An investigation into the association between acute

cardiovascular events, cardiovascular disease, and COVID-

19 prognosis of admissions to a North West England
hospital: a quantitative data analysis.

A dissertation submitted to The University of Manchester for the

degree of Master of Public Health (MPH) in the Faculty of Biology,
Medicine, and Health.

Year of submission: 2021

Student ID: 9538438

School of Health Sciences

 Table of Contents

List of Tables 4
List of Figures 4
List of Abbreviations 5
Abstract 6
Declaration 7
Intellectual Property Statement 7
Acknowledgements 8
Chapter 1: Introduction 9
1.1 Background of COVID-19 9
1.2 Global burden of COVID-19 10
1.3 COVID-19 in the United Kingdom 11
1.4 Cardiovascular Disease: Definition and Diagnosis 12
1.5 Acute Cardiovascular Event: Definition and Diagnosis 13
1.6 CVD and ACE: Prevalence in the UK 15
1.7 Potential mechanism for cardiovascular complications caused by COVID-19 15
1.8 Research question 16
1.9 Aims and Objectives 16
1.9.1 Aim 16
1.9.2 Objectives 16
1.10 Importance of this study 17
Chapter 2: Literature Review 18
2.1 Search Strategy 18
2.1.1 Strategy #1: CVD and COVID-19 18
2.1.2 Strategy #2: ACE and COVID-19 19
2.2 The impact of CVD on COVID-19 prognosis 20
2.2.1 CVD and COVID-19 severity 20
2.2.2 CVD and COVID-19 mortality 24
2.3 The impact of ACE on COVID-19 prognosis 27
2.4 What is already known, and what this study adds 29
Chapter 3: Methods 30
3.1 Study overview 30
3.2 Study setting 30
3.3 Population 31
3.3.1 Study population 31
3.3.2 Inclusion and exclusion criteria 31
3.4 Study variables 31
3.4.1 Outcome variables 31
3.4.2 Exposure variables 32
3.4.3 Potential confounding variables 33
3.5 Data collection 33
3.6 Data management and storage 33
3.7 Missing data and data organisation 34
3.8 Data analysis 35
3.8.1 Analysis of objective one 35
3.8.2 Analysis of objective two 35
3.8.3 Analysis of objective three 35
3.8.4 Analysis of objective four 36

2
 3.8.5 Analysis of objective five 36
3.9 Ethical considerations 36
Chapter 4: Results 38
4.1 Summary statistics 38
4.2 Prevalence of CVD in COVID-19 fatality 40
4.3 Prevalence of ACE in COVID-19 fatality 40
4.4 Unadjusted odds ratios (ORs) 41
4.4.1 Cardiovascular diseases 41
4.4.2 Acute cardiovascular events 43
4.5 Adjusted analysis 44
4.5.1 Logistic regression modelling 44
4.5.2 Explanation of final model 48
4.5.3 Additional analysis 49
4.5.4 Adjusted odds ratios 52
Chapter 5: Discussion 53
5.1 Introduction 53
5.2 Summary of results 53
5.3 COVID-19 fatality in admissions with underlying health conditions 53
5.3.1 COVID-19 fatality in admissions with CVD 53
5.3.2 COVID-19 fatality in admissions with ACE 53
5.4 Results from logistic regression analysis 54
5.4.1 Overall summary 54
5.4.2 Impact of confounding variables 54
5.5 Strengths of this study 56
5.6 Limitations of this study 57
5.7 Impact of results on clinical practice 59
5.8 Future research 60
5.9 Conclusion 61
References 62
Appendices 74

Word Count: 15,783

3
 List of Tables

Table 1: Search strategy #1 using MEDLINE and Cochrane Database of Systematic Reviews
Table 2: Search strategy #2 using MEDLINE and Cochrane Database of Systematic Reviews
Table 3: Overview of findings from literature search for COVID-19 and CVD
Table 4: Overview of findings from literature search for COVID-19 and ACE
Table 5: Ethnicities of residents in Preston, England
Table 6: Exposure variables of study, with variable type and measurement
Table 7: Potential confounding variables of study, with variable type and measurement
Table 8: Summary statistics table for the records included within the data analysis
Table 9: Summary statistics table comparing death and survival for each variable
Table 10: Prevalence of any CVD, and COVID-19 death, in the study sample
Table 11: Prevalence of any ACE, and COVID-19 death, in the study sample
Table 12: Unadjusted ORs for each individual CVD, and any CVD condition, with 95% CIs
Table 13: Unadjusted ORs for each individual ACE, and any ACE, with 95% CIs
Table 14: Logistic regression model including CVD and ACE
Table 15: Logistic regression model including CVD, ACE, and Age
Table 16: Logistic regression model including CVD, ACE, Age, and Ethnic Group
Table 17: Logistic regression model including CVD, ACE, Age, Ethnic Group and IMD Decile
Table 18: Logistic regression model including CVD, ACE, Age, Ethnic Group, and Sex
Table 19: Logistic regression model including CVD, ACE, Age, Ethnic Group, Sex and LoS
Table 20: Final logistic regression model including CVD, ACE, Age, Ethnic Group, Sex, and LoS
Table 21: Additional logistic regression model including Age, Ethnic Group, Sex, LoS, and CVD & ACE
Table 22: Key for CVD & ACE variables shown in Table 21
Table 23: Adjusted ORs and 95% CIs taken from final logistic regression model

List of Figures

Figure 1: Definitions of various cardiovascular diseases (CVDs)

Figure 2: Definitions of various acute cardiovascular events (ACEs)
Figure 3: Flowchart detailing the process of record exclusion.

4
 List of Abbreviations

ACE: Acute cardiovascular event

ACS: Acute coronary syndrome
CBD: Cerebrovascular disease
CDSR: Cochrane database of systematic reviews
CHD: Coronary heart disease
CI: Confidence interval
COVID-19: Novel coronavirus disease 2019
CVD: Cardiovascular disease
ECG: Electrocardiogram
HCP: Healthcare professional
HMRC: Her Majesty’s Revenue and Customs
ICU: Intensive care unit
JCVI: Joint Committee on Vaccination and Immunisation
LoS: Length of stay
MA: Meta-analysis
MI: Myocardial infarction
N-STEMI: Non-ST segment elevation myocardial infarction
OR: Odds ratio
PCR: Polymerase chain reaction
PHEIC: Public Health Emergency of International Concern
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses
PVD: Peripheral vascular disease
RPH: The Royal Preston Hospital
RR: Risk ratio
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2
SR: Systematic review
STEMI: ST segment elevation myocardial infarction
VD: Vascular Dementia
WHO: World Health Organization

5
 Abstract

Background
The COVID-19 pandemic has led to numerous premature deaths across the globe, with an increased
frequency of severe disease and mortality, in those with underlying health conditions. The available
evidence demonstrates that individuals with cardiovascular disease are more at risk of severe
COVID-19 disease and mortality, however, very few studies investigate if individuals who have
experienced an acute cardiovascular event, may also have an increased risk of severe COVID-19
disease, and fatality.

Aim
This study aims to investigate if hospital admissions who have been diagnosed with any underlying
cardiovascular disease, or any previous acute cardiac event, prior to COVID-19 diagnosis, are at an
increased risk of COVID-19 related fatality.

Method
Demographic and clinical hospital admission data for the period 1st February 2020 to 31st January
2021, was provided for this study, by The Royal Preston Hospital. A logistic regression model was
formed to explore which demographic and clinical variables confounded the relationship between
cardiovascular disease, acute cardiovascular events, and COVID-19 fatality.

Results
2,655 hospital admissions included for analysis. Those with underlying cardiovascular disease were
found to be at an increased risk of COVID-19 fatality, which remained significant when controlling for
demographic factors such as age, sex, and ethnicity, and the clinical factor of length of hospital stay.
Hospital admissions who had experienced an acute cardiovascular event, prior to COVID-19
diagnosis, had an increased non-significant risk of COVID-19 fatality, that non-significant remained
when adjusting for other factors.

Conclusion
Cardiovascular disease was associated with increased odds of COVID-19 fatality even when
accounting for other variables. Previous acute cardiovascular events did not show a significant
increased risk of COVID-19 fatality. Future research on a larger scale is needed to further examine
the risk of COVID-19 fatality, in hospital admissions, or other individuals, who have experienced
acute cardiovascular events.

6
 Declaration

To the best of the authors knowledge, all work within this dissertation is original, except where
otherwise indicated; all information taken from other sources has been referenced appropriately.
No portion of the work referred to in this dissertation has been submitted in support of an
application for another degree or qualification at The University of Manchester, or any other
university/institute of learning.

Intellectual Property Statement

I. The author of this dissertation (including any appendices and/or schedules to this
dissertation) owns certain copyright or related rights in it (the “Copyright”) and she has
given The University of Manchester certain rights to use such Copyright, including for
administrative purposes.
II. Copies of this dissertation, either in full or in extracts and whether in hard or electronic
copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as
amended) and regulations issued under it or, where appropriate, in accordance with
licensing agreements which the University has entered into. This page must form part of any
such copies made.
III. The ownership of certain Copyright, patents, designs, trademarks and other intellectual
property (the “Intellectual Property”) and any reproductions of copyright works in the
dissertation, for example graphs and tables (“Reproductions”), which may be described in
this dissertation, may not be owned by the author and may be owned by third parties. Such
Intellectual Property and Reproductions cannot and must not be made available for use
without the prior written permission of the owner(s) of the relevant Intellectual Property
and/or Reproductions.
IV. Further information on the conditions under which disclosure, publication and
commercialisation of this dissertation, the Copyright and any Intellectual Property and/or
Reproductions described in it may take place is available in the University IP Policy, in any
relevant Dissertation restriction declarations deposited in the University Library, and The
University Library’s regulations.

7
 Acknowledgements

A massive thank you to my supervisor Dr Tracey Farragher for supporting and guiding me
throughout this dissertation. Your knowledge and expertise have been invaluable to me and I’m so
grateful for the time you’ve spent giving me advice, helping me to learn STATA, and always being
contactable by email for all the questions I have had!

Also, thank you to Dr Ali Omer and the data sciences team at The Royal Preston Hospital for sorting
and providing the data used within this dissertation. The NHS has been under an extreme amount of
pressure over the past 18 months, and I really appreciate you taking the time to provide me with
this data, enabling me to complete a dissertation on a topic I’m so passionate about.

Nan and granddad, I cannot thank you enough for continuing to support me throughout university. I
have completed my master’s degree with love and support from you both, just like my
undergraduate, and I have always had someone to turn to, to celebrate my successes and for advice
when times have been tough.

Alex, this year has been tough on us both, I know that doing this postgraduate degree and leaving
my job has put our life on hold and I cannot thank you enough for the love, understanding, and
compassion you have shown me over the past 12 months. You have never complained when I’ve had
to work late, or miss out on events, and I appreciate that so much.

Mum, this dissertation was inspired by you. After seeing you so unwell with acute myocarditis in
2017 and living with the fear of losing you at 20-years old, I felt that I was guided into cardiac-related
research. I had to better understand acute cardiovascular events, to try and make a difference one
day, to people like you.

The last 18-months have been terrifying and difficult; a global pandemic, a situation I never could
imagine living through. There have been such sad times, but it has been heart-warming to see how
communities have joined together, to support those people who needed it the most.

This dissertation is dedicated to all who have lost their lives, to COVID-19.

8
 Chapter 1: Introduction

1.1 Background of COVID-19

COVID-19 is a highly contagious, communicable disease, caused by the novel coronavirus SARS-CoV-
2; SARS-CoV-2 was first isolated in December 2020, in a group of patients presenting with
pneumonia-like illness in Wuhan, China (1–3). SARS-CoV-2 is transmitted through respiratory
droplets, or smaller aerosols, from an infected person, often when they cough, sneeze or speak; the
virus is spread more easily in crowded or poorly ventilated areas, between people who are in close
proximity to each other (4).

By the 30th January 2020, human cases of COVID-19 had been identified in eighteen countries
outside of China, this prompted the WHO to declare COVID-19 a Public Health Emergency of
International Concern (PHEIC); following on from this declaration, COVID-19 was characterised as a
worldwide pandemic on 11th March 2020 (5).

In the majority of cases, COVID-19 is a relatively mild and self-limiting illness, which can be treated
with over-the-counter medications, at home, however, some individuals can experience a more
severe disease, which can lead to hospitalisation and for some patients, fatality (6). Patients with
severe COVID-19 disease typically experience dyspnoea (shortness of breath), and hypoxaemia (low
blood oxygen levels), approximately 7 days after the onset of initial symptoms (7). Severe COVID-19
can lead to sepsis, severe multi-organ failure and an overwhelming inflammatory response, leading
to hypercoagulability, the blockage of arteries/veins caused by blood clots (8,9).

In some individuals, the effects of COVID-19 can be experienced for weeks, and sometimes months,
following initial diagnosis; this is known as ‘post COVID-19 syndrome’ or more informally as ‘long
COVID’ (10). A cohort study, completed in China in September 2020, found that six months after
acute COVID-19 infection, 63% of respondents (n=1038) were still experiencing muscle weakness
and fatigue, 26% (n=437) continued to experience sleep disturbances, and 23% (n=367) reported
continued feelings of anxiety, or depression (11). Further to this, individuals who had been more
severely ill with COVID-19 still displayed abnormalities on chest imaging and impaired lung function,
sixth months after COVID-19 diagnosis (11).

Although there is no strict definition for what is classified as severe COVID-19 disease, the COVID-19
Severity Index tool was designed to aid clinicians in deciding which patients with COVID-19 are to be
considered severe, and whom may deteriorate quickly (12). The COVID-19 Severity Index provides

9
medical and nursing staff with a patient score ranging from 0 (very mild disease) to 23 (most severe
disease), in addition, there are suggested actions provided for each category, with prompt critical
care assessment advised for patients scoring 5 or above (12).

1.2 Global Burden of COVID-19

As of 18th May 2021, over 163 million cases of COVID-19 have been recorded worldwide (13).
The global death toll for COVID-19 is currently recorded as almost 3.4 million, however, when
considering the disparities in testing ability, and the recording of COVID-19 related deaths across
different countries, data analysis has demonstrated that the number of worldwide fatalities caused
by COVID-19, may be closer to 7 million (13,14).

The burden of COVID-19 cases has challenged, and often exceeded the capacity of intensive care
units, in hospitals across the globe, furthermore, healthcare staff have experienced unprecedented
levels of stress, exhaustion, and anxiety surrounding the risk of COVID-19 transmission to their
family members (15).

The COVID-19 pandemic has caused food shortages across the globe; the restrictions imposed by
governments has limited the movement of workers, altered the needs of consumers, due to more
time spent at home, and caused widespread disruptions in the food supply chain (16). Further to
this, the price of several basic food products such as maize and wheat, have increased by up to 66%;
this has led to an increase in the number of individuals experiencing food insecurity, and
malnourishment, worldwide; COVID-19 has exacerbated the already alarming rates of poverty, in
low- and middle-income countries (17,18).

Evidence demonstrates that individuals with underlying health conditions, such as chronic kidney
disease, respiratory disease, and cardiovascular disease, are at an increased risk of severe COVID-19,
furthermore, it is estimated that up to 9% of the global population have at least one of these health
conditions, increasing their risk of severe COVID-19 disease, and COVID-19 related fatality (19).
Understanding which underlying health conditions can increase an individual’s risk of severe COVID-
19 is vital information to assist clinicians, and healthcare staff, with providing patients with
appropriate, and effective treatment.

10
1.3 COVID-19 in the United Kingdom
The index case of COVID-19, in the UK, was identified on 23rd January 2020; this was isolated in an
individual who had recently travelled to the Hubei province of China (20). Following on from this,
two months later (23rd March 2020), the UK had recorded 12,635 cases of COVID-19, which further
increased to 177,185 by 30th April 2020 (21). However, the accuracy of these figures is questionable;
testing was only available to HCP or hospitalised patients, up until May 2020 (22), therefore, the
actual number of COVID-19 cases in the UK, may have been higher.

The ZOE study, aiming to identify potential cases through symptomatic reporting, was established in
March 2020 by King’s College London, individuals were asked to report their symptoms, or lack of,
through a mobile phone application (23). On 12th June 2020, the number of confirmed daily COVID-
19 cases in the UK was recorded as 1,058, polymerase chain reaction (PCR) testing was available to
all UK residents at this stage, however, testing capacity was low; the ZOE study estimates there was
closer to 86,000 individuals whom may have had COVID-19, on this date, however, this figure is
based on symptomatic reporting, not confirmed testing (21,24).

On 23rd March 2020, the UK Prime Minister announced a national lockdown, this restricted
individuals to only making essential trips, and also suspended social gatherings and large events,
such as weddings (25). Further to this, to inhibit the spread of COVID-19, the use of face coverings
within public places (such as shops, banks, and transport hubs), became mandatory in the UK, from
24th July 2020 (26). Compliance with measures imposed by the government began to decline shortly
after their introduction, with qualitative research suggesting that the primary reason for non-
compliance is the lack of trust individuals have, in key figures of the UK government (27,28). National
restrictions were eased in July 2020, however, local and regional lockdowns were introduced shortly
after, following on from this, the UK entered its third, and final, national lockdown on 6th January
2021, which began to ease in March 2021 (29).

The aim of the UK government’s response to COVID-19 was to mitigate spread and reduce the
number of cases, however, the measures imposed by the government impacted the economy, and
the health of individuals (30,31). Between June and July 2020, a high number of individuals reported
anxiety symptoms in an Office for National Statistics (ONS) survey, furthermore, this increase was
considerably larger in vulnerable groups such as disabled adults, and adults with health conditions
(32). Between June and September 2020, 314,000 job redundancies were recorded, the highest

11
figure since records began, furthermore, data from Her Majesty’s Revenue and Customs (HMRC)
demonstrates the number of UK employees fell by almost 800,000, in the same time period (30).

On 2nd December 2020, the first COVID-19 vaccine for the UK, developed by Pfizer/BioNTech, was
approved for use outside of clinical trials (33). The Joint Committee on Vaccination and
Immunisation defined a structured list for vaccine distribution, with older adults, frontline health
and social care workers, and those with underlying health conditions taking priority; these groups
were chosen based on available data that indicated older adults and those with health conditions
made up the majority of COVID-19 deaths, and frontline health and social care workers had an
increased risk of personal exposure (33). As of 15th June 2021, almost 80% of adults in the UK, had
received their first COVID-19 vaccination (21).

