long immunity from SARS-Cov-2 – the virus that causes COVID-19 – will last with vaccines is unknown. It is also unknown if new vaccines will need to be generated every year because of mutations in the virus, which commonly happens with flu. One other potential way that COVID-19 could be prevented would be to use medicines that act as anti-viral agents – but there are currently no such treatments available.

  Our project aims to begin to address this by examining medicines that are already used in clinical practice but for different diseases. Based on knowledge of how these medicines work, we have found that some medicines may be useful as anti-viral medicines. If this is true, they could be used to help to prevent COVID-19 alongside vaccines. This project will use data to test if people taking some medicines might also be protected from infection with SARS-Cov-2. These analyses will be supplemented by laboratory analyses where we will test these medicines to see if they can neutralise the effect of SARS-CoV-2.

  If these medicines are shown to have a protective signal in these analyses, this could lead to randomised controlled trials to test if they do prevent infection with SARS-CoV-2. If they work in clinical trials, this could mean the medicines could be used alongside vaccines for the prevention of COVID-19 infection and improve the population’s health.

Background & Aims

• Background

  

  Cardiovascular disease impact on susceptibility to and poor outcomes from COVID-19

  Patients with cardiovascular disease are at increased risk of developing COVID-19 and of poor outcomes of COVID-19, such as admission to hospital or intensive care, or of dying. This could be due to cardiovascular conditions themselves (e.g., heart disease, stroke), their risk factors (e.g., age, raised blood pressure), medications, or combinations of these. Understanding which patients are affected and why will help in developing strategies to reduce this risk.

  Impact of infection with coronavirus on patients with cardiovascular disease

  The direct impacts include immediate complications (e.g., acute heart injury, stroke) and potentially increased risk of heart attack, stroke and other cardiovascular events in the longer term, through inflammation, blood clotting risk or other factors. However, the nature and extent of these direct effects are not well understood.

  Impact of the COVID-19 pandemic on the treatment and care of cardiovascular disease patients

  The response by the government and health services to the COVID-19 pandemic also has indirect impacts on the presentation, diagnosis, management and outcomes of cardiovascular diseases. The numbers of people attending hospital with heart attack and stroke declined dramatically in the lead up to and after the announcement of lockdown (as demonstrated by the 4C Initiative). Further, patients were more often arriving too late for beneficial acute treatments (e.g., clot busting drugs) and after potentially preventable complications had developed. To inform government and NHS policy, we urgently need a deeper understanding of these unintended consequences.

• Aims

  We aim to answer three broad questions (see the protocol for more detail):

  1. What are the effects of cardiovascular diseases, their risk factors and medications on susceptibility to and poor outcomes (including admission to hospital, requirement for intensive care and death) from COVID-19 disease?
  2. What is the direct impact of SARS-CoV-2 infection on acute cardiovascular complications as well as on medium and longer-term cardiovascular risk?
  3. What is the indirect impact of the COVID-19 pandemic and the government and NHS response to it on the presentation, diagnosis, management and outcomes of cardiovascular diseases.

CVD-COVID-UK Consortium Membership, Governance and Project Approvals

• Membership, Governance & Project Approvals

  An inclusive, open and transparent consortium has been established to work on the CVD-COVID-UK project. Membership comprises data custodians, data scientists with methodological and analytical expertise (statisticians, epidemiologists, health informaticians, bioinformaticians, computer scientists and others) and clinicians (including cardiologists, stroke physicians, vascular surgeons and others), all of whom have signed up to an agreed set of principles.

  To become a member of the consortium, please e-mail: bhfdsc@hdruk.ac.uk. You will be sent a copy of the principles document that you must agree to before becoming a member of the consortium.

  The Approvals and Oversight Board of CVD-COVID-UK consists of representatives from data custodians, data controllers, researchers and lay members, coordinated by the operations team of the BHF Data Science Centre and chaired by the BHF Data Science Centre Director. Signed-up consortium members have access to project proposal forms to submit to the Approvals and Oversight Board for review. Project proposals must be within scope of the ethical and regulatory approvals of the CVD-COVID-UK programme of work, which covers the relationship between cardiovascular disease and COVID-19.

  For any queries regarding governance, membership or project submissions, please e-mail: bhfdsc@hdruk.ac.uk