i

THE ROLE OF NURSE PRACTITIONERS IN PRIMARY CARE IN OPTIMIZING
RISK STRATIFICATION FOR CORONARY HEART DISEASE IN CANADIAN
WOMEN: AN INTEGRATIVE REVIEW

by
Parveen Sangha
B.S.N University of the Fraser Valley, 2008

PROJECT SUBMITTED IN PARTIAL FULFILLMENT OF
THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE IN NURSING
FAMILY NURSE PRACTITIONER STREAM

UNIVERSITY OF NORTHERN BRITISH COLUMBIA
September 2016
© Parveen Sangha, 2016

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Abstract
Coronary heart disease (CHD) is the most common cause of morbidity and mortality in
Canadian women. Despite advances in screening and research, CHD continues to pose a
significant health care burden to Canadian women. This integrative literature review explores
how a Nurse Practitioner (NP) in primary care can optimize risk stratification for CHD in
Canadian women. A systematic search of the contemporary literature identified 11 key articles.
These were analyzed using the Critical Appraisal Skills Programme tools to assess relevance and
the strengths and weaknesses of the evidence. Three key themes emerged from the literature and
are explored in detail: the limitations of current risk prediction models for risk stratification in
women; the emergence and evolving importance of female-specific risk factors; and additional
adjunctive testing (coronary artery calcium screening) that may improve the accuracy of risk
prediction models in women. Recommendations based on the above themes with respect to NP
practice, education, and research are identified. Female-specific risk stratification, improving NP
education, and areas for further research including the need for screening beyond traditional risk
prediction models are highlighted.
Keywords: coronary heart disease, cardiovascular diseases, women, screening, risk
assessment, risk stratification, risk factors, primary prevention, risk assessment tools, coronary
artery calcium screening, integrative review, literature review.

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Table of Content
Abstract……………………………………………………………………………............ ii
List of Tables……………………………………………………………………………... v
Acknowledgements……………………………………………………………………….. vi
Chapter 1

Introduction………………………………………………………………. 1

Chapter 2

Background and Context ………………………………………………... 4
Cardiac Anatomy and Physiology…………………………………………. 5
Pathophysiology of Coronary Heart Disease……………………………… 5
Coronary Heart Disease Risk Factors………………………..……………. 8
Traditional Established Risk Factors……………………………… 9
Non-traditional Risk Factors in Women. …………………………. 14
Risk Stratification……...……...…………………………………………… 18
Lifetime Risk for Developing CHD…………………………………...……20
Clinical Guidelines for CHD Prevention……………………..…………… 22
Risk Stratification beyond Traditional Risk Prediction Models: Adjunctive
Tests.……………………………………………………………………….. 25
Gender disparities and the Management of CHD…………………………. 26
Primary Care.…….…………………………………………………..……. 27
Nurse Practitioner in Primary Care…………………….…………..…….... 28

Chapter 3

Search Methods…………………………………………………………… 30
Stage 1: Identification of Search Strategy……………………………….… 30
Stage 2: Preliminary Search……………………………………………….. 32
Stage 3: Focused Search…………………………………………………… 34
Stage 4: Analysis and Reporting…….…………………………………….. 34

Chapter 4

Findings…………………………………………………………………… 36
The Limitations of Current Risk Prediction Models in Women…………... 36
The Emergence and Evolving Importance of Female-Specific Factors …... 42
Additional Adjunctive Testing that may Improve the Accuracy of Risk
Stratification in Women…………………………………………………… 49

Chapter 5

Discussion………………………….……………………………………….55
Limitations of Current Risk Stratification Models in Clinical Practice …… 55
The Importance of Female-Specific Risk Factors……………..……...…… 57
Consideration of Adjunctive Screening Methods in Practice…...……….… 60
Primary Care in Canada……………………………………….……..……. 62
Recommendations………………………….....………………………….… 63
Recommendations for Practice………………………………………….…. 64
Choose the most appropriate risk stratification tool and adjunctive
imaging…………………………………………………………….. 64

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Be aware of female-specific cardiovascular risk factors………….. 65
Recommendations for Education……………..…………………….……… 66
Recommendations for Research ……………………………...…………… 66
Limitations ………………………………………………………………… 69
Conclusions………………………………………………………………... 70
Glossary……………………………………………..……………………………………... 71
References……………………………………………..…………………………………… 80
Appendix A: Cardiovascular Risk Stratification Models……………………………….…. 91
Appendix B: CASP Tools………………………………………………………………….. 94

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List of Tables
Table 1: Traditional and non-traditional risk factors……………………………….…………. 9
Table 2: Categories of Cardiac Risk Factors……………………………………….……….…. 21
Table 3: Classification of Risk in Women..……………………………………………….…….. 24
Table 4: Eligibility criteria for literature review inclusion and exclusion criteria…………….. 31
Table 5: Search terms and MeSH terms for the literature review……………………………… 32
Table 6: Results of the Database Search ……………………………...……………………….. 34
Table 7: Two new Algorithms for global risk prediction: Model A and Model B ……………... 37
Table 8: Risk scores from ATP III, RRS and Framingham CVD models………………………. 39
Table 9: Cardiovascular Risk Scores in men and women…………………………...…………. 41
Table 10: Results for primary outcomes for depression…………………………………………43
Table 11: Model One and Model Two………………………………………………………….. 45
Table 12: Cox proportional-hazard regression for CHD endpoints over a 10-year follow-up... 45
Table 13: Model One and Model Two………………………………………………………….. 50
Table 14: Summary of recommendations for practice, education and research……………….. 68

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Acknowledgements
Special thanks to Linda Van Pelt and Dr. Davina Banner-Lukaris
for their crucial contributions to this project.
The author would like to thank all of the UNBC family nurse practitioner faculty, students, and
clinical preceptors for their guidance, support and wisdom.
Finally, the author would also like to extent gratitude to friends and family
for their unconditional love and support throughout this journey.

1
CHAPTER 1
Introduction
Cardiovascular disease (CVD) is the most significant cause of death worldwide (World
Health Organization [WHO], 2015). In 2010, CVD accounted for 16 million deaths worldwide,
totalling 30% of all deaths for that year (Gaziano, Prabhakaran, & Gaziani, 2014). CVD is a
group of diseases that affect the structure and function of the heart and blood vessels (Heart and
Stroke Foundation of Canada [HSFC], 2014). Examples of diseases that fall under the category
of CVD include coronary heart disease (CHD), cerebral vascular disease, and peripheral arterial
disease (WHO, 2015). According to the Heart and Stroke Foundation of Canada (2014), the most
common cause of death among Canadian women is CHD, also known as coronary artery disease
(CAD). CHD will be the focus of this project. CHD and CAD are terms that are used
interchangeably among healthcare professionals and for the purposes of this research project, the
term CHD will be used for clarity.
CHD is a disorder of the coronary arteries that typically results from atherosclerotic
plaque build-up (Silverthrone, 2016). The narrowing of the coronary arterial lumen diameter
impedes blood flow to the surrounding heart muscles, leading to serious and potentially fatal
consequences, such as a myocardial infarction (MI) (Silverthrone, 2016). The development of
atherosclerosis in CHD is associated with the presence and accumulation of cardiac risk factors,
both modifiable (smoking, physical inactivity, poor dietary habits, diabetes, hypertension) and
non-modifiable (age, sex, gender, family history of premature CHD) (Bashore, Granger, Jackson,
& Patel, 2016). Multiple studies have found the incidence of CHD to be substantially increased
in certain populations (Bashore et al. 2016). While the risk for CHD rises with age in both men
and women, women that develop CHD have significantly increased morbidity and mortality

2
compared to men (AHA [AHA], 2016). Part of this increased risk may be related to the limited
recognition of the prevalence of CHD in women, the higher incidence of most risk factors and
comorbid conditions in females and the limited uptake of diagnostic and therapeutic intervention
in women (Mosca, 2006). As such, greater attention is needed to address and prevent or delay
CHD in this “at risk” population. For this reason, this literature review will focus on potential
strategies to optimize screening and mitigate the risk of CHD in women.
The most well-known and widely used general risk assessment tool, endorsed by all of
the major global cardiovascular societies (Canadian Cardiovascular Society (CCS)/American
College of Cardiology (ACC)/AHA/European Heart Society), is the Framingham risk score
(FRS). However, FRS has significant limitations and may under or over-estimate cardiovascular
risk in women (Ridker et al., 2015). Several other risk assessment models, based on a variety of
different study cohorts, have been developed worldwide. Each tool has strengths and weakness
in terms of prediction variables (i.e. age, sex, hypertension, smoking status, diabetes mellitus,
and lipid values) and endpoints (i.e. CHD death, nonfatal MI, coronary insufficiency or angina,
coronary revascularization, fatal or nonfatal stroke, transient ischemic attack, intermittent
claudication etc.); however, the sheer number of tools is a clear indication there is currently no
single risk assessment tool focused specifically on women. As a result of the sheer number and
variety of risk stratification tools, a review of all tools would be beyond the scope of this project.
Instead, the goal of this review is to answer the following question: How can NPs in a primary
care setting optimize CV risk stratification for CHD in Canadian women?
To answer the above research question, an integrative review of the literature was
performed. The goal of this literature review is to provide a set of recommendations that can be
incorporated into primary care clinical practice to optimize the screening and prevention of CHD

3
in women. The following section will provide general background on CHD and highlight its
significance within the Canadian healthcare system. This will be followed by a summary of the
literature review methods and key findings. Finally, a discussion of the key emerging themes
with recommendations and potential strategies for NPs in Canada to optimize screening and
mitigate the risk of CHD in women will be presented.

4
CHAPTER 2
Background and Context
Approximately 42,900,000 women worldwide are affected with some form of CVD.
Furthermore, women have a one in three risk for developing CHD during their lifetime (WHO,
2015). Therefore, CHD in respect to women has been chosen as the topic of this project.
According to the HSFC, CHD is currently the leading cause of mortality among Canadian
women (HSFC, 2014). CHD is a largely preventable disease, in which risk can be mitigated
through optimal control of cardiovascular risk factors (Gleeson, 2009). According to the
Framingham Heart Study, optimal control of cardiac risk factors will considerably lessen one’s
risk for developing CHD (Lloyd-Jones et al., 2006). Assessing for the presence of cardiovascular
risk factors with effective and appropriate screening is considered an essential aspect of every
primary care practice. Screening for CHD is among one of the first steps primary care providers
can take towards decreasing CHD related morbidity and mortality in Canadian women and the
burden CHD poses on the health care system.
To explore this further, an overview of CHD will first be presented, including a brief
overview of normal cardiac anatomy and physiology, the pathophysiology of CHD, the
association between cardiac risk factors and the development of CHD in women, along with a
brief discussion on lifetime risk of CHD. Finally, clinical guidelines for CHD prevention will be
reviewed, followed by a discussion of the current limitations of risk stratification for CHD in
women.

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Cardiac Anatomy and Physiology
Figure 1: Typical coronary anatomy.

An adult heart is approximately the size
of a fist, weighs less than one pound, and
consists mostly of cardiac muscle, known as
myocardium (Silverthrone, 2016). The heart is
divided by a septum into a left and right halve.
There are two chambers per side, a right and left
atrium, which delivers blood to their respective
ventricle and the right and left ventricle, which

Picture retrieved from http://patient.info/diagram/heartcoronary-arteries-diagram

delivers blood to the pulmonary (right-side) or systemic (left-side) circulation (Silverthrone,
2016). Four major valves within the heart ensure forward flow of the blood: the atrioventricular
valves, which are located between the atria and ventricles (tricuspid and mitral), and the
semilunar valves, which are located between the ventricles and major arteries (pulmonary artery
and aorta) (Silverthrone, 2016). The major arteries, such as the aorta, pulmonary trunk, and
coronary arteries, arise from the base of the heart (Silverthrone, 2016). The coronary arteries
branch out from the root of the aorta and supply blood to the myocardium (Silverthrone, 2016).
The coronary circulation consists of the right and the left coronary artery, which further divide
into multiple branches, which vary from heart to heart (Silverthrone, 2016).
Pathophysiology of Coronary Heart Disease
CHD is a disorder of the coronary arteries that results in the narrowing of the coronary
arterial lumen and ultimately reduces myocardial blood supply, creating a state of deprivation
that impairs myocardial metabolism (Silverthrone, 2016). A temporary state of myocardial
metabolic impairment will result in a myocardia ischemia, while a persistent impairment or

6
complete occlusion of a coronary artery can result in a MI (Silverthrone, 2016). A MI can lead to
irreversible myocardial damage and can be a fatal event (Silverthrone, 2016). In other words,
CHD, along with myocardial ischemia and/or MI, form a pathological continuum in which the
heart’s ability to pump blood is impaired due to deprivation of oxygen and nutrient enriched
blood to the myocardium (Silverthrone, 2016). The following section will further address the
pathological processes of CHD in women, including obstructive causes, coronary microvascular
disease (CMD), coronary vasospasm, and dysfunctional endothelium.
Obstructive coronary heart disease. CHD is a disorder of the coronary arteries that
involves narrowing of the lumen diameter from atherosclerotic plaque formation or plaque
rupture (Albornoz & Trybuldki, 2012). Specifically, atherosclerosis is a pathological process that
involves the accumulation and hardening of plaque along the inner arterial wall (Berger, Elliott
& Gallup, et al, 2009). The progression of atherosclerotic plaque formation ultimately leads to
cell death and subsequent build-up of cellular debris that intensifies the inflammatory process
elicited by the damaged endothelium and
Figure 2: Coronary artery disease

immune response (Albornoz & Trybuldki,
2012). This continuous histological and
molecular change in plaque and inflammatory
processes eventually leads to stenosis of the
artery from plaque rupture or plaque erosion,
resulting in hypoperfusion of the myocardium
(Albornoz & Trybuldki, 2012). Plaque rupture
occurs when lipid or collagen-rich hard plaque
disrupt from a primary atherosclerotic lesion,

Picture retrieved from http://www.yorkheart.com
/images/content/CoronaryArteryDisease.jpg

7
which can potentially cause an obstruction with a coronary artery (Albornoz & Trybuldki, 2012).
Atherosclerosis remains the primary cause of CHD in women and although it often can begin
early in life, usually symptoms do not occur for several decades. Despite this lengthy incubation
period, the ultimate consequence of atherosclerosis can occur suddenly without warning and lead
to severe consequences such as MI and death.
Coronary microvascular disease. CMD is a disorder of the small coronary arteries that
manifests from abnormal coronary flow reserve in the absence of obstructive disease (Edwards,
2012), usually defined as ≥ 50% stenosis in one or more epicardial coronary arteries (Reis et al.,
2001). This disorder occurs as a consequence of diffuse mild to moderate plaque deposits and
coronary wall vasospasm or damage in the microvascular coronary arteries that then results in
myocardial ischemia (National Heart Lung and Blood Institute of Diseases and Conditions
Index], 2006). CMD is a more common in women (NHLBI, 2006). For example, a study on the
evaluation of ischemic syndrome in women (WISE) revealed that over 50% of women
presenting with chest pain had no evidence of significant obstructive disease on coronary
angiography (Edwards, 2012). These women were noted to have worse outcomes in comparison
to other women because of the inability to angiographically detect disease in the microvascular
circulation (Edwards, 2012). CMD remains a difficult disease to diagnose since the affected
small caliber coronary arteries are not easily visualized on coronary angiography (Edwards,
2012).
Vasospasm and dysfunctional endothelium. Coronary vasospasm occurs with diffuse
or focal contraction of the smooth muscles in the coronary arterial wall and can result in either
transient myocardial ischemia or MI (Kaski, Crea & Meran, 1986). Alike to CMD, coronary
vasospasm is similarly more common in women (Albornoz & Trybuldki, 2012). Although

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vasospasm usually occurs at the site of atherosclerotic plaques of variable severity, it can also
occur in angiographically normal coronary arteries (Pinto, Beltrame & Crea, 2015).
Dysfunctional endothelium is another pathological factor that contributes to CHD in women.
This pathological dysfunction occurs in the endothelial lining of the coronary arteries, causing
less vasodilation and blood flow due to a lack of nitric oxide, a potent vasodilator (Edwards,
2012). Causes of endothelial dysfunction are not fully understood but a contributing factor is
thought to be related to damage to vessel walls from plaque deposits that lead to a vessel
remodelling (Consultantlive, 2006).
The etiology of CHD in men and women can be different; however, more basic science and
clinical research is needed before more definitive conclusions can be made.
The following section will continue to investigate the differences between the sexes in
respect to CHD by exploring traditional and non-traditional cardiac risk factors and their impact
on the development of CHD in women as compared to men.
Coronary Heart Disease Risk Factors
Cardiovascular risk factors are conditions or habits that raise your risk for developing
CVD, particularly with CHD (NHLBI, 2015). CVD risk factors, also referred to as “cardiac risk
factors”, are categorized as either traditional or non-traditional risk factors. These can be further
delineated as modifiable and non-modifiable. These risk factors contribute towards the
development of all forms of CVDs, but are highly associated with CHD. Table A includes a list
of traditional and non-traditional risk factors. Traditional risk factors are similar in both men and
women. However, non-traditional risk factors are often more prevalent in women. Essentially,
the accumulation of any risk factors will promote the development of CHD in both men and
women (HSFC, 2014).

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Table 1: Modifiable vs. non-modifiable & traditional vs. non-traditional risk factors
Traditional risk factors
Non-traditional risk factors
Modifiable • Hypertension (HTN)
• mental health (i.e. depression and
stress)
• diabetes type two and insulin
resistance
• pregnancy complications
• dyslipidemia
• metabolic syndrome
• smoking
• physical inactivity
• poor dietary consumption
• obesity
Non• family history of CHD
• inflammatory markers (i.e. hsCRP)
modifiable • age
• genetic markers
• post-menopausal state
• co-morbid states (i.e. PCOS,
autoimmune disorders)
• pregnancy complications
Traditional established risk factors. Traditional risk factors also referred to as major,
conventional, established and well-established risk factors, include variables that have been
thoroughly researched in terms of their direct association with CHD in both men and women.
The following section examines traditional risk factors and highlights their association CHD with
women in comparison to men.
Family history. A positive family history for CHD is a significant risk factor for CHD in
both women and men. According to the National Cholesterol Education Program (NCEP) and
the Adult Treatment Panel (ATP) III guidelines for CHD prevention for women, a positive
family history is defined as a having a first degree relative (i.e. mother, father, brother, sister)
with the occurrence of CHD before the age of 65 in female relatives and before the age of 55 in
male relatives. Furthermore, having a positive family history of CHD in female relatives,
especially in a sister, is considered to be a stronger risk factor (Gulati & Bairey Merz, 2015).

