1. PHARM 40500 Critical Analysis and Communications
PROTOCOL
Assessing The Efficacy Of Aspirin
For The Primary Prevention Of Heart
Attacks
4th
year project protocol, submitted to the
University of Manchester in partial fulfilment of
the MPharm degree
By: Mujahid Al-amin (7300253)
April 2013
School of Pharmacy and Pharmaceutical
Sciences
Supervisor: Dr Jill Barber

2. Declaration
“I understand the nature of plagiarism and that it is a serious academic offence. I
confirm that no material in the project has been plagiarised.”
Signed: Mujahid Al-amin Date: 14/04/2013

3. Executive Summary
Introduction – Cardiovascular disease has the highest mortality rate in the world
causing approximately 17.1 million annual deaths, of which 7.2 million (12% of all
deaths worldwide) are due to ischaemic coronary heart disease resulting in
myocardial infarction (MI).
Hundreds of clinical trials have given conclusive evidence that aspirin is effective
in the treatment and secondary prevention of myocardial infarction, hence why
aspirin is used often in clinical practice. However there is no clearly accepted
standard for when aspirin should be used for the primary prevention of MI. Results
from primary prevention trials using aspirin have been less conclusive due to the
use of different doses and various study populations. Current literature remains
unclear as to what daily dose of aspirin is best for the primary prevention of
myocardial infarction, and whether or not aspirin is equally effective in both men
and women. Due to these gaps in the literature, this study will evaluate whether
daily low dose aspirin is effective for the primary prevention of myocardial
infarction in both men and women, and at what dose.
Aim – To evaluate whether daily low dose aspirin is effective for the primary
prevention of myocardial infarction in healthy men and women. Objectives – (1)
To determine the effectiveness of 75 mg aspirin daily in the primary prevention of
myocardial infarction. (2) To determine the effectiveness of 160 mg aspirin daily in
the primary prevention of myocardial infarction. (3) To compare the efficacy of two
different daily doses of aspirin and determine the balance of risks and benefits in

4. the primary prevention of myocardial infarction. (4) To compare the effects of daily
low dose aspirin in men and women.
Method – The study duration will be 5 years and will be a randomised, double-
blinded, placebo-controlled trial. Participants will consist of healthcare
professionals recruited from local hospitals and randomised into one of three
groups taking either a placebo tablet, 75 mg aspirin tablet or 160 mg aspirin tablet
daily. Each participant will receive monthly calendar packs (every 6 months)
containing their respective intervention, and at the end of every month each
participant will complete an online questionnaire to identify any adverse effects
and/or relevant clinical endpoints (e.g., myocardial infarction and/or death). The
results will be statistically analysed using relative risk calculations, the chi-squared
test and multiple logistic regression analysis.
Implications to public health and pharmacy – This study could be offering a
treatment method for the primary prevention of myocardial infarction, and thus
reduce the incidence of MI. This would ultimately reduce the burden on an already
stretched and scarcely resourced healthcare system, whilst potentially increasing
the life expectancy of these sufferers and improving their quality of life.

5. Contents
Declaration.............................................................................................................................2
Executive Summary................................................................................................................3
Contents.................................................................................................................................5
1. Introduction.......................................................................................................................6
1.1 Mechanism of Action of Aspirin..............................................................................................7
1.2 Aspirin and Myocardial Infarction...........................................................................................8
1.2.1 Secondary Prevention of Myocardial Infarction................................................................9
1.2.2 Primary Prevention of Myocardial Infarction....................................................................9
1.2.3 Limitations Of These Studies...........................................................................................12
1.3 Study Hypothesis...................................................................................................................13
2. Aim and Objectives..........................................................................................................14
2.1 Aim........................................................................................................................................14
2.2 Objectives..............................................................................................................................14
3. Method.............................................................................................................................15
3.1 Study Design..........................................................................................................................15
3.2 Study Population...................................................................................................................17
3.3 Research Procedures.............................................................................................................20
4. Data Analysis Plan............................................................................................................22
4.1 Sample Size...........................................................................................................................22
4.2 Statistical Analysis Of Results................................................................................................24
5. Impact of Research..........................................................................................................26
6. Timeline............................................................................................................................28
7. Limitations........................................................................................................................28
8. Acknowledgements..........................................................................................................31
9. References.......................................................................................................................32
10. Appendices.....................................................................................................................35
Appendix 1: Participant Information Package.............................................................................35
Appendix 2: Consent Form..........................................................................................................42
Appendix 3: Data Collection Tool................................................................................................44

6. 1. Introduction
It is well known that a heart attack is a serious medical emergency and if you
suspect that you or someone you know is having a heart attack, dial 999 and ask
for an ambulance1
as it could mean the difference between life and death. A heart
attack is known medically as a myocardial infarction (MI) and is caused by an
acute obstruction of a coronary artery, usually one in which blood flow is already
compromised by the presence of atherosclerotic plaque.2
The plaque can rupture
which leads to platelet aggregation, causing a blood clot to develop at the site of
rupture. The clot then blocks the supply of blood running through the coronary
artery1
to the heart muscle, causing necrosis of myocardial tissue due to
ischaemia i.e., causing MI.
Cardiovascular disease in its various forms is the leading cause of death
worldwide, ranking first in both developing and developed countries. The total
number of annual deaths due to cardiovascular disease is approximately 17.1
million (29% of all deaths).2
Of these deaths, 7.2 million are due to ischaemic
coronary heart disease resulting in myocardial infarction2
and as such constitutes
an immense public health problem. Coronary heart disease is the most common
cause of death in the UK. In England alone between April 2010 and April 2011
there were just over 92,000 heart attacks.1
Although mortality rates from coronary heart disease have been falling in the UK
since the late 1970s due to modern treatments and the development of effective

7. drug therapies, up to half of people who have an acute myocardial infarction die
within 30 days of the event; over 50% of these deaths occur from a complication
of an MI before medical assistance arrives or the patient reaches hospital.3
About
one third of all deaths occur within the first hour, usually as the result of an acute
fatal arrhythmia.3
Patients who survive a heart attack are at high risk of further
cardiovascular events and often develop life-threatening complications which can
occur rapidly after a heart attack and are a leading cause of death.1
Both the National Health Service (NHS)1
and British Heart Foundation (BHF)4
advise that a person suffering from a suspected heart attack should be given an
aspirin 300mg tablet (if it's easily available and they are not allergic to aspirin) to
slowly chew and then swallow whilst waiting for the ambulance to arrive. They
advise this because aspirin is an anti-platelet drug which thins the blood and thus
helps to restore blood supply to the heart i.e., it may prevent the myocardial
infarction. A significant number of sufferers die before treatment can begin,
therefore it would be preferable to be proactive in preventing heart attacks rather
than being reactive to a heart attack when it occurs and trying to prevent its re-
occurrence. Hence primary and secondary prevention in patients at risk is crucial
to reducing the incidence of MI.
1.1 Mechanism of Action of Aspirin
Aspirin is an antiplatelet drug which works by irreversibly acetylating the cyclo-
oxygenase (COX) enzyme.5
There are at least two different forms of cyclo-
oxygenase: COX-1 and COX-2. Aspirin is non-selective and irreversibly inhibits
both forms by acting as a false substrate. In the process of inhibiting COX, the

8. acetyl group on aspirin breaks away and then bonds to the alcohol group of
serine, forming an ester (see Figure 1). This has the effect of blocking the active
site of the enzyme.
Figure 1. Aspirin mechanism of action: Irreversible acetylation of cyclo-
oxygenase (COX).6
Normally arachidonic acid (an unsaturated fatty acid) enters the active site of COX
and is converted to prostaglandins which have diverse effects within the body,
including inflammation and transmission of pain information to the brain.5
However
COX-1 also produces thromboxane A2 (TXA2) which is a vasoconstrictor and is
responsible for the aggregation of platelets resulting in the formation of blood
clots.5
Therefore by inhibiting COX-2, aspirin has analgesic and anti-inflammatory
effects and by inhibiting COX-1, it inhibits platelet aggregation hence why it's
known as a blood thinner. Since heart attacks are primarily caused by blood clots,
this explains why aspirin is used to treat and help prevent a myocardial infarction;
due to its mechanism of action.
1.2 Aspirin and Myocardial Infarction
There have been many meta-analyses performed and hundreds of clinical trials
investigating the use of aspirin to prevent myocardial infarction over the last few
decades. For the purposes of this study only the most relevant, most reliable and
most valid studies have been chosen for review.

