PAKSEHAT: Pakistan Study of Premature Coronary Atherosclerosis in Young Adults

Sponsor

Tabba Heart Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT05156736

Collaborator

Getz Pharma (Industry)

2,000

Enrollment

Location

71.9

Anticipated Duration (Months)

27.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Coronary heart disease (CHD) is a major cause of morbidity, disability, mortality, and health expenditures worldwide. A wealth of studies has demonstrated that people of South Asian ancestry have a higher risk of CHD and particularly premature CHD than most other racial/ethnic groups, and recent research suggests that this risk is higher in Pakistanis than in Indians-the two largest SA groups. Pakistan is the 5th most populous country in the world, and despite these concerning trends, so far there has been a scarcity of large studies evaluating the prevalence of cardiovascular risk factors and subclinical coronary atherosclerosis in young-to-middle-aged Pakistanis. Also, there is currently no cardiovascular risk score specifically tailored to younger Pakistani men and women. The PAKistan Study of prEmature coronary atHerosclerosis in young AdulTs (PAK-SEHAT) aims at addressing these important gaps. PAK-SEHAT is an ongoing prospective cohort study that will enroll 2,000 asymptomatic Pakistani men aged 30 to 45 years and women aged 45 to 55 years from the general population, free of clinically overt cardiovascular disease. Participants will undergo a comprehensive baseline exam including coronary computed tomography angiography, and will be followed for incident events and repeat testing for 5 years. PAK-SEHAT will allow to determine the prevalence, severity, determinants, and prognostic significance of early atherosclerosis in apparently healthy young-to-middle-aged Pakistanis. This knowledge can help inform primordial and primary prevention strategies, enhanced cardiovascular risk stratification, and potential plaque-screening approaches in Pakistan, all of which can ultimately help reduce the burden of CHD in the country. In this report investigators describe the rationale, objectives, methods, and discuss the potential implications of the PAK-SEHAT study.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerotic Plaque Diabetes Mellitus, Type 2 Hypertension Stroke

Detailed Description

Study Objectives The primary objectives of PAK-SEHAT are: 1) characterize the prevalence and severity of subclinical coronary atherosclerosis among young-to-middle aged Pakistani men and women free of clinical CVD, and 2) understand the impact, in terms of 5-year rates of CVD events, of using the prognostic information provided by CCTA and the other study tests and measurements to optimize cardiovascular prevention management in young-to-middle-aged Pakistani adults.The secondary objectives of the study are to 1) determine the prevalence of known and unknown diabetes, hypertension, dyslipidemia, and other cardiovascular risk factors among young-to-middle aged Pakistani men and women free of clinical CVD; 2) identify the determinants of subclinical coronary atherosclerosis in this population; 3) estimate the incidence of diabetes, hypertension, dyslipidemia, and other cardiovascular risk factors at 5 years of follow-up; 4) identify independent risk factors and markers of incident clinical CVD among young asymptomatic Pakistanis; and 5) develop a 5-year risk score for the prediction of incident CVD events in young-to-middle-aged Pakistani men and women.

Study Design PAK-SEHAT is an ongoing, observational, community-based, prospective cohort study, with a target study population of 2,000 participants and a planned prospective follow up of 5 years after study enrollment.

Study Population Investigators plan to recruit 2,000 young-to-middle aged adult Pakistani men and women with no known clinical ASCVD. Because the focus of this study is to investigate the prevalence, severity, and determinants of early coronary atherosclerosis in Pakistani adults, focus will be on apparently healthy (i.e., without known clinical CVD) young-to-middle native Pakistanis. Also, because premature coronary events are more frequent and usually observed at younger ages in men than in women, the age range of male participants at enrollment will be 30-45 years, while this will be 45-55 years for female participants; and enrollment will use a 3:1 male:female ratio.

Sampling Strategy: PAK-SEHAT aims to be as representative as possible of the general Pakistani population, and a multi-stage cluster sampling strategy will be used to identify candidates to participate in the study. A cluster is defined as a Union Council (UC), which is the smallest administrative division in Pakistan defined by the Government, with an approximate population of 30,000 people each. The first stage of the sampling process occurs at the province level, which is the largest administrative division in the country, and participants will be recruited from all four Pakistani provinces and the Federal territory of Islamabad. Next, districts will be selected, and within those, the UCs. Using the country's most updated census data, one district from each province will be selected. Stratified sampling will be done using rural and urban proportions declared by Pakistan's government. The sampling of the districts will be stratified based on their rural and urban distribution, which should be representative of the province's rural/urban proportion. Within each district, one urban and one rural UC will be selected based on convenience. Households within the UC will be selected by systematic sampling. The sampling interval will be calculated using census data on population size and desired sample from each UC. The last stage is participant selection from each household. Only one member of each will be allowed to participate.