10
Hypertension. Hypertension (HTN) is defined at a systolic blood pressure of 140 mmHg
or higher and a diastolic blood pressure of 90 mmHg or higher, or the current use of antihypertensives. HTN is a major risk factor for CHD in both sexes (Gulati & Bairey Merz, 2015).
The incidence of HTN differs among the sexes as well as with age. For example, the overall
incidence of HTN is higher in women than men (Gulati & Bairey Merz, 2015). Furthermore,
more men have HTN before the age of 45, whereas more females tend have HTN after the age of
65 years, with a similar rate of HTN between the sexes from age 45 to 65 (Gulati & Bairey Merz,
2015). Moreover, uncontrolled HTN in women 30 to 74 years of age have an approximately 6%
risk for experiencing a coronary event in 10 years; however, 56% of these events could be
prevented with blood pressure control (Ridker, Libby, & Burning, 2015). The degree of blood
pressure lowering actually has a linear association with risk reduction (Ridker et al., 2015). All
national and international clinical guidelines support screening for high blood pressure and
providing treatment for hypertension through both lifestyle and pharmacological therapies for the
primary prevention of CHD (Weintraub et al., 2011). Common treatments include restriction of
dietary sodium and the use of pharmaceutical agents such as beta-blockers, calcium channel
blockers, ACE inhibitors and diuretics.
Dyslipidemia. Dyslipidemia refers to disease in the arteries that results from lipids and
lipo-proteins transport pathways (Genest & Libby, 2015). The lipoprotein disorder that is most
associated with increasing the incidence of MIs and deaths from CVD is high levels of lowdensity lipo-protein (LDL). Dyslipidemia is common in females and includes changes in lipid
profiles, particularly an increase in LDL-C and triglycerides (Gulati & Bairey Merz, 2015).
Furthermore, adverse changes in lipids in women have also been noted to accompany menopause
during middle adulthood (Gulati & Bairey Merz, 2015).

11
Type two diabetes and insulin resistance. Diabetes, pre-diabetes, and metabolic
syndrome are major cardiovascular risk factors (Ridker et al., 2015). In fact, the presence of
diabetes is thought of as an equivalent risk to aging 15 years, which is an impact almost as
comparable to smoking, if not worse (Ridker et al., 2015). Diabetes is also associated with CHD
in both sexes (Gulati & Bairey Merz, 2015). However, diabetes confers a threefold to sevenfold
greater increased CHD risk among females, in comparison to only twofold to threefold increase
in males (Gulati & Bairey Merz, 2015). Diabetic females also have a higher association with
mortality from CHD than non-diabetic females and diabetic males (Huxley, Barzi &Woodward,
2006). Interestingly, a previous history of gestational diabetes will increase the risk of
developing diabetes by fourfold during the first four months after pregnancy (Ratner, 2007).
Gestational diabetes also increases the lifelong risk for developing diabetes and CHD for the
infant (Ratner, 2007). Diabetic patients in general have a higher burden of atherosclerotic disease
in major arteries and directly increase the risk for microvascular disease (Ridker et al. 2015).
Insulin resistance often starts before clinical symptoms of diabetes occur and is known to
promote atherosclerosis, and in some studies is seen as an independent risk factor for coronary
thrombosis (Ridker et al. 2015). For example, the Nurses Health Study revealed women who
developed type two diabetes had a threefold-elevated relative risk for MI before a diagnosis was
even made (Ridker et al. 2015). Due to the strong association between diabetes and CHD and the
delay in clinical symptoms for diabetes type two, preventative screening for diabetes and CHD in
all individuals is essential.
Metabolic syndrome. Metabolic syndrome increases the risk for CHD in both sexes, as it
incorporates multiple well-established risk factors within its syndrome, such as HTN and obesity
(Ridker et al., 2015). Metabolic syndrome is defined as the presence of central obesity or

12
abdominal obesity (waist measurement) >90 to 94cm for men and >80cm for women (varies on
ethnicity) (HealthlinkBC, 2014). Also, to meet the criteria for metabolic syndrome a patient must
also have two or more of the following: triglycerides greater than 1.7mmol/L; hypertension
(greater than 130/85mmhg or taking antihypertensives); HDL-C less than 1.03mmol/L for males,
and less than 1.3mmo/L for females; a fasting blood sugar greater than 5.6mmol/L
(HealthlinkBC, 2014). According to Statistics Canada (2013), metabolic syndrome affects both
sexes equally with no significant differences between the sexes. Despite the fact that metabolic
syndrome remains a contentious issue, in which many clinicians question it as an actual
diagnosis, the combination of components within this state have overall worsening effects on
cardiac health in both sexes and is worth considering.
Smoking. Aside from aging, smoking is the single most important risk factor for
developing CHD (Gulati & Bairey Merz, 2015; Ridker et al., 2015). For example, smokers in
comparison to non-smokers have a two to fourfold increase for developing CHD and stroke. In
fact, 35 to 40% of deaths related to smoking can be attributed to underlining CHD (Ridker et al.,
2015). Importantly, females tend to suffer more harmful effects from smoking than men (Gulati
& Bairey Merz, 2015). Recent studies have demonstrated a 25% higher risk for CHD and plaque
rupture in female smokers (Gulati & Bairey Merz, 2015). Females who smoke die 14.5 years
earlier, whereas males who smoke die 13.2 years earlier (Gulati & Bairey Merz, 2015).
Essentially, smoking has unfavorable acute effects that include altering sympathetic tone, blood
pressure, and myocardial blood supply. Also, long-term smoking affects the pathogenesis of
atherosclerosis and coronary thrombus formation in multiple ways (Ridker et al. 2015). For
example, smoking enhances oxidation of LDL cholesterol and impairs endothelium-dependent
coronary artery vasodilation (Ridker, Libby, & Burning, 2015). Smoking has adverse hemostatic

13
and inflammatory effects including an increase of hsCRP, fibrinogen, and hemocysteine (Ridker
et al. 2015). Smoking is also linked to spontaneous platelet aggregation, increased monocyte
adhesion to endothelial cells, and adverse alterations in endothelium-derived fibrinolysis and
antithrombotic factors, such as the tissue pathway factor inhibitors (Ridker, et al. 2015).
Physical activity. Numerous epidemiological studies on the effects of physical activity
have shown its direct correlation with reducing cardiovascular morbidity, mortality, and allcause mortality in both sexes (Ridker, et al. 2015). The cardioprotective effect of physical
activity has been linked to multiple biological mechanisms (Ridker et al. 2015). Firstly, regular
physical activity has been shown to reduce myocardial oxygen demand and increase exercise
capacity (enhance cardiorespiratory fitness), which correlates to lower levels of coronary artery
risk (Ridker et al., 2015). In addition, physical activity lowers systolic and diastolic blood
pressure, improves insulin sensitivity, glycemic control, endothelial function, and endogenous
fibrinolysis; it also lowers dyslipidemia and vascular inflammation such as CRP levels (Ridker et
al. 2015). Lastly, regular physical activity assists in controlling body weight by lowering the
level of adiposity, which is another cardiovascular risk factor (Ridker et al. 2015).
Dietary consumption. International cross cultural studies have shown strong correlations
between dietary habits affecting multiple CHD risk factors, such as HTN, type two diabetes, and
inflammation in both sexes (Ridker et al. 2015). In addition, dietary patterns consistent with
certain individual foods and nutrients have been shown to prevent the development of CHD
(Ridker et al. 2015). For example, women that follow the Dietary Approaches to Stop
Hypertension (DASH) (Hellar, 2016) diet have reported a reduction in systolic blood pressure by
7.1mmHg in those without HTN and 11.5 mmHg in those with HTN (Ridker et al. 2015). The
DASH-type diet emphasizes the intake of fruits, vegetables, and other plant based foods, such as

14
beans and nuts, a moderate intake of fish and whole grains with a limited amount of processed
foods, red meats, refined carbohydrates, and dairy (Hellar, 2016). Furthermore, at a 20-year
follow-up, those women that followed either a DASH-type or similar diet, such as the
Mediterranean Diet Index, had lower instances of CHD and stroke (Fung, et al., 2009). Overall,
following a heart healthy diet, such as the DASH diet, has substantial positive effects on
cardiovascular health by reducing cardiac risk factors such as HTN among the sexes.
Obesity. A body mass index greater than 30kg/m2 is defined as obesity. According to
Statistics Canada (2014), the prevalence of obesity has increased and affected 20.2% of
Canadians in 2014. From 2003 to 2014, obesity increased among males from 15% to 21.8% and
in women from 14.5% to 18.7% (Statistics Canada, 2014). Obesity is an epidemic associated
with many chronic diseases such as hypertension, diabetes type two, and CHD (Tjepkema, 2006).
According to the Framingham Heart Study, the rate of diabetes, particularly among those with a
BMI > 30kg/m2, has doubled over the past three decades. Studies, such as the Nursing Study,
found obesity as a strong predictor of diabetes, which is a risk factor for CHD (Oh et al, 2005).
Furthermore, studies have linked a higher rate of mortality from CHD in obese women compared
to women with a BMI < 23kg/m2 (NHANES, 2004). According to the Framingham study, obese
females also demonstrate a decrease in life expectancy of approximately 7.1 years (as cited in
Gulati & Bairey Merz, 2015). However, the level of activity a patient engages in also contributes
significantly to CHD. Recent studies suggest that physically fit obese females are not at a higher
risk for CHD, whereas non-physically fit lean females are at a higher risk, so BMI is not
conclusive alone of individual risk (Gulati & Bairey Merz, 2015).
Non-traditional risk factors in women. Non- traditional risk factors, also referred to as
unconventional or non-established risk factors, include variables that have not been thoroughly

15
researched in terms of their direct association with CHD in either men or women. Nontraditional risk factors include the following: inflammatory markers such as high sensitivity creactive protein (hsCRP), post-menopausal state, mental health such as depression and stress,
and co-morbid states such as polycystic ovary syndrome (PCOS) and autoimmune disorders. The
following section summarizes some of the emerging non-traditional risk factors and highlights
their possible association with the development of CHD in women.
High sensitivity c-reactive protein. HsCRP is yet to be firmly established as a causal risk
factor for CHD, although this biomarker may enhance CHD risk detection in women (Cook,
Buring, & Ridker, 2006). In the Women’s Health Study, when hsCRP was utilized within a
global risk assessment tool, it was able to improve CHD risk prediction in women (Cook et al.
2006). Currently hsCRP is not included in the guidelines for routine screening and is
recommended as an additional test only in specific intermediate risk patients (Gulati & Bairey
Merz, 2015).
Post-menopausal state. Aging is one of the most dominant risk factors for CHD in both
females and males (Gulati & Bairey Merz, 2015). However, females tend to experience coronary
events 10 years after males (Gulati & Bairey Merz, 2015). For instance, women age 55 years old
or older are considered at risk for disease whereas men are already considered at increased risk at
age 45 (Gulati & Bairey Merz, 2015). The incidence of mortality from a coronary event is twice
more likely to occur in women than in men during middle adulthood, but eventually affects all
sexes equally in late adulthood (Gulati & Bairey Merz, 2015). Numerous adverse changes that
contribute to the increased risk in CHD occur in women after menopause (Ridker et al. 2015).
For example, metabolism of glucose and lipids are altered causing a rise in LDL cholesterol and
glucose intolerance and a decline in HDL cholesterol as well as changes in hemostatic factors

16
and vascular function (Ridker et al. 2015). The normal changes that occur in the menopausal
stage are driven by a decline in endogenous estrogen and from the hormonal changes in which
estradiol levels decline and androgen levels begin to dominate (Ridker et al. 2015). Furthermore,
hormonal replacement therapy after menopause has demonstrated to reduce the incidence of
CHD (Ridker et al. 2015). Due to the cardioprotective effects of estrogen, its natural decline
during menopause highlights the importance of adequate screening for CHD in women of this
age (Ridker, et al. 2015). Among the phases of menopause, the early phase, known as premature
ovarian insufficiency (POI), is proposed to have the largest impact on cardiovascular health. POS
is referred to as “natural menopause” that occurs before 40 years of age and affects
approximately 1% of women (van Lennep, Heida, Bots, & Hoek, 2015). Primary prevention
strategies targeting females in this cohort may help mitigate the risk of CHD in women.
Mental health and depression. Depression is noted to be more common among women
than men, in fact it is diagnosed twice more often in women than men (Jairath, 2001). The
pathophysiology associating depression with CHD is not clearly understood; however, some
studies propose that the secondary effects of depression, such as weight gain and decreased
physical activity, are the cause of CHD in this population (Jairath, 2001). Depression in both
men and women can led to issues with adhering to medical and behavioural interventions aimed
towards health promotion and disease prevention. In addition, recent research studies on women
with heart disease have proposed that the female myocardium may be more susceptible to both
physical and emotional stress (Mayo Clinic, 2016). Nonetheless, more research on the
association between depression and stress in women and CHD is needed before definitive
conclusions and recommendations can be made.

17
Polycystic ovary syndrome. PCOS is also the most common endocrine and metabolic
disorder among premenopausal women (Sanchon, 2012). PCOS is mainly defined as a
hyperandrogenic disorder where affected patients present with an arrangement of manifestations
that essentially include clinical and/or biochemical hyperandrogenism along with ovulatory
dysfunction and/or polycystic ovarian morphology (Azziz, 2006). Furthermore, PCOS in women
has been highly associated with developing CHD (Gulati & Bairey Merz, 2015). Women with
PCOS are more prone to develop metabolic syndrome, impaired glucose tolerance, and insulin
resistance, which are all well-established risk factors for developing CHD (Gulati & Bairey Merz,
2015). However, more research is required before PCOS can be considered an independent risk
factor for CHD (Shaw, Bairey Merz, Azziz, et al., 2008).
Autoimmune disorders. Abroad range of chronic diseases are considered autoimmune
(AI) (Amaya-Amaya, Montoya-Sanchez & Rojas-Villarraga, 2014). The majority of AI
conditions are found to affect women this includes autoimmune thyroid and liver diseases,
systemic lupus erythematosus, rheumatoid arthritis, scleroderma, multiple sclerosis and
idiopathic thrombocytopenic purpura (Kasper et al. 2016). AI conditions share common
mechanisms, such as gender disparity, genetic and epigenetics factors, environmental triggers
and abnormal pathophysiological mechansims (Amaya-Amaya et al. 2014). For example,
atherosclerosis is an autoimmune-inflammatory disease process that is associated with infectious
and inflammatory factors that is characterized by altered lipoprotein metabolism (Amaya-Amaya
et al. 2014). The altered immune system subsequently activates the proliferation of smooth
muscle cells, restricting arteries, and formation of atheroma (Amaya-Amaya et al. 2014). The
rates of CHD in women affected with autoimmune disease are greater than those in men affected
by similar conditions (Mayo clinic, 2016). As an example, the rates of CHD in women with

18
rheumatoid arthritis or systemic lupus erythematosus are higher than those observed in age and
gender matched males (Mayo clinic, 2016). It remains unclear how autoimmune disorders confer
additional risk to women – additional research is needed (Kasper et al. 2016).
Radiation therapy for breast cancer. Advances in breast cancer therapies are improving
survival in early breast cancer; however, the gains are being attenuated by increasing CAD risk
(Jones et al. 2007). Whether the increased CAD risk is due to the breast cancer therapies or to the
disease itself (which is associated with some of the same risk factors for CAD) remains unknown
(Sharma & Gulati, 2013). The effects of radiation therapy for breast cancer as a potential risk
factor is an area of active research and will be discussed further below.
Reproductive factors. Reproductive factors provide an early window into a woman’s
CHD risk; however, their contribution to CHD risk stratification is uncertain (Parikh, 2016). The
impact of reproductive complications during pregnancy on developing subsequent CHD remains
unclear and will be reviewed below.
Other potential emerging risk factors include genetic markers, reproductive hormone
therapy, endometriosis, functional hypothalamic amenorrhea, HIV infection, and homocysteine
levels (Gulati & Bairey Merz, 2015; Kasper et al. 2016; Mayo Clinic, 2015). Further research is
required to understand these emerging risk factors as the linkages remain unclear. Thus, these
will not be addressed in this review.
Risk Stratification
As previously discussed, one of the significant problems contributing to risk stratification
for disease in women is the implementation of screening tools that fail to include valuable
information for screening, such as gender-specific presentations and risks for CHD. Risk
stratification is understood as “a formal estimate of the probability of a person's succumbing to a

19
disease or benefiting from a treatment for that disease” (Risk stratification, 2009, para 2).
Through risk stratification, primary care providers attempt to identify an individuals’ CV risk,
along with the presence, quantity and severity of risk factors. Risk is calculated using a risk
prediction calculation that assigns individuals to either a low, moderate, or high level of risk.
Based on this risk assessment, primary prevention measures designed to delay or mitigate risk,
including pharmacological and/or behavioral interventions, can be instituted (Ridker, et al. 2015).
For many years, the use of risk stratification models, such as the FRS has been the
cornerstone for CHD prevention. In primary care, the FRS is the most widely recognized risk
assessment tool and is featured in multiple clinical practice guidelines on primary and secondary
prevention across both genders. In fact a survey that was conducted by Gupta et al. (2012),
suggested that FRS was implemented for CV risk stratification in approximately 2/3 of Canadian
PCPs. However, more than 100 risk assessment models based on a variety of different study
cohorts exist, many of which have been noted to have limitations in women. Examples of some
commonly used risk assessment tools in addition to the FRS include: the American Treatment
Panel (ATP) III CHD risk score, the Reynolds Risk Score (RRS) for women, the ACC/AHA
Cardiovascular (ASCVD) Risk Calculator, and the Multi-Ethnic Study of Atherosclerosis
(MESA) risk tool. Each tool differs in terms of prediction variables (i.e. age, sex, hypertension,
smoking status, diabetes mellitus, and lipid values) and endpoints. In order to better demonstrate
the variation between tools, a table outlining similarities and differences among select tools has
been provided in Appendix A.
This “risk based triage system” has been implemented for almost half a century as it was
assumed it would appropriately identify at-risk patients that would benefit from primary
prevention strategies (Ridker et al., 2015, p. 891). In any case, “if the relative benefit of a