9. 1.2.1 Secondary Prevention of Myocardial Infarction
It's clear that the efficacy of aspirin for secondary prevention of cardiovascular
disease is well established.7-9
The Antithrombotic Trialists' Collaboration reviewed
287 studies on antiplatelet therapy, mostly using aspirin and involved 212,000
patients (i.e., 135,000 using antiplatelet therapy or control and 77,000 using
different antiplatelet regimens).7
The participants of these trials comprised of high
risk patients with prior occlusive vascular events, meaning these trials were not
restricted to those who had survived a myocardial infarction but also included
patients who suffered from unstable and stable angina, transient ischemic attacks
and occlusive strokes.7,10
The meta-analysis showed that aspirin prevents about
25% of serious vascular events and concluded that aspirin when begun promptly
and continued long-term reduces risks of subsequent myocardial infarction,
stroke, and vascular death.7,10
Antiplatelet therapy, with aspirin being the most
studied, has been well documented to reduce the risks of subsequent
cardiovascular events such as acute MI, thus the benefit from aspirin substantially
outweighs its possible adverse effects (i.e., increased risk of bleeding). It's now
common clinical practice to use daily low dose aspirin for the secondary
prevention of MI as its use is supported by the NHS1
and the National Institute for
Health and Clinical Excellence (NICE) guidelines,11
based on the results of these
clinical trials which all agree and support each other's findings, and have been
thoroughly reviewed.
1.2.2 Primary Prevention of Myocardial Infarction
For the primary prevention of myocardial infarction, the literature is less clear
about the clinical benefit of aspirin. There are some studies showing a favourable

10. risk–benefit ratio for aspirin in primary prevention in those who are at high risk of
cardiovascular disease12-17
but the absolute benefit is small and is accompanied by
an increased risk of bleeding. Therefore for aspirin to be beneficial in reducing risk
of a first myocardial infarction, the risk of a future cardiovascular event must
outweigh the risk of bleeding. Patients who have not suffered from a myocardial
infarction (but may have cardiovascular risk factors such as hypertension or
angina) generally have a lower baseline risk, so there will be less absolute benefit
from aspirin in primary prevention for the same relative risk reduction.9
The US Preventive Services Task Force performed a systematic overview of five
primary prevention trials of aspirin9,12
which when combined had more than 53,000
participants (see Table 1. for the characteristics of the five randomised trials).
Their findings showed that aspirin reduced the risk of myocardial infarction in
patients with hypertension,16,18
chronic stable angina,18,19
males with risk factors for
occlusive vascular disease,15,18
and in patients with at least one major risk factor
for coronary heart disease.17,18
Table 1. Baseline characteristics of study populations in primary prevention trials.9,13-17
Variable
British
male
doctors13
Physicians’
Health
Study14
Thrombosis
prevention
trial15
Hypertensio
n Optimal
Treatment16
Primary
Prevention
Project17
Year 1988 1989 1998 1998 2001
Location UK US UK Worldwide Italy
No. of patients
(women)
5,139 (0) 22,071 (0) 2,540 (0) 18,790
(8,831)
4,495 (2,583)
Participants
included
Male
physicians
Male
physicians
Men at high
risk for heart
disease
Diastolic BP
of 100–115
mmHg
> 1 major
risk factor for
CHD
Mean age
(range)
NA; 53%
> 60
years
53 years
(40–84)
57.5 years
(45–69)
61.5 years
(50–80)
NA; 69%
> 60 years

11. Daily aspirin
dose
500 mg 325 mg on
alternate days
75 mg 75 mg 100 mg
Treatment
duration (years)
5.8 5 6.8 3.8 3.6
Annual risk of
CHD event
among control
groups
0.89% 0.48% 1.24% 0.36% 0.43%
BP = blood pressure. CHD = coronary heart disease. NA = not available.
Overall the risk of cardiovascular events was significantly decreased by aspirin,
however it increased the risk of haemorrhagic stroke and major gastrointestinal
bleeding.9,12
The US Preventive Services Task Force concluded that aspirin should
be used in patients with >1% annual risk of coronary heart disease,9,12
as the
potential benefit of aspirin will be greater than its potential adverse effects in these
individuals. The American Heart Association guidelines concur, recommending
that low-dose aspirin should be considered for primary prevention in patients who
have a higher coronary heart disease risk.9,20
The literature on primary prevention of myocardial infarction in healthy individuals,
with no history of cardiovascular disease, is diverse and not consistent.18
For
example, the randomised placebo controlled UK study on British male doctors
found "there was no significant difference in the incidence of myocardial infarction
or stroke" between the control group and the treatment group.13
However the US
male Physicians' Health Study (which had a much larger sample size and used a
lower dose of aspirin) concluded "this trial of aspirin for the primary prevention
of cardiovascular disease demonstrates a conclusive reduction in the risk of
myocardial infarction" but only in those aged 50 years or older.14
(See Table 1. for
the similarities and differences between these studies).

12. In women, a prospective cohort study on over 87,000 healthy nurses living across
11 states of the US was conducted and included 6 years of follow up.21
This study
suggested that taking aspirin regularly may reduce the risk of first myocardial
infarction in women.18,21
However a large randomised placebo controlled trial
known as the Women's Health Study (which had almost 40,000 healthy female
participants who were monitored for 10 years), found that 100 mg aspirin given on
alternate days lowered the risk of stroke in women, but had no effect on either
myocardial infarction or death.18,22
1.2.3 Limitations Of These Studies
There is no clearly accepted standard for when aspirin should be used in primary
prevention. The evidence doesn't unequivocally support the use of aspirin in
people who are at risk of cardiovascular disease as the literature is not conclusive,
but the evidence suggests aspirin may be beneficial in preventing a myocardial
infarction, however it would depend on the risk-benefit ratio of the individual. The
published literature on healthy individuals (i.e., the Physicians' Health Study and
the Women's Health Study) is lacking and the findings are controversial and
somewhat conflicting. These trials examined healthy individuals but only of one
gender, and aspirin was taken on alternate days rather than on a daily basis,
which may have influenced the overall effect of aspirin. Also the doses of aspirin
used in these trials differed greatly, and although both trials compared aspirin to a
placebo, neither trial investigated the effects of different doses of aspirin in healthy
people. For example, the Physicians' Health Study suggests that 325 mg of
aspirin on alternate days (equivalent to 162.5 mg of aspirin per day) is enough to

13. reduce the risk of MI in men,14
but this does not mean that this dose is the
optimum dose; perhaps a lower dose may have the same effect. However the
Women's Health Study concludes aspirin does not prevent MI in healthy women,22
but these women were only taking 100 mg of aspirin on alternate days (equivalent
to 50 mg of aspirin per day). The literature does not suggest whether the
difference in these results is due to the difference in gender or due to the different
doses used. Perhaps if the Women's Health Study used a higher dose of aspirin
similar to the dose in the Physicians' Health Study, a different conclusion may
have been drawn. Without directly comparing the same doses of aspirin in both
healthy men and women for the same duration and monitored in the same way, it
cannot conclusively be determined if aspirin has more of a beneficial effect in men
rather than women.
1.3 Study Hypothesis
The hypothesis of this study is that daily low dose aspirin will be beneficial in the
primary prevention of myocardial infarction in healthy men and women aged 45
and older.

