International Journal of Endorsing

HEALTH SCIENCE RESEARCH

Study Protocol Doi: 10.29052/IJEHSR.v12.i3.2024.XX-XX

Corresponding Author Email:
Accepted Article | This is not yet the definitive version of record; it is to give early visibility of the article | An open access article published ahead of print under the

PARADISE-PK Study: Prospective

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assessment of Atherosclerotic Received 01/03/2024

Accepted 26/03/2024
Cardiovascular Disease (ASCVD) risk in First Published 02/05/2024

adults (30 years & above) in Pakistan:

A multi-year study investigating incidence, © The Author(s). 2024 Open Access This article
is distributed under the terms of the Creative

validation, and management strategies. Commons Attribution 4.0 International License

(http://creativecommons.org/licenses/by/4.0/)
Tariq Ashraf
Karachi Institute of Heart Disease (KIHD), Karachi-Pakistan

Abstract
Background: This study aims to conduct a 10-year follow-up to assess ASCVD risk in Pakistan among
individuals aged 30 years and above without a known history of ASCVD. The focus will be on evaluating
ASCVD risk over this specific 10-year timeframe. The study will also validate risk assessment scores for
identifying high-risk individuals and examine the incidence rate of ASCVD events during long-term follow-
up.
Methodology: In this prospective cohort study, ASCVD risk in adults will be assessed by selecting
participants aged 30 and above through a non-probability convenient sampling technique. The sample size
of 3,513 will be stratified across Pakistan's provinces. Alongside demographics and clinical history, the study
will calculate 10-year, 30-year, and lifetime ASCVD risks, incorporating genetic assessment for Apo B.
Personalized management recommendations based on ASCVD risk will be provided, and a six-month follow-
up will track ASCVD events. The data analysis will employ descriptive statistics and subgroup analysis for
comprehensive insights.
Discussion: Given the rising ASCVD prevalence, this study is crucial for understanding disease patterns and
identifying high-risk individuals among adults aged 30 and above in Pakistan. It contributes valuable
information to the knowledge base on ASCVD, guiding preventive measures for policymakers and healthcare
professionals. The ultimate goal is to reduce ASCVD incidence, lessen the burden, and enhance
cardiovascular health.

Keywords
ASCVD Risk Assessment, Cardiovascular Disease Prevention, Apo B Genetic Assessment, Public Health
Intervention

Published by Advance Educational Institute and Research Centre

 International Journal of Endorsing Health Science Research Int. j. endorsing health sci. res.