20
prevention intervention is similar across all levels of risk, then the greatest absolute benefit will
occur among persons with the highest absolute risk” (Ridker et al., 2015, p. 891). If primary
prevention strategies are distributed according to the level of risk, those in greater need will
receive treatment and thus maximum benefit, while adverse risks and costs associated with
treatment can be avoided in those at low risk of developing CHD (Ridker et al., 2015).
Risk stratification for CHD often occurs at a primary care level, in which primary care
providers, such as NPs would implement these risk prediction models to screen their patients for
the presence of cardiac risk factors. Risk stratification is generally a two step-process. The first
step includes using a suitable tool, such as the FRS, that categorizes patients who are eligible for
primary preventative care into one of the three mentioned subgroups: low, moderate, or high risk
(Ridker et al., 2015). Each subgroup represents a level of risk for developing CHD typically over
a 10-year time frame (Ridker et al., 2015). The level of risk for developing CHD and/or
experiencing a coronary event is calculated based on the patient’s number of risk factors. This
level of risk is also referred to as a risk score, or estimated risk percentage that guides
practitioners towards the next step in care.
Lifetime Risk for Developing CHD
The relative risk of developing CHD and experiencing a subsequent coronary event is
related to the number of co-existing cardiovascular risk factors (Lloyd-Jones et al., 2006). The
risk of developing CHD appears proportional to the intensity and number of risk factors (LloydJones et al., 2006). The Framingham Heart Study assessed the long-term outcomes of individuals
with optimal, non-optimal, or major cardiovascular risk factors (Lloyd-Jones et al., 2006). Table
B summarizes these different categories of risk factors (Ridker et al., 2015)

21
Table 2: Categories of Cardiac Risk Factors
Category of risk
Cardiac Risk factors
Optimal risk
Includes individuals who:
factors
• do not have diabetes
• have untreated systolic blood pressure that is less than 120 mmHg
• have untreated diastolic blood pressure that is less than 60mmHg
• are non-smokers
• have a total cholesterol of < 4.7 mmol/L
Non-optimal risk
Includes individuals who:
factors
• are non-smokers
• do not have diabetes
• have a total cholesterol between 4.8 to 5.1 mmol/L
• have untreated systolic blood pressure that is 120 to 139 mmHg or a
diastolic blood pressure of 80 to 89 mmHg
Major Risk Factors Includes individuals who:
(well established
• have untreated hypertension >160/100
traditional & non• are smokers
traditional)
• have diabetes
• have a total cholesterol of > 6.2 mmol/L
The absence of risk factors both markedly lowers lifetime risk for CHD and prolongs
survival. For example, the lifetime risk for developing CHD is considerably less in individuals
with optimal risk factors than those with at least one non-optimal risk factor. The risk is also
significantly lower in individuals with optimal risk factors in comparison to those with two or
more major risk factors. However, this lifetime risk is merely a representation of the average
experience among the large cohorts under study, therefore caution should be taken when
applying this research to individual health outcomes (Lloyd-Jones et al., 2006). Furthermore,
given the fact that the relative risk for developing CHD and experiencing a subsequent coronary
event is reflected in the number of co-existing non-optimal, elevated, and major cardiac risk
factors, risk stratification has become an essential component of preventative health care. With
effective screening, we can stratify and thus mitigate risk at earlier stages of disease progression.

22
The following section provides a summary on current practice guidelines that promote risk
stratification practices in women for CHD prevention.
Clinical Guidelines for CHD Prevention
According to the Institute of Medicine, clinical guidelines are defined as "statements that
include recommendations intended to optimize patient care that are informed by a systematic
review of the evidence and an assessment of the benefits and harms of alternative care options.”
(as cited in NHLBI, n.d., para 4). Clinical practice guidelines are recommendations created for
health care practitioners to follow when caring for patients with particular conditions. For
instance, several guidelines on CVD prevention have been put forth by national societies such as
the CCS and American heart (AHA). For the most part, clinical practice guidelines stem from
both the best evidence based research available and expert opinion. Several clinical practice
guidelines exist that address CVD prevention in the general population. The guidelines most
applicable to the background and context of this project include the “Guidelines for the
Prevention of CVD in Women—2011 Update” by Mosca et al. (2011) and the ACC/AHA
Guidelines for Cardiovascular Risk Assessment by Golf (2014). The guidelines by Mosca et al.
(2011) were commissioned by the AHA and targeted women specifically (Mosca, et al., 2011).
The second set, although not specific to women, addressed essential aspects of cardiovascular
risk assessment (Golf, 2014). There are limited Canadian-based guidelines that link directly to
the research question thus American guidelines were selected for this review.
The revised guidelines by Mosca et al. (2011) are endorsed by several scientific and
national organizations, such as the World Health Organization, to reduce the pervasiveness of
CVD in women (Mosca et al., 2011). The updated guidelines include many specific risk factors
for developing CHD that are unique to women and more importantly they recognize that the

23
female gender is an independent risk factor for CHD (Mosca et al., 2011). According to the
guidelines, the aggregation of one or more major risk factors, including lifestyle and genetic
factors, would result in a woman being considered at risk (Mosca et al., 2011). Importantly,
novel risk factors such as preeclampsia, gestational diabetes, pregnancy complications,
inflammatory biomarkers, and conditions more common in women (lupus and rheumatoid
arthritis) are included in the 2011 guidelines (Mosca et al., 2011). The guidelines list depression
as a possible risk factor for CVD, as it contributes to poor adherence to both preventative
therapies and behavioural interventions (Mosca et al., 2011). The guidelines also address
ethnicity and race as among the top non-modifiable risk factors for CVD in women (Mosca et al.,
2011). Acknowledgement of these additional novel risk factors can lead to earlier identification
of risk and earlier implementation of primary prevention interventions for CVD in women
(Mosca et al., 2011).
The 2011 updated guidelines for the “Evaluation of CVD Risk” include: 1) medical
history, family history, pregnancy complication history 2) CVD symptoms 3) Depression
screening in women with CVD 4) Physical examination including blood pressure, body mass
index, waist size 5) Laboratory tests including fasting lipoproteins and glucose, Framingham risk
assessment if no CVD, or diabetes (Mosca et al., 2011). After this initial evaluation of CVD risk,
clinicians are to use the adopted and modified “Classification of CVD Risk in Women,” which is
presented within this guideline, to determine a patient’s level of risk prior to the consideration of
appropriate primary prevention interventions (Mosca et al., 2011).
The 2011 guidelines continue with the 2007 approach to general “Classification of Risk
in Women” as “At High Risk”, “At Risk”, or “Optimal Risk” based on evidence from studies
that supported the algorithm from 2007 even though event rates differed amongst different ethnic

24
groups (Mosca et al., 2011). However, the 2011 update has added an “Ideal Cardiovascular
Health” category to replace the “Optimal Risk” category for those with absence of clinical CVD.
The idea is that if ideal cardiovascular health is maintained, it will reduce the lifetime risk of
CVD events, lower healthcare costs, and improve quality of life in old age (Mosca et al., 2011).
The updated 2011 guidelines “Classification of Risk in Women” are summarized in Table 3.
Table 3: Classification of Risk in Women (Mosca et al., 2011)
High Risk
• Clinically manifest CHD, clinically manifest cerebrovascular disease,
clinically manifest peripheral arterial disease, abdominal aortic aneurysm,
(≥1 high-risk
end-stage or chronic kidney disease, diabetes mellitus, and 10-yr predicted
states)
CVD risk ≥10%.
At Risk
• Cigarette smoking, SBP ≥120 mmHg, DBP ≥80 mmHg, or treated
hypertension, total cholesterol ≥200 mg/dL, HDL-C <50 mg/dL, or treated
(≥1 major risk
for dyslipidemia, Obesity, particularly central adiposity, poor diet, physical
factor[s])
inactivity, family history of premature CVD occurring in first-degree
relatives in men <55 y of age or in women <65 y of age, metabolic
syndrome, evidence of advanced subclinical atherosclerosis (i.e., coronary
calcification, carotid plaque, or thickened IMT), poor exercise capacity on
treadmill test and/or abnormal heart rate recovery after stopping exercise,
• systemic autoimmune collagen-vascular disease (i.e., lupus or rheumatoid
arthritis) and history of preeclampsia, gestational diabetes, or pregnancyinduced hypertension.
Ideal
• Total cholesterol <200 mg/dL (untreated), BP <120/< 80 mmHg
cardiovascular
(untreated), fasting blood glucose 100 mg/dL (untreated), BMI <25 kg/m2,
health
abstinence from smoking, physical activity at goal for adults >20 y of age:
≥150 min/wk. moderate intensity, ≥75 min/wk. vigorous intensity, or
combination and healthy (DASH-like) diet.
Furthermore, the 2011 guideline updates acknowledge the use of either the RRS or the
for a 10-year global CHD risk assessment. However, the new guidelines do not endorse regular
screening of hsCRP, since there is no data for improved clinical outcomes based on a reduction
of hsCRP, which is a RRS requirement (Mosca et al., 2011).
Although not specific for women, the 2014 ACC/AHA Guidelines for Cardiovascular
Risk Assessment does address issues of ethnicity (Golf, 2014). It serves a solid framework for
primary care clinicians because it includes stroke as an adverse cardiac outcome, it emphasizes

25
shared decision making between the physician and patients, and it estimates a 10-year risk of
atherosclerotic CVD in African Americans and non-Hispanic whites (Golf, 2014). The
ACC/AHA guidelines and the respective atherosclerotic CVD risk calculator included in the
guidelines can be adjusted based on individual expertise and clinical judgment to enhance the
accuracy and reliability of risk assessment tools and guidelines (Golf, 2014). The ACC/AHA
guidelines attempt to meet the needs of a more diverse population with the inclusion of their
latest atherosclerotic CVD risk calculator (Golf, 2014).
The revised atherosclerotic CVD risk calculator includes a 10-year risk assessment
starting at age 40 and a lifetime risk calculation between 20-39 years of age (Golf, 2014).
Importantly, it also emphasizes shared decision making between the physician and patient
regarding level of risk, adverse effects of pharmacotherapy, risk reduction with drug therapies,
and contemporary lifestyle modifications (Golf, 2014). The ACC/AHA guidelines attempt to
meet the needs of a more diverse population with the inclusion of their latest atherosclerotic
CVD risk calculator (Golf, 2014). While the Atherosclerotic CVD Risk Calculator has its
limitations, it can be tailored to meet the needs of ethnic women until validated female-specific
multi-variate risk assessment tools are constructed (Golf, 2014).
The above guidelines will be highlighted throughout this review for a variety of reasons:
they are contemporary; they highlight key challenges when trying to implement risk stratification
in a multicultural society; and they clearly demonstrate the limitations of currently available risk
stratification tools in women.
Risk Stratification beyond Traditional Risk Prediction Models: Adjunctive Tests
Three measurements proposed as potential adjuncts to traditional risk assessment
screening include the ankle-brachial index which measures the blood pressure difference

26
between the arm and the leg, the carotid intima-media thickness as measured on a carotid
ultrasound, and the coronary artery calcium (CAC) score (Golf, 2014). Of these, CAC screening
has the most compelling emerging data in women (Kelkar et al., 2016; McClelland et al., 2015;
& Polonsky et al., 2010). The CAC score is calculated during a standard cardiac computed
tomography scan and measures of the amount of calcium in the walls of the epicardial coronary
arteries that supply the heart (Golf, 2014). The potential impact of CAC screening on risk
stratification in women will be discussed in the following chapters.
Gender Disparities in the Management of CHD
Gender is an independent risk factor for CHD, thus there are multiple issues that pertain
solely to the management of CHD in women. There is a lack of awareness regarding the
prevalence of CHD in women (Mosca, 2006). For example, many primary care providers have
misperceptions of CHD in women and often do not recognize that CHD presents differently in
women (Banner et al., 2011; Maas & Appleman 2010). There is also evidence to suggest that
women do not recognize their risk, minimize their symptoms and are less likely to seek help in a
timely manner (Albarran et al., 2007). Unfortunately women are more likely to have
comorbidities, unique risk factors, a different pathophysiology of CHD compared to men,
atypical symptoms such as nausea, vomiting, indigestion, and upper back pain, and often women
may require female-specific management strategies (HSFC, 2014; Mosca, 2006; Sharma &
Gulati, 2013). Women are also less likely to undergo diagnostic and therapeutic cardiovascular
procedures that investigate for CHD (Daly et al., 2005). For example, a large cohort study by
Daly et al. (2005) revealed women who presented with stable angina were not referred to
appropriate specialists, nor were their symptoms thoroughly investigated.
Furthermore, the impact of CHD on women has traditionally been underappreciated,

27
largely because of the higher incidence rates of CVD at younger ages in men (Maas & Appleman,
2010). However, CHD remains a major cause of death among women (Maas & Appleman 2010).
This fact dispels the traditional misperception that females are at low cardiovascular risk that is
still held by many health care professionals (Sharma & Gulati, 2013). Furthermore,
misconceptions of low female risk results in delays in investigation, diagnosis, and treatment of
CHD in women compared to men (Miracle, 2006). Several studies have documented the time
from symptom to first medical provider contact and time from hospital admission to reperfusion
is considerably longer in women than men (Collins, 2012). Likewise, studies that examined men
and women admitted to a coronary care unit for acute coronary syndrome, found that men were
more likely to undergo coronary artery bypass graft surgery and be referred to cardiac
rehabilitation programs than women (Colella al., 2015). The outcomes in women are
significantly worse mainly, because they receive treatment at a later stage and often have
multiple co-morbidities at the time of treatment (Banner et al., 2011). Furthermore, women
remain underrepresented in clinical trials of CVD (O’ Neal et al., 2013). The many differences in
CHD management among the sexes are well documented and it is clear that in order to provide
optimal care gender differences must be taken into consideration (McKibben, 2016). Ideally
these differences should be reflective in all aspects of CHD management including the initial
steps pertaining to its prevention. The following section will provide a brief overview of primary
care and the role of the NP.
Primary Care
Primary care is an important concept within the public health care system and has a
strong mandate for disease prevention and health promotion (Government of Canada, 2012).
Primary care includes health care services that can be accessed directly by patients who are

28
seeking medical attention (Martin, 2015). Primary care includes health promotion and disease
prevention. Healthcare systems that focus on preventing diseases as opposed to treating diseases
after they present are not only patient-focused but also more cost effective and efficient (Center
for Disease Control and Prevention (CDC), 2013). This branch of medicine is known as
preventative medicine and its main focus is to prevent or delay the progression of diseases
(Martin, 2015). Preventative medicine includes actions aimed towards “the anticipation,
communication, prediction, identification, prevention, education, risk assessment, and control of
communicable diseases and illnesses, and exposure to endemic, occupational, and environmental
threats” (Preventative Medicine, 2015). These actions promote the desired outcome to protect,
promote, and maintain health and overall wellbeing in order to prevent disease, disability, and
death (American College of Preventative Medicine [ACPM], 2016). Preventative medicine is
fundamental to the practice of all health care providers to keep individual patients, communities,
and defined populations as healthy as possible (ACPM, 2016). Ongoing research is thus needed
to ensure primary prevention strategies are evidence based, current, and tailored to specific atrisk populations. Since CHD prevention is largely undertaken in primary care settings, which
encompasses a mandate for preventing disease, primary care was chosen as the context and
clinical practice setting for this project.
Nurse Practitioner Practice in Primary Care
On a daily basis, thousands of Canadians seek primary care services. At the centre of
such services is the primary care provider, typically a General Practitioner or family Nurse
Practitioner (Canadian Institute for Health Information [CIHI], 2016). The family NP is a
category of NPs that work in various settings, such as in primary care, where they provide
several aspects of PHC services to those in need, including preventative care. NPs are health care

29
professionals who have chosen to complete additional advanced training at a graduate level to be
competent in the skill sets to diagnosis and manage a wide range of acute and chronic illnesses.
Each province outlines its own scope of practice for NPs, yet this scope is very similar across the
country. For example, the legislated scope of practice for NPs in BC and Ontario allows NPs to
manage patients through various health care services, such as administrating and ordering
screening and diagnostic tests, prescribing interventions and medications, and referring patients
for further specialty care services (College of Nurses of Ontario [CNO], 2016; College of
Registered Nurses of British Columbia [CRNBC], 2016). NPs are able to provide primary care
services to diverse patient populations and integrate knowledge from a variety of scientific and
health profession sources, including nursing and medicine. NPs have the scope of practice,
competency, and skill sets to provide appropriate primary care, including evidence-based
cardiovascular risk assessment. For this reason, NPs, as primary care providers, are well
positioned to optimize cardiovascular risk stratification for CHD in Canadian women.
The following section will discuss the search methods that were undertaken to select the
most relevant literature in order to answer the research question: How can NPs in a primary care
setting optimize CV risk stratification for CHD in Canadian women?