14. 2. Aim and Objectives
2.1 Aim
To evaluate whether daily low dose aspirin is effective for the primary prevention
of myocardial infarction in healthy men and women.
2.2 Objectives
1. To determine the effectiveness of 75 mg aspirin daily in the primary
prevention of myocardial infarction.
2. To determine the effectiveness of 160 mg aspirin daily in the primary
prevention of myocardial infarction.
3. To compare the efficacy of two different daily doses of aspirin and
determine the balance of risks and benefits in the primary prevention of
myocardial infarction.
4. To compare the effects of daily low dose aspirin in men and women.

15. 3. Method
3.1 Study Design
This will be a randomised, double-blinded, placebo-controlled trial designed to
determine whether low-dose aspirin (75 mg and 160 mg) prevents myocardial
infarction in healthy males and females. There are 3 arms to this study: one group
will be taking a placebo daily, another group will be taking 75 mg aspirin daily and
the third group will be taking 160 mg aspirin daily. All three interventions will be
given in tablet form and shall look the same in appearance (shape, size and
colour). These daily doses have been chosen based on the gaps found in the
literature; the Physicians' Health Study only comprised of healthy males where as
the Women's Health Study only comprised of healthy females. Another major
difference between these studies is that the dose given to the males
(approximately 162.5 mg of aspirin per day) was more than three times higher
than the dose given to the females (approximately 50 mg of aspirin per day). As
the higher dose did show a beneficial effect in men, a daily dose of 160 mg of
aspirin has been chosen to see whether the same results could be reproduced in
men, and to ascertain what effect this dose will have on healthy women. A daily
dose of 75 mg of aspirin has also been chosen to see whether or not this slightly
higher dose than the one used in the Women's Health Study helps to prevent
myocardial infarction in either men or women.
The eligible participants will be stratified by two variables (gender, followed by age
group; 45-59 years old and 60-75 years old), then randomised to one of the three
treatment groups by the lead researcher using block-randomisation software. This
will ensure an equal distribution of characteristics meaning each treatment group

16. will have the same number of men and women of each age range (this avoids
confounding which eliminates selection bias). The duration of this study will be 5
years as this will be sufficient time to observe if the intervention given has had an
effect, plus this length of time is comparable to similar clinical trials with similar
aims and methods used. Before recruitment of participants can begin, ethical
approval from the University of Manchester ethics committee and the National
Research Ethics Service (NRES) must first be obtained.
The participants will be healthcare professionals recruited from hospitals in the
Greater Manchester area. The reasons for using healthcare professionals are
because they are likely to be more understanding of the importance of this study
therefore more compliant, and more likely to remember to take their medication as
their daily lives revolve around healthcare. Also they are likely to grasp the
potential benefits of such a study and the possible risks of a long term intervention
more easily, plus they are likely to be more accurate when relaying information
about their health status (i.e., are more likely to recognize if they are having an
adverse reaction and record it).
Before the clinical trial begins, each participant will be given their own personal
participant ID number, before being randomised into one of the three intervention
groups. At the start of the trial and every 6 months thereafter, a supply of monthly
calendar packs containing the intervention treatment (either the placebo or one of
the strengths of aspirin) will be delivered to each hospital by members of the
research team. These calendar packs will be labelled "A", "B" or "C" according to
which intervention they contain (only Bayer HealthCare who will be manufacturing

17. and providing the calendar packs and the lead researcher will know which
intervention is A, B or C). To avoid participants getting the wrong calendar pack,
intervention A will be packaged in red calendar packs, intervention B will be in
blue calendar packs and intervention C will be in green calendar packs. Although
the calendar packs will be colour coded, the tablets within packs A, B and C will
look identical. This trial will be double blinded as both the participants and the
researchers delivering these calendar packs will not know which calendar packs
contain the aspirin or the placebo. On the days the researchers deliver the
calendar packs to the hospitals, they will have a list of participant ID numbers with
their corresponding intervention group letter A, B or C.
3.2 Study Population
This study aims to recruit approximately 4,700 healthcare professionals from the
Greater Manchester area (for more details see section 5.1 Sample Size). The
main reason for choosing this area is because the research team will be working
from the University of Manchester, so for convenience it is more prudent to recruit
healthcare professionals from the surrounding hospitals and more practical and
economical when it comes to delivering the calendar packs. Plus Greater
Manchester is a large area with many hospitals each of which employ a great
number of healthcare professionals.
To recruit these healthcare professionals, the chief executives of the hospitals
within this area (Central Manchester University Hospitals, The Christie, Salford
Royal Hospital, Wythenshawe Hospital and North Manchester Hospital) will be
contacted and meetings arranged in order to discuss why this study is worthwhile,

18. and to present the benefits of adopting this study. Once the heads of these
hospitals are onboard, they can reach out to their employees and begin recruiting
healthcare professionals via lectures and staff conferences where they will be a
more captive audience. Participant information packages (see Appendix 1 for
more information) will be supplied to these hospitals and distributed to those who
are interested in participating, along with an attached consent form to obtain
written informed consent. Written informed consent is needed to prove the
participants' understanding and willingness to share confidential information such
as medical records (for more information, see Appendix 2). If some of these
suggested hospitals decline to be a part of this study and the sample size cannot
be met, then hospitals in the surrounding areas (e.g., Royal Bolton Hospital, The
Royal Oldham Hospital and Cheadle Royal Hospital) will be contacted.
Participants will be eligible to participate in this study provided they meet the
following inclusion criteria and they do not meet any of the exclusion criteria;
The participant must:
• Be working as a healthcare professional or has previously worked as a
healthcare professional.
• Be aged between 45-75 years old. Myocardial infarction becomes more
common with increasing age.
• Have a BMI of 18-35. Individuals with a BMI outside of this range are not
classed as healthy individuals.

19. However, the participant must not:
• Have a history of chronic illnesses or sufferer from any serious health
conditions i.e., a history of cardiovascular disease, cerebrovascular
disease, cancer, peptic ulcers, bleeding disorders or asthma.22
• Have a history of side effects to aspirin, hypersensitivity to aspirin or have
aspirin intolerance.22
• Be taking aspirin or any other NSAIDs (nonsteroidal anti-inflammatory
drugs such as ibuprofen, naproxen, diclofenac) more than once a week.22
• Be currently taking regular medications such as anticoagulants,
antidepressants or corticosteroids.22
However if aged 60 or older then the
use of statins regularly is acceptable. (If participants need to take
medications at some point during the trial e.g., to treat an infection or for
pain relief, they must contact the researchers and inform them of this. The
researchers will advise whether the participant needs to stop taking their
intervention and for how long).
• Be a current smoker. Participants who are ex-smokers and have stopped
smoking for 2 years or more are eligible to participate.
• Consume more than 21 units of alcohol per week if male, or more than 14
units of alcohol per week if female.
(For female participants an additional exclusion criterion is that they must not be
pregnant if they wish to participate. Should they become pregnant during the trial
period, they will be withdrawn from the study).

