The design and rationale of SAVE BC: The Study to Avoid CardioVascular Events in British Columbia

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is highly heritable, particularly when it occurs at a young age. The screening of individuals with premature ASCVD, although often recommended, is not routinely performed. Strategies to address this gap in care are essential. We designed the Study to Avoid CardioVascular Events in British Columbia (SAVE BC) as a prospective, observational study of individuals with a new diagnosis of very premature ASCVD (defined as age ≤ 50 years in males and age ≤ 55 years in females) and their first‐degree relatives (FDRs) and spouses. FDRs and spouses will undergo screening for cardiovascular (CV) risk factors and subclinical ASCVD using a structured screening algorithm. All subjects will be followed longitudinally for ≥10 years. The overall goal of SAVE BC is to evaluate the yield of a structured screening program for identifying individuals at risk of premature ASCVD. The primary objectives of SAVE BC are to identify and follow index cases with very premature ASCVD and their FDRs and to determine the diagnostic yield of a structured screening program for these individuals. We will collect data on CV risk factors, medication use, CV events, and healthcare costs in these individuals. SAVE BC will provide insight regarding approaches to identify individuals at risk for premature ASCVD with implications for prevention and treatment in this population.

1. INTRODUCTION

Although rates of atherosclerotic cardiovascular disease (ASCVD) have declined overall over the past decade, this improvement has not extended to young individuals, for whom rates of hospitalization for acute myocardial infarction have remained unchanged1 or are increasing.2 Young individuals at risk for ASCVD are not, in general, identified by current clinical practice guidelines and risk calculators,3 suggesting that new approaches to identify these individuals are needed. One potential way to identify young individuals at risk for ASCVD and institute preventive strategies is by screening the family members of patients with very premature ASCVD.

ASCVD has long been recognized to have a strong familial component. Having a first‐degree relative (FDR) with premature ASCVD significantly increases risk,4, 5, 6 which is reflected in the doubling of the calculated 10‐year Framingham Risk Score (FRS) cardiovascular (CV) risk among individuals with a family history of premature ASCVD.7 The heritability of ASCVD is highest when it occurs at a younger age8, 9, 10, 11 and with multiple affected relatives.12

Given the increased risk to FDRs of patients with premature ASCVD, screening of individuals with a family history of premature ASCVD is recommended.7, 13, 14 In reality, such screening rarely occurs.15 In the American College of Cardiology Evaluation of Preventive Therapeutics (ACCEPT) study, <1% of patients with premature ASCVD had a discharge plan to screen family members.16 Similarly, the EUROpean Action on Secondary Prevention Through Intervention to Reduce Events II (EUROASPIRE II) study showed that only 11% of the siblings, and 5.6% of the children, of patients with premature ASCVD were screened for CV risk factors.17

We designed the Study to Avoid CardioVascular Events in British Columbia (SAVE BC) to address these gaps in screening FDRs of patients with very premature ASCVD and to help elucidate the molecular causes of very premature ASCVD. Here we present the rationale and design of SAVE BC.

2. METHODS

2.1. Study overview and objectives

SAVE BC is designed as a long‐term (≥10 years), prospective, observational cohort study of incident cases of very premature ASCVD (defined below) and their FDRs. Index cases are identified at provincial sites with cardiac catheterization programs (a total of 5 sites in the Canadian province of British Columbia), and active cascade screening is undertaken to identify eligible FDRs and spouses. An overview of the study workflow is shown in Figure 1. The major hypothesis being tested is that a structured screening program will identify individuals at risk of ASCVD who would benefit from preventive therapies.

Figure 1.

Overview of study workflow. Abbreviations: ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CTCA, computed tomography coronary angiography; FDR, first‐degree relative

The principal objectives of SAVE BC are (1) to identify and follow longitudinally index cases with very premature ASCVD and their FDRs and spouses; and (2) to determine the diagnostic yield of a structured screening program for the FDRs and spouses of patients with very premature ASCVD. Secondary objectives are (1) to examine the cost–benefit of a structured screening program for the FDRs and spouses of patients with very premature ASCVD; (2) to develop novel knowledge translation strategies to communicate the risk of very premature ASCVD to patients, healthcare providers, and the public; and (3) to identify novel genetic factors that influence the risk of developing very premature ASCVD.