30
CHAPTER 3
Search Methods
In order to address the research question, an integrative review of the contemporary
literature was undertaken. This review provides an opportunity for literature of various sources
and mixed methodologies to be explored. Subsequently, the most current evidence based
research will be drawn upon to enhance future primary care practice and patient outcomes. The
literature review is presented below in four stages: 1) conceptualization and search strategy, 2)
preliminary search, 3) focused search, and 4) analysis and reporting.
Stage I: Conceptualization and Search Strategy
This project is based on the clear need for better guidance for primary care providers
towards optimizing CV risk stratification for CHD in Canadian women. The review is both
timely and highly relevant for NPs as they work with women on a daily basis in a primary care
setting and have a clear primary prevention mandate that encompasses individuals, communities,
and defined at-risk populations. The following research question was established: How can NPs
in a primary care setting optimize CV risk stratification for CHD in Canadian women? To ensure
that the most relevant and current literature was reviewed, multiple eligibility criteria, including
strict inclusion and exclusion criteria, were utilized. Eligibility criteria are listed in Table 4. All
forms of CHD were factored into the searches, with preference given to articles that also
discussed risk factors for CHD and/or risk stratification in women.

31
Table 4: Eligibility criteria for literature review inclusion and exclusion criteria
Inclusion criteria
Exclusion criteria
- Literature published in the English
- Studies conducted in an acute care or
language from January 2006 to June 2016
specialty setting, i.e. hospital or CCU
- Articles addressing CHD
- Articles pertaining to risk assessment with
cardiac surgery (coronary artery bypass
- Articles addressing risk assessment, risk
graft [CABG])
stratification, or risk screening
- Articles that address other CVDs as the
- Articles addressing primary prevention
main focus such as CHF and sudden
- Articles addressing cardiovascular or
cardiac death, secondary prevention or
coronary risk factors
diagnosis and treatment of CHD.
- Primary care or primary health care, and
community care
- Primary care provider (i.e. nurse
practitioner or general practitioner)
- No restrictions on geography with priority
given to studies conducted within Canada,
the US, and Europe
Since CHD in women is associated with numerous cardiovascular risk factors and comorbid conditions, many articles within the searches focused largely on risk stratification with
individual risk factors, such as hormonal changes and depression. Relevant articles that focused
on screening and risk stratification for CHD in general were also included, as these provide a
breath of research pertaining to risk stratification for CHD that can be applied to the target
population. Research articles on CVDs as their main focus, without specific attention to CHD,
were excluded in order to maintain a narrow and concise collection of relevant studies that
pertain to the research question. Since the focus of this project is to improve NP practices in
Canadian primary care settings, all studies were screened for their applicability to this context.
However, since the majority of risk factors for CHD are similar among populations worldwide,
studies relevant to the research question that were conducted in other countries were considered
for review. To capture the most up-to-date evidence, preference was given to articles conducted
within the last ten years. However, to ensure that all relevant studies were obtained, landmark

32
studies beyond 10 years were also screened. Due to the large body of literature that was obtained,
preference was given to systematic reviews and meta-analysis that combined large data fields.
Stage II: Preliminary Search
A preliminary search of relevant literature was first conducted using the Google Scholar
database. The purpose of this preliminary search was to orientate the researcher to the literature
and associated search terms. The initial search conducted in this phase of the project used the
following search terms: CHD, women, and screening. This produced 23,200 results. The initial
250 articles were reviewed to determine the relevant articles and to establish a set of
comprehensive and pertinent search terms in preparation to utilize them for the main literature
search. For example, based on the initial preliminary search key search terms under each article
title, such as screening, risk stratification, and risk assessment were considered for the main
search. Following this, a comprehensive literature search of peer-reviewed articles using the
Medline, CINHAL, PubMed, PsycARTICLES and Cochrane databases were undertaken. In
order to keep the search focused and relevant to NP in primary care settings, combinations of key
search terms and/or medical subject headings (MeSH) were incorporated into searches. The
search terms and MeSH headings that were utilized are outlined in Table 5.
Table 5: Search terms and MeSH terms for the literature review
Population/Problem “women”; “coronary artery disease” OR “coronary heart disease” OR
“CVD” OR “cardiovascular risk”
Intervention
“cardiovascular screening” OR “risk assessment” OR “risk prediction
algorithms” OR “risk score” OR “risk prediction score” OR “risk
prediction model” OR “novel risk factors” OR “Framingham risk score”
“Reynolds Risk Score” OR “non-traditional risk factors” OR “risk
stratification”; “preventative medicine” OR “primary prevention”; “nurse
practitioner” OR “primary care provider” OR “physician” OR “general
practitioner” or “coronary artery calcium screening”
Context
“primary health care” OR “primary care”
Outcome
“cardiovascular risk factors” OR “coronary risk factors”; “morbidity and
mortality”; “MI” OR “coronary event in women”

33
Following an initial database search, titles and abstracts of articles were screened for
relevance. During this phase, all duplicate articles were removed. The initial database search of
Medline utilized the MeSH terms such as “risk assessment” OR “risk stratification” OR
“screening” AND “coronary artery disease” OR “coronary heart disease” AND “women” OR
“adults” produced 715 articles. All 715 titles were screened and 40 articles from relevant titles
and/or abstracts were reviewed. Publication dates were initially not included to allow for
screening of older influential articles. After careful initial review, manuscripts published between
2006 and the present were given priority.
Literature was selected using a rigorous process that included assessing all articles for
their relevancy to the research topic and question, their scientific rigor, and their appropriateness
to clinical practice. In order to ensure all relevant literature was included, reference lists of all
articles were hand searched. A wide variety of articles were eligible for this review including
critical reviews, meta-analyses, systematic reviews, randomized control trials, experimental
designs, cohort studies, survey studies, and qualitative studies. A significant proportion of
articles were not eligible for the final review and discussion; however, many articles contained
valuable information that was used to provide clarity and background context on risk
stratification, screening, CHD, and the role of NP practice within the context of a primary care
setting. Table 5 outlines the search results obtained from all four online databases, including the
total number of results obtained, results without duplicates, results with titles and abstracts
screened, and final results following eligibility criteria.

34
Table 6: Results of the database search
Database
Search results
Results without
Duplicates
Medline
CINHAL
Cochrane Review
PubMed
PsycARTICLES
Total

715
820
54
1802
66
3,457

430
620
25
510
60
1,645

Articles selected
based from
titles/abstracts
40
54
3
165
4
266

Results based on
eligibility Criteria
2
5
0
3
1
11

Stage III: Focused Search
A focused search was undertaken to generate the final cohort of articles. Within this
search all abstracts were reviewed and eligibility criteria were applied. The number of
manuscripts was thus reduced to the 11 most relevant articles. During this stage a detailed review
on the quality of evidence and relevancy to the research question and topic was undertaken. This
critical appraisal process was guided and supported with checklists and tools provided by Critical
Appraisal Skills Programme (CASP). Three examples of CSAP checklists that were utilized
during this stage are included in Appendix B. The final selection of articles for inclusion in this
integrative review consisted of 11 independent primary studies.
Stage IV: Analysis and Reporting
The final cohort of articles were read in detail and reviewed thoroughly. Following
individual review using the CASP tools, the articles were analyzed in detail and presented
thematically. Analysis of the literature identified three major themes that together help answer
the above primary research question of this integrative review:
1.) The limitations of current risk prediction models for risk stratification in women.
2.) The emergence and evolving importance of female-specific risk factors.
3.) Additional adjunctive testing (coronary artery calcium screening) that may improve the
accuracy of risk prediction models in women

35
Three articles discussed the limitations of current risk stratification tools in women. Five
articles addressed the emergence and evolving importance of female-specific risk factors. Finally,
three articles highlighted additional adjunctive testing (coronary artery calcium screening) that
may improve the accuracy of risk prediction models in women. The following section will
provide an overview of the findings of this review.

36
CHAPTER 4
Findings
This project is an integrative review that seeks to explore how NPs in a primary care
setting can optimize CV risk stratification of CHD in Canadian women. In order to answer this
research question, a systematic search process, as outlined in the previous chapter, was
undertaken and the selected literature was reviewed for its content and methodological rigor. A
final cohort of 11 articles was captured for analysis. Through the literature analysis three major
themes emerged: 1) The limitations of current risk prediction models for risk stratification in
women; 2) The emergence and evolving importance of female-specific risk factors; 3) Additional
adjunctive testing (coronary artery calcium screening) that may improve the accuracy of risk
prediction models in women. These themes will now be presented.
The Limitations of Current Risk Prediction Models for Risk Stratification in Women
Currently, risk assessment tools are the cornerstone of risk stratification in both men and
women. Three studies were captured in this review that explored the outcomes of risk prediction
models that can be utilized in a primary care setting, such as Framingham risk based models, the
RRS, and ACC/AHA (ASCVD) Risk Calculator in populations that included women. Findings
from these studies reveal some major limitations to current risk assessment tools that must be
considered in order to improve future CV risk stratification in women. The following section will
now elaborate on these findings.
Ridker, Buring, Rifai and Cook (2007) conducted a study that explored cardiovascular
risk algorithms for women, based on a large panel of traditional and novel risk factors.
Participants for this study included 24,558 women derived from the Women's Health Study, a
cohort of multiethnic US women, 45 years of age or greater, with no evidence of CVD (Ridker et

37
al. 2007). Baseline novel biomarkers and major traditional risk were assessed in all participants
(Ridker et al. 2007). One third of participants (validation cohort, n = 8158) were assigned to a
validation data set, while the remaining two thirds (derivation cohort, n = 16 400) were randomly
assigned to the derivation data set (Ridker et al., 2007). The analysis used a combination of end
points including MI, ischemic stroke, coronary revascularization, and cardiovascular mortality
with an average follow-up of 10.2 years.
Two novel algorithms for global risk prediction based on the RRS were developed from
the derivation cohort: Model A and Model B. Details for each model are presented in
Table 7.
Table 7: Two new algorithms for global risk prediction based on the RRS: Model A and Model B
Model A
Model B
• Age,
• Age,
• systolic blood pressure,
• systolic blood pressure,
• current smoking status,
• hemaglobin A1C with diabetics,
• apolipoprotein B-100,
• current smoking status,
• apolipoprotein A-I,
• total and HDL-C,
• hsCRP, and
• hsCRP, and
• history of MI in parents before the age of
• history of MI in parents before the age of
60
60

Both models were tested using the validation cohort and the predicted and observed 10year cardiovascular event rates were compared. Summary statistics (Entropy, Yates Slope, Brier
Score, and C statistic) were calculated with each test cohort and compared with covariates used
in the ATP III or the FRS. Based on the summary statistics, models A and B demonstrated
improved measures of fit, discrimination, and calibration as they appropriately reclassified 40 to
50% of women into either a higher or lower risk category (Ridker et al., 2007). In fact, a
significant portion of women predicted to have low (5 to 10%) or intermediate (10 to 20%) 10year risk estimate using ATP-III risk scores were appropriately reclassified as either lower or

38
higher with the new models. Based on this study, incorporating a larger number of traditional
and novel risk factors, such as inflammatory markers, haemoglobin A1c and family history, into
risk scores provides for more accurate risk stratification in women. This will provide a more
accurate picture of risk in women and can thus inform more appropriate risk management, which
ultimately could reduce incidence of CHD in women. This study highlights the opportunity for
improved risk stratification with female-specific screening tools. It also clearly demonstrates that
the modified RRS may be a better option for risk stratification for CHD in women.
The focus of this study in terms of population, risk factors, and anticipated outcomes
were clear and the cohorts, being adequately powered and female-based, were clear strengths.
Nonetheless, the study was not without its limitations. The population sample was mostly
comprised of Caucasian females within a limited socioeconomic range. This limits the
generalizability of the findings to other populations. Furthermore, data on blood pressure, obesity,
and family history were based on self-report, creating a potential for bias (Ridker et al., 2007).
However, it should be noted that the majority of women in the WHI were healthcare
professionals and thus may be better at self-reporting than the general population (Kurth et al.,
2005). The following study by Cook et al. (2012) confirms these findings in a multiethnic
diverse female population.
Similar to the findings of the previous study, a prospective cohort design study conducted
by Cook et al. (2012) found the RRS superior to other commonly used risk prediction models in
women. In this study, the clinical performance of the RRS was compared with two Framingham
risk based scores, the ATPIII-FRS-CHD and FRS-CVD. The study sample was selected from an
independently validated case cohort from the Women’s Health Initiative Observational Study
(WHI-OS) that included 93,676 originally healthy postmenopausal American women of

39
multiethnic backgrounds between 50 to 79 years of age (Cook et al., 2012).
The final sample of 1,722 included women of Hispanic, Asian, African American and
Caucasian backgrounds. A sub-cohort of 2000 cases, based on the same eligibility criteria, were
further stratified to match both ethnicity and age. Event rates in the final cohort included 752
cases with MIs, 754 with ischemic strokes, and 216 with CVD related deaths (Cook et al., 2012).
In the study by Cook et al., (2012), average predicted risk was calculated using published
equations from the FRS for CHD, FRS for CVD, and RRS for CVD. Calibration plots were used
to compare observed and predicted risk sampling. Each model was recalibrated to produce an
average predicted risk that equalled the overall incidence of major CVD at 10 years due to the
different endpoints examined by each tool (Cook et al., 2012).
Cook et al. (2012) found that the RRS was relatively well calibrated for endpoints for
major CVD, whereas the ATP-III-FRS-CHD overestimated CHD risk since the predicted values
were higher than those observed. The FRS-CVD model overestimated for major CVD (Cook et
al., 2012). The RRS and the ATP-III-FRS-CHD demonstrated better discrimination than the
FRS-CVD; however, the RRS demonstrated better discrimination for African American and
Caucasian women (Cook et al., 2012). Calculated risk scores for each model are listed in the
table below (Cook et al., 2012).
Table 8: Risk scores from ATP III, RRS, and Framingham CVD models
Risk
ATP III
RRS
Framingham CVD models
Average Risk
3.8%
4.6%
10.9%
Estimated risk >10%
5.5%
10.3%
41.1%
Estimated Risk > 20%
0.5%
2.6%
10.6%
Overall, this study demonstrated that the RRS was better at predicting risk in a
multiethnic female population than either the ATPIII-FRS-CHD risk score or the FRS-CVD
score with a higher c statistic (0.765 versus 0.757; P=0.03), positive net reclassification

40
improvement (NRI; 4.9%; P=0.02), and positive integrated discrimination improvement (4.1%;
P<0.0001) (Cook et al., 2012). Similar to the previous study, the RRS was better calibrated than
the Framingham-based models in this large external validation cohort and demonstrated
improved discrimination in multiethnic women.
Clear strengths of the study included the multiethnic population and 10 year outcome
measures. The large, adequately powered sample was derived from the ethnically diverse WHIOS population. However, the study was not without limitations. The sample was comprised of
women of older age, thus generalizability of the findings to younger women is limited (Cook et
al., 2012). Traditional risk factors are less predictive with age, thus the findings may be also be
less precise (Cook et al., 2012). Also, the calibration of tools may have been suboptimal as the
endpoints used to generate the three different risk scores differed with each other and with the
primary endpoints used in the WHI-OS and thus required recalibration (Cook et al., 2012).

Nonetheless, the endpoints for all three tools were recalibrated for major CVD endpoints (MI,
ischemic stroke, coronary revascularization, and cardiovascular mortality) and thus the results
were relevant when considering primary prevention in the ethnically diverse Canadian female
population (Cook et al., 2012).
The next study captured in this review examined five current risk stratification tools in a
larger multiethnic population and provides additional valuable insights to the conclusions drawn
by Ridker (2007) and Cook (2012). In a landmark study undertaken by DeFilippis et al. (2015),
the limitations of current risk prediction models were again identified, particularly with respect
to women. DeFilippis et al. (2015) evaluated the discrimination and calibration of four risk
prediction algorithms derived from 1998 to 2008: 1) FRS-CHD 2) FRS-CVD 3) ATPIII-FRSCHD and 4) RRS in comparison to the ACC/AHA pooled risk calculator from 2014. The

41
analysis was conducted using the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The
final population consisted of 4,227 middle-aged men and women of Caucasian, African
American, Hispanic, and Chinese backgrounds from 6 different communities, aged 50 to 74,
without prior CVD or diabetes. At an average of 10.2 years of follow-up, Hosmer-Lemeshow
calibration plots were used to assess for discordance between observed and expected event rates
for the target end points of all five risk scores (DeFilippis et. al., 2015). All risk calculators were
examined for their designated endpoints, thus the number of expected events and the number of
observed events were reported for each specific target end point.
As outlined in the table below, the ACC/AHA pooled risk calculator, along with the FRSCHD, FRS-CVD, and the ATPIII-FRS-CHD all overestimated the risk of cardiovascular events
in women by 48%, 8%, 46% and 67% respectively.
Table 9: Estimation of cardiovascular risk scores in men and women.
Risk Score
Men Risk Score %
Women Risk Score %
FRS-CHD
53%
48%
FRS-CVD
37%
8%
ATPIII-FRS-CHD
154%
46%
ACC/AHA pooled risk calculator
86%
67%
RRS
9%
- 21%
In this study, all four models based on the FRS overestimated risk by 25% to 115% in
women. In contrast, the RRS was superior in both calibration and discrimination but
underestimated risk by 21% in some women. Based on this study, the RRS had the best fit for
CV risk stratification in women; however, it was not without its limitations. While the population
was significantly more diverse than the studies conducted by Ridker (2007) and Cook (2012),
there were several issues with applying risk scores to the MESA cohort that could have
contributed to the systematic over and underestimation of risk by all of the above tools. Risk
factors may have a less pronounced effect on modern versus older cohorts partly due to the

42
prevalence of more effective baseline medical therapy. It is also possible there may have been a
selection bias at cohort enrollment (healthy cohort effect) or incomplete capture of all
cardiovascular events. Regardless, DeFilippis et al. (2015)’s diverse multiethnic cohort likely
best represents modern Canadian women and thus it provides further evidence that the RRS may
be the best tool for optimizing risk stratification for CHD.
In summary, the three studies highlighted above confirm there is currently no ideal risk
stratification tool for women. There is a clear need for female-specific risk stratification tools
that incorporate gender, age, and ethnicity, in addition to novel and emerging risk factors in
women.
The Emergence and Evolving Importance of Female-Specific Risk Factors
As described in the background section, multiple novel and emerging factors affecting
women have been identified. The body of literature pertaining to novel and emerging risk factors
is growing rapidly. However, there were few studies that specifically focused on risk
stratification in women. In the search of the contemporary literature, five pivotal articles that
discuss the impact of independent novel and/or emerging risk factors for CHD in women were
identified and will be summarized below. The first two studies were by O’ Neil et al. (2016). The
first study examined depression as an independent cardiovascular risk factor in women and the
second looked at the effect of adding depression to the Framingham risk equation. The third
study by van Lennep et al. (2014) assessed the effect of hormonal changes on cardiovascular risk.
The fourth study by Parikh (2016) examined the impact of reproductive complications during
pregnancy on developing subsequent CHD. The fifth study by Darby et al. (2013) evaluated the
effects of radiation therapy for breast cancer as a potential risk factor. All five studies address
potential emerging risk factors in women and thus help answer the overall research question.