20. 3.3 Research Procedures
The participants will be asked to take their treatment every day, and once a month
to complete a short online webform/questionnaire regarding compliance, risk
factors, the occurrence and severity of any side effects and the occurrence of
relevant clinical end points (e.g., a myocardial infarction or symptoms of
cardiovascular disease). For more details regarding the information to be collected
from each participant on a monthly basis, see Appendix 3. All participant
information will be anonymized from the researchers and the data collected will be
kept confidential (see Appendix 1).
When a participant reports a relevant clinical end point, their medical records will
be reviewed and the diagnosis of a myocardial infarction will be confirmed only if
they meet the criteria for myocardial infarction as set out by the World Health
Organization. Death will be confirmed to be from cardiovascular causes on the
basis of an examination of autopsy reports, death certificates, medical records,
information obtained from the next of kin.22
Death from any other cause will be
confirmed on the basis of a death certificate and medical records.22
Death from all
causes during the trial will be recorded.
If at any point during the trial it becomes evident that there is a higher than normal
rate of death seen in the participants (e.g., suicides), or if a significant number of
the participants are suffering from serious side effects, then this trial will be
stopped immediately. The health and safety of the participants must and will come
first. Based on the literature and previous clinical trials, such an outcome is highly
unlikely (especially given that the proposed daily doses of aspirin to be used are

21. low doses) and similar doses have been used in other trials without any serious
incidents. Also, should a participant change their mind and wish to discontinue
being in the study, they are free to withdraw from the trial. They will be asked for
their reason(s) for withdrawing, but will not have to give a response. If they should
ask for it, then any data collected from them will also be destroyed.
However if the trial shows very promising results (i.e., many more deaths or
serious health problems are being prevented in comparison to the placebo group,
and it can be shown this was due to the aspirin dose the participants were taking),
then the placebo group will be switched to an aspirin dose. In this instance It
would be unethical to withhold the aspirin dose from the placebo group. The
results obtained from that point would then be analysed and written up in a
preliminary report to be published and peer reviewed by the scientific community,
however the trial will continue for the duration of the study to obtain more data.

22. 4. Data Analysis Plan
4.1 Sample Size
In order to draw meaningful conclusions from any data obtained, the sample size
of the study must be large enough to produce statistically significant results i.e., to
produce the minimum clinically significant difference (MCSD). The MCSD is the
smallest difference in the data that is "worth" detecting (i.e., the effect size).25
For
a result to be significant, the probability of it occurring by chance (the p-value)
must be less than the level of significance (α). This study will use a 0.05 level of
significance, meaning the confidence interval will be 95%. Therefore if the p-value
calculated for the results is less than 0.05, this means there is a 95% probability
that the results obtained were not due to chance, and are therefore statistically
relevant. To work out a sample size that is appropriate for this study a power
calculation is needed, because the power (β) is the probability that a statistical
test will detect a significant difference between the results obtained from the
different intervention groups.25
A sensitivity analysis (shown in Table 2.) was
carried out using the following formula (shown in Figure 2.), with a range of effect
sizes (∆):
Figure 2. Formula for sample size calculation.25
In this formula:
• n is the number of participants needed in each group.

23. • p1 is the percentage of the UK population aged under 75 who died from
cardiovascular disease or coronary heart disease (approximately 20%).
This percentage was taken from the British Heart Foundation's Coronary
Heart Disease Statistics (2010 edition).26
• p2 is a lower percentage than p1, dependent upon the effect size from
taking 75 mg aspirin daily (see Table 2. for the values used for p2).
• f (α, β) has the value of 10.5 at 90% power or the value of 7.9 at 80%
power (when using α=0.05).25
The formula shown in Figure 2. calculates the sample size needed for 2 groups,
however this study is using three groups (a placebo group, 75 mg aspirin group
and a 160 mg aspirin group). The reason for p2 being based on the 75 mg aspirin
dose is because the lower dose of aspirin will have a smaller effect size. A smaller
effect size requires a larger sample size in order to truly detect a significant
difference between this lower dose of aspirin and the placebo. The higher dose of
aspirin (160 mg daily) should have a larger effect size, therefore fewer participants
in this group will be needed for the detection of a significant difference. Therefore
if the same sample size calculated for the lower dose of aspirin is also used for the
higher dose of aspirin, there will be a sufficient number of participants to detect a
significant difference in the lower dose group, and more than enough participants
to detect a significant difference in the higher dose group.
For the purposes of this study, an effect size of 3% or more would demonstrate
aspirin helps in the primary prevention of myocardial infarction.

24. Table 2. Sensitivity analysis on sample size. (This shows the sample sizes needed when
using different values for the power and a range of effect sizes).
β
(Power)
α (Level of
Significance)
Range, p1-
p2 (%)
∆
(Effect
Size)
n = No. of
Participants In
Each Arm
Total No. of
Participants
Needed
90% 0.05 20-17 3% 3,513 10,539
80% 0.05 20-17 3% 2,643 7,929
90% 0.05 20-16 4% 1,932 5,796
80% 0.05 20-16 4% 1,454 4,362
90% 0.05 20-15 5% 1,208 3,624
80% 0.05 20-15 5% 909 2,727
90% 0.05 20-14 6% 818 2,454
80% 0.05 20-14 6% 616 1,848
This study will use 80% power as randomised controlled trials usually use this
value. To use an effect size of 3% would mean the minimum number of
participants needed to carry out this study is 7,929. Recruiting this many health
care professionals from the hospitals in the Greater Manchester area who are
eligible and actually willing to participate seems highly unlikely. Plus it would be
impractical for such a small research team (lead researcher plus 3 part-time
assistant researchers) to monitor all the participants health status effectively, thus
jeopardising their safety which is unacceptable. Therefore it has been decided to
use an effect size of 4%, meaning a total sample size of at least 4,362 participants
is needed.
4.2 Statistical Analysis Of Results
To determine whether the results between the three groups are significantly
different, the groups will be compared using chi-squared tests. The chi-squared

25. test compares observed results to results that are expected in accordance with the
study's hypothesis.27
It is used to establish whether the null hypothesis should be
accepted (when p-value > 0.05) or rejected (when p-value < 0.05), therefore a null
hypothesis must first be made:
Null Hypothesis - daily low dose aspirin will not be beneficial in the primary
prevention of myocardial infarction in men or women aged between 45-75.
The observed results in this study will be the data collected from all the
participants to see who suffered from myocardial infarction and who did not. The
expected result will be the percentage of the UK population aged under 75 who
suffered from MI. Therefore the group receiving the placebo should have a similar
outcome to that of the expected data from the literature, but the 2 groups taking
differing doses of aspirin (i.e., the observed data from these 2 groups) may show a
different outcome. The formula for the chi-squared test is shown in Figure 3.
Figure 3. Formula for the chi-squared test.27
"Chi-square (X2
) is the sum (∑) of the
squared difference between the observed
(o) and the expected (e) data, divided by the expected data in all possible
categories."27
In addition to the chi-squared test, relative risk ratios will be calculated for the 3
groups. This is to determine the risk of myocardial infarction occurring in both the
aspirin groups relative to the placebo group. The relative risk will indicate the
effectiveness of each daily dose of aspirin, and will allow for the efficacy of these