Introduction predicted risk despite harboring a high lifetime risk

profile13. Acknowledging this discrepancy, the 2018
Cardiovascular diseases (CVD) pose a formidable
AHA/ACC cholesterol guideline advocates for
challenge as the leading cause of premature
estimating lifetime or 30-year ASCVD risk for
mortality globally, affecting diverse populations
individuals under 4014.
across income societies1. The dynamic interplay of
sex and age significantly influences the trajectory
Transitioning from risk assessment to lipid
and prognosis of atherosclerotic cardiovascular
modulation, mainly focusing on low-density
diseases (ASCVD)2,3. Previously perceived as an
lipoproteins (LDL), unveils a pivotal role in
ailment predominantly afflicting affluent older
atherogenesis. LDL assumes primary responsibility
men, ASCVD has undergone a transformative shift,
in cholesterol transport15. The strategic modulation
emerging as an epidemic impacting the
of lipid profiles has emerged as a central goal for
productivity of both young men and women. This
cardiovascular prevention, concentrated on
resonance is particularly pronounced in
mitigating cardiovascular risk through targeted
communities with varying economic backgrounds,
reduction of LDL-cholesterol using diverse lipid-
including high-income and low-to-middle-income
lowering agents. Recent attention has shifted
settings4. The far-reaching consequences of
towards compounds offering nuanced insights into
premature CVD extend beyond the individual,
pro-atherogenic risk, with apolipoproteins playing
exerting socioeconomic strains on families and
an essential role in regulating lipoprotein
societies, especially in lower-income communities5.
metabolism and garnering significant attention in
Recognizing the gravity of this situation, the World
atherosclerosis16.
Health Organization (WHO) initiated the "25 by 25"
campaign, aiming to curtail premature mortality
Among the various apolipoproteins,
from non-communicable diseases, with over 60%
apolipoprotein B (Apo B) emerges as a crucial
attributed to CVD, by 25% before 20256.
component integral to all atherogenic lipids,
including very low-density lipoproteins (VLDLs),
While global data on gender- and age-specific
intermediate-density lipoproteins (IDLs), LDLs, and
variations in CVD risk factors and outcomes have
chylomicrons17. Existing literature underscores
been extensively documented7,8, the local evidence
substantial variability in the lipid composition of
in Pakistan underscores a crucial research gap. A
Apo B lipoproteins, positioning Apo B as superior
contemporary ST-elevation acute coronary
to total cholesterol and triglyceride levels in
syndrome (STE-ACS) cohort in Pakistan reveals a
predicting cardiovascular risk18. However, the
noteworthy 12% of premature cases (<40 years) 9. A
predictive role of Apo B versus LDL-cholesterol
study by Ullah et al.10, comprising 15,106
remains controversial. While some studies
participants from the Cardiac Registry of Pakistan
advocate for Apo B as a more precise predictor of
Catheterization Percutaneous Coronary
cardiovascular risk than LDL-cholesterol and non-
Intervention, reports 7.4% of patients under 40
high-density lipoprotein cholesterol (non-HDL)18,19,
years. However, comprehensive local evidence on
a recent extensive study involving over 300,000
the incidence of ASCVD among the young
patients did not establish the superiority of Apo B
population remains scarce.
over LDL-cholesterol in assessing cardiovascular
risk20. This divergence in findings is mirrored in the
Current risk assessment guidelines, exemplified by
2021 ESC Guidelines on Cardiovascular Disease
the 2019 ACC/AHA Cardiovascular Risk Assessment
Prevention in Clinical Practice21. Consequently, a
Guidelines, predominantly employ race- and sex-
series of comprehensive studies is imperative to
specific Pooled Cohort Equations (PCE) for
delineate the precise role of Apo B as a predictor
predicting 10-year CVD risk, specifically in adults
of cardiovascular diseases (CVDs).
aged 40 to 7511,12. However, these guidelines need
more direct applicability to young adults, who
often exhibit a paradox of low 10-year ASCVD

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In light of Pakistan's escalating ASCVD burden, Consent

early identification and optimal management of Informed consent will be obtained from potential
modifiable risk factors become imperative for trial participants by designated and appropriately
prevention. While conclusive studies are lacking, trained personnel. Emphasizing the voluntary
expert recommendations underscore the utility of nature of participation, comprehensive information
"total/absolute CVD risk" assessment in guiding about the study objectives, potential risks, and
management decisions22. This study, utilizing the benefits will be provided. Additional consent
ASCVD risk score and WHO risk score system, aims provisions for the collection and use of participant
to evaluate ASCVD risk in young individuals, data and biological specimens in ancillary studies,
categorizing risks into low, intermediate, and high if applicable, will be clearly communicated and
groups to guide tailored interventions, be it lifestyle obtained.
modifications, non-pharmaceutical management,
or pharmaceutical interventions, at each specific Confidentiality
stage. To protect confidentiality, stringent measures will
be in place for the collection, sharing, and
Methodology maintenance of personal information about
potential and enrolled participants. Data
The objective of this trial
anonymization and secure storage protocols will
This study aims to conduct a 10-year follow-up to
be implemented before, during, and after the trial.
assess atherosclerotic cardiovascular disease
All research personnel involved in data handling
(ASCVD) risk among individuals aged 30 years and
will undergo training on confidentiality protocols.
above in Pakistan without a known history of
ASCVD. The primary objective is to evaluate
Declaration of Interests
ASCVD risk over this specific 10-year timeframe.
A statement declaring financial and other
The study will also validate risk assessment scores
competing interests for principal investigators for
for identifying high-risk individuals and examine
the overall trial and each study site will be provided.
the incidence rate of ASCVD events during long-
Any conflicts of interest will be transparently
term follow-up.
disclosed, upholding the integrity of the research.