43
The five articles will now be presented.
A prospective longitudinal study conducted by O’ Neil et al. (2016a) explored depression
as a possible independent risk factor for CHD in women. The analysis was conducted with 860
women aged 24 to 94 years that were randomly selected from the Geelong Osteoporosis Study
(1993–2011) in South-Eastern Australia (O’ Neil et al., 2016a). Structured clinical interviews
from the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Non-Patient
Edition (SCID-I/NP) was used to make the diagnosis of a depressive disorder and included:
major depressive disorder, bipolar disorder, dysrhythmia, minor depression, substance-induced
mood disorder, and mood disorder from medical conditions (O’ Neil et al., 2016a). The primary
study outcomes included cardiac death, MI, and coronary revascularization (O’ Neil et al.,
2016a). Secondary outcomes included unstable angina and non-coronary conditions (i.e. atrial
fibrillation, chest pain, pericarditis and coronary steal syndrome) (O’ Neil et al., 2016a). The
relationship between baseline depression and the 18-year incidence of developing CHD, adjusted
for anxiety, typical risk factors, and atypical risk factors, is summarized in the table below (O’
Neil et al., 2016a).
Table 10: Results for primary outcomes for depression
Baseline depression
Adjusted Odds Ratio
Baseline depression adjusted for
2.39
anxiety
Baseline depression adjusted for
3.22
typical risk factors
Baseline depression adjusted for
3.28
atypical risk factors

Convenience interval
95% (1.19–4.82)

p value
0.01

95% (1.45–6.93)

0.003

95% (1.36–7.90)

0.08

Over the study period, 83 participants (9.6%) experienced at least one cardiac event (O’
Neil et al., 2016a). Of these, 47 participants (57%) had a CHD event. A total of four cardiac events
occurred in individuals with baseline anxiety disorder, 13 with baseline depression, with the

44
remaining events occurring in individuals without a psychiatric diagnosis. Results support
depression as a potential independent and long-term predictor for CHD in women (O’ Neil et al.,
2016a). The analysis of the study findings revealed that the association between depression and
the incidence of CHD was significant when adjusted for typical (p = 0.003) but not atypical (p =
0.08) risk factors.
Strengths of the study included random selection from a large national sample, use of
objective CHD biomarkers, and assessing outcomes over a lengthy time frame. In addition, the
current gold standard metric for assessing depression and anxiety in non-psychiatric populations
was utilized, thus having greater relevance to contemporary clinical practice. Some limitations
were noted during the appraisal of the study. For instance, there is the potential for recall bias
when reporting retrospective data on depressive episodes (Andrews et al., 1999). Regardless,
retrospective data is widely accepted in psychiatric research (Kessler et al., 2007). In addition,
the number of ‘hard’ CHD cardiovascular events was relatively small. A second study, also by O’
Neil et al. (2016b), expands on this study by evaluating the effect of adding depression as an
independent risk factor to the FRS to predict CHD.
Currently, depression is not considered in formal risk prediction models, such as the FRS.
Given the encouraging results above, this prospective longitudinal study also by O’ Neil et al.
(2016b), explored the effect of adding depression to the Framingham Risk Equation (FRE)
model. A total of 862 Australian women, enrolled between 1993 and 2011, were included in the
study. Utilizing the same primary and secondary outcomes, the “augmented” FRE (FRS
including depression screening) only marginally improved risk prediction compared to the
standard FRE in this female sample. Results from both risk models are summarized in the Tables
below.

45
Table 11: The specificity and sensitivity for the augmented and usual Framingham risk equation
Risk score
AUC
Specificity
Sensitivity
Augmented FRE
0.77
0.70
0.75
FRE
0.75
0.73
0.67

Although the augmented FRE demonstrated marginally improved accuracy when
compared to the standard FRE, it overestimated the number of cardiovascular events (O’ Neil et
al. (2016b).
Table 12: Cox proportional-hazard regression for CHD endpoints over a 10-year follow-up
FRE variables
HR
95% CI
p value
Age
1.04
1.01, 1.08
0.005
Smoker
2.70
1.16, 2.29
0.02
HDL (mmol/L)
0.43
0.16, 1.18
0.10
Total cholesterol (mmol/L)
1,28
.95, 1.73
0.10
Systolic blood pressure (mmHG)
1.00
0.98, 1.02
0.89
Blood pressure medications
2.36
1.09, 5.11
0.03
FRE variables plus depression
Age
Smoker
HDL (mmol/L)
Total cholesterol (mmol/L)
Systolic blood pressure (mmHG)
Blood pressure medications
Baseline depression status

HR

95% CI

p value

1.05
2.26
0.44
1.23
1.00
2.34
2.62

1.02, 1.08
0.95, 5.38
0.17, 1.15
0.90, 1.68
0.98, 1.02
1.07, 5.14
1.22, 5.60

0.003
0.07
0.09
0.18
0.95
0.03
0.01

There were several limitations to this study. Depression is a heterogeneous syndrome and
can impact individuals differently in regards to symptoms, genesis, chronicity and severity (O’
Neil et al. (2016b). Due to insufficient power, the augmented FRE may not have been able to
effectively capture depressive symptomatology (O’ Neil et al. (2016b). As importantly, although
the augmented FRE demonstrated marginally improved accuracy in comparison to the usual
model, it came at the expense of a small but significant increase in the number of false positive
results and thus lead to overestimation of risk (O’ Neil et al. (2016b). Primary care providers
need to be aware of these limitations. Adequately powered long term studies are thus needed to

46
clarify the future role of depression screening in CHD risk stratification in women.
As discussed in the background, hormonal changes that are unique to women, such as
declining estrogen levels in postmenopausal women or those with ovarian insufficiency, have
been proposed to increase the risk of developing CHD. A landmark meta-analysis conducted by
van Lennep et al. (2014) explored the association between primary ovarian insufficiency (POI)
and the subsequent risk of developing CHD.
Ten observational studies comprising 190,588 women (follow-up of 4 to 37 years) and a
total of 9440 cardiovascular events (2026 CHD, 6438 stroke, and 976 CVD) were analyzed
(Roeter van Lennep et al., 2014). The meta-analysis demonstrated that POI was associated with
an increased risk of developing or dying from CHD (hazard ratio of CHD of 1.69, 95% CI, 1.292.21, p1⁄40.0001) (van Lennep et al., 2014). However, no reliable link was noted between POI
and the long-term risk for developing stroke (van Lennep et al., 2014). They concluded that POI
was an independent yet modest risk factor for CHD but not for stroke (van Lennep et al., 2014).
This study supports the speculation that hormonal changes in women can increase the risk of
developing CHD. While POI was noted to have only a modest effect on developing CHD, this
study draws attention to the potential of hormonal changes to impact cardiovascular health in
women.
In addition to POI, reproductive complications, such as preeclampsia and gestational
diabetes, have also been proposed to increase the risk of developing CHD in women. A landmark
WHI-OS explored the association between reproductive factors and CHD (Parikh, 2016). The
sample included 72 982 women with a mean age of 63 years and a total of 4607 CHD events
(Parikh, 2016). A Cox proportional hazard model for CHD was developed and included age,
pregnancy status, number of live births, age of menarche, menstrual irregularity, age at first

47
birth, stillbirths, miscarriages, infertility ≥1 year, infertility cause, and breastfeeding (Parikh,
2016). Reproductive factors were added to established CHD risk prediction models (Parikh,
2016). A final model with reproductive factors in addition to established CHD risk factors was
created. Models were assessed for improvement in C statistic, net reclassification index, and
integrated discriminatory index (Parikh, 2016).
In the final model the following factors had a positive association with CHD: younger
age at first birth, number of stillbirths, number of miscarriages, and lack of breastfeeding (Parikh,
2016). A modest improvement in model discrimination by adding reproductive factors was noted
(C statistic increased from 0.726 to 0.730; integrated discriminatory index, 0.0013; P<0.0001)
(Parikh, 2016). There was no improvement in net reclassification of risk for developing CHD in
women (net reclassification index events, 0.007; P=0.18) (Parikh, 2016). Lastly, reclassification
was slightly improved for women without events (net reclassification index non-events, 0.002;
P=0.04) (Parikh, 2016). As a result, while we await the results of adequately powered
prospective long-term studies, NPs should cautiously consider adding screening for reproductive
complications when assessing risk for developing CHD and providing preventative health
education to women.
Strengths of the above study included the WHI population, which is a rare source of longterm data on reproductive and pregnancy risk factors (Parikh, 2016). In addition, all outcomes
were carefully standardized and CHD outcomes were rigorously assessed (Parikh, 2016).
However, important limitations included a lack of pertinent data on reproductive conditions
known to be associated with CHD in previous studies, i.e. preeclampsia, pregnancy induced
hypertension, gestational diabetes, gestational age, and infant birth weight and size (Parikh,
2016). Moreover, risk factors prior to pregnancy were not assessed and data on dyslipidemia and

48
diabetes mellitus were obtained through self-report (Parikh, 2016). These limitations highlight
the need for future studies that include validated pregnancy complications such as gestational
diabetes mellitus, preeclampsia, gestational age, and infant size (Parikh, 2016).
A fifth study in this theme examined the effects of breast cancer therapy on future CHD
risk. Radiation therapy for breast cancer figured prominently in the emerging risk factors
literature. Breast cancer is the second most common cause of death in Canadian women (Darby,
2013). Therefore, understanding the association between breast cancer treatment and CHD can
help NPs conduct more comprehensive CV risk assessments in a large percentage of Canadian
women.
A landmark population-based case-control study was conducted by Darby et al. (2013) to
explore the impact of radiotherapy for breast cancer on future CVD risk. Study participants
included 2163 women that received radiotherapy for breast cancer between 1958 and 2001 in
Sweden and Denmark (Darby, 2013). Major coronary events (i.e., MI, coronary revascularization,
or death from ischemic heart disease) were evaluated at a mean follow-up of 30 years (Darby,
2013). In total, 963 women had major coronary events and 1205 were included in the control arm
(Darby, 2013). The mean radiation doses to the entire heart and to the left anterior descending
coronary artery were estimated at 4.9 Gray (range 0.03 to 27.72), a measure of total radiation
energy. An increase in coronary events was linked with a mean radiation dose to the heart over
7.4% per Gray (95% confidence interval, 2.9 to 14.5; P<0.001) without an obvious minimal
threshold level (Darby, 2013). The increase occurred within the first five years post radiotherapy
and continued into the third decade (Darby, 2013). Post radiotherapy, the relative increase in the
rate of major coronary events per gray was equivalent among women with and without baseline
cardiovascular risk factors (Darby, 2013).

49
The main strength of the above study was the cohort, which only included women with
cancer that had not recurred, thus avoiding confounding from prior cancer therapy (Darby, 2013).
The main limitation of the study was that individual CT-based information on radiotherapy was
unavailable for many of the women enrolled in the 50’s and 60’s, as they were treated before the
era of three-dimensional CT-based planning (Darby, 2013). However, 20 more recent
consecutive CT scans confirmed that the patient-to-patient variation in mean radiation dose to
the heart was relatively small and thus was unlikely to have influenced the results (Darby, 2013).
In summary, exposing the heart to ionizing radiation during radiotherapy for breast cancer
increased future rates of ischemic heart disease (Darby, 2013). The increase was proportional to
the mean dose received by the patient (Darby, 2013). The pros and cons of adding prior radiation
exposure to current risk stratification tools in Canadian women requires further evaluation in
large, adequately powered, prospective studies.
Although factors other than those reviewed above may impact CV risk in women, the
five studies summarized above make it clear that emerging risk factors, beyond traditional risk
factors, may be driving the observed sex differences in developing CVD. In order to optimize
CV risk screening in women, emerging risk factors such as depression, hormonal changes, breast
cancer treatment, and reproductive complications during pregnancy warrant further discussion
and research.
Additional Adjunctive Testing that may Improve the Accuracy of Risk Prediction Models
in Women
Additional adjunctive testing (coronary artery calcium screening) that may improve the
accuracy of risk prediction models in women was the final major theme that emerged in the
above search of the literature. Several adjunctive tests were addressed in the guidelines and
reviewed in the background section, including coronary artery calcium (CAC), carotid intima

50
thickness and ankle brachial index (Golf, 2014 & Mosca et al. 2011). However, coronary artery
calcium (CAC) screening was captured in the literature review as the most promising and
important consideration when exploring risk stratification in women. Three key studies address
the use of this adjunctive test (the CAC score) to improve risk stratification in women. The three
studies will now be presented.
In a study by Polonsky et al. (2010), the inclusion of CAC screening to a risk prediction
model based on traditional risk factors was examined to see if this would improve risk
stratification and discrimination for CVD (Polonsky et al., 2010). The CAC score was calculated
on standard cardiac computed tomography scanners (Polonsky et al., 2010). Computed
tomography scans were obtained with minimal radiation exposure (less than one millisievert of
radiation) and no documented adverse events, as intravenous contrast was not needed for scan
acquisition (Polonsky et al., 2010). A total of 5,878 male and female participants from the MultiEthnic Study of Atherosclerosis (MESA), with a median follow-up at 5.8 years, had their risk of
developing CHD calculated using either Model One (no CAC score) or Model Two (included a
CAC score) (Polonsky et al., 2010). The two models are summarized in Table 13 (Polonsky et
al., 2010).
Table 13: Model One and Model Two
Model One
Age, sex, smoking status, systolic blood
pressure, antihypertensive medication use, total
and high-density lipo-protein cholesterol, and
race/ethnicity.

Model Two
Age, sex, smoking status, systolic blood
pressure, antihypertensive medication use, total
and high-density lipo-protein cholesterol, and
race/ethnicity. Model 2 used these risk factors
plus the Coronary Artery Calcium score

Cox proportional hazards models were used to estimate the 5-year risk of developing
CHD (Polonsky et al., 2010). At follow-up, 209 CHD events (MI or death) had occurred
(Polonsky et al., 2010). Analysis of the data revealed that Model Two, which included CAC

51
screening, was better at predicting risk than Model One (net reclassification improvement=0.25;
95% confidence interval, 0.16-0.34; ≤P.001). For example, a larger percentage of the overall
cohort was appropriately classified into either a higher or lower risk category by Model Two
(77%) than by Model One (69%) (Polonsky et al., 2010). Importantly, utilizing Model Two with
the adjunctive CAC score, 23% of participants that had events were appropriately reclassified as
high risk and 13% without events were appropriately reclassified as low risk (Polonsky et al.,
2010). The addition of CAC scoring to a traditional risk factor based prediction model not only
improved accuracy but also appropriately reclassified individuals into higher risk categories
(Polonsky et al., 2010).
Several limitations in the above study should be acknowledged. The results were based
on a limited population, thus further validation in additional populations is needed (Polonsky et
al., 2010). Few high-risk individuals were included in the study, consequently the results are not
be generalizable to higher risk populations (Polonsky et al., 2010). Furthermore, the participants
included in the MESA cohort were made aware of their CAC score results, which may have
influenced subsequent behavior and ultimately long term cardiovascular health (Polonsky et al.,
2010).
Findings were confirmed in a similar but more recent study conducted by McClelland et
al. (2015). In this key study, McClelland et al. (2015) derived and validated a novel risk score
known as the Multi-Ethnic Study of Atherosclerosis (MESA) risk score. The MESA risk score
incorporated CAC screening with traditional risk factors to estimate the 10-year risk of
developing CHD (McClelland et al., 2015). The algorithm was validated in the MESA cohort, a
prospective community-based population of 6,814 sex-balanced multiethnic (39% non-Hispanic
Caucasians, 12% Chinese Americans, 28% African Americans and 22% Hispanic Americans)

52
participants. Ages ranged from 45 to 84 years with no history of clinical heart disease at baseline
(McClelland et al., 2015). External validation was conducted in both the Heinz Nixdorf Recall
Study and the Dallas Heart Study. In the derivation cohort, addition of CAC screening to the
MESA risk score lead to significantly improved discrimination (C-statistic 0.80 vs. 0.75;
p<0.0001) (McClelland et al., 2015). In the validation cohorts, both improved discrimination and
calibration were noted with a C-statistic of 0.779 in the Heinz Nixdorf Recall Study and 0.816 in
the Dallas Heart Study (McClelland et al., 2015). The calibration was improved in both studies
with an average predicted 10-year risk of developing CHD within 0.5% of the actual observed
event rate in both sexes (McClelland et al., 2015). In summary, using a risk score that
incorporates a CAC score with traditional risk factors improved the tool’s ability to predict the
risk of developing CHD over a 10-year time interval (McClelland et al., 2015). Based on this
study, the MESA risk score may be an appropriate risk score for NPs to adopt in some Canadian
women with multiethnic backgrounds.
Strengths of the above study included a modern, community-based multiethnic derivation
cohort and independent validation in two external cohorts. This allowed for greater
generalizability. However, the study was not without limitations. While the MESA is a
multiethnic cohort, there were still many ethnicities that were not included, such as Chinese and
South Indian participants. As these populations feature prominently in many parts of Canada, the
generalizability of the results to populations beyond those included in the MESA cohort remains
unknown. Validation in a truly global population is thus still needed.
The latest transformative study by Kelkar et al. (2016) explored the use of CAC
screening for CV risk stratification in 2363 asymptomatic men and women with low to
intermediate baseline FRS (Kelkar et al., 2016). All participants underwent CAC screening using

53
standard cardiac computed tomography scanners with an average follow-up of 14.6 years. Allcause mortality was estimated with Cox proportional hazards models (Kelkar et al., 2016). The
prevalence and extent of CAC was greater in women than in men, possibly because the 1072
women in the study were older (55.6 years) than the 1291 men (46.7 years) (Kelkar et al., 2016).
In total, 18.8% of the women and 15.1% of men had CAC scores ≥ 100 (P=0.029) (Kelkar et al.,
2016). Irrespective of age, the 15-year adjusted mortality hazard ratio in the women was 1.44fold higher than in the men (P=0.022) (Kelkar et al., 2016). Appropriately, the 15-year mortality
rate was only 5% in women with a CAC score of zero, but increased to 23.5% for women with
an elevated coronary artery calcium score ≥ 400 (P<0.001) (Kelkar et al. 2016). In addition, a
higher mortality risk was noted in women with a CAC score >10 compared to men with a similar
score (Kelkar et al., 2016). This key study demonstrated that CAC screening could effectively
identify high-risk women who only have a low to intermediate predicted risk of developing CHD
when using current risk stratification tools (Kelkar et al., 2016). It remains unclear why CAC
may portend a worse prognosis in women than in men. Further validation using larger external
cohorts is needed.
The primary strength of the above study was the long duration of follow-up. Significant
limitations of this study included the study cohort, as all patients were enrolled at a single centre,
and the use of cardiovascular mortality as the sole primary outcome. Both limitations decrease
the generalizability of the findings.
In summary, an integrative review of the literature was conducted and a final cohort of 11
articles were reviewed and critically apprised. Three major themes emerged from the selected
literature: the limitations of current risk prediction models for risk stratification in women; the
emergence and evolving importance of female-specific risk factors; and additional adjunctive

54
testing (coronary artery calcium screening) that may improve the accuracy of current risk
prediction models in women. Recommendations based on the identified themes, with respect to
NP practice, education, and research, will be presented in the next chapter.