26. doses to be compared against one another, as well as against the placebo (thus
fulfilling objectives 1, 2 and 3). Relative risk ratios will also be used to calculate the
risk of other clinically significant outcomes such as death from other
cardiovascular causes, risk of gastro-intestinal problems (and risk of any other
side effects of aspirin e.g., increased risk of bleeding), and death from any cause.
These will be used to assess the risk-benefit ratio of taking either dose of aspirin
when compared to taking placebo (fulfilling objective 3).
For each relative risk, the two-sided p-value and the 95% confidence interval will
be calculated. This will be followed by a multivariate logistic regression analysis,
which will be utilised to control for any confounding variables (such as age,
gender, BMI, alcohol use, amount of exercise, ethnicity and family history of
myocardial infarction) and ascertain whether any significant differences in the
base-line characteristics of the participants (e.g., gender) had an impact on the
results (fulfilling objective 4). In this way, the aim and objectives of this study
should be achieved (refer to section 3. Aim and Objectives for more
information).All statistical analyses will be performed using SPSS version 16.0. A
statistician at the University of Manchester may be consulted when analysing the
results obtained, but all participant information will be anonymized to maintain
confidentiality.
5. Impact of Research
This research study could impact the healthcare system by offering a treatment
method for the primary prevention of myocardial infarction, and thus reduce the
incidence of MI in the general population. As previously stated, up to 50% of

27. people who have an acute myocardial infarction die within 30 days of the event,
and over half of these deaths occur from a complication of an MI before medical
assistance arrives or the patient reaches hospital.3
By preventing these fatal
myocardial infarctions, this study could potentially increase people's lifespan and
avoid the need for hospitalisation.
People who survive a myocardial infarction often develop life-threatening
complications1
as a result, which vastly reduces their quality of life and their life
expectancy. These patients are also at high risk for further cardiovascular events
and often require a combination of life-long secondary preventative medication
(and sometimes surgeries). Therefore by preventing both these non-fatal
myocardial infarctions and any following life-threatening complications, a higher
risk for further cardiovascular events and a reduction in both quality of life and life
expectancy could all be avoided.
In 2009, the total NHS expenditure was around £130 billion28
and from this,
cardiovascular disease cost the NHS approximately £9 billion29
(equating to 7% of
the total NHS expenditure). However by reducing the incidence of myocardial
infarction occurring (by using a thoroughly researched drug such as aspirin which
is cheap and easily accessible), this would reduce the need for hospital
admissions due to MI, reduce the need for surgeries in relation to MI, and also
lower the amount of medications being prescribed on the NHS. Hence this study
could have a huge impact by reducing costs to the NHS and by saving lives.

28. 6. Timeline
Table 3. An approximate timeline for this study.30
Action Month Year
1 2 3 4 5 6 1 2 3 4 5 6
Ethical approval from NRES &
university committee
Recruitment of healthcare
professionals
Data collection using online
questionnaires
Data analysis
Write-up of report and additional
analyses
Final publication
7. Limitations
As with any prospective study using voluntary participants, a possible limitation of
this study is too many participants withdrawing from the study, resulting in an
insufficient sample size to obtain meaningful results. There are a variety of
reasons why participants may choose to withdraw:
• They are free to drop out of the study at any time should they simply
change their minds.

29. • Or free to withdraw from the study because they no longer wish to continue
participating due to suffering prolonged adverse effects (which may be
inconveniencing their daily lives).
However some participants may be forcibly withdrawn from the study, for example
if participants:
• Were suffering from severe side effects.
• Became chronically ill and required long-term medication (e.g., developed
cancer).
• Became pregnant.
• Health and safety was at risk if they continued in the trial.
Since the duration of this study is 5 years, unforeseen circumstances may cause
some participants to have to change address or perhaps an opportunity such as a
new job/promotion in another part of the country, meaning they could no longer
participate. Although the power calculation (see 5.1 Sample Size for more
information) suggests that 4,362 participants is the minimum needed for this
study, to avoid the sample size becoming too small over the study's duration,
recruitment of at least 4,700 participants (increasing the minimum sample size
needed by an extra 7.5%) will be the target for this study.
The study sample to be used (as outlined in section 4.2 Study Population) will only
consist of healthcare professionals working in the Greater Manchester area, and
who are relatively healthy and aged between 45-75 years old. This sample is not
strictly representative of the general population, however for this study to use
people younger than 45 years old would not be ethically justifiable. Healthy

30. individuals who are in the age range of 20-40 years old are not likely to suffer from
a myocardial infarction within the next 5 years, however increasing age is a risk
factor for myocardial infarction as the rate of MI increases dramatically in those
aged 50 and older. Hence why those aged less than 45 years old will be excluded
from this study. Also those who are aged older than 75 years will be excluded as
this is a 5 year study and it is less likely that individuals above this age will remain
healthy for the duration of the study i.e., older individuals tend to have more health
problems and may at some point require the use of regular medication (e.g.,
NSAIDs for arthritis). The reasons for using healthcare professionals have been
explained in section 3.1 Study Design, and the reasons for choosing the Greater
Manchester area have been explained in section 3.2 Study Population.
Another possible limitation of this study is compliance. If a large proportion of the
participants only take the intervention half of the time then this could significantly
impact the precision of the results and affect any conclusions drawn. If no benefit
can be observed by the end of the trial then it could be concluded this was due to
a lack of compliance rather than a lack of efficacy of the drug. The main reason for
recruiting healthcare professionals is to reduce this possible limitation. Healthcare
professionals who are fully informed of the risks and benefits of this study and
agree to participate are likely to be more compliant. Also the frequency and
severity of side effects is known to affect compliance, hence by only using low
doses of aspirin, the risk and severity of any possible side effects will be
minimised (in the Physicians' Health Study, in which the aspirin dose was 325 mg
on alternate days, the rate of gastro-intestinal discomfort was 0.5% which is very
low). Although compliance issues may be a limitation, it is expected that the

31. participants of this study will have a high adherence, meaning a medication
possession ratio (MPR) of 80% or higher.
Adherence will be assessed through participants self-reports via the monthly
online questionnaire (see Appendix 3 for more information). Because this study
will rely on participant self-reports, this in itself could be a further limitation as it is
possible some participants may give false reports in regards to their compliance.
However this possibility seems unlikely as there is no financial incentive for the
participants, the participants will be encouraged to be completely honest and
truthful when completing their monthly self-reports (see Appendix 1 and 3), and
the participants are all healthcare professionals whose professions dictate they
must be honest and trustworthy.
There is also the possibility of practical problems such as participants not being
able to collect their calendar packs from the researchers on the specified delivery
dates. If this should occur, participants will be encouraged to contact the research
team as soon as possible to arrange an alternate delivery date to their hospital, or
to arrange a time for the participant to collect their calendar packs from the
researchers at the University of Manchester (see Appendix 1).
8. Acknowledgements
I wish to express my most sincere gratitude towards my module supervisors for
their support and to my academic advisor Dr Jill Barber for her guidance and
advice throughout this project. Special thanks to Waqas Hussain and Samera Ali
for their comments and ideas to improve this protocol, they were invaluable and
truly helpful. I wish to thank all my closest friends for their enthusiastic assistance,

32. endless encouragements and many great laughs along the way (insha-Allah may
there me many more to come). I thank Allah for the blessings and opportunities
given to me throughout my life, and for the strength to persevere through all the
challenges presented.
Last but not least, my deepest gratitude towards my beloved family for all they
have done for me. I thank them for their moral and spiritual guidance when it was
most needed, and for inspiring me to make the best of myself and to always help
others. I am forever indebted to my parents for their understanding, never-ending
patience and limitless support throughout my studies.
9. References
1. National Health Service (2012) Heart Attack [WWW] Available from:
http://www.nhs.uk/conditions/Heart-attack/Pages/Introduction.aspx [Accessed
09/02/13].
2. Harris, R. (2012) Global Epidemiology of Cardiovascular Disease. In:
Epidemiology of Chronic Disease: Global Perspectives. Ohio: Michael Brown,
pp. 25-27. Available at:
http://samples.jbpub.com/9781449653286/Chapter2.pdf