2.2. Patient population and inclusion/exclusion criteria

Inclusion and exclusion criteria are shown in Table 1. Index cases are defined as males age ≤ 50 years or females age ≤ 55 years with new presentation of ASCVD. For FDRs (parents, siblings, and children of index cases) and spouses, the inclusion criterion is age ≥ 19 years. Subjects will be excluded if they are unwilling or unable to provide informed consent or unable to attend screening and follow‐up visits (see below). Spouses are included in SAVE BC because of the high spousal concordance of modifiable CV risk factors18 and to enable assignment of inheritance patterns of genetic variants identified in offspring.

Table 1.

Inclusion and exclusion criteria for index patients and FDRs/spouses

	Inclusion Criteria	Exclusion Criteria
Index patients	Male age ≤ 50 years or female age ≤ 55 years Diagnosis of ASCVD, defined on the basis of STEMI or NSTEMI, or UA or stable angina with angiographically proven >50% occlusion in ≥1 coronary artery, or CABG or PCI procedures Able and willing to provide written informed consent	Angiographic evidence of SCAD Kawasaki disease Takayasu arteritis Giant cell arteritis Fibromuscular disease Moyamoya syndrome Extracranial carotid aneurysms Inability to attend screening or follow‐up visits
FDRs/spouses	FDRs (parents, siblings, children age ≥ 19 years) or spouses of index patients	Inability to attend screening or follow‐up visits
	Able and willing to provide written informed consent

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass grafting; NSTEMI, non–ST‐segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SCAD, spontaneous coronary artery dissection; STEMI, ST‐segment elevation myocardial infarction; UA, unstable angina.

Recruitment into SAVE BC began in January 2016 and is currently occurring at 2 tertiary hospital sites in the lower mainland of British Columbia (Vancouver General Hospital and St. Paul's Hospital). Beginning in 2018, the 3 additional provincial sites with cardiac catheterization programs will be added, with a plan to be fully operational province‐wide by 2020.

2.3. Screening, data collection, and storage

Index cases, FDRs, and spouses undergo a structured, standardized screening algorithm (Figure 2). This includes clinical assessment with medical history, medication use, and physical examination (including physician measured‐blood pressure), anthropometric assessment, and assessment of patient‐reported health‐related quality of life using the EuroQol 5 dimensions (EQ‐5D) questionnaire.19 Laboratory assessment includes measurement of fasting lipids, glucose, creatinine, complete blood count, C‐reactive protein, and thyroid function.

Figure 2.

The SAVE BC screening protocol. All participants in SAVE BC will undergo a structured clinical and laboratory screening process. For FDRs and spouses, CV risk will be assessed by means of the FRS, modified for family history. FDRs will further undergo imaging by means of CAC scoring if age ≥ 45 years. FDRs age < 45 years will be assessed by means of CTCA. Spouses, in whom risk is assumed to be lower, will be assessed by carotid U/S. Abbreviations: CAC, coronary artery calcium; CBC, complete blood count; CRP, C‐reactive protein; CTCA, computed tomography coronary angiography; CV, cardiovascular; FDR, first‐degree relative; FRS, Framingham Risk Score; HbA1c, glycated hemoglobin; Lp(a), lipoprotein(a); SAVE BC, Study to Avoid CardioVascular Events in British Columbia; TSH, thyroid‐stimulating hormone; U/S, ultrasound

FDRs undergo screening for subclinical atherosclerosis based on age‐specific criteria (Figure 2). FDRs who are age ≥ 45 years are screened by means of a coronary artery calcium (CAC) score, whereas FDRs age < 45 years are screened via computed tomography coronary angiography (CTCA), which will be reported based on standardized criteria.20 This approach is based on data showing that the majority of coronary plaque in young individuals with a family history of premature ASCVD is noncalcified and would, therefore, be missed if only CAC scoring were performed.21 Spouses, whom we hypothesize will generally be at lower risk than FDRs, will be screened by carotid ultrasound, to minimize exposure to ionizing radiation.

Results of these investigations are made available to the patients' primary‐care and specialist physicians and other healthcare providers. Individual management decisions are left to the discretion of the treating physicians. All subjects are assessed by a certified genetic counselor and provided with counseling regarding the inherited nature of premature ASCVD.

To investigate cost–benefit and health outcomes, we will collect data on direct healthcare costs using provincial administrative health records held by Population Data BC and Vital Statistics, which include information on direct healthcare costs, prescription drug utilization, hospital admissions, surgery, and death. In addition, we will collect data on indirect costs, including absenteeism, presenteeism, and unpaid work productivity loss, using the Valuation of Lost Productivity questionnaire.22

Study data are entered into a secured, password‐protected, web‐based application.