It is thought that the UK’s vaccination programme has prevented over 10,000 premature deaths in
older adults, however, some critics suggest the UK’s response to COVID-19 has been uncoordinated
and poorly communicated (34,35).

1.4 Cardiovascular Disease (CVD): Definition and Diagnosis

Cardiovascular disease (CVD) is a broad term for a variety of disorders, caused by atherosclerosis
(plaque build-up inside arteries) and thrombosis (blockage of an artery or vein, due to blood clot),
which affect the heart and/or blood vessels, in the body (36,37). The World Health Organization
(WHO) definitions, for some of the different types of cardiovascular disease, is detailed below in
Figure 1. Research has demonstrated that individuals with underlying CVD are almost three-times
more at risk of severe COVID-19, and COVID-19 related fatality (38,39). Acknowledging that these
patients are more at risk of a poor COVID-19 prognosis, allows healthcare staff to prioritise
resources effectively, this in turn may lead to fewer deaths, and more favourable outcomes for
patients.
(40)(41)

12
 Definitions for CVD
• Coronary heart disease – disease affecting blood vessels which supply the myocardium
(heart muscle).
• Peripheral arterial/vascular disease – disease affecting blood vessels which supply
peripheries (arms and legs).
• Cerebrovascular disease – disease affecting the blood vessels which supply the brain.
• Vascular dementia – form of dementia which is caused by reduced blood flow to the
brain.

Figure 1: Definitions of various CVDs, taken from WHO & NHS (40,41).

In most cases, there are no presenting symptoms to indicate that an individual has CVD, the
condition is often diagnosed after an acute cardiovascular event, caused by CVD, such as a
myocardial infarction (MI) or stroke (40). Risk factors for CVD include cigarette smoking,
hypertension, and high cholesterol, in addition, non-modifiable influences such as age, gender and
ethnicity, are also considered risk factors for CVD (37). The majority of CVDs can be prevented by
behavioural modifications such as smoking cessation and dietary changes (40).

1.5 Acute Cardiovascular Event (ACE): Definition and Diagnosis

Currently, there is no literature available that explicitly defines an acute cardiovascular event (ACE),
however, for the purpose of this study, the definition for acute coronary syndrome (ACS) will be
used as a guide (42); an acute cardiovascular event will be defined as any situation in which the
heart or blood vessels become compromised, either due to blockage (atherosclerosis or thrombosis,
as defined above) or other aetiology, such as infection. This will include myocardial infarction (N-
STEMI), acute myocarditis, unstable angina, and stroke.

13
 Diagnostic Criteria for ACE
• Myocardial infarction – Elevated cardiac troponin levels alongside one of the following:
ischaemia symptoms, significant ST-segment-T wave changes/left bundle branch block,
Q-wave changes in ECG, imagining showing new loss of myocardium or wall movement
abnormality, evidence of intracoronary thrombus.
• Acute myocarditis – Elevated cardiac troponin levels, abnormal 12 lead ECG, abnormal
left or right ventricular ejection, oedema.
• Stroke – Caused by disruption of blood flow to the brain. Weakness in limbs, speech
difficulties and drooped face.
• Unstable angina – Primary symptom of chest pain. Unstable angina attacks are
(43–46)
unpredictable and may persist despite resting.

Figure 2: Definitions of various ACEs (43-46).

Acute cardiovascular events are included within this study, as CVD can increase an individual’s risk of
experiencing an ACE (40). This study takes a particular focus on ACE as previous research has
demonstrated although CVD increases an individual’s risk of severe COVID-19 (38,39), little evidence
is available to examine the impact that ACE have alone, on COVID-19 prognosis. Further to this,
there is evidence to suggest that COVID-19 infection may in fact lead to ACE and cardiovascular
disturbances such as arrythmias (irregular heartbeat), myocardial (heart muscle) damage, and
thrombosis (47); this evidence demonstrates the importance of investigating the impact ACE may
have on COVID-19 prognosis, when experienced both before, and after, diagnosis.

As shown above in Figure 2, myocardial infarction (MI) and acute myocarditis (AM) are both ACE;
CVD increases an individual’s risk of experiencing an MI, however, acute myocarditis is often
triggered by an overwhelming immune response, caused by infection; although different in
aetiology, both an MI and acute myocarditis can cause permanent damage to the myocardium
(heart muscle) (40,48,49). Individuals who have experienced previous ACE may also have CVD, as
CVD is a risk factor for some ACE, such as myocardial infarction (40); for this reason, CVD may be a
confounder in the relationship between ACE and COVID-19 outcomes, which this study aims to
investigate.

14
1.6 CVD and ACE: Prevalence in the UK
It is currently estimated that there is 7.6 million people in the UK, living with CVD; this is
approximately 14% of adults, over the age of sixteen (50,51). In the UK, 27% of all recorded deaths,
are attributable to CVD, furthermore, on average, three women die every hour, from coronary heart
disease (50,52); these figures demonstrate the true magnitude of the problem of CVD, in the UK. In
the UK, there are over 100,000 admissions to hospitals every year, for myocardial infarction; this
equates to approximately 1 admission every 5 minutes (50).

Since 23rd March 2020, over 468,000 individuals with COVID-19, have been admitted to hospital,
cumulative data for those occupying mechanical ventilation beds is unavailable, however, at the
peak of the pandemic on 24rd January 2021, there was 4,077 patients with COVID-19, in mechanical
ventilation beds (21). Further to this, as of 16th June, the UK has seen 1,888 deaths per million
people, the 19th highest death toll, worldwide (53).

Although there is no data available that demonstrates the number of COVID-19 hospital patients
with CVD, the high prevalence of CVD in the UK coupled with the increased risk of severe COVID-19,
and COVID-19 related fatality in individuals with CVD, presents the question of did the UK see such
high COVID-19 hospitalisations and deaths as a result of the underlying prevalence of CVD
(38,39,50). Clinical research can result in access to new treatments, and lead to systematic
application of these throughout a healthcare system, benefiting patients and improving mortality
(54); thoroughly investigating the factors which increase an individual’s risk of poor COVID-19
prognosis, such as CVD, can provide healthcare professionals with the knowledge and resources
needed to improve treatments for patients with COVID-19, who have underlying health conditions,
and potentially lead to fewer deaths, and more favourable outcomes.

1.7 Potential mechanism for cardiovascular complications caused by COVID-19

Early research demonstrates that COVID-19 may lead to the development of cardiovascular
complications, such as myocardial injury, myocarditis and arrythmias (55). It has been suggested that
the overwhelming inflammatory response, seen in patients with COVID-19, may hasten the
development of new cardiovascular complications (56), further to this, findings from animal studies
indicate that ACE2, a crucial protein for virus entry, may also be a contributing factor, to this
proposed mechanism (57). Although this evidence is comprehensive, further research is needed to
fully understand the mechanism(s) responsible for cardiovascular complications, caused by COVID-
19.

15
1.8 Research question
Do previous acute cardiovascular events, or underlying cardiovascular disease, increase an
individual’s risk of COVID-19 related fatality, in those that were hospitalised with COVID-19, or
acquired COVID-19 in hospital?

Research completed over the past eighteen-months strongly illustrates that those individuals with
underlying health conditions, such as CVD, are at an increased risk of severe COVID-19 disease
requiring hospitalisation, and COVID-19 related fatality (58–60). However, there is a lack of research
that investigates if individuals who have experienced previous acute cardiovascular events, such as
an MI or acute myocarditis, are also at an increased risk of severe COVID-19 disease, or death.

Understanding if individuals who have experienced previous ACEs are at an increased risk of severe
COVID-19, or COVID-19 related fatality, is crucial information; this knowledge would enable
healthcare professionals to determine the best course of treatment for such patients.

As previously mentioned, there is considerable evidence to suggest individuals with CVD are at an
increased risk of severe COVID-19 disease, and COVID-19 related fatality, however, there is a lack of
evidence investigating if individuals who have experienced ACEs, are also more at risk (38,39). The
above research question aims to address this gap in the evidence base, and improve outcomes for
COVID-19 patients, who have experienced previous ACEs.

1.9 Aims and Objectives

1.9.1 Aim
To determine if individuals admitted to hospital with COVID-19, or who have acquired COVID-19
whilst in hospital, are more at risk of COVID-19 related fatality, due to their underlying CVD or
previous ACE.

1.9.2 Objectives
1. Complete a review of the existing literature to determine what is already known about the
relationship between CVD and COVID-19, and ACE and COVID-19.
2. Estimate the prevalence of any CVD in hospital admissions who experienced fatal COVID-19
and compare this to the prevalence of any CVD in hospital admissions with COVID-19 who
survived.

16
 3. Estimate the prevalence of any ACE in hospital admissions who experienced fatal COVID-19
and compare this to the prevalence of any ACE in hospital admissions with COVID-19 who
survived.
4. Determine which clinical and demographic variables confound the relationship between
CVD, ACE, and COVID-19 fatality, in hospital admissions.
5. To investigate if hospital admissions with any CVD, and any ACE, are more at risk of COVID-
19 fatality, when compared to admissions with just CVD or ACE, or neither.

1.10 Importance of this study

Individuals with underlying CVD are at an increased risk of severe COVID-19 disease, and COVID-19
related fatality (19), however, there is limited evidence available which examines if previous ACE are
also a risk factor for COVID-19 disease severity, or fatality. Alongside further investigating CVD as a
risk factor for COVID-19 severity and fatality, this study will also examine if there is an association
between previous ACE and disease severity, and if previous ACE also impact an individual’s chances
of survival, when diagnosed with COVID-19; a risk factor which is considerably under researched.

The study will provide valuable information to healthcare professionals, enabling them to accurately
identify patients who may be more at risk of deterioration when diagnosed with COVID-19, and
provide the appropriate management and treatment, in a timely manner. The information provided
from this study may also assist healthcare professionals with predicting the course of a patient’s
disease, which will in turn lead to more effective care.

This study will also examine the impact of other variables on an individual’s risk of severe COVID-19,
and COVID-19 related fatality; statistical methods will be used to examine age, ethnicity, gender, as
potentially confounding variables, and assess the impact that these factors, may have on disease
trajectory, and survival.

To the best of the author’s knowledge, this study will be the first of its kind which examines the
impact that ACE may have on the severity of COVID-19 experienced by hospital patients, and if an
individual’s chances of survival from COVID-19, is impacted by previous ACE.

17
 Chapter 2: Literature Review

2.1 Search Strategy

A search of the literature was completed to assess the evidence base for COVID-19 and CVD, and
COVID-19 and acute cardiovascular events; MEDLINE and the Cochrane Database of Systematic
Reviews (CDSR) were searched. MEDLINE was chosen as this database contains an abundance of
references to biomedical journal articles, relevant to this choice of dissertation topic, furthermore,
the CDSR was included within the search strategy as it includes a substantial amount of healthcare
related systematic reviews, which is again highly relevant, to this choice of topic (61,62).
The aim of the below search strategies was to identify literature relating to COVID-19 and CVD, and
COVID-19 and ACEs; a broad search strategy was used to capture all relevant evidence, and
understand any association, concerning these topics.

The term ‘cardi* disease’ was used in search #1 to capture literature containing cardiac disease and
cardiovascular disease. The term ‘SARS-CoV-2’ was also included in both searches to capture
literature that used the name of the virus, in place of the disease name (COVID-19) (2). The term
‘novel coronavirus 2019’ was also included in both searches, to capture early literature before
COVID-19 was officially named, in February 2020 (5). ‘Cardi* disease’ AND the terms listed below in
Table 1 were used to capture literature which included cardiac disease or cardiovascular disease,
and at least one of the terms listed in Table 1, related to COVID-19.

2.1.1 Strategy #1: CVD and COVID-19

MEDLINE Database (searched 01/06/2021)

Search terms Number of results
Cardi* disease AND (COVID-19 OR SARS-CoV-2 OR novel coronavirus 2019) 188
Cochrane Database of Systematic Reviews (searched 01/06/2021)
Search terms Number of results
Cardi* disease AND (COVID-19 OR SARS-CoV-2 OR novel coronavirus 2019) 0

Table 1: Search strategy #1 using MEDLINE and Cochrane Database of Systematic

Reviews.

The search on MEDLINE obtained 189 results, however, the CDSR yielded zero results. From the 189
results on MEDLINE, the search was further restricted to include only systematic reviews (SR) and
meta-analyses (MA); systematic reviews and meta-analyses provide an overview of the results from
primary studies, furthermore, each study included within a systematic review or meta analyses has

18
been individually assessed for quality (63). A substantial amount of research related to COVID-19 has
been completed over the past eighteen-months; due to time and resource constraints, the author of
this dissertation felt it was more appropriate to only include SR and MA, to understand the current
research and provide them with a suitable background of knowledge.

When the above search strategy was further restricted, 6 systematic reviews and meta-analyses
were obtained; after screening of titles and abstracts, 5 papers were considered relevant to this
study. These papers will be examined further, below in Table 3.

2.1.2 Strategy #2: ACE and COVID-19

MEDLINE Database (searched 01/06/2021)

Search terms Number of results
Myocardial infarction OR myocarditis AND (COVID-19 OR SARS-CoV-2 OR 378
novel coronavirus 2019)
Cochrane Database of Systematic Reviews (searched 01/06/2021)
Search terms Number of results
Myocardial infarction OR myocarditis AND (COVID-19 OR SARS-CoV-2 OR 0
novel coronavirus 2019)

Table 2: Search strategy #2 using MEDLINE and Cochrane Database of Systematic

Reviews.

The search strategy shown in Table 2 obtained 378 results on MEDLINE, however, as with the
strategy shown in Table 1, the CDSR yielded no results. The search above was further restricted to
include only systematic reviews and meta-analyses; 2 results remained.

, (65), (66), (67), (68)

19
 2.2 The impact of CVD on COVID-19 prognosis(64), (65), (66), (67), (68)

Study Design Participants Research Focus Outcome Findings

measures
Bae et al. Systematic 51 studies, Investigating the Relative risk of Relative risk of developing
(2021) (64) Review & including impact of CVD, developing severe COVID-19 was higher
meta- 48,317 and its risk factors, severe COVID- in those with CVD risk factors
analysis. participants. on fatal COVID-19 19, or COVID-19 such as hypertension (OR
outcomes, fatality. 2.50, 95% CI 2.15 to 2.90),
according to age. diabetes (OR 2.25, 95% CI
1.89 to 2.69), and higher in
those with confirmed CVD
(OR 3.11, 95% CI 2.55 to
3.79).
Matsushita Systematic 25 studies, Investigating if Relative risk of Risk factors for CVD such as
et al. review & including CVD and its risk developing hypertension (OR 2.87, 95%
(2020) (65) meta- 76,638 factors predict severe COVID- CI 2.09 to 3.93) and diabetes
analysis. participants severe COVID-19. 19. (OR 3.20, 95% CI 2.26 to 4.53)
were associated with a higher
risk of severe COVID-19, as
was male gender (OR 1.73,
95% CI 1.50 to 2.01).
Confirmed CVD was also
associated with an increased
risk of severe COVID-19 (OR
4.97, 95% CI 3.76 to 6.58).
Aggarwal Meta- 18 studies, Investigating the Odds ratios for Underlying CVD associated
et al. analysis. 4,858 association severe COVID-19 with increased risk of severe
(2020) (66) participants between CVD and disease, and COVID-19 disease (OR 3.14,
worse COVID-19 overall risk of 95% CI 2.32 to 4.24).
prognosis. COVID-19 all- Underlying CVD also
cause fatality. associated with COVID-19
mortality (OR 11.08, 95% CI
2.59 to 47.32).
Li et al. Systematic 10 studies, Evaluating the Odds ratios for Underlying CVD (OR 4.85,
(2020) (67) review & 3,118 impact of CVD, in-hospital 95% CI 3.07 to 7.70),
meta- participants hypertension, and COVID-19 hypertension (OR 3.67, 95%
analysis.
acute cardiac mortality. CI 2.31 to 5.83), and acute
injury on COVID- cardiac injury (OR 21.15, 95%
19 prognosis. CI 10.19 to 43.94) are all
factors significantly
associated with higher odds
of COVID-19 related
mortality.
Ssentongo Systematic 25 studies, Investigating Relative risk Underlying CVD had 2nd
et al. review & 65,484 COVID-19 ratios for each of highest risk ratio (RR 2.25,
(2020) (68) meta- participants outcome in 11 included 95% CI 1.60 to 3.17) from the
analysis.
patients with underlying 11 comorbidities included.
underlying comorbidities. This was closely followed by
comorbidities. hypertension (RR 1.82, 95%
CI 1.43 to 2.32) and diabetes
(RR 1.48, 95% CI 1.02 to
2.15); two risk factors for
CVD.
Table 3: Overview of findings from literature search for COVID-19 and CVD.

2.2.1 CVD and COVID-19 Severity

Three of the systematic reviews above in Table 3, examine the impact that CVD has on COVID-19
disease severity (64–66). The definitions of ‘severe COVID-19’ are similar across all three reviews;
Bae et al. and Aggarwal et al. (64,66) define severe COVID-19 based on physiological observations
(oxygen saturations <93% in room air, respiratory rate above 30 breaths per-minute), respiratory
distress, and the need for mechanical ventilation or intensive care unit (ICU) admission. The
definition of severe disease in the review completed by Matsushita et al. is based solely on
respiratory distress, mechanical ventilation and ICU support, with no consideration of physiological
observations (65).

The review completed by Bae et al. (64) examines the impact of COVID-19 disease severity in
hospital patients from five countries, with CVD risk factors, hypertension (elevated blood pressure)
and diabetes, and in patients with confirmed CVD; this review found that patients with confirmed
CVD were over three-times more likely to develop severe COVID-19 disease (OR 3.11, 95% CI 2.55 to
3.79), when compared to individuals with no CVD. Bae et al. stratified the prevalence of CVD and
COVID-19 outcomes by age group in their MA; age is considered itself to be a risk factor for severe
COVID-19 (64,69).

This stratification may be considered a strength of this review as it allows the authors to control for
the confounding effect of age, on COVID-19 disease severity (70), however, age was stratified using
the mean age of patients, therefore, various age groups may have been combined which could be
considered a limitation of results accuracy. Furthermore, no other factors that may confound the
relationship between CVD and severe COVID-19, such as ethnicity, deprivation status or gender (71–
73), were controlled for in the SR completed by Bae et al. (64); this may also be considered a
limitation of this review.