Participant Enrollment Community based door-to-door surveying will be the primary method of participant recruitment both in rural and urban areas. However, a critical first step will be to identify the local stakeholders of the selected area/community. The research team will arrange meetings with these leaders to inform them about the study and have their support to work with the local community. Once engaged, those leaders will be asked to help disseminate the study and contact individual participants for enrollment. Another important resource when identifying and enrolling eligible participants are Government front-line health workers, known as Lady Health Workers. These are residents of the area and their primary responsibility is to provide preventive healthcare and promote health among women, men, and children. They maintain logs of the residents living in their area of action and can serve as a good resource to identify and reach potential participants.

After receiving the line-listing of potential candidates for participation, study personnel will visit those individuals at their households and screen them for eligibility using a structured questionnaire. Individuals who are deemed eligible to participate in the study will be provided with detailed information about the study, invited to ask questions, and asked to provide written informed consent for participation. If the potential participant is not literate, then, in the presence of a family member, the consent form will be read to the participant, and thumb impression will be taken for consent. The family member will serve as witness and will provide the signature or the thumb impression (as appropriate) on the consent form.

All the participants will undergo study measurements at mobile health set-up except first 100 participants. The first 100 participants will be from urban Sindh and will have their measurements at the study hospital to have a dry run of the study procedures. It will help us to identify the challenges in the study flow and to rectify them before starting the mobile set-up. For rest of the participants, measurements will be taken at the mobile health set-up.

After consenting, participants will be inquired about convenient times for them to visit the mobile health set-up that will be used for data collection in those areas .Then, the study team will visit the participants' households on the agreed time and bring them to the mobile set-up. Participants will be brought in groups of 4-5 at a time to utilize working hours and transport resources efficiently.

Baseline Evaluation Once enrolled, all participants will undergo a comprehensive set of baseline evaluations, some of which will be repeated using identical methods during study follow-up .

Study interview and questionnaires. Participants will be interviewed by trained study personnel. Sociodemographic data, and information on past and present medical history, family history, lifestyle will be collected using structured questionnaires.

Blood pressure and ankle-brachial index (ABI). Systolic and diastolic blood pressure will be measured in each participant using a DINAMAP monitor (General Electric), With participants sitting in a comfortable position for 5 minutes. Three readings will be taken and their average will be used in subsequent analyses. Lying blood pressure will also be measured in the participants' arms and legs and the ankle-brachial index will be calculated.

Anthropometry and body composition. Height (cm) will be measured through wall mounted measuring tape. Body composition will be analyzed using the Tanita-MC-780 U body composition analyzer.

Blood measurements and genetics. Trained study personnel will draw approximately 30 mL of venous blood from each participant. Approximately 10 mL of blood will be biobanked and stored at -80C to allow for future additional research studies, including genetic testing. The latter will include but not limited to testing for ApoE Genotype (information about risk of heart disease and response to amounts of dietary fat), 9p21 Genotype (risk of MI and CAD at an early age), KIF6 Genotype (risk of heart disease and reduction of MACE with statins), LPA Intron 25 (increased risk of heart disease), 4q25 A-Fib genotype (risk of atrial fibrillation and risk of stroke due to atrial fibrillation). In participants who do not consent for genetic testing, their 10 mL of biobanked blood may be used in non-genetic analyses but not for studies involving genetic testing.

Cardiac CT scans. Participants will first undergo a non-contrast-enhanced cardiac CT for coronary artery calcium (CAC) scoring, followed by a contrast-enhanced CCTA. Toshiba Aquilion Multislice CT scanners and prospective ECG triggering will be used. Participants will be evaluated before the CT scan by study personnel and if the heart rate is above 65 bpm will be pre-treated with a β-blocker (or ivabradine if contraindicated) to achieve a target heart rate of ~60 bpm. Sublingual nitroglycerin will be administered as per standard protocols approximately 3 minutes before the CCTA scan, and intravenous contrast will be injected at a rate of 5.5-7 ml/s depending on the body habitus of the participant; for an average patient, the dose of contrast is expected to be approximately 60-80 mL. The non-contrast-enhanced images will be transferred to the Cardiology CT core lab at Tabba Heart Institute and evaluated by trained radiologists who will quantify CAC according to Agatston's method.