33. 3. Tidy, C. (2012) Acute Myocardial Infarction [WWW] Available from:
http://www.patient.co.uk/doctor/acute-myocardial-infarction [Accessed
09/02/13].
4. British Heart Foundation (n.d.) Heart Attack [WWW] Available from:
http://www.bhf.org.uk/heart-health/conditions/heart-attack.aspx [Accessed
09/02/13].
5. Martindale: The Complete Drug Reference (2011) Aspirin [WWW] Available
from: http://www.medicinescomplete.com/mc/martindale/current/2601-
s.htm#m2601-a5-256-e [Accessed 09/02/13].
6. University of California (n.d.) Esters [WWW] Available from:
http://chemwiki.ucdavis.edu/index.php?
title=Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Ch
apter_12:_Acyl_substitution_reactions/Section_12.4:_Esters&bc=0 [Accessed
09/02/13].
7. Antithrombotic Trialists' Collaberation. Collaborative meta-analysis of
randomised trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002; 324: 71–
86. Correction. ibid.141.
8. Baigent C, et al. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the
primary and secondary prevention of vascular disease: collaborative meta-
analysis of individual participant data from randomised
trials. Lancet 2009; 373: 1849–60.
9. Hung, J. (2003) Aspirin for Cardiovascular Disease Prevention. The Medical
Journal of Australia, 179 (3), pp. 147-152.
10. Hennekens, C. (2002) Update on Aspirin in the Treatment and Prevention of
Cardiovascular Disease [WWW] Available from:
http://www.ncbi.nlm.nih.gov/pubmed/12512736 [Accessed 09/02/13].
11. National Institute for Health and Clinical Excellence (2007) MI: secondary
prevention [WWW] Available from:
http://www.nice.org.uk/nicemedia/live/11008/30493/30493.pdf [Accessed 09/02/13].
12. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention
of cardiovascular events: a summary of the evidence for the US Preventive
Services Task Force. Ann Intern Med 2002; 136: 161-172.
13. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin
in British male doctors. BMJ 1988; 296: 313-316.
14. Final report on the aspirin component of the ongoing Physicians' Health Study.
Steering Committee of the Physicians' Health Study Research Group. N Engl
J Med 1989; 321: 129-135.

34. 15. Thrombosis prevention trial: randomised trial of low-intensity oral
anticoagulation with warfarin and low-dose aspirin in the primary prevention of
ischaemic heart disease in men at increased risk. The Medical Research
Council's General Practice Research Framework. Lancet 1998; 351: 233-241.
16. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-
pressure lowering and low-dose aspirin in patients with hypertension: principal
results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT
Study Group. Lancet 1998; 351: 1755-1762.
17. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised
trial in general practice. Collaborative Group of the Primary Prevention
Project. Lancet 2001; 357: 89-95.
18. Martindale: The Complete Drug Reference (2011) Cardiovascular Risk
Reduction [WWW] Available from:
http://www.medicinescomplete.com/mc/martindale/current/850-a3-1-f.htm
[Accessed: 09/02/2013].
19. Juul-Möller S, et al. Double-blind trial of aspirin in primary prevention of
myocardial infarction in patients with stable chronic angina
pectoris. Lancet 1992; 340: 1421–5.
20. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for primary
prevention of cardiovascular disease and stroke. 2002 update: consensus
panel guide to comprehensive risk reduction for adult patients without
coronary or other atherosclerotic vascular diseases. American Heart
Association Science Advisory and Coordinating Committee. Circulation 2002;
106: 388-391.
21. Manson JE, et al. A prospective study of aspirin use and primary prevention of
cardiovascular disease in women. JAMA 1991; 266: 521–7.
22. Ridker PM, et al. A randomized trial of low-dose aspirin in the primary
prevention of cardiovascular disease in women. N Engl J
Med 2005; 352: 1293–1304.
23. Kenny, T (2012) Myocardial Infarction (Heart Attack), [WWW] Available from:
http://www.patient.co.uk/health/myocardial-infarction-heart-attack [Accessed:
09/02/2013].
24. NHS Health Research Authority (n.d.) National Research Ethics Service
[WWW] Available from: http://www.nres.nhs.uk/ [Accessed: 30/03/2013].
25. Steinke, D. (2013) Sample Size Calculation For Two Groups, from
PHAR40500 Critical Analysis and Communications. University of Manchester,
Stopford Building on 8th
March. Available from: Blackboard. [Accessed
09/03/2013].

35. 26. British Heart Foundation (2010) Coronary Heart Disease Statistics (2010
edition) [WWW] Available from: http://www.bhf.org.uk/publications/view-
publication.aspx?ps=1001546 [Accessed 14/03/2013].
27. Penn State Lehigh Valley (n.d.) Chi-Square test [WWW] Available from:
http://www2.lv.psu.edu/jxm57/irp/chisquar.html [Accessed: 30/03/2013].
28. Association of the British Pharmaceutical Industry (2011) NHS Expenditure In
The UK [WWW] Available from: http://www.abpi.org.uk/industry-
info/knowledge-hub/medicines/Pages/nhs-expenditure.aspx#fig1 [Accessed:
30/03/2013].
29. British Heart Foundation (n.d.) Economic Costs [WWW] Available from:
http://www.bhf.org.uk/research/heart-statistics/economic-costs.aspx
[Accessed 14/03/2013].
30. Steinke, D. (2013) Writing a Research Protocol, from PHAR40500 Critical
Analysis and Communications. University of Manchester. Available from:
Blackboard. [Accessed 05/02/2013].
10. Appendices
Appendix 1: Participant Information Package
Participant Information Package
Assessing the efficacy of aspirin for the primary prevention of heart attacks

36. Introduction
You are invited to participate in our research study. The purpose of this package is
to provide interested potential participants with all the information they need in
order to make an informed decision before agreeing to take part in our 5 year
clinical trial. The following sections explain the details of this study, what you can
expect from us and what information will be asked of you should you choose to be
involved. It is crucial that you fully understand how we will use that information
before giving consent. If you still have any questions after reading through this
package, please do not hesitate to contact us either by telephone or email (our
contact information can be found at the end of this package).
Who will conduct the research?
A small team of researchers (a lead researcher plus 3 part-time assistant
researchers) from the University of Manchester will be conducting the research.
The lead researcher will oversee the study and constantly monitor the participants'
health status. The part-time assistant researchers will aid the lead researcher in
identifying eligible participants, and monitoring participants' health on a regular
basis. They will also deliver the colour coded, monthly calendar packs (containing
either intervention A, B or C) every 6 months to the hospitals taking part in this
study. The research team may get in contact with participants to either obtain
more information (e.g., medical records if a participant is admitted into hospital
during the study) or to discuss any concerns or queries. Some of the teaching staff
at the University of Manchester may be consulted when analysing the results
obtained, but all participant information will be anonymized to maintain
confidentiality.
What is the study about?
This study is examining whether or not daily low dose aspirin can help prevent
myocardial infarctions (MI) in healthy individuals. Many studies have shown
aspirin is effective for those who have had an MI previously, and some studies
have shown aspirin has some efficacy in those who are at risk of having an MI.
However there are very few studies that investigate aspirin's effectiveness in
preventing myocardial infarction in healthy people.
Cardiovascular disease in its various forms is still the leading cause of death
worldwide, ranking first in both developing and developed countries. The total
number of worldwide annual deaths due to cardiovascular disease is
approximately 17.1 million (29% of all deaths).2
Of these deaths, 7.2 million are
due to ischaemic coronary heart disease resulting in myocardial infarction2
and as
such constitutes an immense public health problem. Coronary heart disease is the