21
Publication bias is the largest source of type 1 error (increase of false positive results) in meta-
analyses (74); Bae et al. utilise the trim-and-fill method in their MA which reduces the potential for
publication bias, this may be considered a strength of their review (64,75). Furthermore, in the MA
for the less than 50 years-of-age group, the low I2 statistic suggests a low level of heterogeneity
amongst papers, indicating that included studies are similar and can be combined, this may be
considered a strength of this review (76), however, the I2 statistic can have considerable bias when
the MA is small (77); Bae et al. included only two studies in their MA for patients aged 50 years, or
less (64).

The review completed by Matsushita et al. (65) includes twenty-five studies, with the majority of
these studies including hospital patients; the review is similar to that of Bae et al. (64), examining if
CVD and its risk factors, increase the severity of COVID-19 disease. Matsushita et al. found that
individuals with confirmed CVD were almost five-times more likely to develop severe COVID-19 (OR
4.97, 95% CI 3.76 to 6.58), when compared to those without CVD.

Male gender is understood to be a risk factor for severe COVID-19 (73), and therefore may act as a
confounding variable in the observed association between CVD, and severe COVID-19 disease. This is
something that Matsushita et al. did acknowledge within their introduction, however, only four of
the included studies controlled for gender; controlling for confounding variables leads to a more
accurate estimate of the true association between the exposure (CVD) and the outcome (severe
COVID-19 disease), therefore, this may be considered a limitation of the SR (65,78).

Further to the above, the MA completed by Matsushita et al. (65) demonstrated that studies with a
larger age gap between individuals with severe COVID-19 compared to those without severe COVID-
19, had a greater relative risk of severe COVID-19, according to the presence of CVD and its risk
factors; this indicates that age may also be a confounding factor in the observed relationship
between CVD and severe COVID-19 disease. Only four studies in the review completed by
Matsushita et al. adjusted for age as a confounding factor, this again, may be considered a limitation
of the review (65).

Of the twenty-five studies included in the systematic review by Matsushita et al. (65), twenty-one
were completed in China; because of this, patients may have been included within multiple studies,
which may reduce the accuracy of the findings, and this may be considered a limitation of the
review. Further to this, with 84% of the included studies being completed in one country, it may be

22
difficult to apply the findings from the review completed by Matsushita et al. (65), to different
countries and settings; restricting the generalisability of findings from this review may also be
considered a limitation (79).

As previously mentioned, the I2 statistic indicates the level of heterogeneity across papers, included
within a meta-analysis, with a lower I2 statistic indicating similarity across papers and their ability to
be combined for analysis (76); none of the I2 statistics for the meta-analyses completed by
Matsushita et al. exceeded 75%, which is thought to be the benchmark for high heterogeneity (80),
therefore, this may be considered a strength of this review.

The review completed by Aggarwal et al. (66) evaluated the association between CVD and COVID-19
prognosis; the review included eighteen studies, with sixteen of these from China, and two from the
USA. Aggarwal et al. determined within their analysis that individuals with underlying CVD are over
three-times more likely to develop severe COVID-19 (OR 3.14, 95% CI 2.32 to 4.24), when compared
with individuals without CVD.

The meta-analysis completed by Aggarwal et al. (66) does not state how many, if any, studies
included, considered, and controlled for confounding factors such as age and gender, which may be
considered a limitation. However, Aggarwal et al. did complete a meta-regression analysis to assess
the impact of gender and age on COVID-19 disease severity; the regression found that age had no
significant impact on the pooled odds ratio, which contradicts previous findings from studies which
suggest as age increases, as does the risk of severe COVID-19 (66,81,82). Further to this, in the meta-
regression analysis, as the percentage of female gender increased, as did the odds ratio for severe
disease, which contradicts other studies which found male gender to be a confounding factor in the
relationship between CVD and COVID-19 disease severity, not female (73,83).

Some research suggests that males are more at risk of severe COVID-19 due an increased prevalence
of behavioural risk factors, such as smoking (83), however in China, where 89% of the studies
included within the review were completed, smoking prevalence is much lower in women, so this
would not explain the results of the meta-regression analysis, in the review by Aggarwal et al.
(66,84). The meta-regression analysis completed by Aggarwal et al. (66) may be considered a
strength of the study, as this information may identify potential risk factors for severe COVID-19,
that were not previously considered.

23
As noted with the review completed by Matsushita et al. (65), the meta-analysis completed by
Aggarwal et al. (66) also includes a majority number of studies completed in China, this may be
considered a limitation of the as patients may have been included in multiple studies, reducing the
accuracy of results, furthermore, the high number of studies from one country reduces the
generalisability of findings (79), which again, may be considered a limitation of this meta-analysis.

2.2.2 CVD and COVID-19 Mortality

Three of the reviews, above in Table 3, examine the impact that CVD has on COVID-19 related
mortality (66–68).

Li et al. (67) evaluate the impact that CVD, hypertension and acute cardiac injury, have on the risk of
COVID-19 mortality, their review found that those with CVD are almost five-times more likely (OR
4.85, 95% CI 3.07 to 7.70) to die due to COVID-19, those with hypertension are almost four-times
more likely (OR 3.67, 95% CI 2.31 to 5.83), but more notably, those with acute cardiac injury are over
twenty-one-times more likely to die due to COVID-19 (OR 21.15, 95% CI 10.19 to 43.94), when
compared to individuals without any of the above listed morbidities. The wide 95% confidence
interval reported for acute cardiac injury from Li et al. (67) indicates the estimate of the odds ratio
lacks precision; a larger sample size may be needed for this group, to increase the rigor of this result
(85).

Acute cardiac injury is evidenced by an elevation of troponin, a cardiac biomarker, in the blood (86).
The review completed by Li et al. (67) demonstrates that individuals with elevated troponin levels
have a significantly higher risk of mortality, related to COVID-19, when compared with those who
have normal troponin levels. These findings may be considered a strength of the review, as they
provide healthcare professionals with the knowledge that raised troponin levels may act as an
indicator for COVID-19 survival, for hospital patients. However, the MA for acute cardiac injury only
included eight papers, and there was a high level of heterogeneity (I2 = 72.4%); this raised I2 statistic
suggests considerable variation in the included studies, therefore, this may be considered a
limitation, and further studies are needed to truly determine the association between acute cardiac
injury, and COVID-19 mortality.

This investigation by Li et al. (67) into the association between acute cardiac injury and COVID-19
mortality is somehow similar in nature to the purpose of this study, which aims to determine if
individuals who have experienced previous acute cardiac events, have an increased risk of COVID-19

24
mortality. However, this study does differ from that completed by Li et al. (67) as it includes acute
cardiovascular events further back in time, prior to COVID-19 diagnosis, whereas Li et al. only
investigated patients whose acute cardiac injury occurred in hospital, after COVID-19 diagnosis.

The meta-analysis completed by Li et al. (67) used unadjusted odds ratios due to limited data on
multivariable outcomes, this analysis does not account for potential confounding variables which
may lead to a lack of accuracy in the estimation between CVD, hypertension, or acute cardiac injury,
and COVID-19 mortality; this may be considered a limitation of this review (78).

Further to the above, all studies included within the review by Li et al. (67) were completed in
Wuhan, China; this may be considered a strength to the review as this is the location where the
COVID-19 pandemic originated, and this review provided healthcare practitioners with vital early
research into a disease with unknown risk factors, however, it may also be considered a limitation as
there is narrow generalisability of results, and it may be problematic to apply the review findings, in
other countries (5,79).

The review completed by Ssentongo et al. (68) examined the association between various pre-
existing health conditions, including CVD, and COVID-19 related mortality. Ssentongo et al. (68)
found that individuals with underlying CVD had the second highest risk ratio of all eleven evaluated
conditions (RR 2.25, 95% CI 1.60 to 3.17), this was closely followed by two CVD risk factors;
hypertension (RR 1.82, 95% CI 1.43 to 2.32), and diabetes, (RR 1.48, 95% CI 1.02 to 2.15).

Ssentongo et al. (68) included twenty-five studies, involving over 65,000 participants within their
review and meta-analysis, furthermore, the included studies were from various countries; China,
United States of America, Italy, and South Africa. The inclusion of studies from various countries
across the globe may be considered a strength of this review, as it appears to increase the
generalisability of findings to other settings (79), however, it may also be considered a limitation; the
countries included within the review completed by Ssentongo et al. (68) are all high-income or
upper-middle-income countries (as defined by The World Bank), therefore, the findings of this
review may be problematic to apply in lower income countries, such as those in the continent of
Africa (87).

Current research suggests that individuals who are of Black or Asian ethnicity are known to be more
at risk of COVID-19 related mortality, when compared with individuals of white ethnicity (88),

25
further to this, those of Black or Asian ethnicity are more likely to develop CVD, hypertension, or
type 2 diabetes, when compared to individuals of white ethnicity (89). In the review by Ssentongo et
al. (68), not all included studies provided data on the ethnicity of participants; ethnicity may be a
confounding factor in the relationship between CVD and COVID-19 mortality, therefore, this may be
considered a considerable limitation of the review, as confounding factors can lead to an inaccurate
estimation of the relationship between exposure (CVD), and outcome (COVID-19 mortality) (78).
Further to the above, the odds ratios for frequent outcomes may bias the estimation of the
relationship between exposure and outcome, towards a stronger association (90), for this reason,
the pooled estimates within the meta-analysis completed by Ssentongo et al. may be amplified, and
this may be considered another limitation, of this review (68).

When considering the review by Ssentongo et al. (68), it is difficult to ascertain if the large number
of participants from the included studies (n=65,484), is a strength or limitation; a large sample size
allows for a more precise estimation of the relationship between exposure and outcome to be
determined, and allows for wider generalisability of results, however, it must be considered that a
sample size which is too large, may enhance the observed differences and lead to inaccurate
inferences being made (91,92); this may have caused an overestimation of the association between
CVD and COVID-19 mortality, in the review completed by Ssentongo et al. (68).

The previously mentioned review, completed by Aggarwal et al. (66), also examines the association
between CVD and COVID-19 mortality. The meta-analysis completed by Aggarwal et al.
demonstrated that hospital patients with underlying CVD were eleven-times more likely to die, due
to COVID-19 (OR 11.08, 95% CI 2.59 to 47.32), however, there was no significant association found
between CVD, and mortality in severe COVID-19 disease (OR 1.72, 95% CI 0.97 to 3.06) (66).

The general strengths and limitations of the review completed by Aggarwal et al. have been
discussed above in section 2.2.1, however, it is worth considering that the meta-analysis for CVD and
mortality in severe COVID-19 disease, included only three studies, with an I2 heterogeneity statistic
of 0% (66). Guidance suggests that a meta-analysis can be completed with two or more studies, and
the low I2 statistic seen in the meta-analysis of CVD and mortality in severe COVID suggests there is
low variance across the studies, and they can be combined for a pooled odds ratio (76), however, it
must be noted that including only a small number of studies within a meta-analysis may bias the I2
statistic, and this may be considered a limitation of the review and analysis completed by Aggarwal
et al. (66,77).

26
 All studies included within the mortality analysis cohort, were from China; this may limit the
generalisability of the findings from the meta-analysis, and it may be problematic to apply these
results to settings in other countries, furthermore, as all studies were completed in China, some
patients may have had data included within more than one study, which may have impacted the
overall results; these factors may be considered limitations of the review, completed by Aggarwal et
al. (66,79).

2.3 The Impact of ACE on COVID-19 Prognosis (93), (94)

Study Design Participants Research Focus Outcome measures Findings

Sawalha Systematic 14 studies, An investigation An assessment of the 81% of patients survived to

et al. review. including 14 into effectivity of discharge, favourable
(2021) patients myocarditis/myope treatments used for outcomes seen in patients
(93) ricarditis, acquired COVID-19 related treated with steroid therapy.
following a myocarditis/myoperi Effectivity of colchicine and
diagnosis of COVID- carditis. glucocorticoids is uncertain.
19.
4 of 14 patients had
hypertension, and 1 of 14
patients had cardiomyopathy
(disease affecting heart muscle
size, shape and/or thickness).
Raukar & Systematic Information A review of the An assessment of Recommendations that all
Cooper review. not given myocardial effects what emergency athletes should be asked about
(2021) of SARS-CoV-2 in action plans should previous SARS-CoV-2 infection,
(94) athletes. be in place, for prior to event participation,
athletes experiencing then appropriate cardiac
myocardial related screening can be completed if
illness. necessary. Sports personnel
should be appropriately
trained to deliver CPR and use
an AED.

Table 4: Overview of findings from literature search for COVID-19 and ACE.

As demonstrated above in Table 4, little evidence in the form of systematic reviews, is available to
examine this topic; although the reviews completed by Sawalha et al. and Raukar and Cooper
provide valuable information in the context of ACE and COVID-19 (93,94), they do not provide
information that meets the aims of this study; assessing if previous ACE increase an individual’s risk
of severe COVID-19, or COVID-19 related fatality.

27
The review completed by Sawalha et al. (93), includes 14 cases; of these 14, 4 had underlying
hypertension and 1 case had cardiomyopathy; both cardiovascular related factors, prior to COVID-19
diagnosis. This review examines myocarditis, an ACE, following a diagnosis of COVID-19, and
assesses which treatments are the most beneficial for COVID-19, however, this dissertation aims to
examine the opposite of this – if ACE prior to COVID-19 diagnosis, can increase an individual’s risk of
severe COVID-19, and COVID-19 related fatality.

Sawalha et al. have used the PRISMA checklist, to guide their search for studies, and their inclusion
criteria; this may be considered a strength of the review completed by Sawalha et al. as the criteria
that navigates the inclusion of studies into a systematic review, can influence the results (95),
however, Sawalha et al. do not discuss the heterogeneity of the included studies or provide any
explanation as to how bias was reduced, which is also suggested within the PRISMA checklist for
systematic review; this may be considered a limitation of this review (93,96).

Further to the above, the review completed by Sawalha et al (93), only includes case report studies;
case reports have no control population, and for this reason, are particularly vulnerable to selection
bias, therefore, this may be considered a limitation of the review (97).

Although the systematic review completed by Sawalha et al. does not provide any information that
addresses the aim of this dissertation, it does provide vital information about the potential
complications of COVID-19, and the efficacy of various treatment options such as glucocorticoids,
and steroid therapy (93).

The systematic review completed by Raukar and Cooper (94) provides vital information relating to
the myocardial complications experienced by athletes, caused by COVID-19. The review completed
by Raukar and Cooper does not follow the format for a traditional systematic review; there is no
discussion about how studies were selected or assessed for quality, and no consideration of
potential bias, furthermore, the review meets a limited number of points, from the PRISMA
systematic review checklist (94,96).

The findings from the review, completed by Raukar and Cooper, provide those who work in sport,
with valuable guidance relating to the screening and management of athletes following a diagnosis
of COVID-19, and this may be considered a strength of the review, however, the review does not

28
examine the impact of previous ACE on COVID-19 disease severity, and fatality, which is the aim of
this dissertation.

The search strategy shown in section 2.1.2 emphasises a considerable gap in research, demonstrated
by the lack of available evidence that investigates the impact that previous ACE may have on an
individual’s risk of severe COVID-19 disease, or COVID-19 related fatality.

Both reviews completed by Sawalha et al. (93) and Raukar and Cooper (94) provide crucial
information about the potential myocardial complications caused by COVID-19, and how best to
manage and treat COVID-19, however, neither review meets the aims or objectives of this
dissertation, which is to investigate if previous ACE increase an individual’s risk of severe COVID-19
disease, and COVID-19 related fatality.

2.4 What is already known, and what this study adds

As previously discussed, individuals with underlying CVD are at an increased risk of severe COVID-19
disease, and COVID-19 related fatality, however, the evidence examining if previous ACE impact an
individual’s COVID-19 disease trajectory or prognosis, is extremely limited.

This study will examine if individuals who have experienced previous ACE, are at an increased risk of
severe COVID-19 disease, or fatality, and this will be compared with outcomes for individuals with
CVD, and individuals with neither. Only a few studies, included above in the critical literature
analysis (Table 3 and 4), measure and control for confounders; this study will recognise and adjust
for non-modifiable confounders such as age, gender, and ethnicity, and potentially modifiable
confounders such as smoking status, BMI, and deprivation status.

Providing valuable information to healthcare professionals involved in the care and treatment of
patients with COVID-19, who have experienced previous ACE or have underlying CVD, may help
predict the course of disease for these patients, enabling them to receive more effective care.
Furthermore, understanding who is more at risk of severe COVID-19 disease, or fatality, may help
resources be allocated more efficiently, leading to more favourable outcomes for patients.

29
 Chapter 3: Methods

3.1 Study Overview

The following study is a secondary analysis of routine data, using anonymised patient admission data
provided by The Royal Preston Hospital (RPH), in Preston, England. The data used for this study is
admissions to The Royal Preston Hospital with COVID-19, or who acquired COVID-19 whilst in
hospital for another diagnosis, between 1st February 2020 and 31st January 2021. This study aims to
estimate the prevalence of COVID-19 mortality in admissions with CVD and compare this to
admissions with no CVD. Furthermore, the prevalence of COVID-19 mortality in admissions with
previous ACE will be estimated and compared to admissions with no previous ACE. Data in this study
was analysed using prevalence calculations, and logistic regression models.

The admission data obtained also included demographic admission information such as age, sex,
IMD Decile, and ethnicity. Further to this, the data included admission information such as length of
stay in hospital, previous ACE data, and CVD diagnosis data.

Ethical approval was received from the National Health Service (NHS) for this study, and permission
to use data from The Royal Preston Hospital was obtained from the appropriate data guardians.

3.2 Study Setting

Preston is a city in the North West region of England, with a population of approximately 140,000
residents, with 50.1% being male, and 49.9% female, further to this, the mean age of an individual in
Preston is 36.9 years, with 78.5% of Preston residents aged eighteen years, or older (98). The local
authority of Preston is within the most 20% deprived areas in England, furthermore, 6.1% of Preston
residents currently claim unemployment related benefits (99,100). Preston is home to residents of
varying ethnicities (98), these are detailed below in Figure 3.