2.4. Sample collection and storage

Two 6‐mL EDTA tubes of venous blood will be drawn once every 3 years for isolation of plasma, serum, and buffy coat as well as 1 tube of saliva using self‐collection kits (DNA Genotek, Ottawa, ON, Canada), and 1 PAXgene (Qiagen, Hilden, Germany) tube for collection of RNA. After centrifugation, plasma, serum, and buffy coat are transferred in 500‐μL aliquots to 1.5‐mL cryogenic tubes (Thermo Fisher Scientific, Waltham, MA) and stored at −80 ° C.

2.5. Follow‐up and outcomes

Index cases will be followed annually. FDRs and spouses will be followed annually if assessed to be at moderate or high CV risk (based on FRS modified for family history) and according to national guidelines,7 or every 3 years if assessed to be at low CV risk. An honorarium is offered to patients for each study visit. Medical histories including change in risk factors, medications, and new CV events (see Supporting Information, Appendix, in the online version of this article) will be updated at each visit and recorded. Repeat laboratory profiles will be obtained at each visit.

SAVE BC is approved by the clinical Research Ethics Board of the University of British Columbia (certificate # H17–01110). All participants provide written informed consent.

2.6. Sample‐size calculations

We estimated enrollment using data obtained from Cardiac Services BC, in collaboration with the BC Center for Improved Cardiovascular Health (ICVHealth). These data indicate that between 2000 and 2016, 8709 males and 3812 females were diagnosed angiographically with very premature ASCVD, for a mean of 783 patients per year in British Columbia. We estimate an 80% participation rate, and further estimate 20% dropout, for a total of 501 subjects recruited per year, or ~100 index cases recruited per year at each of the 5 sites. We estimate that each index case will have on average 2 FDRs/spouses, and further estimate a 60% recruitment rate and 20% dropout rate, for ~1 FDR/spouse recruited per index case. Based on our provincial rollout plan, we expect to recruit 3200 individuals in the first 5 years of SAVE BC (1600 index cases and 1600 FDRs/spouses) and an additional 5000 individuals (2500 index cases and 2500 FDRs/spouses) from years 6 to 10.

2.7. Statistical analysis

Summary of the baseline characteristics, including demographics, comorbidities, psychosocial factors, CV risk factors, FRS, and the Reynolds Risk Score will be described using mean ±SD or median (interquartile range) for continuous variables, and counts and proportions for categorical variables. Patient characteristics will be summarized according to the following 3 groups: index patients, FDRs, and spouses. We will use generalized linear mixed models to test for differences in baseline characteristics among groups while accounting for potential correlations for members of the same family. Potential familial dependence will be examined and adjusted using appropriate methods, such as random‐effects model or generalized estimating equations. Factors such as age, education, ethnicity, and geography that might affect care patterns will be explored by including them as covariates. As control groups, we will use data from the Canadian Heart Health Survey23 as a disease‐free general population control, as well as from the Global Registry of Acute Coronary Events (GRACE) registry24 as a control group of patients with established coronary disease (not specifically premature disease). The diagnostic yield of screening in this population will be investigated in terms of the percentage of FDRs/spouses found to harbor subclinical disease or who would qualify for preventive treatments (lipid‐lowering therapy or antihypertensive therapy) based on their assessed level of risk, according to national guidelines.7

To examine cost–benefit of screening, we will assess the proportion of FDRs and spouses who were receiving evidence‐based therapies prior to this study, and the known absolute risk reduction and cost of evidence‐based interventions in these individuals (including management of blood lipids, diabetes, hypertension, and smoking cessation). As treatment decisions will be left to the discretion of the treating physicians, we will not directly assess the effect of any treatments provided on the basis of the screening performed. Instead, we will perform modeling to forecast the expected health outcomes, cost (both direct and indirect), and effect on quality‐of‐life of identifying, screening, and treating‐to‐target this patient population.

2.8. Knowledge dissemination and translation

To aid in integrative knowledge translation, we have assembled a Patient Partner Committee, composed of 6 individuals from various geographic regions of British Columbia, who either have a history of premature ASCVD or are FDRs or spouses of someone with premature ASCVD. We hold quarterly teleconferences with the Patient Partner Committee to obtain their input on the design of SAVE BC, recruitment progress, operational issues, and plans for data analysis and dissemination. We have also developed a public website (http://www.savebc.ca) to communicate about the project to the public, as well as to study participants, to improve retention in the study.