55
CHAPTER 5
Discussion
The goal of this project was to explore how NPs in a primary care setting can optimize
CV risk stratification for CHD in Canadian women. A systematic literature search was
performed and 11 key studies were selected for review. Three key themes emerged from the
literature and were reviewed in the last chapter:
•
•
•

The limitations of current risk prediction models for risk stratification in women.
The emergence and evolving importance of female-specific risk factors.
Additional adjunctive testing (coronary artery calcium screening) that may improve the
accuracy of risk prediction models in women
Recommendations based on the above themes that emerged from this integrative review

will now be presented. Female-specific risk stratification, improving NP education, and areas for
further research including the need for screening beyond traditional risk prediction models will
be highlighted.
Limitations of Current Risk Stratification Models in Clinical Practice
Risk prediction models are currently the foundation of cardiovascular screening and are
used to delay or prevent the development of CHD in both men and women (Ridker et al., 2015).
In this integrative review, CV risk prediction models, and associated factors, were evaluated for
their ability to effectively risk stratify women for CHD. Understanding the limitations of the
current risk stratification tools will not only help NPs avoid many pitfalls but also select,
implement and interpret risk scores with greater confidence.
Screening risk assessment tools are considered a key part of primary care as they serve to
guide practitioners towards initiating the most appropriate strategies to prevent or delay the
development of disease. The bulk of care for women at risk for developing CHD is undertaken
within the primary care context. As such, specific primary care services, including both medical

56
and behavioural interventions, are commonly initiated in a primary care setting to reduce the risk
of developing CHD in women (Ridker et al., 2015). Targeting the modifiable risk factors with
blood pressure control, lipid management, and effective diabetes control have all been shown to
be effective primary prevention strategies to stop or delay the development of CHD (Ridker et al.,
2015). Behavioural modifications such as instituting a low fat diet, encouraging regular physical
activity, and smoking cessation are also crucial components of a comprehensive primary care
primary prevention strategy (Ridker et al., 2015). The effectiveness of the above interventions is
assessed by ensuring patients are below the guideline-recommended targets for blood pressure,
cholesterol, serum glucose, and body mass index. However, if screening tools fail to accurately
assess the risk of developing CHD, optimal primary prevention strategies may not be
implemented. All of the above is rendered moot if we are unable to appropriately identify
Canadian women who are truly at increased risk of developing CHD.
The three key studies reviewed in the previous chapter identified multiple issues with
current CV risk prediction models that limit their ability to accurately predict CV risk in women
(Cook, 2012; DeFilippis et. al., 2015; Ridker, 2007). For example, DeFilippis et al (2015)
demonstrated that the AHA/ACC pooled cohort risk calculator, along with the FRS for CHD,
FRS for CVD, and the ATPIII-FRS-CHD all overestimated the risk of cardiovascular events in
women by 48%, 8%, 46% and 67% respectively in 4,227 modern middle-aged men and women
of Caucasian, African American, Hispanic, and Chinese backgrounds. Unfortunately, over
treatment with the initiation of unnecessary medical therapies, with all of the ensuing costs and
possible side effects, may occur if women are inappropriately put in a high-risk category. Timely
and appropriate risk stratification is thus the cornerstone of any comprehensive primary
prevention strategy (Cook, 2012; DeFilippis et. al., 2015; Ridker, 2007).

57
The majority of risk tools examined in this review, including all Framingham risk based
models, were based on cohorts that do not represent the current diverse Canadian female
population. Most of the risk-based scoring systems were not only based on homogeneous,
geographically limited, white-dominated male cohorts but also were developed before effective
primary prevention drug and behavioural therapies had been widely accepted and employed
(DeFilippis et al., 2015). Although the latest ASCVD risk calculator is based on a more diverse
population and was designed to surpass previous risk tools such as the Framingham CHD risk
score and ATP-II, it was validated in cohorts that are at least 30 years old. The applicability of
risk scores based on cohorts from several decades past is problematic at best.
The question remains: how can NPs in a primary care setting optimize CV risk
stratification for CHD in Canadian women? The answer to at least part of this question is by
selecting the best modern risk assessment tool for the diverse Canadian female population.
Specific recommendations are summarized in the Table below.
The Importance of Female Specific Risk Factors
Several of the key studies reviewed above demonstrated improved risk stratification in
women by integrating traditional, non-traditional, and emerging risk factors as well as adjunctive
screening methods (Cook, 2012; DeFilippis et. al., 2015; Ridker, 2007). For example, Ridker at
al. (2007) developed and validated the RRS after several studies found inaccuracies when using
Framingham-based risk scores to assess risk in diverse female populations. The RRS was one of
the first risk assessment tools designed to predict the risk of developing CHD in women. It
integrated traditional and novel risk factors in an effort to more accurately risk stratify women
(Ridker at al., 2007). As reviewed above, the RRS added inflammatory markers (i.e. highsensitivity C-reactive protein), haemoglobin A1C, and family history to the traditional risk

58
factors (i.e. age, hypertension, smoking, diabetes mellitus, and total and high-density lipoprotein
cholesterol) that make up most of the Framingham based risk scores (Ridker, et al. 2007). Ridker
et al. (2007) demonstrated an improvement in risk prediction for total CV events in women with
the RRS in comparison to other risk prediction models. The main criticism of the study was a
lack of subgroups that included higher risk women as it was limited to Caucasian female health
care professionals within a narrow socioeconomic range. These concerns were partially
alleviated when DeFilippis et al. (2015) validated the RRS in more diverse and slightly higher
risk populations and still found it superior to other risk prediction models, including the FRS and
the newest AHA/ACC risk calculator.
Mosca et al. ‘s (2011) AHA guidelines on risk stratification for CHD prevention in
women acknowledge the use of both the RRS and Framingham based risk scores to predict the
10-year risk of developing CHD. However, the guidelines do not yet endorse regular screening
with hsCRP since there is no data for improved clinical outcomes based on a reduction of hsCRP,
which is a key measurement included in the RRS (Mosca et al., 2011). In contrast, Golf’s (2014)
ACC/AHA guidelines suggest assessing hsCRP only in women for whom their risk score is
intermediate or uncertain. As reviewed in the background section, hsCRP is not yet considered
an independent predictor for CHD despite multiple studies demonstrating an association with
future coronary events. For instance, in a study conducted in 14,719 asymptomatic women, those
with metabolic syndrome and a baseline hsCRP >3.0 mg/l were twice as likely to experience a
coronary event in the future in comparison to women without metabolic syndrome and a hsCRP
<3.0 mg/l (Ridker, Buring, Cook & Rifai, 2003).
While hsCRP may not yet be considered an independent predictor of CHD events, the
Reynold Risk Score, which incorporates hsCRP, was shown in all three landmark studies to be

59
better calibrated than the Framingham-based models in large external validation cohorts with
improved discrimination in multiethnic women (DeFilippis, 2015). It should be noted that the
RRS also includes family history, which is not included in the Framingham-based scores. Family
history is currently the most effective clinical method for determining someone’s genetic risk. As
summarized in the recommendations below, by selecting the RRS as their default tool for
screening, an NP may improve risk stratification for CHD, and subsequently clinical outcomes,
in Canadian women.
Finally, despite emerging evidence, none of the risk prediction tools discussed above
incorporated the emerging female-specific risk factors identified in this review, such as
depression, female-specific hormonal changes, reproductive complications during pregnancy,
and radiotherapy for breast cancer (Darby, 2013; Parikh, 2016; O’ Neil et al., 2016; O’ Neil et al.,
2016b; van Lennep et al., 2014). For example, O’ Neil (2016) demonstrated that the addition of a
depression screen to a traditional risk based model may improve risk stratification in women.
Similarly, Parikh (2016) demonstrated that a detailed reproductive history may improve risk
prediction in women. Finally, Darby (2013) showed that exposing the heart to ionizing radiation
during radiotherapy for breast cancer appeared to increase future rates of ischemic heart disease.
Although not part of any current risk assessment tool or recommended by any of the current
guidelines, understanding the association between these novel female-specific risk factors and
CHD can help NPs conduct more comprehensive CV risk assessments. Further research to help
clarify the strengths and limitations of all of the emerging female-specific risk factors in large
validation cohorts is still needed; however, in addition to choosing the most appropriate risk
stratification tool, an NP should recognize that these emerging female-specific risk factors may
be important when optimizing risk stratification and providing effective primary prevention for

60
Canadian women at risk of developing CHD.
Consideration of Adjunctive Screening Methods in Practice
According to the ACC/AHA guidelines presented by Golf (2014), coronary artery
calcium (CAC) screening has been proposed as an additional adjunctive imaging test that may
improve the accuracy of CV risk prediction models in women. Three separate studies have
shown that CAC may be a predictor of subsequent cardiovascular events (Kelkar et al., 2016;
McClelland et al., 2015; Zed & Budoff, 2015). Furthermore, the addition of a CAC score to
traditional risk-based models improved their accuracy and discrimination (Gulai, 2016 & Kelkar
et al., 2016). Importantly, the study by Kelkar et al. (2016) found that CAC screening effectively
reclassified high-risk women, allowing them to receive appropriate tailored primary prevention
therapies. At present, the latest ACC/AHA guidelines by Golf (2014) only recommend CAC
screening when the predicted risk of developing CHD is deemed intermediate or is somehow
inconclusive when using traditional risk-based models. Further research examining the link
between CAC and long term cardiovascular outcomes is still needed (Gulati, 2016). For example,
Khellar (2016) did not examine the long-term effects of primary prevention interventions based
on their reclassified risk stratification results. Additional challenges associated with CAC
imaging include costs, the long terms risks associated with radiation exposure (albeit small), and
the long-term psychological implications of receiving an elevated CAC score. In British
Columbia, the cardiac computed tomography scans used to calculate CAC scores do not use
intravenous contrast and typically can be performed with less than 1 millisievert of radiation
exposure (J. Leipsic, personal communication, September 08, 2016). CAC screening is covered
by the British Columbia Medical Services Plan and can be ordered at any of the tertiary care
centres in British Columbia by primary health care providers (J. Leipsic, personal

61
communication, September 08, 2016). Although CAC screening may be an important test to
include in an NP’s armamentarium, long-term data tied to hard cardiovascular outcomes (death
and MI) is still needed (Gulati, 2016).
While both the RRS and adjunctive CAC screening show promise, the MESA risk score
may be the most complete and appropriate risk stratification tool for Canadian women. The
MESA risk score includes mostly traditional risk factors, but it was developed and validated in
the MESA cohort, a sex-balanced diverse population designed to represent the multiethnic US
population. Although not endorsed for all patients in the current guidelines, the MESA risk score
includes CAC screening as part of its risk prediction equation. The MESA risk score
incorporated CAC screening with traditional risk factors to estimate the 10-year risk of
developing CHD (McClelland et al., 2015). The algorithm was validated in the MESA cohort, a
prospective community-based population of 6,814 sex-balanced multiethnic participants
(McClelland et al., 2015). Ages ranged from 45 to 84 years with no history of clinical heart
disease at baseline. External validation was conducted in both the Heinz Nixdorf Recall Study
and the Dallas Heart Study. In the derivation cohort, addition of CAC screening to the MESA
risk score lead to significantly improved discrimination (C-statistic 0.80 vs. 0.75; p<0.0001)
(McClelland et al., 2015). In the validation cohorts, both improved discrimination and calibration
were noted with a C-statistic of 0.779 in the Heinz Nixdorf Recall Study and 0.816 in the Dallas
Heart Study (McClelland et al., 2015). The calibration was improved in both studies with an
average predicted 10-year risk of developing CHD within 0.5% of the actual observed event rate
in both sexes (McClelland et al., 2015). Based on this study, the MESA risk score may be an
appropriate risk score for NPs to adopt with some Canadian women with multiethnic
backgrounds. However, the study was not without limitations. While the MESA is a multiethnic

62
cohort, there were still many ethnicities that were not included, such as Chinese and South Indian
participants. As these populations feature prominently in many parts of Canada, the
generalizability of the results to populations beyond those included in the MESA cohort remains
unknown. Validation in a truly global population is thus still needed.
Primary Care in Canada
With primary care in Canada being the context for this integrative review, the
implications for optimizing risk stratification within this setting warrants further discussion. In
particular, implementing the recommendations set forth by this project in a Canadian primary
care context are not without their issues. The strategies for optimizing risk stratification in
Canadian women, such as which risk tool to choose and when to order a CAC score, are still
being debated in the guidelines and are the subject of ongoing research. Furthermore,
implementing different screening practices, such as the MESA risk score, the RRS, and the FRS
within one jurisdiction can create confusion for both primary care providers and their patients. A
patient may be assessed as having a different baseline risk and thus may be treated more or less
aggressively with primary prevention therapies. Similar issues may arise in terms of monitoring
changes or trends in risk factors when primary care providers are all using different screening
tools. At a minimum, primary care providers must be aware of the strengths and limitations of
each major screening tool and understand why a certain tool may been chosen in a specific
population. The reason why an NP may chose the RRS or MESA risk score to screen a South
Indian female patient in Canada needs to be clearly communicated to both the patient as well as
their primary care colleagues. It is only through improved communication and education that
screening for CHD in Canadian women will be truly optimized.

63
Another important consideration for primary care providers is the role of adjunctive
testing in cardiovascular risk assessment. CAC screening has been identified in the body of
literature as a promising method for optimizing risk stratification in women. However, several
challenges associated with its broad scale adoption in primary care settings warrant further
discussion. For example, what are the costs of ordering a CAC score in comparison to other
adjunctive imaging tests? What are the long term psychological effects of having an elevated or
“high risk” calcium score? Although CAC screening can now be performed without intravenous
contrast and with minimal radiation exposure, it is not currently endorsed as a routine test in all
patients (Gulati, 2016). Importantly, adjacent screening methods such as CAC screening may not
be covered in certain jurisdictions or may fall outside the knowledge base or scope of practice of
some primary care providers. Coverage will increase as research accumulates and the guidelines
are updated; in contrast, the second issue can only be addressed with improved education both
during primary care training and in subsequent continuing primary care education venues.
Nonetheless, CAC screening is available in British Columbia and primary care providers,
including Nurse Practitioners, can appropriately order CAC screening if deemed clinically
indicated. Although not yet endorsed by the guidelines in all patients, CAC screening will likely
play a major role in the Canadian primary care practice of the future.
Recommendations
The goal of this project was to explore how NPs can optimize CV risk stratification for
CHD in Canadian women. A literature review was conducted and 11 articles were selected for
review, critical appraisal, and discussion. As discussed, three key themes emerged from the
literature and were explored in detail: the limitations of current risk prediction models for risk
stratification in women; the emergence and evolving importance of female-specific risk factors;

64
and additional adjunctive testing (coronary artery calcium screening) that may improve the
accuracy of risk prediction models in women. Recommendations based on the above themes in
respect to NP practice, education, and research will now be presented.
Recommendations for Practice
Choose the most appropriate risk stratification tool and adjunctive imaging. The
RRS was one of the first risk assessment tools designed to predict the risk of developing CHD in
women. It integrated traditional and novel risk factors in an effort to more accurately risk stratify
women (Ridker at al., 2007). Ridker et al. (2007) demonstrated an improvement in risk
prediction for total CV events in women with the RRS in comparison to other risk prediction
models. By simply selecting the RRS as their default tool, an NP may improve risk stratification
for CHD in Canadian women. The RRS is easily accessible online to both the public and primary
health care providers in Canada. The RRS can be performed in all primary care settings in a
timely fashion and with minimal costs, thus it is an important addition to a Canadian NPs
armamentarium when screening women for CHD. While the RRS shows promise, the MESA
risk score may be even better at risk stratifying multiethnic Canadian women. The MESA risk
score had superior accuracy and discrimination when compared to traditional risk based tools
(McClelland et al. 2015 & Polonsky et al., 2010) and was validated in a sex-balanced diverse
population. Although not supported by the current guidelines, the MESA risk score includes
CAC screening as part of its risk prediction equation. The MESA risk score is also accessible
online to both the public and primary health care providers. As with the RRS, the MESA risk
score can be performed in all primary care settings in a timely fashion and with minimal costs,
thus it is also an important addition to a Canadian NPs armamentarium when screening women
for CHD.