37. most common cause of death in the UK, and approximately 146,000 people in the
UK suffer from an MI every year.23
Research has shown that up to 50% of people who have an acute myocardial
infarction die within 30 days of the event, and over half of these deaths occur from
a complication of an MI before medical assistance arrives or the patient reaches
hospital.3
About one third of all deaths occur within the first hour, usually as the
result of an acute fatal arrhythmia.3
Patients who survive a heart attack are at high
risk of further cardiovascular events and often develop life-threatening
complications which can occur rapidly after a heart attack and are a leading cause
of death.1
Both the National Health Service (NHS)1
and British Heart Foundation (BHF)4
advise that a person suffering from a suspected heart attack should be given an
aspirin 300mg tablet whilst waiting for an ambulance to arrive. A significant
number of people die before treatment can even begin, therefore it would be
preferable to be proactive in preventing heart attacks rather than being reactive to
a heart attack when it occurs and then trying to prevent its re-occurrence. This
study is exploring the use of aspirin to prevent myocardial infarctions in a healthy
population.
Why have I been chosen?
You have been chosen because you are a healthcare professional working in the
Greater Manchester area. As a healthcare professional you are more likely to
remember to take the medication every day as your daily life revolves around
healthcare and helping others. Also you are more likely to grasp the benefits of
this study and to fully understand the possible risks of a long term intervention,
plus you are likely to be more accurate when relaying information about your
health status (e.g., recognising if you are having an adverse reaction and then
recording it). However, to be eligible for this study, you must meet certain criteria
which are set out below:
The participant must:
• Be working as a healthcare professional or has previously worked as a
healthcare professional.
• Be aged between 45-75 years old. Myocardial infarction becomes more
common with increasing age.
• Have a BMI of 18-35. Individuals with a BMI outside of this range are not
eligible to participate in this study.
However, the participant must not:

38. • Have a history of chronic illnesses or sufferer from any serious health
conditions i.e., a history of cardiovascular disease, cerebrovascular
disease, cancer, peptic ulcers, bleeding disorders or asthma.
• Have a history of side effects to aspirin, hypersensitivity to aspirin or have
aspirin intolerance.
• Be taking aspirin or any other NSAIDs (nonsteroidal anti-inflammatory
drugs such as ibuprofen, naproxen, diclofenac) more than once a week.
• Be currently taking regular medications such as anticoagulants,
antidepressants or corticosteroids. However if aged 60 or older then the
use of statins regularly is acceptable. (If participants need to take
medications at some point during the trial e.g., to treat an infection or for
pain relief, they must contact the researchers and inform them of this. The
researchers will advise whether the participant needs to stop taking their
intervention and for how long).
• Be a current smoker. Participants who are ex-smokers and have stopped
smoking for 2 years or more are eligible to participate.
• Consume more than 21 units of alcohol per week if male, or more than 14
units of alcohol per week if female.
(For female participants an additional exclusion criterion is that they must not be
pregnant if they wish to participate. Should they become pregnant during the trial
period, they will be withdrawn from the study).
What do I have to do?
If you decide to participate and sign a consent form, you will be emailed a link to
an online questionnaire, which you must complete. The purpose of this
questionnaire is to gather some basic background information about you and your
medical history, so that the research team can verify your eligibility to be included
in this study. Once this has been completed, the lead researcher will assign you
your own personal participant ID number and inform you of the start date for when
the clinical trial will begin (sent to you via email).
There will be 3 intervention groups in this study; one group will be taking a
placebo daily, another group will be taking 75 mg aspirin daily and the third group
will be taking 160 mg aspirin daily. All three interventions will be given in tablet
form and will look the same in appearance. Once all the participants have
received their personal ID numbers, you will be randomly assigned into one of
these 3 groups. As this clinical trial will be double blinded, neither the researchers
(except the lead researcher who will perform the randomisation) nor the
participants themselves will know which intervention they will be taking.
At the start of the trial and every 6 months thereafter, a supply of monthly calendar
packs containing the intervention treatment (either the placebo or one of the

39. strengths of aspirin) will be delivered to each hospital by members of the research
team (you will be informed of the delivery dates via email). These calendar packs
will be labelled "A", "B" or "C" according to which intervention they contain. To
avoid participants getting the wrong calendar pack, intervention A will be
packaged in red calendar packs, intervention B will be in blue calendar packs and
intervention C will be in green calendar packs. Although the calendar packs will be
colour coded, the tablets within packs A, B and C will look identical. On the days
the researchers deliver the calendar packs to the hospitals, they will have a list of
participant ID numbers with the corresponding intervention group letter A, B or C
next to each ID number. On the delivery dates you will need to meet with the
researcher and tell them your participant ID number so that you may be given your
assigned calendar packs for the following 6 months. If you cannot meet with the
researcher on the specified delivery date, you will need to contact the research
team (either by telephone, email or via the website) and arrange for an alternative
delivery date, or agree a time when you can pick up your calendar packs from the
research team's office at the University of Manchester.
A few days before the trial begins, you will be told which intervention (A, B or C)
you will be taking for the duration of the trial, and be given a link to a website (both
sent via email). The email will also contain instructions regarding how to login to
this website, as it has been made for only you (the participants) to gain access to.
This website will have the same short online questionnaire for you to complete
each month (different from the first questionnaire regarding your background
information). This shorter questionnaire will allow the research team to monitor
your health, gather information regarding your adherence to the intervention, and
alert them to any signs of possible adverse effects and the occurrence of any
health problems (this includes seeing your GP and any admission to a hospital for
the duration of the trial). Therefore it is vital that you are honest about how often
you take your medication and open about the development of any side effects or
need for medical attention. If you should forget to take a dose, do not try to make
up for it by taking more than one tablet in a day. Instead leave the missed dose in
the calendar pack so that at the end of the month when you fill in the short online
questionnaire, you can count how many doses you missed that month and record
it online. The website will be another way for the research team to contact you,
and for you to contact them should you have any queries or problems at any point
during the study.
What are the risks or benefits to taking part?
It is well known that all drugs can produce side effects, and aspirin is no
exception. The proposed daily doses of aspirin (75 mg and 160 mg) to be used in
this study are low doses, especially considering that the recommended maximum
daily dose of aspirin is 4000mg. High doses of aspirin on a regular basis can lead
to erosion of the gastric mucosa, ulceration, haematemesis and melaena5
(both