2.9. Study organization

SAVE BC was conceived by the co–principal investigators and developed in conjunction with the Steering Committee (see Supporting Information, Appendix, in the online version of this article). The Steering Committee is responsible for oversight and guidance of the study and for requests for access to study data and samples. (A list of core laboratories also is available in the Supporting Information, Appendix, in the online version of this article.)

3. RESULTS

As of December 2017, we had recruited 248 index patients who met eligibility criteria for the SAVE BC program. Cascade screening of these families resulted in the identification and recruitment of 64 FDRs and 47 spouses. The demographics and characteristics of the index patients, FDRs, and spouses are shown in Table 2. The mean age of index patients was 46.6 years, and 73.4% were male. The mean age of FDRs and spouses was 48.7 ±17 years and 46.3 ±6 years, respectively.

Table 2.

Characteristics of study patients by group

	Index	FDR	Spouse
Subjects enrolled, n	248	64	47
Mean age, y	46.6	48.7	46.3
Male sex	73.4	43.8	29.8
Presentation
STEMI	21.4	—	—
NSTEMI	34.3	—	—
UA	13.3	—	—
Stable angina	25.4
Angina/other	6.0	—	—
Median no. of vessels affected (IQR)	2 (1–3)	—	—
Treatment
PCI	60.9	—	—
CABG	21.0	—	—
Medical/other	17.7	—	—

Abbreviations: CABG, coronary artery bypass grafting; FDR, first‐degree relative; IQR, interquartile range; NSTEMI, non–ST‐segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST‐segment elevation myocardial infarction; UA, unstable angina.

Data are presented as % unless otherwise noted.

4. DISCUSSION

Premature ASCVD is highly heritable, which implies an increased risk to family members. Despite recommendations from major professional societies that FDRs of such individuals be assessed for CV risk, rates of screening are low and are not normally a formal part of discharge planning after a CV event. We designed SAVE BC to address this gap in care, to understand the ability of a screening program for families with premature ASCVD to identify individuals who may benefit from preventive therapies, and to investigate the genetic and molecular causes of very premature ASCVD.

Although several studies have been conducted on patients with early‐onset CVD,25, 26, 27, 28, 29 SAVE BC is unique in many respects (Table 3). Most important, the inclusion of FDRs in SAVE BC is, to our knowledge, unique among contemporary studies of premature ASCVD and affords the opportunity to understand burden of risk factors and subclinical disease in these individuals, as well as to assess the yield of family‐based screening. Second, the prospective and longitudinal nature of our study allows the opportunity to understand the risk of these individuals over time, and the potential benefit of early identification. This approach also enables us to explore the value of genetic or epigenetic markers in unaffected individuals on incident disease. In particular, the long (≥10 years) planned follow‐up of SAVE BC makes it unique. Finally, our age of onset is lower than the traditional definition of premature CVD used in some prior studies. Because the heritability of ASCVD is highest when it occurs at a younger age,10 we hypothesize that focusing on these very young index cases may identify a more extreme phenotype of premature ASCVD and be more likely to identify cases enriched for genetic factors. Based on these considerations, we believe that SAVE BC will offer a valuable complement to other contemporary studies on premature ASCVD.

Table 3.

Comparison with other studies of premature ASCVD

Study	Inclusion Criteria	Design	Sample Size	FDRs Included	Reference
GENESIS‐PRAXY	ACS at age 18–55 years	Prospective	1576	No	27
YOUNG‐MI	First type 1 MI at age ≤ 50 years	Retrospective	1685	No	28
VIRGO	Acute MI at age 18–55 years	Prospective	3000 (2000 females and 1000 males)	No	29
SAVE BC	Males age ≤ 50 years and females age ≤ 55 years with ASCVD	Prospective	Projected: 3200 (1600 index and 1600 FDRs/spouses) by end of Year 5	Yes	N/A

Abbreviations: ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; FDR, first‐degree relative; GENESIS‐PRAXY, Gender and Sex Determinants of Cardiovascular Disease: Premature Acute Coronary Syndrome; MI, myocardial infarction; N/A, not applicable; SAVE BC, Study to Avoid CardioVascular Events in British Columbia; VIRGO, Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients; YOUNG‐MI, Study of Young Patients With Myocardial Infarction.

Among FDRs of individuals with premature ASCVD, increased CV risk can partly be accounted for by an increased burden of traditional CV risk factors.30, 31, 32 However, the high heritability of very premature ASCVD suggests the presence of genetic factors, as well. The specific genetic factors that underlie ASCVD remain largely unexplained. Major genetic variants with large effect size, such as mutations in the LDL receptor (LDLR) gene, are only present in a very small percentage (~2%) of patients with early‐onset myocardial infarction.33 A high genome‐wide polygenic risk score that increases risk of ASCVD may be present in an additional ~20% of patients.34 A long‐term goal of SAVE BC will be the identification of novel genomic risk factors for very premature ASCVD.