Study Design
Access to Data
To achieve a comprehensive understanding of
Access to the final trial dataset will be restricted to
ASCVD risk in the adult Pakistani population, this
authorized personnel involved in data analysis and
research project will employ a robust prospective
interpretation. Any contractual agreements limiting
cohort study design. This method enables the
such access for investigators will be transparently
systematic observation of participants over an
disclosed. The data will be safeguarded to maintain
extended period, allowing for the identification of
its integrity and protect participant confidentiality.
potential risk factors and the dynamic evolution of
ASCVD risk.
Study Registration
Transparent research practices will be maintained,
Ethics
as evidenced by the registration of the study's
Stringent ethical standards will be adhered to
protocol on ClinicalTrials.gov (Registration#
throughout the study, aligning with the principles
NCT06316453). This registration ensures
outlined in the declaration of Helsinki. Ethical
accessibility to the study's detailed protocol,
approval, denoted by Pakistan Medical Association
promoting transparency and accountability in
Committee on Ethics (Registration number:
research practices. The online availability further
AU/098/LKI/12 on 15th April 2024), underscores the
facilitates dissemination of information to the
commitment to safeguarding participants' rights,
broader scientific community.
privacy, and well-being.

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Enrollment Assessment for eligibility

Excluded: Not meeting inclusion

criteria/refused to participate

Baseline Data Collection

Assessment ASCVD Risk Assessment

Selecting Patients for Apo B Genetic

Assessment

Personalized Management
Recommendations:
Management Based on ASCVD risk assessments,
personalized management recommendations
will be provided to all participants.

Follow-up Protocol:
Follow-Up Every six-month follow-up will be conducted to
track ASCVD events.

Figure 1: Diagram describing the flow of participants throughout the study

Principle Investigators Selection Sample Size Calculation

The Principal Investigators (PIs) for this study will be The sample size, determined by insights from a
carefully selected based on their distinguished study by An et al.6, which showcased a median 10-
expertise in cardiovascular research and affiliation year ASCVD risk of 0.6% in a sizable sample of
with reputable medical institutions across different 414,260 young adults. To enhance the robustness
provinces in Pakistan. The chosen PIs will of our study and account for potential
demonstrate a comprehensive understanding of observational bias and missing clinical
ethical considerations, collaborative skills, and characteristics, the initially identified sample size
leadership qualities essential for overseeing the has been increased by a factor of 1.5. This
study's diverse and geographically dispersed adjustment ensures a more comprehensive
components. representation, resulting in a final sample size of
3,513 individuals, specifically young and healthy

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participants. To accurately reflect the diverse Participant Recruitment