40. symptoms of gastric bleeding). However participants will be taking a much lower
dose of aspirin therefore such side effects are unlikely. The side effects of aspirin
are generally mild, with the most common adverse effect being gastro-intestinal
irritation such as nausea or heartburn. We advise all participants to take their
intervention with or after food to further minimise the possibility of any gastro-
intestinal symptoms.5
Patients who are hypersensitive to aspirin have suffered
from bronchospasm (though mainly in asthmatics), angioedema and skin
reactions. Therefore to minimise the possibility of these adverse effects,
hypersensitive patients and asthma suffers will not be eligible to participate in this
study.
Should any participant suffer from any of the adverse effects mentioned, they
must report it via the website (or telephone) so that the researcher team can
advise accordingly. You may be advised to consult with your GP, or to stop taking
the intervention temporarily or perhaps stop taking it entirely. Ultimately the lead
researcher has the right to withdraw you from the study at any time, as your health
and safety is of paramount importance.
The potential benefits is that aspirin is a treatment that is used to treat
cardiovascular events and cerebrovascular disorders such as stroke, and is used
in the secondary prevention of these life threatening conditions. But to prevent
them from happening in the first place would be much more preferable, and the
results of this study will help to clarify if aspirin can be used for the primary
prevention of myocardial infarction.
Do I have to take part?
It is entirely your choice whether or not to take part in this study. You should not
feel forced or coerced into having to participate. The decision to take part must be
your choice, and no one else should decide for you. Although this study has been
designed to have minimal intrusion into your daily life, there are possible risks as
well as potential benefits to taking part. This information package is providing you
with all the information you would need to help enable you to make a fully
informed decision. We strongly advise you to carefully consider everything in this
package, and to contact us if you have any queries before agreeing to take part.
Please be aware that if you consent to taking part, you will always have the right
to withdraw from the study at any time.
Confidentiality
Any and all the information that the participants share with the research team will
be kept confidential. The information sent via the online questionnaires will be
stored on encrypted, password-protected servers at the University of Manchester,
with only the research team having access to it. Any notes and records made by

41. the research team will be locked and stored in a secure file room, and any
information that does not get used in the final report will be destroyed. The results
of this study will be published but the participants will be anonymized (using their
participant ID numbers) and any personal information will remain confidential.
What happens next?
Once you have fully read through this package and are satisfied with the answers
to any questions you may have and you wish to participate in this study, you must
then read and sign the consent form. This is to show that you fully understand and
agree to what will be needed from you to safely and successfully carry out this
study. Once you have signed the consent form, please hand it in at your hospital's
reception by the end of this month. If you decide not to take part, please return
both the participant information package and the consent form to the staff room.
Participants will be contacted by email soon after the consent forms have been
signed and collected by the research team, detailing instructions for completing
the first online questionnaire about your background information, and a start date
for the trial.
What will happen to the results?
The results of this study and a discussion of their analysis will be written up in a
final report, which will be subjected to peer review. A summary of the results will
be sent to you in a letter and a copy of the report itself will be made available
should you request it.
Who has reviewed the study?
The University of Manchester ethics committee and the National Research Ethics
Service have both reviewed this study and given their approval. Their purpose is
to protect the rights, safety, dignity and well-being of research participants whilst
promoting ethical research that is of potential benefit to participants, science and
society.24
If you have any questions about this study, please contact:
Lead researcher Mujahid Al-amin
School of Pharmacy
University of Manchester

42. Tel: 0161 730 0253
Email: mujhaid.al-amin@manchester.ac.uk
Appendix 2: Consent Form
Consent Form
1. I confirm that I have read the participant information package and
understand the requirements of the study as stated in the patient
information package.

43. 2. I agree to complete the online questionnaire each month for the duration of
this study, and to be honest and open about my health status and
adherence to the intervention.
3. I confirm that I have had adequate opportunity to ask any questions about
the study and research process, and that they have been answered
satisfactorily.
4. I understand that my participation is voluntary and that I can leave the study
at any time. If I should choose to withdraw from this study, I understand that
I can request to have my information destroyed.
5. I understand the potential risks and benefits of participating in this study.
6. I consent to sharing information regarding my health status, and allow the
researchers of this study to examine my medical records and speak to my
physicians if needed.
7. I understand the purpose of the data and give permission for it to be viewed
by relevant individuals at the University of Manchester.
8. I agree to participate in this study.
Name: Signature: Date:
Contact details:

44. Appendix 3: Data Collection Tool
Once participants have read and understood the patient information package and
signed the consent form, they will be emailed a link to the first webform. This is to
gather the following background information about each participant before the trial
begins:
• Name
• Address
• Age and date of birth
• Gender
• Job title and place of work
• Hours of work per week, or state if retired.
• Marital status/single
• Ethnicity
• Physical activity/exercise on a weekly basis
• Hobbies, interests and leisure activities
• Height and weight - BMI calculator will be incorporated into the webform
• Family medical history (any history of myocardial infarction/heart disease in
the family? Any family history of any other diseases?)
There will also be questions relating to the inclusion/exclusion criteria, to ensure
participants are eligible to be in this study. The first webform will appear similar to
this:
Questions Yes No
1. Do you have a history of:
• Cardiovascular disease
• Cerebrovascular disease
• Cancer
• Peptic ulcers
• Blood disorders
• Asthma
Tick Yes or
No
2. Do you have any chronic illnesses or conditions?
If answered yes, please state in the box below what what conditions/illnesses
you suffer from in this box:
3. Do you have a history of side effects to aspirin?

45. 4. Are you hypersensitive to aspirin?
5. Do you have aspirin intolerance?
6. Do you take aspirin or any nonsteroidal anti-
inflammatory drugs (NSAIDs) more than once a week?
7. Do you take any medication regularly? i.e., on a daily
or weekly basis?
If answered yes, please state in the box below what the medication is and the
indication it is for, the daily dosage regimen (i.e., how many times a day you
take the medication) and the duration of the treatment:
8. Have you been diagnosed with high blood pressure?
If answered yes, please state in the box below what your last blood pressure
reading was. If you are taking any medication to treat this, please fill out
question 7.
9. Have you been diagnosed with high cholesterol?
If answered yes, please state in the box below what your last cholesterol level
was. If you are taking any medication to treat this, please fill out question 7.
10. Have you ever been a regular smoker? i.e., smoked
cigarettes on a daily basis?
If answered yes, please state in the box below how many cigarettes you
smoked on average a day, and state when you stopped smoking? (If you are
still a regular smoker, then you are not eligible to be in this study).
11. Do you drink alcohol on a regular basis? i.e., a daily
or weekly basis?
If answered yes, please state in the box below how many units of alcohol you
drink on average per week.

46. Once this first webform has been filled in and sent off, the information will be
received only by the University of Manchester computer servers which are
encrypted and password-protected. Only the research team will have access to
the participants' information. The research team will verify whether each
participant is eligible, then pass the eligible participants' forms on to the lead
researcher so that he can assign and email the participants their participant ID
numbers (then later randomise the participants into the three intervention groups).
In this way, the researchers will not know which participants have been given
which ID numbers, therefore keeping the study blinded.
Once the participants receive their personal ID number via email, they will officially
be included in this study. Once the trial begins, each month the participants will
have to login to a website to record and send data. The participant's ID number
will be their username, and their passwords will be their surname followed by the
first letter of their first name in order to login the first time. Having logged in, each
participant will then change their password to one of their own choosing for the
duration of the trial. This website will have a new, shorter webform for the
participants to fill in each month. It will have a BMI calculator included in the
webform, and will have the following questions:
Questions Yes No
1. Have you missed any of your daily doses in the last
month?
If answered yes, please state in the box below how many days have been
missed this last month.
2. Have you suffered from any adverse effects in the last
month?
If answered yes, please state in the box below what these adverse effects are
and how long they have lasted (or if more appropriate, the date they started)
3. Have you been taking any other medications in the
last month?
If answered yes, please state in the box below why you are taking other
medications, what medications you are taking, how many times a day are you
taking these medications and for how long.

47. 4. Have you been to see you GP for any reason in the
last month?
If answered yes, please state in the box below why you went to see a GP, and
what was the result of your visit. Have you been diagnosed with something
and/or prescribed any medication?
5. Have you been admitted into hospital for any reason
in the last month?
If answered yes, please state in the box below why you were admitted into
hospital, and what was the diagnosis? Were you prescribed any medication?
(if so please state what was prescribed and for how long)