CV imaging in FDRs with a family history of premature ASCVD can assess an individual's response to both measured and unmeasured risk factors over the time of exposure as reflected by age. Increased CAC has been reported in FDRs of patients with premature ASCVD,35, 36 and expert consensus statements have recommended the selective use of CAC scoring in individuals with a family history of premature ASCVD.37 However, a limitation of CAC scoring is that it does not assess noncalcified plaque, and therefore it may not detect the earlier stages of atherosclerosis. FDRs of patients with premature ASCVD have a high burden of plaque by CTCA, of which most is noncalcified, particularly in younger individuals.21 Notably, asymptomatic FDRs of individuals with extremely premature ASCVD (onset at age < 40 years) have been shown to have increased plaque volume with high‐risk features, notably the presence of low‐density noncalcified plaque.38 In SAVE BC, we use CAC scoring to risk‐stratify FDRs, unless they are very young (age < 45 years), in which case we use CTCA. Emerging data suggest that CTCA can identify patients who benefit from statin therapy based on the presence of nonobstructive coronary artery disease.39 We believe SAVE BC will add to our understanding of the diagnostic yield of CTCA in patients with a family history of very premature CVD.

4.1. Anticipated outcomes

SAVE BC will determine the clinical utility, diagnostic yield, and cost‐effectiveness of a population‐based screening program for very premature ASCVD. Because routine screening programs for families with premature ASCVD do not currently exist in British Columbia, one early outcome will be an increase in the number of FDRs and spouses identified, screened, and treated with preventive therapies, such as lipid‐lowering and antihypertensive therapy, in patients with indications for these treatments based on national treatment guidelines.7, 40 Based on the experience with cascade screening for familial hypercholesterolemia,41 we expect that the earlier recognition of individuals at high risk for future events will lead to improvements in long‐term CV outcomes. Some FDRs identified in SAVE BC will not meet current guideline‐based indications for treatment, based on their estimated short‐term risk. However, these individuals may ultimately benefit from treatment to reduce their long‐term risk. The role of primary prevention in such individuals is currently being studied in the Eliminate Coronary Artery Disease (ECAD) trial.42

4.2. Future substudies

Planned substudies include comparison of sex and gender differences in clinical features and outcomes of index cases and FDRs; assessment of the frequency of candidate gene variants, such as pathogenic mutations of the LDLR gene, in index cases; association between DNA methylation profiles of unaffected FDRs and risk of future events; and burden of polygenic risk scores for ASCVD in index cases and FDRs.

4.3. Study limitations

One limitation of SAVE BC is that recruitment will be based in a single Canadian province. Although we are not aware of data that would suggest that this population is not representative of other Canadian jurisdictions, it is possible that the results may not apply to other provinces or countries. A future expansion of the program could include establishing similar programs at other Canadian sites or international sites. A further limitation is that the study does not include a matched control population. We will use existing population‐based controls of healthy patients or patients with ASCVD to perform comparisons, where appropriate. Finally, our sample‐size calculations are based on projected number of participants to be recruited, rather than representing a formal power calculation for a specific outcome.

5. CONCLUSION

ASCVD is highly heritable, particularly when it occurs at a young age. However, knowledge of its heritability, and the availability of proven and cost‐effective measures to reduce CV risk, have not translated into system‐wide approaches to identify and screen high‐risk families. SAVE BC aims to fill this gap in care and to expand our understanding of the determinants, outcomes, and treatment of premature ASCVD. In the longer term, this unique, prospectively recruited, and longitudinally followed cohort, with appropriately collected biological samples, will provide a rich opportunity to explore genetic and molecular factors in determining premature ASCVD risk, outcome, and response to treatment. These efforts will advance the use of precision medicine approaches for the diagnosis, prevention, and treatment of premature ASCVD in at‐risk family members.

Supporting information

Appendix S1. SAVE BC Steering Committee

SAVE BC Study Sites

SAVE BC Core Laboratories

Definition of End‐points

Brunham LR, Lynch K, English A, et al. The design and rationale of SAVE BC: The Study to Avoid CardioVascular Events in British Columbia. Clin Cardiol. 2018;41:888–895. 10.1002/clc.22959