population across Pakistan, stratification based on Participants will be recruited using a deliberate
the 2017 census data will be employed, ensuring non-probability convenient sampling technique,
representation from all four provinces and acknowledging the diverse nature of the
optimizing the study's applicability and population. Informed consent, highlighting the
generalizability. voluntary nature of participation, will be a
cornerstone of the recruitment process, fostering
Participant Selection ethical and transparent engagement.
To ensure a representative sample reflective of the
diverse demographic landscape, we will utilize a Baseline Assessment
deliberate and considered non-probability A dedicated online portal and proforma will be
convenient sampling technique for participant meticulously employed for baseline data collection.
recruitment. Each participant will be assigned a unique tracking
ID, systematically recorded in an online registry.
Inclusion criteria This comprehensive baseline assessment will
The inclusion criteria will include individuals of any capture demographic information, clinical history
gender aged 30 and above, ensuring a diverse (including hypertension, diabetes, smoking, and
representation to encompass a broad spectrum of positive family history of ischemic heart disease),
experiences and risk factors within this age group. and key biometric measures (blood pressure, lipid
This comprehensive criterion facilitates an in-depth profile, BMI), forming a robust foundation for
examination of atherosclerotic cardiovascular subsequent analyses.
disease (ASCVD) risk factors, specifically targeting
individuals without pre-existing cardiovascular ASCVD Risk Assessment
conditions, thereby enhancing the inclusivity of our Utilizing validated tools such as the Pooled Cohort
study. Equations (PCE) for 10-year ASCVD risk, the 30-year
ASCVD risk prediction tool, and lifetime ASCVD risk
Exclusion criteria categories, participants will undergo a thorough
Exclusion criteria will be applied meticulously, risk assessment. This multi-dimensional approach
excluding individuals with a confirmed diagnosis of ensures a nuanced understanding of short and
ASCVD or cancer to focus specifically on those long-term cardiovascular risks.
without pre-existing cardiovascular conditions. This
strategic exclusion ensures a cohort free from Genetic Risk Assessment
confounding factors, enabling a more precise The genetic risk for ApoB will be meticulously
evaluation of ASCVD risk in the chosen assessed by genotyping the APOB rs1042031
demographic. Additionally, participants who variant. Subsequently, the calculation of the
express a refusal to provide informed consent will genetic risk score (GRS) based on risk alleles will
be excluded, prioritizing ethical considerations and provide a personalized insight into genetic
respecting individual autonomy in participation. predispositions related to ASCVD risk.
This meticulous approach to participant selection
enhances the study's internal validity and Personalized Management Recommendations
strengthens the reliability of the findings. Participants will receive personalized management
recommendations derived from the ACC/AHA
Recruitment & Assessment Procedures Cardiovascular Risk Assessment Guidelines. These
Efficient and thorough recruitment and assessment tailored suggestions may encompass dietary
procedures will be implemented to ensure the programs, lifestyle modifications, and, when
comprehensive examination of ASCVD risk factors indicated, pharmaceutical therapies like statins,
among participants. aiming to mitigate identified risks effectively.

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Follow-up Procedures (7.5% to <20%), or high risk (≥20%). The 30-year

A structured follow-up protocol will be ASCVD risk assessment will utilize the formula
implemented, involving regular contact every six proposed by Pencina et al.23, classifying
months through phone and email. This proactive participants based on their risk for "hard" and
approach allows for ongoing participant "general" CVD events. The lifetime ASCVD risk
engagement and the collection of crucial data. evaluation will categorize individuals into risk
Long-term follow-up will extend to tracking ASCVD groups, distinguishing between optimal, not
events, including coronary mortality, myocardial optimal, elevated, and major risk factors,
infarction, stroke, and other relevant occurrences, determined by specific risk criteria. For Genetic Risk
contributing to a comprehensive understanding of Assessment of ApoB, the study will compute the
disease progression. Genetic Risk Score (GRS) based on genotyping the
APOB rs1042031 variant, following the
Data Analysis and Validation methodology outlined by Shahid SU et al.24. The
Demographic and clinical traits will undergo unweighted GRS for ApoB will be derived through
rigorous analysis using descriptive statistics. an additive approach, assigning values of 0, 1, and
Subgroup analyses, considering factors such as 2 for protective homozygous, heterozygous, and
gender, age, and province, will provide a nuanced risk homozygous genotypes, respectively. This
perspective on ASCVD risk factors. Statistical tests resulting GRS for ApoB will range from 0 (indicating
tailored to data types and study goals will be the absence of risk alleles) to 2 (both alleles
applied to validate ASCVD risk assessments and identified as risk alleles for APOB rs1042031) in an
ascertain the frequency of events. individual.