Ethnicity % Of Preston residents who identify as this ethnicity

White 80.2%
Mixed 2.4%
Asian/Asian British 15.5%
Black/African/Caribbean/Black British 1.2%
Other 0.8%

Table 5: Ethnicities of residents in Preston, England (90).

30
Since 14th March 2020, Preston has had 17,920 cases of COVID-19, confirmed with a PCR swab, this
equates to approximately 12.8% of Preston’s population, further to this, COVID-19 has been
listed on 354 death certificates, in Preston (21).

Figures to demonstrate the exact number of COVID-19 patients requiring care at The Royal Preston
Hospital, is not available, however, the Lancashire Teaching NHS Trust (inclusive of The Royal
Preston, and Chorley and South Ribble Hospital) have had 3,293 hospital admissions of individuals
with confirmed COVID-19, since 21st March 2020 (21,101).

3.3 Population
3.3.1 Study Population
Admissions to The Royal Preston Hospital with COVID-19 disease, or those who have acquired
COVID-19 whilst in hospital due to another diagnosis, between 1st February 2020 and 31st January
2021. Throughout the rest of this study, the term “COVID-19 admissions” may be used to describe
the study population; this includes admissions to The RPH with COVID-19, or those who have
acquired COVID-19 during their stay.

3.3.2 Inclusion and Exclusion Criteria

Inclusion criteria
All admission data of those aged 18-years or older, who have been admitted to The Royal Preston
Hospital due to deterioration of COVID-19 disease, or admissions who have acquired COVID-19
whilst already in hospital, between 1st February 2020 and 31st January 2021.

Exclusion criteria
Admission data for those who are under 18-years of age. Admission data for those younger than 18-
years of age have been excluded as this study aims to investigate the relationship between CVD,
ACE, and COVID-19, in adults.

3.4 Study Variables

3.4.1 Outcome Variables
COVID-19
The data provided for this study, from The Royal Preston hospital, only includes records of
admissions who have been diagnosed with COVID-19, either prior to or on admission; therefore, all
data included within this study is from COVID-19 positive patients.

31
Death caused by COVID-19
As all data provided for this study is that of admissions with confirmed COVID-19; an admission
record is considered to have the outcome of death caused by COIVD-19 if the record shows their
discharge type to be ‘death’.

3.4.2 Exposure variables

The exposure variables for this study include:
• Experience of previous ACE
• Diagnosis of CVD

Variable Type of variable Measurement

Experience of previous ACE Binary Yes or no
Diagnosis of CVD Binary Yes or no

Table 6: Exposure variables of study, with variable type and measurement.

Cardiovascular Disease (CVD)

An admission is considered to have CVD if their record data from The Royal Preston Hospital displays
one, or multiple, of the following conditions:
• Coronary heart disease
• Peripheral arterial/vascular disease
• Cerebrovascular disease
• Vascular dementia

All CVD data in the records provided by The Royal Preston Hospital, was for admissions who had
been formally diagnosed with one, or multiple, forms of CVD, prior to COVID-19 disease.

Acute Cardiovascular Events (ACE)

An admission is considered to have experienced a previous ACE if their record data from The Royal
Preston Hospital displays one, or multiple, of the following events:
• Acute myocarditis
• Myocardial infarction
• Stroke
• Unstable angina

32
All ACE data in the records provided by The Royal Preston Hospital, was for admissions who had
experienced one, or multiple ACEs, prior to COVID-19 disease.

3.4.3 Potential confounding variables

The potential confounding variables for this study include:
• Age
• Sex
• Ethnicity
• IMD Decile
• Length of hospital stay

Variable Type of variable Measurement

Age Continuous Years of age
Sex Binary Male or female
Ethnicity Categorical White or Non-White
IMD Decile Categorical Categories 1 (Most Deprived) to 10 (Least Deprived)
Length of hospital stay Continuous Number of days

Table 7: Potential confounding variables of study, with variable type and

measurement.

3.5 Data Collection

All data used within this study was routinely collected, for the purpose of the observation and
treatment of admissions, at The Royal Preston Hospital; no elements of the dataset were collected
solely for the purpose of this research. The relevant data needed for this research was anonymised
and organised by the research science team at The RPH, then provided to the author of this study.

3.6 Data Management and Storage

Data from The Royal Preston Hospital was provided to the author of this study via a hospital trust
account; this account granted the author remote, and secure, access to the required data. All
admission data was anonymised and coded to protect identities. The author of this study was only
granted permission to access the data through the remote trust desktop application, and the data
could not be transferred or saved onto the author’s personal IT equipment. All the data used within
the study was checked for accuracy, and any identified errors were discussed with the data
guardians, at The Royal Preston Hospital.

33
3.7 Missing Data and Data Organisation
The dataset provided by The Royal Preston Hospital included 2,835 admission records. The author
excluded 180 records due to age restrictions within the inclusion criteria, and pieces of missing data;
all remaining 2,655 records had complete data for each of the variables. Figure 3 below provides a
more detailed summary of the missing data.

Total number of records included in the dataset: 2835

Total number of records excluded: 180

• 31 records excluded due to patient age <18 years
• 143 records excluded due to incomplete ethnicity data
• 1 record excluded due to incomplete sex data
• 4 records excluded due to incomplete IMD decile data
• 1 record excluded due to incomplete length of stay data

Total number of records included within the analysis: 2655

Figure 3: Flowchart detailing the process of record exclusion.

The data provided by The Royal Preston Hospital initially included fourteen different groups, to
categorise a patient’s ethnicity. Due to time constraints, and with ethnicity not being the primary
focus of the study, patient ethnicities were re-categorised into two groups for the purpose of
analysis, “White” and “non-White”. Further to this, patient discharge details included within the
dataset were provided under three categories, “death”, “self-discharge” and “normal discharge”, as
the primary focus of this study is COVID-19 related mortality, “self-discharge” and “normal
discharge” were combined to create a new “survival” category, which was then used alongside
“death” to analyse the data.

The provided data included four types of CVD (coronary heart disease, peripheral vascular disease,
vascular dementia, and cerebrovascular disease), and four types of ACE (myocardial infarction,
unstable angina, acute myocarditis, and stroke), however, no data was present for cases of acute
myocarditis; therefore, this variable was excluded from the analysis.

34
3.8 Data Analysis
The data used within this study was analysed using the STATA (Version 16.0) statistical programme.

3.8.1 Analysis of Objective One

Complete a review of the existing literature to determine what is already known about the
relationship between CVD and COVID-19, and ACE and COVID-19.

• To achieve this objective, a comprehensive literature search of relevant databases was

completed, with the results from this detailed in Chapter 2. The review provided a
reasonable amount of evidence that demonstrated the increased risk of COVID-19 severity
and fatality, in individuals with CVD and its risk factors (hypertension and diabetes).
However, the author identified a gap in evidence as no studies investigating the relationship
between previous ACE and COVID-19 fatality, a key part of this dissertation, were found.

3.8.2 Analysis of Objective Two

Estimate the prevalence of any CVD in hospital admissions who experienced fatal COVID-19 and
compare this to the prevalence of any CVD in hospital admissions with COVID-19 who survived.

• This objective was achieved by calculating the proportion of hospital admissions who had
fatal COVID-19, and a formal diagnosis of CVD, and comparing this to the proportion of
hospital admissions who had a formal diagnosis of CVD, however survived COVID-19.
Comparing these prevalence rates as percentages demonstrates, and allows for comparisons
of, the frequency of the outcome (COVID-19 death) in those who are exposed (CVD
diagnosis) and those unexposed (no CVD diagnosis).

3.8.3 Analysis of Objective Three

Estimate the prevalence of any ACE in hospital admissions who experienced fatal COVID-19 and
compare this to the prevalence of any ACE in hospital admissions with COVID-19 who survived.

• This objective was achieved by calculating the proportion of hospital admissions who had
fatal COVID-19, and experienced an ACE, and comparing this to the proportion of hospital
admissions who had experienced an ACE, however survived COVID-19. Comparing these
prevalence rates as percentages demonstrates, and allows for comparisons of, the

35
 frequency of the outcome (COVID-19 death) in those who are exposed (previous ACE) and
those unexposed (no previous ACE).

3.8.4 Analysis of Objective Four

Determine which clinical and demographic variables confound the relationship between CVD, ACE,
and COVID-19 fatality, in hospital admissions.

• To achieve this objective a multivariate logistic regression model was formed; logistic
regression was considered the most appropriate choice of model for this analysis, as logistic
models are suited to binary outcomes, such as death or survival (102), furthermore, a
multivariate model allowed the author to recognise which variables confounded the
relationship between CVD, ACE, and COVID-19. An initial model, to assess the odds ratio of
COVID-19 death, was formed with CVD and ACE, the variables of interest. From this, other
variables (Age, Sex, Ethnic Group, IMD Decile, and Length of Stay) were then added
individually, in a forward stepwise process, to evaluate the impact of each variable on the
odds ratios for CVD and ACE. The variables which showed significance at the 5% level (p
value<0.05) and had 95% confidence intervals that did not cross the value of 1 (point of no
effect), remained in the final model.

3.8.5 Analysis of Objective Five

To investigate if hospital admissions with any CVD, and any ACE, are more at risk of COVID-19
fatality, when compared to admissions with just CVD or ACE, or neither.

• To achieve this objective, an additional four category variable was created, this included
admissions with both CVD and ACE, admissions with just CVD, admissions with just ACE, and
admissions with neither. This variable was then examined in a new logistic regression model
with all other variables previous identified to be confounders, to identify if CVD and ACE
together, created an additive effect on the risk of COVID-19 fatality.

3.9 Ethical Considerations

Permission to use the data for this study was granted by The Royal Preston Hospital, who also
provided the data to the author through a secure online account, furthermore, approval was also
sought from the NHS to complete this study. No data, such as home addresses or telephone

36
numbers, which may lead to personal identification of the admissions, was accessible by the author
of this study. Each admission record included within the data set used for this study was allocated a
numerical code, protecting identity, and ensuring full anonymisation.

37
 Chapter 4: Results

4.1 Summary Statistics

Variable N %
Total Records 2655 100
Sex
Male 1,482 55.8
Female 1,173 44.2
Age
18-29 years 85 3.2
30-39 years 94 3.5
40-49 years 175 6.6
50-59 years 285 10.7
60-69 years 408 15.4
70-79 years 639 24.1
80+ years 969 36.5
Mean age & SD* 70.4 ± 17.1*
Median age (Overall) & (IQR**) 74 (83,60)**
Median age (Male) & (IQR**) 73 (82,60)**
Median age (Female) & (IQR**) 76 (85,61)**
Ethnicity
White 2,386 89.9
Non-White 269 10.1
CVD
Coronary Heart Disease 567 21.4
Peripheral Vascular Disease 202 7.6
Vascular Dementia 98 3.7
Cerebrovascular Disease 44 1.7
Admissions with any CVD 911 34.4
ACE
Myocardial Infarction 134 5.0
Unstable Angina 42 1.6
Stroke 13 0.5
Acute Myocarditis 0 0
Admissions with any ACE 189 7.1
Discharge Type
Survival 2,024 76.2
Death 631 23.8
Length of Stay (days)
Mean length of stay & SD* 15.7 ± 17.5*
Median length of stay & (IQR**) 10.5 (20.8,4.9)**
IMD Decile
1 (Most Deprived) 279 10.5
2 334 12.6
3 272 10.2
4 281 10.6
5 200 7.6
6 184 6.9
7 183 6.9
8 405 15.3

38
 9 309 11.6
10 (Least Deprived) 208 7.8

SD* = Standard Deviation, IQR** = Interquartile Range

Table 8: Summary statistics table for the records included within the data
analysis.

Variable N N (Death) % N (Alive) %

Total Records 2655 631 23.8 2,024 76.2
Sex
Male 1,482 389 26.2 1,093 73.8
Female 1,173 242 20.6 931 79.4
Age
Mean age by Death & SD* 78.2 years ± 11.7*
Median age by Death & IQR** 80 years (86,71)**
Ethnicity
White 2,386 573 24.0 1,813 76.0
Non-White 269 58 21.6 211 78.4
CVD
Any admission with CVD 911 306 33.6 605 66.4
ACE
Any admission with ACE 189 55 29.1 134 70.9
IMD Decile
1 (Most Deprived) 279 71 25.4 208 74.6
2 334 76 22.8 258 77.2
3 272 47 17.3 225 82.7
4 281 56 19.9 225 80.1
5 200 53 26.5 147 73.5
6 184 48 26.1 136 73.9
7 183 46 25.1 137 74.9
8 405 107 26.4 298 73.6
9 309 78 25.2 231 74.8
10 (Least Deprived) 208 49 23.6 159 76.4
Length of Stay (LoS)
Mean LoS by Death & SD* 14.8 days ± 12.1*
Median LoS by Death & (IQR**) 11.8 days (20.6,6.1)**
SD* = Standard Deviation, IQR** = Interquartile Range

Table 9: Summary statistics table comparing death and survival for each
variable.

Of the 2,655 records analysed, 1,482 (55.8%) were of male admissions, and 1,173 were of female
admissions (44.2%). The mean age of the data sample overall was 70.4 years, with a standard
deviation value of 17.1. The median age of the sample overall was 74 years, with the median age for
males and females alone being similar, at 73 years and 76 years respectively. Of the 2,655 records
included within the final analysis, 631 admissions died from COVID-19, with the average age of this
outcome being 78.2 years. Within the dataset, there was 911 admissions with CVD, and 189

39
admissions with ACE, both prior to COVID-19 diagnosis. More detailed characteristics of the study
sample is shown above, in Table 9 and Table 10.

4.2 Prevalence of CVD in COVID-19 fatality

Estimate the prevalence of any CVD in hospital admissions who experienced fatal COVID-19 and
compare this to the prevalence of any CVD in hospital admissions with COVID-19 who survived.

Cardiovascular Death
Disease (CVD) Yes No Total
Yes 306 (48.5%) 605 911
No 325 (51.5%) 1,419 1,744
Total 631 (100%) 2,024 2,655

Table 10: Prevalence of any CVD, and COVID-19 death, in the study sample.

To meet the above study objective, the proportion of hospital admissions with any CVD who also
died from COVID-19, must be compared to the proportion of hospital admissions with any CVD, who
also had COVID-19, but survived.

Table 10 indicates that hospital admissions with any CVD, made up 306 (48.5%) of the total 631
deaths. Of the total 911 admissions with any CVD condition, 306 (33.6%) died from COVID-19 and
605 (66.4%) survived, thus indicating that a higher proportion of hospital admissions with CVD who
had COVID-19 survived (n=605, 66.4%) compared with the proportion of CVD admissions who had
COVID-19, however died (n=306, 33.6%). This may also be explained as approximately 1 in 3
admissions with any CVD died from COVID-19, and 2 in 3 admissions with any CVD survived COVID-
19.

4.3 Prevalence of ACE in COVID-19 fatality

Estimate the prevalence of any ACE in hospital admissions who experienced fatal COVID-19 and
compare this to the prevalence of any ACE in hospital admissions with COVID-19 who survived.

Acute Cardiovascular Death

Event (ACE) Yes No Total
Yes 55 (8.7%) 134 189
No 576 (91.3%) 1,890 2,466
Total 631 (100%) 2,024 2,655
Table 11: Prevalence of any ACE, and COVID-19 death, in the study sample.

40
 To meet the above study objective, the proportion of hospital admissions with any ACE who also
died from COVID-19, must be compared to the proportion of hospital admissions with any previous
ACE, who survived COVID-19.

Table 11 indicates that hospital patients with previous ACE made up 55 (8.7%) of the total 631
deaths. Of the total 189 hospital admissions with any ACE, 55 (29.1%) patients died from COVID-19,
and 134 (70.9%) survived. This indicates that a higher proportion of hospital admissions with COVID-
19, who had experienced any previous ACE, survived COVID-19 (n=134, 70.9%), compared to the
proportion of hospital admissions, who had experienced any previous ACE, who died from COVID-19
(n=55, 29.1%). This may also be explained as approximately 3 in 10 admissions with any previous
ACE died from COVID-19, and 7 in 10 admissions with any previous ACE, survived COVID-19.

4.4 Unadjusted odds ratios (ORs)

Analysis was completed to determine the unadjusted ORs of the risk of death from COVID-19 in
admissions with CVD, and admissions with previous ACE, using a univariate logistic regression model.
Unadjusted ORs were obtained for each CVD and ACE condition , and two overall ORs were
calculated for occurrence of any CVD, and any ACE. The results from this analysis can be seen below
in Table 12 and 13.

4.4.1 Cardiovascular Diseases

Variable N N (Death) Unadjusted OR* Unadjusted 95% CI**

Coronary Heart Disease (No) 2,088 442 1.00 -
Coronary Heart Disease (Yes) 567 189 1.86 1.52-2.28
Peripheral Vascular Disease (No) 2,543 565 1.00
Peripheral Vascular Disease (Yes) 202 66 1.62 1.19-2.21
Vascular Dementia (No) 2,577 588 1.00 -
Vascular Dementia (Yes) 98 43 2.62 1.74-3.94
Cerebrovascular Disease (No) 2,611 623 1.00 -
Cerebrovascular Disease (Yes) 44 8 0.71 0.33-1.53

Admissions for any CVD condition 911 306 2.00 1.66-2.41

OR*= Odds Ratio, 95% CI**= 95% Confidence Interval

Table 12: Unadjusted ORs for each individual CVD, and any CVD condition, with
95% CIs.

Table 12 above demonstrates that hospital admissions with coronary heart disease (CHD) are 86%
more likely (OR 1.86, 95% CI 1.52-2.28) to experience the outcome of COVID-19 related fatality,

41
compared to admissions with no CHD. The 95% CI indicates that there is a 95% certainty that true
OR for COVID-19 death in admissions with CHD, lies between 1.52 times more likely, and 2.28 times
more likely. Further to this, hospital admissions with peripheral vascular disease (PVD) are 62% (OR
1.62, 95% CI 1.19-1.21) times more likely to die from COVID-19 disease, when compared to
admissions with no PVD. The 95% CI indicates that there is a 95% certainty that the true OR for
COVID-19 death in admissions with PVD lies between 1.19 (19% more likely), and 1.21 (21% more
likely).