65
Besides the time required to perform either screening test in the primary care setting, the
only other additional health care costs associated with performing either the RRS or MESA risk
score are related to ordering either a serum hsCRP level or CAC screening test respectively.
While the MESA risk score utilizes the CAC score as part of its risk equation, it can still be
implemented in primary care practice without it, whereas the RRS must include the hsCRP level.
Regardless, both hsCRP and CAC screening are covered by the Medical Services Plan in British
Columbia if the primary care provider believes they are clinically indicated (J. Leipsic, personal
communication, September 08, 2016). Both screening tools improve risk prediction for CHD in
women. By optimizing screening and ultimately instituting appropriate primary prevention
therapies in at-risk Canadian women, the prevalence of CHD along with its cost burden will be
significantly decreased. Furthermore, the studies above highlighted that an additional imaging
test, CAC screening, may further improve the accuracy of traditional risk prediction tools in
women (Kelkar et al., 2016; McClelland et al., 2015; Zed & Budoff, 2015). Three separate
studies have shown that CAC may be a predictor of subsequent cardiovascular events (Kelkar et
al., 2016; McClelland et al., 2015; Zed & Budoff, 2015). Although CAC screening may be an
important test to include in an NP’s armamentarium, long-term data tied to hard cardiovascular
outcomes (death and MI) is still needed (Gulati, 2016). In the meantime, in select cases, CAC
screening may provide women with an “individualized” risk assessment that is impossible to
generate with current generation risk assessment tools.
The findings of this comprehensive integrative review will impact upon my primary care
practice in the following ways. Firstly, I will take caution when implementing the FRS in women,
knowing that this may over or underestimate risk of CHD. Second, I plan to select my risk
stratification tool based on the characteristics of my patient, including utilizing the RRS score in

66
women without diabetes and the MESA risk score to Canadian women with multiethnic
backgrounds. Finally, I will consider using adjunctive screening, such as CAC, in female patients
with intermediate or ambiguous risk.
Be aware of female-specific cardiovascular risk factors. Five studies looking at
emerging female-specific risk factors were reviewed above and included: depression, femalespecific hormonal changes, reproductive complications during pregnancy, and radiotherapy for
breast cancer (Darby, 2013; Parikh, 2016; O’ Neil et al., 2016; O’ Neil et al., 2016b; van Lennep
et al., 2014). Although not part of any current risk assessment tools or recommended by any of
the current guidelines, it is prudent for a primary care NP to be able to recognize and possibly
incorporate the emerging female-specific risk factors into their practice if their goal is to provide
optimal risk stratification in Canadian women. More comprehensive screening can be achieved
with only a few additional questions, as outlined in the table below.
Recommendations for Education
It is crucial that the following themes are covered in all modern Canadian NP curricula:
the limitations of current risk prediction models for risk stratification in women; the emergence
and evolving importance of female-specific risk factors; and additional adjunctive testing
(coronary artery calcium screening) that may improve the accuracy of risk prediction models in
women.
NPs need to have adequate knowledge on gender disparity and the unique
pathophysiology of CHD in women. Furthermore, with the large number of traditional, novel and
emerging risk factors that impact women, strategies to promote continuing and life-long
education will be key in this rapidly evolving field. With ongoing education, NPs will be better
prepared to thoughtfully adjust and individualize cardiovascular risk assessments in Canadian

67
women. Although not part of any current risk assessment tool or recommended by any of the
current guidelines, an NP will need recognize and incorporate all of the emerging female-specific
risk factors in order to perform optimal risk stratification and deliver comprehensive patientcentred healthcare in Canada.
Recommendations for Research
A common theme in all of the above discussions is a lack of long-term female-specific
cardiovascular outcome data. Besides the RRS and MESA risk score, most of the risk
stratification tools recommended by the current guidelines were not appropriately tested in
female populations. The data on coronary artery calcium screening in women is encouraging but
far from conclusive at this stage. Although female-specific cardiovascular risk factors are now
acknowledged in the literature, none have been incorporated into any of the current risk
assessment tools. Adequately powered long term randomized studies are needed to resolve many
of the unanswered questions in this field. In addition, qualitative studies that explore screening
practices and patient perspectives on CHD risk stratification and treatment, may identify barriers
to implementing optimal risk stratification and primary prevention therapies in the primary care
setting. Furthermore, further research exploring lifetime risk and screening is needed.
In the meantime, it is crucial that all primary care NPs recognize the current limitations of
cardiovascular screening and stay abreast of the emerging data in this area. Only with ongoing
vigilance will NPs be able to provide optimal risk stratification for CHD in Canadian women.
The following table summarizes the recommendations for practice, education and research set
forth by this project.

68
Table 14: Summary of recommendations for practice, education and research
Recommendations for Practice
Practice considerations when implementing current validated risk prediction models with
additional comments and/or rationale:
• Continuous risk screening should be undertaken throughout a women’s lifetime.
• CV risk prediction models should be selected based on patient-specific characteristics (i.e.,
age, gender, and ethnicity)
• Implement RRS in all women without diabetes.
o Includes family history of MI and high-sensitivity C-reactive protein (hs-CRP)
o Does not factor in treated blood pressure
o Considers soft and hard endpoints
• Implement MESA risk score in women of multiethnic background.
o Includes CAC score (but risk can still be calculated without CAC screening)
o Does not factor in family history of CVD (only MI)
o Considers hard and soft endpoints
• Implement adjunctive screening in female patients with intermediate or ambiguous risk
o CAC screening and inflammatory markers (i.e. hsCRP) can both be obtained in
British Columbia if clinically indicated.
• Providers should be aware of the potential limitations FR-based scores prior to implementing
in practice.
o Overestimates and underestimates risk in female patients
o Does not include female specific risk factors.
o Based on older Caucasian cohorts
• Providers should know the potential unique female specific factors (i.e. depression,
reproductive complications, hormonal status, and previous radiation treatment for breast
cancer and implement more frequent screening in such women with unique factors.
Recommendations for Education
Educational requirements for all NPs caring for female patients should include knowledge on the
following area:
• Gender disparity and the unique pathophysiology of CHD in women
• The limitations in risk prediction models for risk stratification in women
• The emergence and evolving importance of female-specific risk factors
• Additional adjunctive testing (coronary artery calcium screening) that may improve the
accuracy of risk prediction models in women
• Emerging risk factors as they are incorporated into contemporary guidelines.
Recommendations for Research
Areas in need of additional research:
• Long-term and sufficiently powered trials evaluating female-specific CV assessment tools.
• CV research utilizing modern, diverse female populations.
• Studies to clarify how to optimally incorporate novel and emerging risk factors into current
risk assessment tools
• Long-term CAC screening studies with hard outcomes (death and MI)
• Long-term data on CAC in association with hard cardiovascular outcomes (death and MI)
and preventative strategies.

69
• Further research exploring lifetime risk and screening is needed.
• Research identifying and exploring patient-orientated research outcomes.
Limitations
The integration of studies for this review was not without its limitations. There was some
inconsistency with language noted across all studies, particularly around CAD and CHD. Both
terms are separately defined, yet were often used interchangeably in studies. This variation
created challenges in terms of determining the exact content of each study and with comparing
and contrasting studies during the analysis phase. While the majority of studies in this review are
applicable to primary care practice, no direct mention was made of NPs. Examples of health care
professionals mentioned in the literature included: general practitioners, cardiologists, and
primary care providers. No studies included in this review were specific to the role of an NP.
Based on their scope of practice, it appears reasonable to apply all of the above findings and
recommendations to NPs in Canada.
There were a number of significant gaps in the literature evaluated for this review. There
were specific limitations in each of the 11 studies included in this review and most have been
discussed in the preceding chapters. The outcomes, also known as endpoints, varied among the
studies and included both “hard” and “soft” endpoints. Ideally, all of the studies would have
assessed hard endpoints (death and MI) as these are most applicable to the primary prevention
literature. There was also a lack in diversity with respect to age, gender, and ethnicity in many of
the study populations. In order to be more applicable to Canadian women, more diverse
multicultural female studies are needed.
There were a number of studies that examined individual factors that were excluded in
this review and further insights may have been garnered had these been included. However,
conducting a review of all individual risk factors and all components of risk scores was beyond

70
the scope of the review. Finally, there were a few applicable randomized controlled trials, thus
most of the evidence comes from case control studies and observational data. Ideally this will
change in the future.
Conclusions
CHD is the most common cause of morbidity and mortality in Canadian women. Despite
advances in screening and research, CHD continues to pose a significant health care burden to
Canadian women. This integrative literature review explored how a Nurse Practitioner in
primary care can optimize risk stratification for CHD in Canadian women. A systematic search
of the contemporary literature identified 11 studies. Analysis of the studies gave rise to three key
themes that were explored in detail: the limitations of current risk prediction models for risk
stratification in women; the emergence and evolving importance of female-specific risk factors;
and additional adjunctive testing (such as CAC screening) that may improve the accuracy of risk
prediction models in women. Female-specific risk stratification, improving NP education, and
areas for further research including the need for screening beyond traditional risk prediction
models, were highlighted. By appreciating the limitations of the current risk assessment tools,
acknowledging the importance of female specific risk factors, and understanding the current role
of adjunctive testing, a primary care NP can truly optimize risk stratification for CHD in
Canadian women.

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Glossary
All citations are from Medical Dictionary (2016) unless otherwise indicated.
algorithms: a set of rules for solving a problem in a finite number of steps, as for finding the
greatest common divisor (“algorithm” n.d.)
androgen: a male sex hormone (as testosterone)
angina pectoris: pain in the centre of the chest, which is induced by exercise and relieved by
rest and may spread to the jaws and arms. Angina pectoris occurs when the demand for blood by
the heart exceeds the supply of the coronary arteries and it usually results from coronary artery
atheroma (Martin, 2015)
ankle-brachial index: is an efficient tool for objectively documenting the presence of lowerextremity peripheral arterial disease (Chan, 2015)
apolipoprotein A-I: a component of high-density lipoprotein (HDL) (U.S. National Library of
Medicine, 2016)
apolipoprotein B-100 (apoB100): a protein that plays a role in moving cholesterol around your
body. It is a form of low-density lipoprotein (LDL)
atherogenesis: the formation of atheroma
atheroma: degeneration of the walls of the arteries due to the formation in them of fatty plaques
and scar tissue. This limits blood circulation and predisposes to thrombosis (Martin, 2015)
atherosclerosis: a disease of the arteries in which fatty plaques develop on their inner walls,
with eventual obstruction of blood flow
atrial fibrillation: very rapid uncoordinated contractions of the atria of the heart resulting in a
lack of synchronism between heartbeat and pulse beat
bipolar disorder: any of several mood disorders characterized usually by alternating episodes of
depression and mania or by episodes of depression alternating with mild nonpsychotic
excitement
c-reactive protein (hsCRP): a protein whose plasma concentrations are raised in infections and
inflammatory states and in the presence of tissue damage or necrosis (martin, 2015)
C statistic: is a standard measure of the predictive accuracy of a logistic regression model
outcomes are binary (Austin & Steyerberg, 2011)
calibration: to standardize (as a measuring instrument) by determining the deviation from a
standard so as to ascertain the proper correction factors

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cerebralvascular disease: any disorder of the blood vessels of the brain and its covering
membranes (meninges). Most cases are due to atheroma and/or hypertension, clinical effects
being caused by rupture of diseased blood vessels (cerebral or subarachnoid hemorrhage) or
inadequacy of the blood supply to the brain (ischemia), due to cerebral thrombosis or embolism
(Martin, 2015)
confidence intervals: a range of values based on the observed data which are likely to contain
the true unknown value for a specified proportion of the time (confidence level) usually
expressed as a percentage (“confidence intervals,” 2010)
cohort study: prospective study (“prospective study,” n.d.)
coronary arteries: the arteries supplying blood to the heart (Martin, 2015)
coronary artery calcium score: a measurement of the amount of calcium in the walls of the
arteries that supply your heart muscle, using a special computed tomography (CT) scan of your
heart. It shows the amount of hardening of the artery wall (a disease called atherosclerosis) that
you have (Lott, 2015)
coronary care unit: a designated ward of a hospital to which the most serious cardiac cases are
transferred for specialist monitoring and treatment (Martin, 2015)
coronary events (CE): adverse events caused by disease processes affecting the coronary
arteries. These may include what are termed “hard” events such as deaths that are attributed to
coronary artery disease and nonfatal MIs, but also occasionally “soft” events such as angina or
revascularizations for worsening coronary artery stenosis (Ye, 2013)
coronary thrombosis: the formation of a blood clot (thrombus) in the coronary artery, which
obstructs the flow of blood to the heart. This is usually due to atheroma and results in the death
(infarction) of part of the heart muscle (Martin, 2015)
coronary revascularization: the restoration of blood flow to ischaemic heart muscle by
coronary angioplasty and stenting or by a coronary artery bypass graft (“coronary
revascularization,” 2010)
coronary steal: A condition characterized by shunting of all relatively well oxygenated blood
from a critical area of low perfusion, to an area of higher perfusion; it is unique as it may be
iatrogenic and occur in pharmacologic stress imaging using dipyridamole to induce
vasoconstriction; this causes a fall in blood flow to the subendocardium distal to the site of the
stenosed coronary artery (“coronary steal,” 2012)
Cox regression (or proportional hazards regression): method for investigating the effect of
several variables upon the time a specified event takes to happen (statsdirect.com, n.d.)

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Critical Appraisal Skills Programme (CASP) tools: a set of eight critical appraisal tools are
designed to be used when reading research, these include tools for Systematic Reviews,
Randomised Controlled Trials, Cohort Studies, Case Control Studies, Economic Evaluations,
Diagnostic Studies, Qualitative studies and Clinical Prediction Rule (CASP, 2013)
Dallas Heart Study: a single-site, multiethnic, population-based probability sample to (1)
produce unbiased population estimates of biologic and social variables that pinpoint ethnic
differences in cardiovascular health at the community level and (2) support hypothesis-driven
research on the mechanisms causing these differences using genetics, advanced imaging
modalities, social sciences, and clinical research center methods (Victor, 2004)
death rate: the ratio of deaths to number of individuals in a population usually expressed as
number of deaths per hundred or per thousand population for a given time
deep vein thrombosis: a condition marked by the formation of a thrombus within a deep vein
(as of the leg or pelvis) that may be asymptomatic or be accompanied by symptoms (as swelling
and pain) and that is potentially life threatening if dislodgment of the thrombus results in
pulmonary embolism
diabetes type two: diabetes mellitus of a common form that develops especially in adults and
most often in obese individuals and that is characterized by hyperglycemia resulting from
impaired insulin utilization coupled with the body's inability to compensate with increased
insulin production—called also adult-onset diabetes, late-onset diabetes, maturity-onset diabetes,
non-insulin-dependent diabetes, non-insulin-dependent diabetes mellitus, type 2 diabetes mellitus
Diagnostic and Statistical Manual of Mental Disorders (DSM): an influential publication of
the American Psychiatric Association in which psychiatric disorders are classified and defined
(“DSM,” 2010)
Dietary approaches to stop hypertension (DASH) diet: a diet that is designed to lower blood
pressure and emphasizes the consumption of fruit, vegetables, grains, and low-fat or non-fat
dairy products
discordance: dissimilar with respect to one or more particular characters
dyslipidemia: a condition marked by abnormal concentrations of lipids or lipoproteins in the
blood
dysthymia: a mood disorder characterized by chronic mildly depressed or irritable mood often
accompanied by other symptoms
endocardium: a delicate membrane, formed of flat endothelial cells, that lines the heart and is
continuous with the lining of arteries and veins (Martin, 2015).
endogenous: by factors within the body or mind or arising from internal structural or functional
causes

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endometriosis: the presence and growth of functioning endometrial tissue in places other than
the uterus that often results in severe pain and infertility
endothelium: an epithelium of mesoblastic origin composed of a single layer of thin flattened
cells that lines internal body cavities (as the serous cavities or the interior of the heart).
endpoints: a point marking the completion of a process or stage of a process (“endpoint” n.d.)
entropy: the degree of disorder or uncertainty in a system
epicardium: the outermost layer of the heart wall, enveloping the myocardium; a serous
membrane that forms the inner layer of the serous pericardium (Martin, 2015).
estradiol: a natural estrogenic hormone that is a phenolic alcohol C18H24O2 secreted chiefly by
the ovaries, is the most potent of the naturally occurring estrogens, and is administered in its
natural or semisynthetic esterified form especially to treat menopausal symptoms
estrogen: any of various natural steroids (as estradiol) that are formed from androgen precursors,
that are secreted chiefly by the ovaries, placenta, adipose tissue, and testes, and that stimulate the
development of female secondary sex characteristics and promote the growth and maintenance of
the female reproductive system; also : any of various synthetic or semisynthetic steroids (as
ethinyl estradiol) that mimic the physiological effect of natural estrogens
external validation: where various differences may exist between the populations used to
develop and test the model (Steyerberg et al., 2001)
fibrinolysis: the usually enzymatic breakdown of fibrin
fit: the degree of correspondence between the observations and the model's predictions
(Nicholson, 2014)
functional hypothalamic amenorrhea: Amenorrhea in this setting, seen in patients who have
experienced rapid weight loss, severely restricted calorie intake, stress or rigorous exercise, may
be part of the female athlete triad of amenorrhea, disordered eating, and osteoporosis (Krueger,
2015)
infertility: not fertile; incapable of or unsuccessful in achieving pregnancy over a considerable
period of time (as a year) in spite of determined attempts by heterosexual intercourse without
contraception
insulin resistance: impaired response to insulin resulting in elevated levels of glucose in the
blood, originally described in diabetics receiving exogenous insulin and later recognized as a key
component of type 2 diabetes and the metabolic syndrome (‘insulin resistance,” 2016)

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integrated discrimination index: a popular tool for evaluating the capacity of a marker to
predict a binary outcome of interest (Kerr, 2012)
ischemia: deficient supply of blood to a body part (as the heart or brain) that is due to
obstruction of the inflow of arterial blood (as by the narrowing of arteries by spasm or disease)
Geelong Osteoporosis Study: a population-based study designed to investigate
the epidemiology of osteoporosis in Australia (Pasco, Nicholson & Kotowicz, 2011)
genetic markers: a readily recognizable genetic trait, gene, DNA segment, or gene product used
for identification purposes especially when closely linked to a trait or to genetic material that is
difficult to identify
gestational diabetes mellitus: diabetes or impaired glucose tolerance that is diagnosed during
pregnancy (Martin, 2015)
haemoglobin A1C: a stable glycoprotein formed when glucose binds to haemoglobin A in the
blood; also : a test that measures the level of haemoglobin A1c in the blood as a means of
determining the average blood sugar concentrations for the preceding two to three months
hazard ratio: a measure of how often a particular event happens in one group compared to how
often it happens in another group, over time (National Institute of Health, n.d.)
Heinz Nixdorf Recall Study: a population-based study that aims to improve the prediction of
cardiovascular events by integrating new imaging and non-imaging modalities in risk assessment
(Mahabadi, 2013)
hemocysteine: an amino acid C4H9NO2S that is produced in animal metabolism by the
demethylation of methionine and forms a complex with serine that breaks up to produce cysteine
and homoserine and that appears to be associated with an increased risk of CVD when occurring
at high levels in the blood
hemostatic: an agent that checks bleeding; especially : one that shortens the clotting time of
blood
high-density lipo-protein cholesterol: a lipoprotein of blood plasma that is composed of a high
proportion of protein with little triglyceride and cholesterol and that is associated with decreased
probability of developing atherosclerosis
HIV infection: any of several retroviruses and especially HIV-1 that infect and destroy helper T
cells of the immune system causing the marked reduction in their numbers that is diagnostic of
AIDS
Hosmer-Lemeshow test: used to determine the goodness of fit of the logistic regression model
(real-statistics.com, n.d.)