Study variables Data Analysis

The study variables encompass a comprehensive The analysis of demographic and clinical
set of data points gathered through a dedicated characteristics within the research population will
online portal and proforma. Participants will receive be conducted using robust descriptive statistics,
unique tracking IDs for recording in an online providing a comprehensive overview. The
registry, capturing vital information, including distribution of ASCVD risk groups will be
demographic information, clinical history, and meticulously determined to identify prevalent
outcome measures. patterns. Subsequently, a thorough subgroup
analysis will be undertaken, considering key factors
Sample collection and transportation such as gender, age, and province, to unveil
In terms of sample collection and transportation, a nuanced insights into potential variations.
nationwide approach will be adopted, employing
standardized protocols for rigorous sample To assess the frequency of ASCVD events and
collection, consent procedures, and clinical validate the accuracy of risk assessment ratings, a
documentation. All collected samples will be diverse set of statistical tests will be employed,
transported to a centralized laboratory, ensuring tailored to the data type and study objectives. This
consistency in processing and analysis. Stringent includes, but is not limited to, Chi-square tests,
temperature control, secure logistics, and quality ANOVA, or logistic regression analysis, depending
control measures will be implemented to safeguard on the nature of the variables under consideration.
sample integrity and uphold the highest standards These tests will facilitate a rigorous evaluation of
in data reliability and validity. the effectiveness and reliability of our risk
assessment models. Additionally, any newly
Outcome Measures emerging statistical methodologies deemed
Participants will be stratified into distinct 10-year appropriate for enhancing the precision of our
ASCVD risk categories, including low risk (<5%), analysis will be thoughtfully incorporated into the
borderline risk (5% to <7.5%), intermediate risk study design.

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Discussion Despite accumulating evidence supporting the

superior accuracy of non-HDL cholesterol (HDL-C)
The assessment of a patient's risk for
and apolipoprotein B (Apo B) in estimating
atherosclerotic cardiovascular diseases (ASCVD) is
atherosclerotic cardiovascular disease (ASCVD)
crucial in guiding preventive cardiology
risk27-31, current major lipid guidelines persist in
interventions. This necessitates a holistic approach
recommending LDL cholesterol (LDL-C) as the
beyond conventional risk-scoring methods25.
primary marker to assess treatment adequacy32,33.
Primary prevention begins with global risk scoring,
The potential advantages of adopting non-HDL-C
using standard office-based factors to calculate
or Apo B as treatment targets require further
ASCVD risk over a specified timeframe, typically 10
validation, underscoring the ongoing need for
years. This risk assessment forms the basis for
continuous efforts to refine ASCVD risk assessment
discussions between clinicians and patients,
and treatment goals.
facilitating the identification of effective
cardiovascular disease (CVD) risk reduction
A thorough evaluation of ASCVD risk should
strategies. Factors enhancing risk, including
encompass traditional factors, risk-enhancing
premature family history, persistently elevated
elements, reproductive history, social
LDL-C, and chronic kidney disease (CKD), along
determinants, and advanced screening tests.
with inflammatory markers like hsCRP and
Integrating these factors into clinician-patient
laboratory measures such as lp(a), play a vital role
discussions is essential for a personalized and
in informing treatment decisions, enabling a more
effective approach to ASCVD prevention.
personalized approach to preventive therapy.

In assessing CVD risk in women, a comprehensive Conflicts of Interest

reproductive history is essential, encompassing None.
factors from menarche to menopause, with specific
attention to elements like preeclampsia, premature Acknowledgement
menopause, and autoimmune diseases as risk-
The authors express their gratitude to the Executive
enhancing factors. The impact of race/ethnicity on
Council of the Pakistan Cardiac Society for
current risk assessment tools must be considered,
providing the platform for conducting and
with certain groups requiring specific attention in
disseminating this study under their guidance and
preventive therapy decisions. Beyond
oversight.
race/ethnicity, the independent effects of social
determinants of health should be integral to
clinician-patient discussions when optimizing Funding
ASCVD risk. Challenges with the 2013 American None.
College of Cardiology (ACC) and American Heart
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ISSN 2307-3748 (Print) ISSN 2310-3841 (Online) Volume 12 Issue 3 [2024]