In addition to the above, hospital admissions who have a diagnosis of vascular dementia (VD) are
2.62 times (OR 2.62, 95% CI 1.74-3.94) more likely to experience fatal COVID-19 disease, when
compared to admissions with no vascular dementia. The 95% CI for this OR indicates that there is a
95% certainty that the true OR for COVID-19 death in admissions with VD lies between 1.74 (74%
more likely), and 3.94 (3.94 times more likely).

In contrast to the previously calculated ORs, it initially appears that hospital admissions with
cerebrovascular vascular disease (CBVD) are 29% less likely to die (OR 0.71, 95% CI 0.33-1.53) from
COVID-19 disease, when compared to admissions with no CBVD. However, as the 95% CI
accompanying this OR includes 1 (95% CI 0.33-1.53), the value of no effect, this is not a statistically
significant finding and there is a 95% certainty that the true OR lies between 0.33 (33% less likely)
and 1.53 (53% more likely).

For any CVD condition, the calculated OR was 2.00 (95% CI 1.66-2.41), indicating that overall,
hospital admissions with any CVD are two-times more likely to die from COVID-19, when compared
to an admission with no CVD. The 95% CI for this OR indicates that there is a 95% certainty that true
OR of COVID-19 death in admissions with any CVD condition lies between 1.66 (66% more likely) and
2.41 (2.41 times more likely).

42
4.4.2 Acute cardiovascular events

Variable N N (Death) Unadjusted OR* Unadjusted 95% CI**

Myocardial Infarction (No) 2,521 597 1.00 -
Myocardial Infarction (Yes) 134 34 1.10 0.73-1.63
Unstable Angina (No) 2,613 618 1.00 -
Unstable Angina (Yes) 42 13 1.45 0.75-2.80
Stroke (No) 2,642 623 1.00 -
Stroke (Yes) 13 8 5.19 1.70-15.90

Admissions for any ACE 189 55 1.32 0.94-1.86

OR*= Odds Ratio, 95% CI**= 95% Confidence Interval
Table 13: Unadjusted ORs for each individual ACE, and any ACE, with 95% CIs.

Table 13 above appears to show that hospital admissions who have experienced a myocardial
infarction (MI) prior to COVID-19 diagnosis, are 10% more likely to die (OR 1.10) from COVID-19,
when compared to admissions who have no previous MI. However, the 95% CI for this OR (95% CI
0.73-1.63) crosses the value of one, which is the point of no effect, making this result statistically
non-significant, at the 5% level. The 95% CI indicates that there is a 95% certainty that the true OR
lies between 0.73 (27% less likely) and 1.63 (63% more likely).

The above calculated ORs also appear to show that hospital admissions who have previously
experienced unstable angina (UA) are 45% more likely (OR 1.45) to experience fatal COVID-19, when
compared to admissions with no previous UA. However, the 95% CI for this OR also crosses the value
of one (95% CI 0.75-2.80), making this result statistically non-significant at the 5% level. The 95% CI
indicates that there is 95% certainty that the true OR of COVID-19 fatality, for admissions with
previous UA, lies between 0.75 (15% less likely) to 2.80 (2.80 times more likely).

Table 13 above demonstrates that hospital admissions who have experienced a stroke are 5.19
times (95% CI 1.70-15.90) more likely to die from COVID-19 disease, when compared to admissions
who have no previous stroke. The 95% CI for this OR indicates that there is a 95% certainty that the
true OR for admissions with a previous stroke lies between 1.70 (70% more likely) and 15.90 (15.9
times more likely). However, the 95% CI is relatively wide, thus indicating that the estimate of the
OR has low precision; this may be due to the low prevalence of stroke in the data for this study, and
a larger sample size may be needed to increase the precision, of the findings (85).

43
For any ACE, the calculated OR was 1.32 (95% CI 0.94-1.86), indicating that overall, hospital
admissions who have experienced previous ACEs are 32% more likely to die from COVID-19, when
compared to admissions who had no previous ACE. The 95% CI for this OR indicates there is a 95%
certainty that the true OR for any ACE lies between 0.94 (6% less likely) and 1.86 (86% more likely).
However, this 95% CI includes the value of 1, indicating that this result is statistically non-significant,
at the 5% level.

4.5 Adjusted analysis

4.5.1 Logistic regression modelling
The fourth objective of this study was to ascertain which clinical and demographic variables
confound the relationship between CVD and ACE, and COVID-19 fatality. A logistic regression model
was formed using STATA (Version 16), with the steps detailed below.

First Model
The first logistic regression model was formed with the variables CVD and ACE.

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD (Yes) 1.98 0.000 1.64-2.40
ACE (No) 1.00 - -
ACE (Yes) 1.08 0.675 0.76-1.53
Table 14: Logistic regression model including CVD and ACE.

Table 14 demonstrates that the OR for death from COVID-19 in a hospital admission with CVD is
1.98, indicating they are 1.98 times (98%) more likely to die from COVID-19, when compared to a
hospital admission with no CVD. Furthermore, the p-value is <0.05, making it significant at the 5%
level, and the 95% CI does not cross 1 (95% CI 1.62-2.40) , the point of no effect. The OR for death
from COVID-19 in a hospital admission who has experienced a previous ACE is 1.08, indicating these
patients are 1.08 times (8%) more likely to die from COVID-19 when compared to hospital
admissions who have not experienced a previous ACE, however, the p-value for this OR is >0.05
making it non-significant at the 5% level, furthermore, the 95% CI (95% CI 0.76-1.53), does cross the
value of 1, the point of no effect.

In this multivariate model, the individual ORs are adjusted for the other variables in the model,
however, ACE was non-significant in this initial model. As ACE is a key outcome of interest, it will
remain in the model to further investigate if other variables adjust the OR for ACE.

44
Second Model
The second model included the addition of the Age variable.

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD (Yes) 1.45 0.000 1.19-1.76
ACE (No) 1.00 - -
ACE (Yes) 1.01 0.951 0.71-1.44
Age (years) 1.04 0.000 1.04-1.05
Table 15: Logistic regression model including CVD, ACE, and Age.

After the addition of the age variable to the model, CVD remains significant, and ACE remains non-
significant, at the 5% level. The addition of age has changed the ORs for CVD, and ACE, indicating
that age is a confounding variable, in the relationship between CVD, ACE, and the risk of COVID-19
death. The OR for age is 1.04, indicating for every 1-year increase in age, the odds of hospital
patients dying from COVID-19 increases by 4% (OR 1.04). The p-value for the age variable is <0.05,
and the 95% CI does not cross through 1 (95% CI 1.04-1.05), the point of no effect, therefore age is a
significant variable and remains in the model.

Third Model
The third model included the addition of the Ethnic Group variable.

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD (Yes) 1.45 0.000 1.19-1.77
ACE (No) 1.00 - -
ACE (Yes) 0.99 0.976 0.70-1.42
Age (years) 1.04 0.000 1.04-1.05
Ethnic Group (Non-White) 1.00 - -
Ethnic Group (White) 0.66 0.015 0.48-0.92
Table 16: Logistic regression model including CVD, ACE, Age, and Ethnic Group.

After the addition of the ethnic group variable to the model, CVD and age remain significant, and
ACE remains non-significant, at the 5% level. The addition of ethnic group has left the OR for CVD
and age unchanged, however, the OR for ACE has slightly reduced to 0.99. This suggests that ethnic
group may have some confounding effect on the relationship between CVD, ACE, and COVID-19
death. The reference category used in this model is “Non-White”, therefore, this model suggests
that hospital admissions who are of White ethnicity, are 34% less likely (OR 0.66) to die from COVID-
19, when compared to hospital admissions with a Non-White ethnicity, when adjusting for CVD, ACE,

45
and age. The p-value for ethnic group is <0.015, and the 95% CI does not cross the value of 1 (95% CI
0.48-0.92), the point of no effect; this indicates ethnic group is a significant variable and remains in
the model.

Fourth Model
This model includes the addition of the IMD Decile variable. As IMD Decile is a variable with >2
categories, a statistical test was also completed to ascertain the significance of the IMD Decile
variable, as a whole.

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD (Yes) 1.45 0.000 1.19-1.77
ACE (No) 1.00 - -
ACE (Yes) 0.99 0.976 0.70-1.42
Age (years) 1.04 0.000 1.04-1.05
Ethnic Group (Non-White) 1.00 - -
Ethnic Group (White) 0.66 0.015 0.48-0.92
IMD Decile (1) 1.00 - -
IMD Decile (2) 0.74 0.135 0.50-1.10
IMD Decile (3) 0.48 0.001 0.31-0.75
IMD Decile (4) 0.56 0.008 0.37-0.86
IMD Decile (5) 0.86 0.487 0.55-1.33
IMD Decile (6) 0.77 0.266 0.49-1.21
IMD Decile (7) 0.77 0.270 0.49-1.22
IMD Decile (8) 0.69 0.056 0.48-1.00
IMD Decile (9) 0.67 0.049 0.45-1.00
IMD Decile (10) 0.63 0.045 0.41-0.99
Table 17: Logistic regression model including CVD, ACE, Age, Ethnic Group and IMD Decile.

In this model, IMD Decile (1), the most deprived category, is used as the comparator. Some
categories of IMD Decile are significantly different from the comparator, IMD Decile (1), however,
the p-value of the IMD Decile variable overall is 0.08, which is >0.05, making this variable non-
significant at the 5% level. In this adjusted model, IMD Decile is not associated with the outcome of
COVID-19 death.

Further to this, the addition of IMD Decile to the model left all other ORs unchanged, suggesting that
IMD Decile is not a confounding variable in the relationship between CVD, ACE, and COVID-19 death.
Due to the non-significance of the IMD Decile variable at the 5% level, it was removed from the
model.

46
Fifth Model
The fifth model includes the addition of the Sex variable.

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD 1.38 0.002 1.13-1.69
ACE (No) 1.00 - -
ACE 1.02 0.918 0.71-1.45
Age (years) 1.05 0.000 1.04-1.05
Ethnic Group (Non-White) 1.00 - -
Ethnic Group (White) 0.67 0.021 0.48-0.94
Sex (Female) 1.00 - -
Sex (Male) 1.49 0.000 1.23-1.80
Table 18: Logistic regression model including CVD, ACE, Age, Ethnic Group, and Sex.

CVD, age, and ethnic group all remained significant at the 5% level after the addition of the sex
variable. The addition of the sex variable to the regression model only slightly changed the ORs for
ACE, age, and ethnic group, however, the OR for CVD was reduced by 0.07, this indicates that sex
may be a confounding variable in the relationship between CVD and the risk of COVID-19 death. The
reference category used for sex was “Female”, therefore, this model indicates that hospital
admissions who are male are 49% more likely (OR 1.49) to die from COVID-19, when adjusting for
CVD, ACE, age, and ethnic group. The p-value for the sex variable is <0.05 and the 95% CI (95% CI
1.23-1.80) does not cross 1, the point of no effect, therefore, sex is a significant variable and will
remain in the model.

Sixth Model
The sixth model included the addition of the Length of Stay (LoS) variable.

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD (Yes) 1.37 0.002 1.12-1.67
ACE (No) 1.00 - -
ACE (Yes) 1.01 0.940 0.71-1.45
Age (years) 1.05 0.000 1.04-1.06
Ethnic Group (Non-White) 1.00 - -
Ethnic Group (White) 0.70 0.040 0.50-0.98
Sex (Female) 1.00 - -
Sex (Male) 1.50 0.000 1.24-1.82
LoS (days) 0.99 0.002 0.983-0.996
Table 19: Logistic regression model including CVD, ACE, Age, Ethnic Group, Sex and LoS.

47
The addition of the LoS variable only slightly changes the ORs of all other variables; this indicates
that LoS has a slight impact on the relationship between CVD, ACE, and COVID-19, however, there is
little evidence to determine that it is a true confounding variable.

CVD, age, ethnic group, and sex all remain significant at the 5% level, ACE remains non-significant.
The OR for age is 0.99, indicating that for every 1-day increase in stay, the odds of a hospital
admission dying from COVID-19 decrease by 1% (OR 0.99). The p-value for LoS is <0.05 and the 95%
CI (95% CI 0.983-0.996) does not cross through 1, the point of no effect, therefore LoS is a significant
variable and will remain in the model.

Final Model

Variable OR p-value 95% CI

CVD (No) 1.00 - -
CVD (Yes) 1.47 0.000 1.19-1.81
ACE (No) 1.00 - -
ACE (Yes) 1.60 0.074 0.95-2.68
Age (years) 1.05 0.000 1.04-1.06
Ethnic Group (Non-White) 1.00 - -
Ethnic Group (White) 0.70 0.035 0.50-0.98
Sex (Female) 1.00 - -
Sex (Male) 1.50 0.000 1.24-1.83
LoS (days) 0.99 0.002 0.983-0.996
Table 20: Final logistic regression model including CVD, ACE, Age, Ethnic Group, Sex, and
LoS.

4.5.2 Explanation of final model

The final model of the logistic regression includes CVD, ACE, age, ethnic group, sex, and LoS.

This model demonstrates that hospital admissions with CVD are 47% more likely (OR 1.47) to die
from COVID-19, when compared to hospital admissions with no CVD, when other variables are
adjusted for. The 95% CI for this OR is 1.19-1.81, indicating that there is a 95% certainty that the true
OR lies between 1.19 (19% more likely), and 1.81 (81% more likely).

This model initially appears to demonstrate that hospital admissions with previous ACE are 60% (OR
1.60) more likely to die from COVID-19, when compared to hospital admissions who have no history
of ACE, when other variables are adjusted for. The 95% CI for this OR is 0.95-2.68, indicating that
there is a 95% certainty that the true OR lies between 0.95 (5% less likely) and 2.68 (2.68 times more

48
likely), however, this 95% CI crosses the point of no effect, the value of 1, therefore, this variable is
non-significant, however, remains in the final model as ACE is a key variable of interest.

The model also demonstrates that for every 1-year increase in age, hospital admissions are 5% (OR
1.05) more likely to die from COVID-19, when other variables are adjusted for. The 95% CI for this
OR is 1.04-1.06, thus indicating that there is a 95% certainty that the true OR lies between 1.04 (4%
more likely) and 1.06 (6% more likely).

The model shows that hospital patients of White ethnicity are 30% less likely (OR 0.70) to die from
COVID-19, when compared to hospital patients of non-White ethnicity, when other variables are
adjusted for. The 95% CI for this OR is 0.50-0.98, indicating that there is a 95% certainty that the true
OR lies between 0.5 (50% less likely), and 0.98 (2% less likely).

The final model also demonstrates that hospital admissions of male sex are 50% more likely (OR
1.50) to die from COVID-19, when compared to hospital admissions of female sex, when other
variables are adjusted for. The 95% CI for this OR is 1.24-1.83, indicating that there is a 95% certainty
that the true OR lies between 1.24 (24% more likely), and 1.83 (83% more likely).

Finally, the model also shows that for every 1-day increase in length of stay, hospital admissions are
1% less likely (OR 0.99) to die from COVID-19. The 95% CI for this OR is 0.983-0.996, indicating that
there is a 95% certainty that true OR lies between 0.983 (1.7% less likely), and 0.996 (0.4% less
likely).

4.5.3 Additional analysis

To further investigate if hospital admissions with both any CVD and any ACE, are more at risk of
COVID-19 fatality, when compared to admissions with just CVD or ACE, or neither, a separate logistic
regression model was created. This model included the previously identified confounding variables,
from Table 20.

Variable OR p-value 95% CI

Age (years) 1.05 0.000 1.04-1.06
Ethnic Group (Non-White) 1.00 - -
Ethnic Group 0.70 0.035 0.50-0.98
Sex (Female) 1.00 - -
Sex (Male) 1.50 0.000 1.24-1.83
LoS (days) 0.99 0.002 0.983-0.996
CVD & ACE (0) 1.00 - -

49
 CVD & ACE (1) 1.47 0.000 1.19-1.81
CVD & ACE (2) 1.60 0.074 0.95-2.68
CVD & ACE (3) 1.03 0.901 0.64-1.67
Table 21: Additional logistic regression model including Age, Ethnic Group, Sex, LoS, and
CVD & ACE.

Category CVD & ACE No. of admissions in sample

CVD & ACE (0) No CVD, No ACE 1,457
CVD & ACE (1) Yes CVD, No ACE 911
CVD & ACE (2) No CVD, Yes ACE 189
CVD & ACE (3) Yes CVD, Yes ACE 98
Table 22: Key for CVD & ACE variables shown in Table 21.

The reference category for CVD & ACE in the above model was hospital patients who have not been
diagnosed with CVD, and not experienced a previous ACE (CVD & ACE (0)).

The above model demonstrates that hospital admissions with diagnosed CVD, but no previous ACE
(CVD & ACE (1)), are 47% (OR 1.47) more likely to die from COVID-19, when compared to hospital
admissions with no CVD and no ACE, when other factors are adjusted for. The 95% CI for this OR is
1.19-1.81; this does not cross the value of one, the point of no effect, therefore it is a significant
variable in the model. The OR and 95% CI for this variable match that of the CVD variable, in the final
logistic regression model (Table 20). The CVD & ACE (1) variable has a p-value less than 0.05,
therefore making it a statistically significant variable, at the 5% level.

The above model also initially demonstrates that hospital admissions with previous ACE, but no CVD
(CVD & ACE (2)), are 60% (OR 1.60) more likely to die from COVID-19, when compared to hospital
admissions with no CVD and no ACE, when other variables are adjusted for. However, the 95% CI for
this OR is 0.95-2.68; this 95% CI does cross the value of 1, the point of no effect, and therefore this is
not a statistically significant variable in the model. Furthermore, the p-value of CVD & ACE (2) is
greater than 0.05, making it a non-significant variable, at the 5% level. The OR and 95% CI of the CVD
& ACE (2) variable match that of the ACE variable in the final model, which is also non-significant at
the 5% level. The 95% CI for this variable is relatively wide, this suggests the estimate of the OR has
low precision, and may be due to the small number of admissions in this category (n=189) (85).

The CVD & ACE (3) variable is hospital admissions who have been diagnosed with CVD and
experienced a previous ACE; this is the variable of interest in this additional analysis. In the above
model, it initially appears that hospital admissions diagnosed with CVD, and previous ACE, are 3%

50
more likely (OR 1.03) to die from COVID-19 when compared to hospital admissions with no CVD or
previous ACE, when other variables are adjusted for. However, the 95% CI for this OR (95% CI 0.64-
1.67) crosses the value of 1, the point of no effect, making this a non-significant variable.
Furthermore, the p-value for CVD & ACE (3) is greater than 0.05, therefore, this variable is non-
significant, at the 5% level.