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hypertension: abnormally high arterial blood pressure that is usually indicated by an adult
systolic blood pressure of 140 mm Hg or greater or a diastolic blood pressure of 90 mm Hg or
greater.
impaired glucose tolerance: a condition in which an individual has higher than normal levels of
glucose in the blood upon fasting or following a carbohydrate-rich meal or ingestion of a glucose
test solution but not high enough to be diagnostic of diabetes mellitus
intermittent claudication: cramping pain and weakness in the legs and especially the calves on
walking that disappears after rest and is usually associated with inadequate blood supply to the
muscles
insulin resistance: educed sensitivity to insulin by the body's insulin-dependent processes (as
glucose uptake, lipolysis, and inhibition of glucose production by the liver) that results in
lowered activity of these processes or an increase in insulin production or both and that is typical
of type 2 diabetes but often occurs in the absence of diabetes
ischemic stroke: stroke caused by thrombosis or embolism
left anterior descending coronary artery: a coronary artery, which is the name given to
arteries that supply the heart muscle with blood (Ahmed, 2015).
lipoproteins: any of a large class of conjugated proteins composed of a complex of protein and
lipid
longitudinal study: one in which participants, processes, or systems are studied over time, with
data being collected at multiple intervals. The two main types are prospective studies and
retrospective studies.
low density lipoprotein (LDL): a lipoprotein of blood plasma that is composed of a moderate
proportion of protein with little triglyceride and a high proportion of cholesterol and that is
associated with increased probability of developing atherosclerosis
major depressive disorder: a mood disorder having a clinical course involving one or more
episodes of serious psychological depression that last two or more weeks each, do not have
intervening episodes of mania or hypomania, and are characterized by a loss of interest or
pleasure in almost all activities and by some or all of disturbances of appetite, sleep, or
psychomotor functioning, a decrease in energy, difficulties in thinking or making decisions, loss
of self-esteem or feelings of guilt, and suicidal thoughts or attempts
Medical Subject Headings (MeSH): s the National Library of Medicine's controlled vocabulary
thesaurus. It consists of sets of terms naming descriptors in a hierarchical structure that permits
searching at various levels of specificity (U.S. National Library of Medicine, 2015)

77
Mediterranean diet: a diet typical of many Mediterranean countries (as Italy and Spain) that
consists mainly of cereals, grains, vegetables, beans, fruits, and nuts along with moderate
amounts of fish, cheese, olive oil, and wine and little red meat
menarche: the beginning of the menstrual function
meta-analyses: quantitative statistical analysis that is applied to separate but similar experiments
of different and usually independent researchers and that involves pooling the data and using the
pooled data to test the effectiveness of the results
mortality: the number of deaths in a given time or place; the proportion of deaths to population
Multi-Ethnic Study of Atherosclerosis (MESA) cohort: a community-based and sex-balanced
population designed to represent the multiethnic population in US.
MI: an acute episode of heart disease marked by the death or damage of heart muscle due to
insufficient blood supply to the heart muscle usually as a result of a coronary thrombosis or a
coronary occlusion and that is characterized especially by chest pain
myocardium: the middle of the three layers forming the wall of the heart (see also endocardium,
epicardium). It is composed of cardiac muscle and forms the greater part of the heart wall, being
thicker in the ventricles than in the atria (Martin, 2015).
net reclassification index: is a statistical tool proposed to assess improvement in model
performance offered by a new method of classification compared to a reference one (Pencina et
al., 2008)
pericarditis: inflammation of the pericardium
peripheral arterial disease: damage to or dysfunction of the arteries outside the heart resulting
in reduced blood flow; especially narrowing or obstruction (as from atherosclerosis) of an artery
(as the iliac artery or femoral artery) supplying the legs that is marked chiefly by intermittent
claudication and by numbness and tingling in the legs
polycystic ovarian syndrome (PCOS): a variable disorder that is marked especially by
amenorrhea, hirsutism, obesity, infertility, and ovarian enlargement and is usually initiated by an
elevated level of luteinizing hormone, androgen, or estrogen which results in an abnormal cycle
of gonadotropin release by the pituitary gland
postmenopausal: having undergone menopause; occurring after menopause
preeclampsia: a serious condition developing in late pregnancy that is characterized by a sudden
rise in blood pressure, excessive weight gain, generalized edema, proteinuria, severe headache,
and visual disturbances and that may result in eclampsia if untreated

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prospective study: an epidemiologic study in which the groups of individuals (cohorts) are
selected on the bases of factors that are to be examined for possible effects on some outcome.
For example, the effect of exposure to a specific risk factor on the eventual development of a
particular disease can be studied. The cohorts are then followed over a period of time to
determine the incidence rates of the outcomes being studied as they relate to the original factors
in question. Called also cohort study (“prospective study, “ n.d.)
pulmonary embolism: embolism of a pulmonary artery or one of its branches that is produced
by foreign matter and most often a blood clot originating in a vein of the leg or pelvis and that is
marked by labored breathing, chest pain, fainting, rapid heart rate, cyanosis, shock, and
sometimes death
radiotherapy: the treatment of disease by means of radiation (as X-rays)
randomized control trial: a clinical trial in which the subjects are randomly distributed into
groups which are either subjected to the experimental procedure (as use of a drug) or which serve
as controls
rheumatoid arthritis: a usually chronic disease that is considered an autoimmune disease and is
characterized especially by pain, stiffness, inflammation, swelling, and sometimes destruction of
joints
risk management: a feature of clinical governance. Risk management principles are applied to
clinical and nonclinical aspects of health care to increase patient safety by identifying potential
hazards, assessing the degree of risk, and reducing the risk or determining an acceptable balance
between risk and benefit. Risk management should include systems for learning from untoward,
significant, or critical incidents and near misses (Martin, 2015)
Rosuvastatin: a statin that is administered orally in the form of its calcium salt especially to treat
hypercholesterolemia
screening: the presumptive identification of unrecognized disease or defect by the application of
tests, examinations or other procedures which can be applied rapidly (‘screening’ 2008)
statin: any of a group of lipid-lowering drugs (as lovastatin and simvastatin) that function by
inhibiting a liver enzyme which controls the synthesis of cholesterol and by promoting the
production of LDL-binding receptors in the liver resulting in a usually marked decrease in the
level of LDL and a modest increase in the level of HDL circulating in blood plasma
stillbirths: the birth of a dead fetus
subclinical: not detectable or producing effects that are not detectable by the usual clinical tests
summary statistics: the information that gives a quick and simple description of the data (i.e.
mean, median, mode, minimum value, maximum value, range, standard deviation, etc.)
(“summary statistics,” 2014)

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systematic reviews: a study that answers a defined research question by collecting and
summarising all empirical evidence that fits pre-specified eligibility criteria (University of
Edinburgh, 2013)
systemic lupus erythematosus: an inflammatory connective tissue disease of unknown cause
that occurs chiefly in women and that is characterized especially by fever, skin rash, and arthritis,
often by acute hemolytic anemia, by small hemorrhages in the skin and mucous membranes, by
inflammation of the pericardium, and in serious cases by involvement of the kidneys and central
nervous system
transient ischemic attack: a brief episode of cerebral ischemia that is usually characterized by
temporary blurring of vision, slurring of speech, numbness, paralysis, or syncope and that is
often predictive of a serious stroke
triglycerides: any of a group of lipids that are esters formed from one molecule of glycerol and
three molecules of one or more fatty acids, are widespread in adipose tissue, and commonly
circulate in the blood in the form of lipoproteins
unstable angina: angina pectoris characterized by sudden changes (as an increase in the severity
or length of anginal attacks or a decrease in the exertion required to precipitate an attack)
especially when symptoms were previously stable
variables: subject to variation or changes
vasospasm: sharp and often persistent contraction of a blood vessel reducing its caliber and
blood flow
Women's Health Study: is a randomized, double-blind, placebo-controlled trial using a 2x2
factorial design, and conducted among 39,876 female health professionals in the United States.
(National Cancer Institute, n.d.)

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Appendix A: Cardiovascular Risk Stratification Models
Models

The
Framingham
Risk Score
(2008)

Prediction Variables Used
-

QRISK and
QRISK2 (20
07)

-

RRS for
women
(2007)

-

European
Systematic
Coronary
Risk
Evaluation
(SCORE)
(2003)

-

Age
Gender
Total cholesterol
HDL cholesterol
Systolic blood pressure
Blood pressure
treatment
Diabetes mellitus
Current smoking
Age
Gender
Total cholesterol
HDL cholesterol
Systolic blood pressure
Blood pressure
treatment
Current smoking
Family history of CVD
in first degree relative
aged <60 years
Region of United
Kingdom (score based
on levels of
unemployment,
overcrowding, car
ownership, home
ownership)
Body mass index
Age
Total cholesterol
HDL cholesterol
Systolic blood pressure
Diabetes mellitus
assessed by A1c
Current smoking
Parental history of MI <
60 years
Serum hs-CRP
Age
Gender
Total cholesterol
HDL cholesterol
Systolic blood pressure
Current smoking
Region of Europe (high
risk vs. low risk region)

Prediction Variables Not
Used
-

-

Endpoints Assessed

Family history of CVD Region of United
Kingdom (score based on levels of
unemployment,
overcrowding, car
ownership, home
ownership)
Body mass index
Serum hs-CRP
Diabetes mellitus
Serum hs-CRP
-

CHD death
Nonfatal MI
Coronary insufficiency or
angina
Fatal or nonfatal ischemic
or hemorrhagic stroke
Transient ischemic attack
Intermittent claudication
Heart failure
CHD death
Nonfatal MI
Coronary
Insufficiency or angina
Coronary
revascularization
Fatal or nonfatal stroke
Transient ischemic attack
Intermittent claudication

-

-

-

Blood pressure
treatment
Region of United
Kingdom (score based
on levels of
unemployment,
overcrowding, car
ownership, home
ownership)
Body mass index
Blood pressure
treatment (yes or no)
Diabetes mellitus
Family history of CVD
Region of United
Kingdom (score based
on levels of
unemployment,
overcrowding, car

Additional
Comments
(i.e. appropriate population)
- Revised to include signs
and complications of
atherosclerosis, i.e.
stroke, transient
ischemic attack,
claudication and heart
failure.

-

-

- Developed from a
prospective cohort of
approximately 25,000
American women
without diabetes.
- Performs well in women
without diabetes.

Cardiovascular death
Nonfatal MI
Nonfatal stroke
Coronary
revascularization

CVD death (including
CHD, arrhythmia, HF,
stroke, aortic aneurysm,
and peripheral vascular
disease)

Was developed to
predict CV risk in
patients from different
ethnic groups living in
England and Wales.

-

-

Recommended in the
2007 European Society
of Cardiology guidelines
on CV disease
prevention in clinical
practice.
Based on approximately
200,000 patients
retrieved from cohort

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ACC/AHA
pooled
cohort hard
CVD risk
calculator
(2013)

-

JBS3 risk
score (2014)

-

MESA risk
score (2015)

-

-

Age
Gender
Total cholesterol
HDL cholesterol
(mg/dL)
Systolic blood pressure
Blood pressure
treatment
Diabetes mellitus
Current smoking (yes or
no)

-

-

ownership, home
ownership)
Body mass index
Serum hs-CRP
Family history of CVD
Region of United
Kingdom (score based
on levels of
unemployment,
overcrowding, car
ownership, home
ownership)
Body mass index
Serum hs-CRP

Age
- Serum hs-CRP
Gender
Ethnicity
Total cholesterol
HDL cholesterol
Systolic blood pressure
Blood pressure
treatment
Diabetes mellitus
Current smoking
Family history of CVD
in first degree relative
aged <60 years
Chronic kidney disease
Atrial fibrillation
Rheumatoid arthritis
Region of United
Kingdom (score based
on levels of
unemployment,
overcrowding, car
ownership, home
ownership)
Body mass index
Age
- Family history of CVD
other than MI
Gender
Ethnicity (non-Hispanic - Region of United
Kingdom (score based
white, Chinese
on levels of
American, African
unemployment,
American, Hispanic)
overcrowding, car
Total cholesterol
ownership, home
HDL cholesterol
ownership)
Lipid lowering
- Body mass index
treatment
Systolic blood pressure - Serum hs-CRP
Blood pressure
treatment
Diabetes mellitus

studies in 12 European
countries.

-

CHD death
Nonfatal MI
Fatal stroke
Nonfatal stroke

-

CHD death
Nonfatal MI
Coronary insufficiency or
angina
Coronary
revascularization
Fatal or nonfatal stroke
Transient ischemic attack
Intermittent claudication

-

CHD death
Nonfatal MI
Resuscitated cardiac
arrest
Coronary
revascularization in
patient with angina

-

-

-

-

Several cohorts of
patients were used to
develop model.
The first risk model
included populations of
both Caucasian and
African-American
patients.

-

-

-

-

-

Released on the Joint
British Societies (JBS)
Includes many of the
same variables from the
QRISK and QRISK2
scores.
Estimates of "heart age"
and long term risk
intervals.

Includes multiple ethnic
backgrounds
Classifies patients using
coronary artery calcium
scoring in addition to
traditional risk factors.
Can be used without
entering a CAC score.

93
-

Current smoking
Family history of MI at
any age
- Coronary artery calcium
score
(Boon, 2014; Golf et al, 2014; Graham et al., 2007; Hippisley-Cox et al., 2007; McClelland, 2015; Ridkar et al., 2007)

94
Appendix B: Critical Appraisal Skills Program: Cohort Study Checklist
Three broad issues to consider when appraising a cohort study:
a) Are the results of the study valid?
b) What are the results?
c) Will the results help locally?
Are the results valid?
1. Did the study address a clear focused
issue?
2. Was the cohort recruited in an acceptable
way?
3. Was the exposure accurately measured to
minimise bias?
4. What the outcome accurately measured to
minimise bias?
5. Has the author identified all-important
cofounding factors? Have they taken
account of the cofounding factors in the
design and/or analysis?
6. Was the follow up of subjects complete
enough? Was the follow up of subjects
long enough?
What are the results of the study?
7. What are the results of the study?
8. How precise are the results?
9. Do you believe the results?
Will the results help locally?
10. Can the results be applied to the local
population?
11. Do the results of the study fit with other
available evidence?
12. What are the implications of this study for
practice?
(CASP, 2013b).

95
CASP: Review Study Checklist
Three broad issues to consider when appraising a cohort study:
a) Are the results of the review valid?
b) What are the results?
c) Will the results help locally?
Are the results of the review valid?
1. Did the review address a clear focused
question?
2. Did the author look for the right type of
papers?
3. Do you think all important, relevant studies
were included?
4. Did the review’s author do enough to
assess the quality of the included studies?
5. If the results of the reviews have been
combined, was it reasonable to do so?
What are the results?
6. What are the overall results of the review?

7. How precise are the results?
Will the results help locally?
8. Can the results be applied to local
population?
9. Were all-important outcomes considered?
10. Are the benefits worth the harms and costs?

(CASP, 2013c)

96
CASP: Randomised Control Trial Checklist
Three broad issues to consider when appraising a cohort study:
d) Are the results of the trial valid?
e) What are the results?
f) Will the results help locally?
Are the results of the trial valid?
1. Did the trial address a clearly focused
issue?
2. Was the assignment of patients to treatment
randomised?
3. Were patients, health workers and study
personnel blinded?
4. Were the groups similar at the start of the
trial?
5. Aside from the experimental intervention,
were the groups treated equally?
6. Were all of the patients who entered the
trial properly accounted for at its
conclusion?
What are the results?
7. How large was the treatment effect?
8. How precise was the estimate of the
treatment effect?
Will the results help locally?
9. Can the results be applied to your context?
(Or to the local population?)
10. Were all clinically important outcomes
considered?
11. Are the benefits worth the harms and costs?

(CASP, 2013d)