This additional analysis demonstrates that admissions who have been diagnosed with CVD and
experienced a previous ACE would appear to be more at risk of COVID-19 fatality, when compared to
hospital admissions with neither diagnosis, however, this is non-significant. The data included only
98 records of patients who had been diagnosed with CVD and experienced a previous ACE,
therefore, this lack of significance may be due to a low sample size. The above model also
demonstrates that hospital admissions with CVD (OR 1.47) are significantly more at risk of COVID-19
fatality when compared to hospital admissions with no CVD and no ACE. Furthermore, the OR for
hospital patients with previous ACE (OR 1.60) is non-significant, as it was in the final logistic
regression model (Table 20).

The OR for CVD & ACE (3), admissions with both any CVD and any ACE, would be higher than the
other categories for CVD & ACE, if the combination of both any CVD and any ACE created an additive
effect, however, this has not been identified in this analysis. When comparing the ORs for each CVD
& ACE group it initially appears that CVD & ACE (2) (no CVD, yes ACE), have the most increased risk
of COVID-19 death, however, this variable was found to be non-significant. Admissions with no CVD
and no ACE (CVD & ACE (0)) have the lowest risk of COVID-19 fatality, followed by CVD & ACE (1)
(yes CVD, no ACE).

51
 4.5.4 Adjusted odds ratios

The odds of dying from COVID-19 in individuals with CVD and ACE, adjusted for other demographic
factors.
Variable N Unadjusted OR* Unadjusted 95% CI** Adjusted OR* Adjusted 95% CI**
CVD
CVD (No) 1,887 1.00 Reference Category
CVD (Yes) 768 2.00 1.66-2.41 1.47 1.19-1.81
ACE
ACE (No) 2,481 1.00 Reference Category
ACE (Yes) 174 1.32 0.94-1.86 1.60 0.95-2.68
Sex
Female 1,173 1.00 Reference Category
Male 1,482 1.29 1.08-1.56 1.50 1.24-1.83
Ethnic Group
Non-White 269 1.00 Reference Category
White 2,386 1.07 0.79-1.46 0.70 0.50-0.98
IMD Decile^
1 279 1.00 Reference Category
2 334 0.82 0.56-1.19
3 272 0.59 0.39-0.90
4 281 0.77 0.51-1.14
5 200 1.08 0.71-1.64
6 184 1.03 0.67-1.59
7 183 1.01 0.65-1.56
8 405 1.00 0.71-1.43
9 309 0.94 0.64-1.36
10 208 0.92 0.60-1.40
Age
Increase per 1 unit (years) 1.05 1.04-1.05 1.05 1.04-1.06
Length of Stay (LoS)
Increase per 1 unit (days) 0.996 0.990-1.00 0.990 0.983-0.996

Table 23: Adjusted ORs and 95% CIs taken from final logistic regression model.

* OR = Odds Ratio ** 95% CI = 95% Confidence Interval

^IMD Decile not included within the final model. Bold text indicates where the 95% CI does not cross
the value of 1 (point of no effect) and therefore significant at the 5% level.

The unadjusted ORs in Table 23 were determined using univariate logistic regression modelling.

52
 Chapter 5: Discussion

5.1 Introduction
The previous chapter detailed the results from a secondary analysis of COVID-19 patient data,
provided by The Royal Preston Hospital. This chapter will discuss and interpret the results in context,
referring to currently available evidence, and will also discuss the impact the study findings may
have on future treatment, policy, and research. Chapter 5 will also highlight the strengths, and
limitations, of this study.

5.2 Summary of results

This study examined the relationship between CVD, previous ACE, and COVID-19 fatality. The results
formed in Chapter 4 demonstrated that a lower proportion of deaths were from admissions with any
CVD, when compared to admissions with no CVD. Further to this, a lower proportion of deaths were
from admissions with any ACE, when compared to admissions with no ACE. The logistic regression
model formed in Chapter 4 also demonstrated that age, sex, ethnic group, and length of hospital
admission were all confounding factors in the relationship between CVD, ACE, and COVID-19 fatality.
A further logistic regression model demonstrated that an admission having both any CVD and ACE,
does not created an additive effect or further increase the risk of COVID-19 fatality.

5.3 COVID-19 fatality in admissions with underlying health conditions

5.3.1 COVID-19 fatality in admissions with CVD
The prevalence calculations in Chapter 4 demonstrated that a higher proportion of admissions with
any CVD survived COVID-19, when compared to the proportion of hospital admissions with any CVD,
who experienced fatal COVID-19. Approximately 1 in 3 admissions with any CVD died from COVID-
19, and 2 in 3 admissions with any CVD, survived COVID-19.

5.3.2 COVID-19 fatality in admissions with ACE

The prevalence calculations in Chapter 4 demonstrated that a higher proportion of admissions with
any ACE survived COVID-19, when compared to the proportion of hospital admissions with any ACE,
who experienced fatal COVID-19. Approximately 3 in 10 admissions with any ACE died from COVID-
19, and 7 in 10 admissions with any ACE, survived COVID-19.

53
5.4 Results from logistic regression analysis
5.4.1 Overall summary
The results of the logistic regression analysis, completed in Chapter 4, demonstrate that hospital
admissions who have been diagnosed with CVD, are of non-White ethnicity, or are of male sex, are
at an increased risk of COVID-19 fatality. Furthermore, the regression analysis also demonstrated
that as an individual’s age increases, as does their risk of COVID-19 fatality, furthermore, it was
shown that as the length of a hospital admission stay increases, the odds of COVID-19 fatality
decrease. The regression analysis showed that previous ACE are not a statistically significant
predictor of COVID-19 fatality.

5.4.2 Impact of Confounding Variables

Age
Age was a confounding variable, in the relationship between CVD and ACE, and COVID-19 fatality.
This result supports findings from previous research, which has suggested age to be a risk factor for
severe COVID-19 disease, and COVID-19 related fatality (81,82). In England and Wales, the mortality
rate for COVID-19 is almost eight-times greater at ages 80-84 years, than it is in the age 60-64 years
group (103), which again supports the evidence that age is a risk factor, for COVID-19 fatality.

Evidence suggests that age may be a risk factor for COVID-19 severity and death due to the
increased prevalence of comorbidities, such as CVD, in older adults (104); the results from this study
support this statement as hospital admissions with CVD were older, than admissions without CVD.
Further to this, the ability of an individual to control viral load is a key indicator in predicting
whether someone will experience mild or severe disease, or if disease will result in fatality; as an
individual ages, as does their immune system, which in turn leads to a reduced ability to fight off
infection, such as COVID-19 (105,106); this evidence may provide reasoning behind why age is a risk
factor for severe COVID-19, and COVID-19 fatality.

Ethnic Group
The data for the ethnicity of patients provided in the dataset from The Royal Preston hospital was
initially categorised into fourteen groups, however, due to time constraints, and ethnicity not being
the focus of this study, the author grouped all patient data into “White” or “non-White” ethnicity,
for the purpose of analysis.

54
Ethnic group was a confounding variable in the relationship between CVD and ACE, and COVID-19
fatality. This result supports research which suggests certain ethnic groups, such as individuals who
are of Black and Asian ethnicity (non-White ethnicity within the analysis of this study), are more at
risk of COVID-19 fatality (88). Further to this, evidence also demonstrates that individuals of South
Asian, African, and African Caribbean ethnicity, are more likely to develop CVD, hypertension and
type-2 diabetes, which are also known to be risk factors for COVID-19 disease severity, and mortality
(64–68).

Sex
The sex of hospital admissions was also a confounding variable in the relationship between CVD and
ACE, and COVID-19 death. This result from the data analysis supports previous research which
suggests male sex is a risk factor for COVID-19 (73).

Although male sex is itself a risk factor for COVID-19 (73), evidence also demonstrates that the risk-
taking behaviour in which men are more likely to participate in, may also contribute to the increased
risk of COVID-19 fatality. Evidence demonstrates that in the UK, a higher prevalence of adult men
smoke, when compared to adult women (107); research has demonstrated that smoking tobacco
may also be a risk factor, for COIVD-19 disease severity and death (108), however, this is early
research and should be interpreted with caution. Further to this, evidence has shown that
individuals who are overweight or obese, are also more likely to experience severe COVID-19
disease, and COVID-19 related fatality (109); in England, 67% of men are considered to be
overweight or obese, however, this is lower for women, at 62% (110).

Risk taking behaviour such as tobacco smoking, and an individual being overweight or obese, may
also contribute to the development of CVD (37), which as previously mentioned, is known to be a
risk factor for severe COVID-19 disease, and fatality (64–68). The evidence suggests that although
male sex itself is a risk factor, male sex may also be a proxy for other risk factors for COVID-19
mortality, such as an individual being overweight or obese, and tobacco smoking. Further to this,
male sex may be a proxy for risk factors for the development of CVD, a known risk factor for COVID-
19, due to the increased likelihood of males participating in risk taking behaviours, as detailed
above.

55
Length of Stay
The length of hospital admission was a confounding variable in the relationship between CVD and
ACE, and COVID-19 fatality. Although the evidence available which examines the length of a hospital
admission and COVID-19 outcome is limited, a study completed by Rees et al. in 2020 did observe
that COVID-19 admissions who were discharged from hospital alive, did on average have a longer
length of stay, than those who had died during their hospital admission (111), however, potential
reasons as to why admissions who survive on average have a longer stay, were not explored by the
authors.

In addition to the above, a retrospective cohort study completed by Guo et al. in early 2021
highlighted some variables which may be considered risk factors for an extended hospital admission
when diagnosed with COVID-19, these factors included female sex and chronic kidney disease (112),
although this information may assist HCPs with predicting the LoS of admissions, Guo et al. the study
did not examine the difference in LoS between admissions who survived COVID-19, and those who
did not. Further to this, the analysis completed by Guo et al. was univariate, therefore, no other
potential confounding factors were adjusted for, which may be considered a limitation of this
evidence.

The association between the length of hospital admission and COVID-19 fatality is an area that
hospital management teams may wish to further investigate.

5.5 Strengths of this study

To the best of the author’s knowledge, this study is the first of its kind, examining what impact
previous ACE may have on COVID-19 disease prognosis, of hospital admissions. Although the
regression analysis determined that previous ACE are not a statistically significant predictor of
COVID-19 fatality, this study may encourage others to complete further research on a larger scale, to
more accurately assess the true impact that ACE have on COVID-19 prognosis. Although other
published studies, like those detailed in Chapter 2, have examined the impact that CVD has on
COVID-19 prognosis, this study further extended the analysis to also include the impact of ACE.

Although the use of pre-collected data may be considered a limitation of this study, as often data is
not collected to meet the needs of the research (113), the data used within this study was collected
by appropriately trained healthcare professionals and then collated and stored by experienced data
scientists, which may be considered a strength of this study. Further to this, this study included all

56
COVID-19 admissions to The Royal Preston Hospital over a 12-month period; the vast volume of this
data may also be considered a strength of this study, as a large sample size can increase the
precision, of results (85).

The data sample used for the analysis within this study included a wide range of ages, ethnicities,
and relatively equal proportions of male and female admissions, because of this, it is reasonable to
suggest that it may be possible to generalise the results to a wider population, such as the adult
residents of Preston (114).

The regression analysis completed in Chapter 4 included variables other than CVD and ACE, used a
multivariate model, which allowed the author to identify and adjust for any confounders, in the
relationship between CVD, ACE, and COVID-19 prognosis. Recognising and adjusting for confounding
variables within an analysis, produces more accurate results (115), therefore, the robust analysis
process demonstrated in Chapter 4 may be considered a strength of this study.

5.6 Limitations of this study

As previously mentioned in section 5.5, the data used for this secondary analysis was routinely
collected hospital admission data; as the data used was not collected for the specific requirements
of this study, it is to be expected that some data required for this research, would be missing (113).
Missing data within quantitative analysis can lead to biased and inaccurate result estimates, and
weaken the generalisability of study findings (116); in this study, 149 records were excluded prior to
analysis, due to missing data, and this may be considered a limitation.

Further to the above, non-response bias may have been introduced into this study, if the admission
data which was excluded, differed significantly from the admission data, which remained for analysis
(117). An example of this is if all missing data included admissions who had any previous ACE; the
analysis completed in Chapter 4 found no association between previous ACE and the risk of COVID-
19 fatality, however, if the sample size for this subgroup had been larger, a statistically significant
result may have been identified (118). To avoid this bias in future studies, a more advanced
technique to deal with missing data, such as multiple imputation, may be used to further improve
the accuracy and precision of results (119).

Multiple imputation is a complex, however useful strategy, used by analysts to replace missing data
with a set of possible values, whilst maintaining the expected variability and unpredictability, of the

57
correct values (120). Using multiple imputation in this study would have prevented the exclusion of
any data records, however, due to inexperience and time constraints, the author of this study was
unable to utilise this method, which again may be considered a limitation of the analysis process,
within this study.

The use of tobacco, and an individual being overweight or obese, have previously been identified as
risk factors for poor COVID-19 prognosis (108,109), furthermore, these factors may also increase an
individual’s risk of developing a chronic condition, such as CVD (37), which further puts them at risk
of COVID-19 fatality (64,65). It is possible that smoking status and the weight of an individual may be
potentially confounding factors in the relationship between ACE, CVD, and COVID-19 prognosis,
therefore, the lack of these variables within the analysis, may be considered a limitation of this
study. Authors of future research may wish to collect primary data to complete a similar analysis to
this study, however, with the inclusion of more identified risk factors for COVID-19 mortality, which
may act as confounding variables.

The dataset provided for this study included only 189 hospital admissions, with data present for any
previous ACE. Furthermore, there was no admission data including acute myocarditis, which was a
variable of interest. Although some acute cardiovascular events were significant variables when
analysed individually, the variable for any ACE consistently remained non-significant at the 5% level,
with a 95% CI that crossed the value of 1, the point of no effect. However, it is possible that due to
the low sample size of admission data with previous ACE, a type II error (null hypothesis incorrectly
accepted, leading to a false-negative result) has occurred and produced an unprecise estimate of the
OR, and 95% CI (118). This may be considered a limitation of the study and is suggestive that further
work on a larger scale is needed, to accurately estimate if previous ACE do increase an admissions
risk of COVID-19 fatality. Authors of further work may wish to include more admission records across
more than one hospital site, which may capture more admissions with ACE data, and provide a more
precise estimate of the true OR.

As the data used in this study’s analysis was not collected for the purpose of this study, information
or misclassification bias may have been present if the variable measurements, from the original data
source at The RPH, were inaccurate, therefore causing admissions to be classified into the incorrect
exposure groups (121). In this study, hospital admissions were considered exposed if they had
experienced a previous ACE or had been formally diagnosed with CVD. The data provided for this
study was limited to a single hospital, therefore, if admissions had experienced a previous ACE or

58
been diagnosed with CVD at a hospital elsewhere, this information was not included within the
dataset used for this study and may have led to the incorrect classification of an admission’s true
exposure status, thus introducing bias. To reduce the potential for this bias in further studies, the
analysis could be completed with primary data involving multiple hospital sites, to limit the
possibility of misclassification.

The COVID-19 vaccination programme began in the UK on 8th December 2020, and priority for
vaccination was given to older adults, and those with underlying health conditions (122,123). The
dataset provided for this study covered the period 1st February 2020, to 31st January 2021; by the
end of January 2021, over 9 million people across the UK had received their first COVID-19
vaccination (21). The COVID-19 vaccines used in the UK have proven to be effective at reducing
disease severity, and the risk of death (124), therefore, it is reasonable to suggest that the
vaccination status of admissions may have been a confounder in the relationship between CVD, ACE
and COVID-19 fatality, however, this variable was not provided and thus may be considered a
limitation of this study.

Effect modifiers were not examined in this study, which may also be considered a limitation. An
example of this being asthma; asthma is associated with the outcome of COVID-19 fatality (125);
however, it is not associated with the exposures, CVD or ACE. To strengthen future work, data for
any known or suspected effect modifiers could be collected and included within data analysis. In
addition, authors of future work may wish to stratify the age of admissions, to further investigate if
the relationship between age, a confounder in the relationship between CVD, ACE, and COVID-19
fatality, differs across each stratum.

Although the results from this study may be generalised to the wider population of Preston, it may
be problematic when attempting to generalise the results to another region of the UK. In South
West England, the prevalence of CVD and its risk factors (hypertension and diabetes) are much
lower than that of the Northwest of England (126,127), further to this, COVID-19 cases have also
been higher in the North, when compared to the South (21), therefore, the results from this study
may not be generalisable to other regions, of the UK.

5.7 Impact of results on clinical practice

This study further supports the growing array of evidence that suggests cardiovascular disease does
increase a hospital admission’s risk of fatality, from COVID-19, however, it must be noted that other

59
variables confound this relationship, as identified in chapter 4. The regression model identified that
individuals with CVD who are of male sex and non-White ethnicity, may be the most at risk of
COVID-19 fatality. Furthermore, the model also determined that as the age of an individual
increases, as does their risk of COVID-19 related death.

The results from this study can provide healthcare professionals and clinicians with an insight into
what admissions with COVID-19, may be the most at risk of deterioration, and fatality. The results
from this study may also assist those in healthcare managerial positions with knowledge on how
best to distribute resources, staff, and funding, to improve and optimise care for hospital patients.
Applying the findings from this study into clinical practice may result in faster, and more effective
treatment, for patients with COVID-19 who are most at risk, thus leading to more favourable
outcomes such as reduced mortality, shorter hospital stays, and a reduced financial pressure on the
healthcare service, in the UK.

5.8 Future research

Several studies have examined the impact that underlying cardiovascular disease has on a hospital
admission’s risk of COVID-19 fatality (64–68), however, to the best of the author’s knowledge, this is
the first study to examine what impact previous acute cardiovascular events have on COVID-19
prognosis.

Although this study found no statistically significant relationship between previous ACE and COVID-
19 fatality, the sample size of this subgroup was relatively small, at only 189 people. Further to this,
there was no data present for acute myocarditis, therefore, this could not be included within the
analysis. Future research on a larger scale may identify a statistically significant link between ACE
and COVID-19, that this study has failed to identify, potentially due to type II error (118). This
research may include a larger number of admission records, across more hospital sites.

This study, and those previously identified within Chapter 2, focus on COVID-19 hospital admissions
(64–68), this may limit the generalisability of findings and restrict how the results from such studies
can be applied to other healthcare settings, such as those within the community. If a study of a
similar nature was completed which included COVID-19 patients within nursing homes, and within
the community, the findings may become beneficial to a wider group of people.

60
This study identified four variables which confounded the relationship between CVD, ACE, and
COVID-19 fatality, however, other factors which were not included within the analysis, such as body
mass index and tobacco smoking, have also been identified as potential risk factors for COVID-19
fatality (108,109); further research could include a wider range of variables to further investigate
which confound the relationship between CVD, ACE, and COVID-19 fatality.

This study categorised the ethnicity of admissions into two groups, from an initial fourteen groups.
Future research which focuses more on ethnicity as a confounder to the relationship between CVD,
ACE, and COVID-19, may detect greater differences in risk between patients of differing ethnicities,
than this study could identify, with just two groups.

5.9 Conclusion
The COVID-19 pandemic has caused worldwide disruption, illness, and fatality, since early 2020; up
to 20th August 2021, the UK alone has seen over 131,000 deaths (21). The findings from this study
demonstrated that hospital patients with underlying CVD, are at an increased risk of COVID-19
fatality. Furthermore, the regression analysis completed in chapter 4 also showed that male sex, and
non-White ethnicity, confound the relationship between CVD, ACE, and COVID-19 fatality.

Understanding who is most at risk of poor COVID-19 outcomes is vital to improving patient care and
reducing fatality. The findings from this study further emphasise the increased risk of COVID-19
death, faced by patients with underlying CVD, a group of diseases which affect over 7 million people
per year, in the UK (50).

61
References
1. Mohapatra RK, Pintilie L, Kandi V, Sarangi AK, Das D, Sahu R, et al. The recent challenges of highly
contagious COVID-19, causing respiratory infections: Symptoms, diagnosis, transmission, possible
vaccines, animal models, and immunotherapy. Chem Biol Drug Des. [Internet]. 2020 [cited 2021
Jun 15]; 96(5):1187–208. Available from: /pmc/articles/PMC7405220/
2. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes
it [Internet]. [updated 2020 Feb; cited 2021 Mar 22]. Available from:
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-
the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it
3. World Health Organization. Coronavirus [Internet]. [no date; cited 2021 Mar 22]. Available from:
https://www.who.int/health-topics/coronavirus#tab=tab_1
4. World Health Organization. Coronavirus disease (COVID-19): How is it transmitted? [Internet].
[updated 2020 Dec 13; cited 2021 May 19]. Available from: https://www.who.int/news-room/q-a-
detail/coronavirus-disease-covid-19-how-is-it-transmitted
5. World Health Organization. Listings of WHO’s response to COVID-19 [Internet]. [updated 2020 Jun
29; cited 2021 May 19]. Available from: https://www.who.int/news/item/29-06-2020-
covidtimeline
6. Altschul DJ, Unda SR, Benton J, de la Garza Ramos R, Cezayirli P, Mehler M, et al. A novel severity
score to predict inpatient mortality in COVID-19 patients. Sci Rep [Internet]. 2020 [cited 2021 Jun
15]; 10(1):16726. Available from: https://doi.org/10.1038/s41598-020-73962-9
7. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med [Internet]. 2020 [cited 2021 Jun
15]; 383(25):2451–60. Available from: https://www.nejm.org/doi/full/10.1056/NEJMcp2009575
8. Thachil J, Juffermans NP, Ranucci M, Connors JM, Warkentin TE, Ortel TL, et al. ISTH DIC
subcommittee communication on anticoagulation in COVID-19. J Thromb Haemost [Internet].
2020 [cited 2021 Jun 15]; 18(9):2138–44. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404846/
9. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019
novel coronavirus in Wuhan, China. Lancet [Internet]. 2020 [cited 2021 Jun 15];395(10223):497–
506. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-
6736(20)30183-5/fulltext
10. National Health Service. Long-term effects of coronavirus (Long COVID) [Internet]. [updated 2021
Jul 4; cited 2021 Aug 2]. Available from: https://www.nhs.uk/conditions/coronavirus-covid-
19/long-term-effects-of-coronavirus-long-covid/
11. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients
discharged from hospital: a cohort study. Lancet [Internet]. 2021 [cited 2021 Aug 2];
397(10270):220–32. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-

62
 6736(20)32656-8/fulltext
12. Liao X, Wang B, Kang Y. Novel coronavirus infection during the 2019–2020 epidemic: preparing
intensive care units—the experience in Sichuan Province, China. Intensive Care Med [Internet].
2020 [cited 2021 Jun 15]; 46(2):357–60. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042184/
13. World Health Organization. WHO Coronavirus (COVID-19) Dashboard [Internet]. [updated 2021
May 18; cited 2021 May 19]. Available from: https://covid19.who.int/
14. Institute for Health Metrics and Evaluation. Estimation of total mortality due to COVID-19
[Internet]. [updated 2021 May 13; cited 2021 May 19]. Available from:
http://www.healthdata.org/special-analysis/estimation-excess-mortality-due-covid-19-and-
scalars-reported-covid-19-deaths
15. Mehta S, Machado F, Kwizera A, Papazian L, Moss M, Azoulay É, et al. COVID-19: a heavy toll on
health-care workers. Lancet Respir Med [Internet]. 2021 [cited 2021 Jun 16]; 9(3):226–8. Available
from: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00068-0/fulltext
16. Aday S, Aday MS. Impact of COVID-19 on the food supply chain. Food Qual Saf [Internet]. 2020
[cited 2021 Aug 9]; 4(4):167–80. Available from:
https://academic.oup.com/fqs/article/4/4/167/5896496
17. The World Bank. Food Security and COVID-19 [Internet]. [updated 2021 May 11; cited 2021 Jun
16]. Available from: https://www.worldbank.org/en/topic/agriculture/brief/food-security-and-
covid-19
18. Laborde D, Martin W, Vos R. Impacts of COVID-19 on global poverty, food security, and diets:
Insights from global model scenario analysis. Agric Econ (United Kingdom) [Internet]. 2021 [cited
2021 Jun 16]; 52(3):375–90. Available from:
https://onlinelibrary.wiley.com/doi/full/10.1111/agec.12624
19. Clark A, Jit M, Warren-Gash C, Guthrie B, Wang HHX, Mercer SW, et al. Global, regional, and
national estimates of the population at increased risk of severe COVID-19 due to underlying
health conditions in 2020: a modelling study. Lancet Glob Heal [Internet]. 2020 [cited 2021 Jun
16]; 8(8):e1003–17. Available from: https://www.thelancet.com/journals/langlo/article/PIIS2214-
109X(20)30264-3/fulltext
20. Lillie PJ, Samson A, Li A, Adams K, Capstick R, Barlow GD, et al. Novel coronavirus disease (Covid-
19): The first two patients in the UK with person to person transmission. J Infect [Internet]. 2020
[cited 2021 May 19]; 80(5):578–606. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127394/
21. Public Health England. Coronavirus (COVID-19) in the UK [Internet]. [updated 2021 May 19; cited
2021 May 19]. Available from: https://coronavirus.data.gov.uk/details/cases
22. Department of Health and Social Care. Coronavirus (COVID-19): getting tested [Internet].

63
 [updated 2021 Feb 27; cited 2021 Mar 11]. Available from:
https://www.gov.uk/guidance/coronavirus-covid-19-getting-tested
23. ZOE, King’s College London. About the ZOE COVID Symptom Study [Internet]. [updated 2021;
cited 2021 Jun 16]. Available from: https://covid.joinzoe.com/about
24. ZOE, King’s College London. Day by day evolution of the infection across the UK [Internet].
[updated 2021; cited 2021 Jun 16]. Available from: https://covid.joinzoe.com/data
25. Prime Minister’s Office, The Rt Hon Boris Johnson MP. Prime Minister’s statement on coronavirus
(COVID-19): 23 March 2020 [Internet]. [updated 2020 Mar 23; cited 2021 May 19]. Available from:
https://www.gov.uk/government/speeches/pm-address-to-the-nation-on-coronavirus-23-march-
2020
26. Hobbs A, Bunn S. COVID-19: July update on face masks and face coverings for the general public
[Internet]. [updated 2020 Jul 24; cited 2021 May 19]. Available from:
https://post.parliament.uk/covid-19-july-update-on-face-masks-and-face-coverings-for-the-
general-public/
27. Williams SN, Armitage CJ, Tampe T, Dienes K. Public perceptions and experiences of social
distancing and social isolation during the COVID-19 pandemic: A UK-based focus group study. BMJ
Open [Internet]. 2020 [cited 2021 Jun 16]; 10(7):39334. Available from:
https://bmjopen.bmj.com/content/10/7/e039334
28. Jeffrey B, Walters CE, Ainslie KEC, Eales O, Ciavarella C, Bhatia S, et al. Anonymised and
aggregated crowd level mobility data from mobile phones suggests that initial compliance with
covid-19 social distancing interventions was high and geographically consistent across the UK.
Wellcome Open Res [Internet]. 2020 [cited 2021 Jun 16]; 5:1–10. Available from:
https://wellcomeopenresearch.org/articles/5-170/v1
29. The Institute for Government. Timeline of UK government coronavirus lockdown [Internet].
[updated 2021 Jun; cited 2021 Jun 16]. Available from:
https://www.instituteforgovernment.org.uk/charts/uk-government-coronavirus-lockdowns
30. HM Government. Analysis of the health, economic and social effects of COVID-19 and the
approach to tiering [Internet]. [updated 2020 Nov 30; cited 2021 Jun 16]. Available from:
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/
file/944823/Analysis_of_the_health_economic_and_social_effects_of_COVID-
19_and_the_approach_to_tiering_FINAL_-_accessible_v2.pdf
31. Department for Health and Social Care. Coronavirus: action plan. A guide to what you can expect
across the UK [Internet]. [updated 2020 Mar 3; cited 2021 Jun 16]. Available from:
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/
file/869827/Coronavirus_action_plan_-_a_guide_to_what_you_can_expect_across_the_UK.pdf
32. Office for National Statistics. Personal and economic well-being in Great Britain: September 2020

64
 [Internet]. [updated 2020 Sep 10; cited 2021 Jun 16]. Available from:
https://www.ons.gov.uk/peoplepopulationandcommunity/wellbeing/bulletins/personalandecono
micwellbeingintheuk/september2020
33. Medicines and Healthcare products Regulatory Agency. UK medicines regulator gives approval for
first UK COVID-19 vaccine [Internet]. [updated 2020 Dec 2; cited 2021 Jun 16]. Available from:
https://www.gov.uk/government/news/uk-medicines-regulator-gives-approval-for-first-uk-covid-
19-vaccine
34. Dyer C. Covid-19: UK government response was overcentralised and poorly communicated, say
peers. BMJ [Internet]. 2020 [cited 2021 Jun 16]; 371:m4445. Available from:
https://www.bmj.com/content/371/bmj.m4445
35. Public Health England. COVID-19 vaccines have prevented 10,400 deaths in older adults
[Internet]. [updated 2021 Apr 8; cited 2021 Jun 16]. Available from:
https://www.gov.uk/government/news/covid-19-vaccines-have-prevented-10-400-deaths-in-
older-adults
36. National Health Service. Cardiovascular disease [Internet]. [updated 2018 Sep 17; cited 2021 May
5]. Available from: https://www.nhs.uk/conditions/cardiovascular-disease/
37. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and
reduction, including lipid modification [Internet]. [updated 2016 Sep 27; cited 2021 May 19].
Available from: https://www.nice.org.uk/guidance/cg181/
38. Singh AK, Gillies CL, Singh R, Singh A, Chudasama Y, Coles B, et al. Prevalence of co-morbidities
and their association with mortality in patients with COVID-19: A systematic review and meta-
analysis. Diabetes, Obes Metab [Internet]. 2020 [cited 2021 Mar 22]; 22(10):1915–24. Available
from: https://pubmed.ncbi.nlm.nih.gov/32573903/
39. Del Sole F, Farcomeni A, Loffredo L, Carnevale R, Menichelli D, Vicario T, et al. Features of severe
COVID-19: A systematic review and meta-analysis. Eur J Clin Invest [Internet]. 2020 [cited 2021
Mar 22]; 50(10):e13378. Available from: https://onlinelibrary.wiley.com/doi/10.1111/eci.13378
40. World Health Organization. Cardiovascular diseases (CVDs) [Internet]. [updated 2021 Apr; cited
2021 May 19]. Available from: https://www.who.int/news-room/fact-
sheets/detail/cardiovascular-diseases-(cvds)
41. National Health Service. Vascular Dementia [Internet]. [updated 2020 Mar 5; cited 2021 Aug 24].
Available from: https://www.nhs.uk/conditions/vascular-dementia/
42. American Heart Association. Acute Coronary Syndrome [Internet]. [updated 2015 Jul 31; cited
2021 May 21]. Available from: https://www.heart.org/en/health-topics/heart-attack/about-heart-
attacks/acute-coronary-syndrome
43. National Institute for Health and Care Excellence. Acute coronary syndromes in adults [Internet].
[updated 2020 Nov 18; cited 2021 May 21]. Available from:

65
 https://www.nice.org.uk/guidance/qs68/
44. Caforio ALP, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, et al. Current state of
knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position
statement of the European Society of Cardiology Working Group on Myocardial and Pericardial
Diseases. Eur Heart J [Internet]. 2013 [cited 2021 May 21]; 34(33):2636–48. Available from:
https://academic.oup.com/eurheartj/article/34/33/2636/408735
45. National Health Service. Angina [Internet]. [updated 2021 Apr 22; cited 2021 Aug 24]. Available
from: https://www.nhs.uk/conditions/angina/
46. National Health Service. Stroke [Internet]. [updated 2019 Aug 15; cited 2021 Aug 24]. Available
from: https://www.nhs.uk/conditions/stroke/
47. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic
mechanisms to clinical perspectives. Nat Rev Cardiol [Internet]. 2020 [cited 2021 Jun 16];
17(9):543–58. Available from: https://www.nature.com/articles/s41569-020-0413-9
48. Saleh M, Ambrose JA. Understanding myocardial infarction. F1000 Res [Internet]. 2018 [cited
2021 Jun 17]; 7:1378. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124376/
49. Tschöpe C, Ammirati E, Bozkurt B, Caforio ALP, Cooper LT, Felix SB, et al. Myocarditis and
inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol [Internet].
2021 [cited 2021 Jun 17]; 18(3):169–93. Available from:
https://www.nature.com/articles/s41569-020-00435-x
50. British Heart Foundation. BHF Statistics Factsheet - UK [Internet]. [updated 2021; cited 2021 May
21]. Available from: https://www.bhf.org.uk/what-we-do/our-research/heart-statistics
51. United States Census Bureau. International Data Base (IDB): United Kingdom [Internet]. [updated
2021; cited 2021 May 21]. Available from: https://www.census.gov/data-
tools/demo/idb/#/country?YR_ANIM=2020&FIPS_SINGLE=UK&dashPages=DASH&ageGroup=BR
52. British Heart Foundation. Heart Attack [Internet]. [updated 2019 Oct; cited 2021 May 21].
Available from: https://www.bhf.org.uk/informationsupport/conditions/heart-attack
53. Our World in Data. Our World in Data: COVID-19 Data Explorer [Internet]. [updated 2021 Jun 16;
cited 2021 Jun 17]. Available from: https://ourworldindata.org/explorers/coronavirus-data-
explorer?tab=table&zoomToSelection=true&pickerSort=desc&pickerMetric=total_cases&hideCon
trols=true&Interval=Cumulative&Relative+to+Population=true&Align+outbreaks=false&country=I
ND~USA~GBR~CAN~DEU~FRA&Metric=Confirmed+deaths
54. World Health Organization. Clinical trials. [Internet]. [no date; cited 2021 Jun 17]. Available from:
https://www.who.int/health-topics/clinical-trials#tab=tab_1
55. Heffernan KS, Michos ED, Gump BB. Coronavirus Disease 2019 (COVID-19) and Cardiac Injury.
JAMA Cardiol [Internet]. 2020 [cited 2021 Jun 4];5(10):1195–8. Available from:
https://jamanetwork.com/journals/jamacardiology/fullarticle/2768165

66
56. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With Mortality in
Hospitalized Patients With COVID-19 in Wuhan, China Supplemental content. JAMA Cardiol
[Internet]. 2020 [cited 2021 Jun 4];5(7):802–10. Available from:
https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524
57. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the
Cardiovascular System: A Review. JAMA Cardiol [Internet]. 2020 [cited 2021 Jun 4];5(7):831–40.
Available from: https://pubmed.ncbi.nlm.nih.gov/32219363/
58. Yin T, Li Y, Ying Y, Luo Z. Prevalence of comorbidity in Chinese patients with COVID-19: systematic
review and meta-analysis of risk factors. BMC Infect Dis [Internet]. 2021 [cited 2021 Jun
17];21(1):1–13. Available from:
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-05915-0
59. Kuno T, Takahashi M, Obata R, Maeda T. Cardiovascular comorbidities, cardiac injury, and
prognosis of COVID-19 in New York City. Am Heart J [Internet]. 2020 [cited 2021 Jun 17];226:24–5.
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227573/
60. Inciardi RM, Adamo M, Lupi L, Cani DS, Di Pasquale M, Tomasoni D, et al. Characteristics and
outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy. Eur Heart J
[Internet]. 2020 [cited 2021 Jun 17];41(19):1821–9. Available from:
https://pubmed.ncbi.nlm.nih.gov/32383763/
61. Cochrane Library. Cochrane Database of Systematic Reviews [Internet]. [no date; cited 2021 Jun
18]. Available from: https://www.cochranelibrary.com/cdsr/about-cdsr
62. National Library of Medicine. MEDLINE: Overview [Internet]. [no date; cited 2021 Jun 18].
Available from: https://www.nlm.nih.gov/medline/medline_overview.html
63. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine.
Plast Reconstr Surg [Internet]. 2011 [cited 2021 Jun 1];128(1):305–10. Available from:
https://journals.lww.com/plasreconsurg/Fulltext/2011/07000/The_Levels_of_Evidence_and_Thei
r_Role_in.46.aspx
64. Matsushita K, Ding N, Kou M, Hu X, Chen M, Gao Y, et al. The relationship of COVID-19 severity
with cardiovascular disease and its traditional risk factors: A systematic review and meta-analysis.
Glob Heart [Internet]. 2020 [cited 2021 Jun 1];1 5(1):64. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546112/
65. Aggarwal G, Cheruiyot I, Aggarwal S, Wong J, Lippi G, Lavie CJ, et al. Association of Cardiovascular
Disease With Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis. Curr Probl Cardiol
[Internet]. 2020 [cited 2021 Jun 1];45(8):100617. Available from: https://www-sciencedirect-
com.manchester.idm.oclc.org/science/article/pii/S0146280620300943
66. Li X, Guan B, Su T, Liu W, Chen M, Bin Waleed K, et al. Impact of cardiovascular disease and
cardiac injury on in-hospital mortality in patients with COVID-19: A systematic review and meta-

67
 analysis. Heart [Internet]. 2020 [cited 2021 Jun 2];106(15):1142–7. Available from: https://heart-
bmj-com.manchester.idm.oclc.org/content/106/15/1142
67. Ssentongo P, Ssentongo AE, Heilbrunn ES, Ba DM, Chinchilli VM. Association of cardiovascular
disease and 10 other pre-existing comorbidities with COVID-19 mortality: A systematic review and
meta-analysis. PLoS One [Internet]. 2020 [cited 2021 Jun 2];15(8):e0238215. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449476/
68. Bae SA, Kim SR, Kim MN, Shim WJ, Park SM. Impact of cardiovascular disease and risk factors on
fatal outcomes in patients with COVID-19 according to age: A systematic review and meta-
analysis. Heart [Internet]. 2021 [cited 2021 Jun 1];107(5):373–80. Available from: https://heart-
bmj-com.manchester.idm.oclc.org/content/107/5/373
69. Centers for Disease Control and Prevention. Certain Medical Conditions and Risk for Severe
COVID-19 Illness [Internet]. [updated 2021 Jun 18; cited 2021 Jul 14]. Available from:
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-
conditions.html
70. Tripepi G, Jager KJ, Dekker FW, Zoccali C. Stratification for Confounding – Part 1: The Mantel-
Haenszel Formula. Nephron Clin Pract [Internet]. 2010 [cited 2021 Jul 14];116(4):317–21.
Available from: https://www.karger.com/Article/FullText/319590
71. Lone NI, McPeake J, Stewart NI, Blayney MC, Seem RC, Donaldson L, et al. Influence of
socioeconomic deprivation on interventions and outcomes for patients admitted with COVID-19
to critical care units in Scotland: A national cohort study. Lancet Reg Heal – Eur [Internet]. 2021
[cited 2021 Jul 14];1:100014. Available from:
https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(20)30005-3/fulltext
72. Patel P, Hiam L, Sowemimo A, Devakumar D, McKee M. Ethnicity and covid-19. BMJ [Internet].
2020 [cited 2021 Jul 14];369:m2282. Available from:
https://www.bmj.com/content/369/bmj.m2282
73. Peckham H, Gruijter NM de, Raine C, Radziszewska A, Ciurtin C, Wedderburn LR, et al. Male sex
identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat
Commun [Internet]. 2020 Dec 9 [cited 2021 Jul 14];11(1):1–10. Available from:
https://www.nature.com/articles/s41467-020-19741-6
74. Harrison F. Getting started with meta-analysis. Methods Ecol Evol [Internet]. 2011 [cited 2021 Jul
14];2(1):1–10. Available from:
https://besjournals.onlinelibrary.wiley.com/doi/full/10.1111/j.2041-210X.2010.00056.x
75. Shi L, Lin L. The trim-and-fill method for publication bias: practical guidelines and
recommendations based on a large database of meta-analyses. Medicine (Baltimore) [Internet].
2019 [cited 2021 Jul 14];98(23):e15987. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571372/

68
76. Deeks J, Higgins J, Altman D. Analysing data and undertaking meta-analyses [Internet]. In: Higgins
J, Thomas J, editors. Cochrane Handbook for Systematic Reviews of Interventions. 2021. [cited
2021 Jul 14]. Available from: https://training.cochrane.org/handbook/current/chapter-
10#section-10-10
77. von Hippel PT. The heterogeneity statistic I2 can be biased in small meta-analyses. BMC Med Res
Methodol [Internet]. 2015 [cited 2021 Jul 14];15(1):1–8. Available from:
https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-015-0024-z
78. Skelly AC, Dettori JR, Brodt ED. Assessing bias: the importance of considering confounding. Evid
Based Spine Care J [Internet]. 2012 [cited 2021 Jul 14];3(1):12. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503514/
79. Burchett HED, Kneale D, Blanchard L, Thomas J. When assessing generalisability, focusing on
differences in population or setting alone is insufficient. Trials [Internet]. 2020 [cited 2021 Jul
14];21(1):1–4. Available from: https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-
020-4178-6
80. Borenstein M, Hedges L, Higgins J, Rothstein H. Introduction to Meta-Analysis. 2nd ed. Chichester:
Wiley; 2021.
81. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased
patients with coronavirus disease 2019: retrospective study. BMJ [Internet]. 2020 [cited 2021 Jul
14];368:m1091. Available from: https://pubmed.ncbi.nlm.nih.gov/32217556/
82. Chen TL, Dai Z, Mo P, Li X, Ma Z, Song S, et al. Clinical Characteristics and Outcomes of Older
Patients with Coronavirus Disease 2019 (COVID-19) in Wuhan, China: A Single-Centered,
Retrospective Study. J Gerontol A Biol Sci Med Sci [Internet]. 2020 [cited 2021 Jul 14];75(9):1788–
95. Available from: https://pubmed.ncbi.nlm.nih.gov/32279081/
83. Dehingia N, Raj A. Sex differences in COVID-19 case fatality: do we know enough? Lancet Glob
Heal [Internet]. 2021 [cited 2021 Jul 14];9(1):e14–5. Available from:
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30464-2/fulltext
84. Parascandola M, Xiao L. Tobacco and the lung cancer epidemic in China. Transl Lung Cancer Res
[Internet]. 2019 [cited 2021 Jul 14];8(1):21–30. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546632/
85. Prel J-B du, Hommel G, Röhrig B, Blettner M. Confidence Interval or P-Value?: Part 4 of a Series on
Evaluation of Scientific Publications. Dtsch Arztebl Int [Internet]. 2009 [cited 2021 Aug
19];106(19):339. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689604/
86. Chapman AR, Adamson PD, Mills NL. Assessment and classification of patients with myocardial
injury and infarction in clinical practice. Heart [Internet]. 2017 [cited 2021 Jul 15];103(1):10–8.
Available from: https://heart.bmj.com/content/103/1/10
87. The World Bank. Data for High income, Upper middle income, Low income [Internet]. [updated

69
 2019; cited 2021 Jul 16]. Available from: https://data.worldbank.org/?locations=XD-XT-XM
88. Public Health England. Disparities in the risk and outcomes of COVID-19 [Internet]. [updated 2020
Aug; cited 2021 Jul 16]. Available from:
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/
file/908434/Disparities_in_the_risk_and_outcomes_of_COVID_August_2020_update.pdf
89. British Heart Foundation. Ethnicity [Internet]. [no date; cited 2021 Jul 16]. Available from:
https://www.bhf.org.uk/informationsupport/risk-factors/ethnicity
90. Ranganathan P, Aggarwal R, Pramesh CS. Common pitfalls in statistical analysis: Odds versus risk.
Perspect Clin Res [Internet]. 2015 [cited 2021 Jul 16];6(4):224. Available from:
https://pubmed.ncbi.nlm.nih.gov/26623395/
91. Faber J, Fonseca LM. How sample size influences research outcomes. Dental Press J Orthod
[Internet]. 2014 [cited 2021 Jul 16];19(4):29. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296634/
92. Biau DJ, Kernéis S, Porcher R. Statistics in Brief: The Importance of Sample Size in the Planning and
Interpretation of Medical Research. Clin Orthop Relat Res [Internet]. 2008 [cited 2021 Jul
16];466(9):2288. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493004/
93. Sawalha K, Abozenah M, Kadado AJ, Battisha A, Al-Akchar M, Salerno C, et al. Systematic Review
of COVID-19 Related Myocarditis: Insights on Management and Outcome. Cardiovasc
Revascularization Med [Internet]. 2021 [cited 2021 Jun 2];23:107–13. Available from:
https://www-sciencedirect-
com.manchester.idm.oclc.org/science/article/pii/S1553838920304978
94. Raukar NP, Cooper LT. Implications of SARS-CoV-2-Associated Myocarditis in the Medical
Evaluation of Athletes. Sports Health [Internet]. 2021 [cited 2021 Jun 2];13(2):145–8. Available
from: https://journals-sagepub-
com.manchester.idm.oclc.org/doi/full/10.1177/1941738120974747
95. McDonagh M, Peterson K, Raina P, Chang S, Shekelle P. Avoiding Bias in Selecting Studies. In:
Hefland M, Chang S, editors. Methods Guide for Effectiveness and Comparative Effectiveness
Reviews [Internet]. Rockville: Agency for Healthcare Research and Quality. 2013. [cited 2021 Jul
21]. Available from https://www.ncbi.nlm.nih.gov/books/NBK126701/
96. PRISMA. PRISMA 2020 Checklis [Internet]. [updated 2020; cited 2021 Jul 21]. Available from:
http://www.prisma-statement.org/
97. Chan K, Bhandari M. Three-minute critical appraisal of a case series article. Indian J Orthop
[Internet]. 2011 [cited 2021 Jul 21];45(2):104. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051113/
98. Nomis, Office for National Statistics. Local Area Report for Areas in England and Wales: Preston
[Internet]. [updated 2020; cited 2021 Jul 22]. Available from:

70
 https://www.nomisweb.co.uk/reports/localarea?compare=E07000123
99. Nomis, Office for National Statistics. Labour Market Profile: Preston [Internet]. [updated 2020;
cited 2021 Jul 22]. Available from:
https://www.nomisweb.co.uk/reports/lmp/la/1946157097/report.aspx?town=preston
100. Lancashire County Council. 2019 Deprivation Analysis [Internet]. [updated 2019; cited 2021 Jul
22]. Available from: https://www.lancashire.gov.uk/lancashire-insight/deprivation/indices-of-
deprivation-2019/2019-deprivation-analysis/
101. Lancashire Teaching Hospitals NHS Foundation Trust. Lancashire Teaching Hospitals: About Us
[Internet]. [no date; cited 2021 Jul 22]. Available from:
https://www.lancsteachinghospitals.nhs.uk/about
102. Rijnhart JJM, Twisk JWR, Eekhout I, Heymans MW. Comparison of logistic-regression based
methods for simple mediation analysis with a dichotomous outcome variable. BMC Med Res
Methodol [Internet]. 2019 [cited 2021 Sep 7];19(1):1–10. Available from:
https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-018-0654-z
103. Raleigh V. Deaths from Covid-19 (coronavirus): how are they counted and what do they show?
[Internet]. [updated 2021 Apr 23; cited 2021 Aug 23]. Available from:
https://www.kingsfund.org.uk/publications/deaths-covid-19
104. Mahase E. Covid-19: Why are age and obesity risk factors for serious disease? BMJ [Internet].
2020 [cited 2021 Aug 23];371:m4130. Available from:
https://www.bmj.com/content/371/bmj.m4130
105. Yang L, Yan LM, Wan L, Xiang TX, Le A, Liu JM, et al. Viral dynamics in mild and severe cases of
COVID-19. Lancet Infect Dis [Internet]. 2020 [cited 2021 Aug 23];20(6):656–7. Available from:
https://pubmed.ncbi.nlm.nih.gov/32199493/
106. Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19 disproportionately affect older
people? Aging. [Internet]. 2020 [cited 2021 Aug 23];12(10):9981. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/
107. Office for National Statistics. Adult smoking habits in the UK: 2019 [Internet]. [updated 2020 Jul;
cited 2021 Aug 23]. Available from:
https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexp
ectancies/bulletins/adultsmokinghabitsingreatbritain/2019
108. Shastri MD, Shukla SD, Chong WC, KC R, Dua K, Patel RP, et al. Smoking and COVID-19: What we
know so far. Respir Med [Internet]. 2021 [cited 2021 Aug 23];176:106237. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674982/
109. Gao M, Piernas C, Astbury NM, Hippisley-Cox J, O’Rahilly S, Aveyard P, et al. Associations between
body-mass index and COVID-19 severity in 6·9 million people in England: a prospective,
community-based, cohort study. lancet Diabetes Endocrinol [Internet]. 2021 [cited 2021 May

71
 6];0(0). Available from: https://www.thelancet.com/journals/landia/article/PIIS2213-
8587(21)00089-9/fulltext
110. NHS Digital. Statistics on Obesity, Physical Activity and Diet, England, 2019 [Internet]. [updated
2019 May 8; cited 2021 Aug 23]. Available from: https://digital.nhs.uk/data-and-
information/publications/statistical/statistics-on-obesity-physical-activity-and-diet/statistics-on-
obesity-physical-activity-and-diet-england-2019/part-3-adult-obesity
111. Rees EM, Nightingale ES, Jafari Y, Waterlow NR, Clifford S, B. Pearson CA, et al. COVID-19 length of
hospital stay: a systematic review and data synthesis. BMC Med 2020 181 [Internet]. 2020 [cited
2021 Aug 23];18(1):1–22. Available from:
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01726-3
112. Guo A, Lu J, Tan H, Kuang Z, Luo Y, Yang T, et al. Risk factors on admission associated with hospital
length of stay in patients with COVID-19: a retrospective cohort study. Nat Sci Reports [Internet].
2021 [cited 2021 Aug 23];11(1):1–7. Available from: https://www.nature.com/articles/s41598-
021-86853-4
113. Talari K, Goyal M. Retrospective studies - utility and caveats. J R Coll Physicians Edinb [Internet].
2020 [cited 2021 Aug 24];50(4):398–402. Available from:
https://pubmed.ncbi.nlm.nih.gov/33469615/
114. Kukull WA, Ganguli M. Generalizability: The trees, the forest, and the low-hanging fruit. Neurology
[Internet]. 2012 [cited 2021 Sep 9];78(23):1891. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369519/
115. Lee PH. Should we adjust for a confounder if empirical and theoretical criteria yield contradictory
results? A simulation study. Sci Rep [Internet]. 2014 [cited 2021 Aug 24];4(1):1–14. Available
from: https://www.nature.com/articles/srep06085
116. Dong Y, Peng C-YJ. Principled missing data methods for researchers. Springerplus [Internet]. 2013
[cited 2021 Aug 24];2(1):1–17. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701793/
117. Cheung KL, ten Klooster PM, Smit C, de Vries H, Pieterse ME. The impact of non-response bias due
to sampling in public health studies: A comparison of voluntary versus mandatory recruitment in a
Dutch national survey on adolescent health. BMC Public Health [Internet]. 2017 [cited 2021 Sep
9];17(1):1–10. Available from:
https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-017-4189-8
118. Columb M, Atkinson M. Statistical analysis: sample size and power estimations. BJA Educ
[Internet]. 2016 [cited 2021 Aug 24];16(5):159–61. Available from:
https://academic.oup.com/bjaed/article/16/5/159/2389876
119. Sterne JAC, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, et al. Multiple imputation for
missing data in epidemiological and clinical research: potential and pitfalls. BMJ [Internet]. 2009

72
 [cited 2021 Sep 9];338(7713):157–60. Available from:
https://www.bmj.com/content/338/bmj.b2393
120. Kang H. The prevention and handling of the missing data. Korean J Anesthesiol [Internet]. 2013
[cited 2021 Aug 24];64(5):406. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668100/
121. Tripepi G, Jager KJ, Dekker FW, Zoccali C. Selection Bias and Information Bias in Clinical Research.
Nephron Clin Pract [Internet]. 2010 [cited 2021 Aug 25];115(2):94–9. Available from:
https://www.karger.com/Article/Fulltext/312871
122. Department of Health and Social Care. Joint Committee on Vaccination and Immunisation: advice
on priority groups for COVID-19 vaccination, 30 December 2020 - GOV.UK [Internet]. [updated
2021 Jan 6; cited 2021 Jun 16]. Available from:
https://www.gov.uk/government/publications/priority-groups-for-coronavirus-covid-19-
vaccination-advice-from-the-jcvi-30-december-2020/joint-committee-on-vaccination-and-
immunisation-advice-on-priority-groups-for-covid-19-vaccination-30-december-2020
123. NHS England. Landmark moment as first NHS patient receives COVID-19 vaccination [Internet].
[updated 2020 Dec 8; cited 2021 Aug 24]. Available from:
https://www.england.nhs.uk/2020/12/landmark-moment-as-first-nhs-patient-receives-covid-19-
vaccination/
124. The World Health Organization. Vaccine efficacy, effectiveness and protection [Internet].
[updated 2021 Jul 14; cited 2021 Aug 24]. Available from: https://www.who.int/news-
room/feature-stories/detail/vaccine-efficacy-effectiveness-and-protection
125. Wang Y, Chen J, Chen W, Liu L, Dong M, Ji J, et al. Does Asthma Increase the Mortality of Patients
with COVID-19?: A Systematic Review and Meta-Analysis. Int Arch Allergy Immunol [Internet].
2021 [cited 2021 Sep 10];182(1):76–82. Available from:
https://www.karger.com/Article/FullText/510953
126. Public Health England. Cardiovascular Disease: South West NHS Region [Internet]. [updated 2020;
cited 2021 Sep 9]. Available from:
https://fingertips.phe.org.uk/profile/cardiovascular/data#page/0/gid/1938133108/pat/44/par/E4
0000006/ati/154/iid/273/age/1/sex/4/cat/-1/ctp/-1/cid/4/tbm/1
127. Public Health England. Cardiovascular Disease: North West NHS Region [Internet]. [updated 2020;
cited 2021 Sep 9]. Available from:
https://fingertips.phe.org.uk/profile/cardiovascular/data#page/0/gid/1938133108/pat/44/par/E4
0000010/ati/154/are/E38000014/cid/4/tbm/1

73
Appendices
Appendix 1: Letter confirming permission to use data from The Royal Preston Hospital

74
75
76