Carotid ultrasound imaging . All participants will undergo carotid ultrasound imaging for assessment of presence of carotid plaque and for carotid intima-media thickness (CIMT) evaluation. This will be assessed with automated measurement over bilateral carotid arteries using a Toshiba Aplio 500 ultrasound system (Otawara, Japan), using B-mode ultrasound examination with a 10-MHz multi-frequency linear array transducer. Participants will be examined in the supine position, and standard measurements will be performed.

Baseline testing sequence. At the mobile set-up, first participants will undergo BP measurement, ABI, anthropometric measurements, and body composition analysis, Then participant will be prepared for CCTA. Blood specimens will be collected when canulated for CCTA, then CCTA will be performed and then carotid ultrasound.

Baseline Data Management and Quality Study data will be collected in tablets and other digital platforms and will be transferred periodically to a central server. The centralized study database will be stored at the Tabba Heart Institute using a secure server, and data privacy and confidentiality will be secured at all times. For quality control purposes, the data collection application in the tablets will have in-built features to limit erroneous data entry and inconsistency in recording of participant's responses. Also, a field coordinator will monitor data collection and spot check 5-10% of the interviews. At the centralized study database, data error reports will be generated on a monthly basis to monitor completeness, invalid values, and inconsistencies in responses. In addition, a live dashboard will be developed for pre-identified key variables to monitor and evaluate the project's progress.

Follow-Up and Event Ascertainment As part of the study follow-up, participants will be contacted at 12, 30, and 60 months (5 years) after baseline. Besides repeat blood tests and imaging testing at 30 and 60 months (Table 2), in each of the three follow-up visits a questionnaire will be used to collect information on ASCVD outcomes. In case of an affirmative answer, participants will be asked to provide additional evidence (e.g. hospital admission records) so that the event can be confirmed. ASCVD events will include myocardial infarction, unstable angina, stable angina, stroke, transient ischemic attack, coronary revascularization, and cardiovascular death.

Published definitions will be used to define each of these incident events. An independent Two cardiologists from the centralized PAK-SEHAT adjudication committee and blinded to the results of the study tests will classify events as definite, probable, or absent, based primarily on available hospital documentation. They will also classify CHD-, CVD- or stroke- related deaths based on hospital records (if available) and verbal autopsy interviews with families. If there is disagreement in event adjudication between the 2 assigned experts, a third independent physician adjudicator will review the evidence to break the tie.

The repeat CCTA at 60 months of follow-up will be used to evaluate the progression/regression of coronary plaque burden.

Statistical Analyses For analyses using baseline data, the frequency and distribution of cardiovascular risk factors (known, unknown), coronary plaque burden, and other key baseline variables using number and frequency (%) for categorial variables and mean (standard deviation) or median (interquartile range) for normally and not normally distributed continuous variables will be described. Specifically for coronary plaque characteristics, the CAC score will be categorized as 0, >0-<100, ≥100, and the distribution of CAC scores and proportion of each stratum will be reported. With regards to CCTA findings, the proportion of participants with any coronary plaque and the distribution of plaque subtypes will be reported with 95% CI. Investigators will also report the frequency of having a maximal coronary stenosis ≥50% and ≥70%, respectively, and the proportion of participants with high-risk plaque features. The distributions of number of coronary vessels with plaque, number of coronary segments affected per participant, and the location of coronary plaques (left main, anterior descending, circumflex, and right coronary artery) will also be described.

In analyses of incident events during follow-up, investigators will use standard survival analysis and time-to-event techniques. Cumulative incidence at 5 years (in %) and incidence rates per 1,000 person-years (with 95% CI) will be computed for the primary and secondary study outcomes. The ASCVD event rates in the PAK-SEHAT population will be compared with those of Pakistanis of the same age and sex free of clinical ASCVD and not included in the study.

Analyses of incidence of cardiovascular risk factors during follow-up will be restricted to individuals at-risk of each of those risk factors.

Investigators will use Cox Proportional Hazards regression models to evaluate the association between important baseline characteristics and incident ASCVD events during follow-up.

Study Design

Study Type:

Observational

Anticipated Enrollment :

2000 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Pakistan Study of Premature Coronary Atherosclerosis in Young Adults (PAK SEHAT)

Actual Study Start Date :

Nov 5, 2021

Anticipated Primary Completion Date :

Nov 1, 2026

Anticipated Study Completion Date :

Nov 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Young Pakistanis Young pakistani population with no history of cardiovascular disease and stroke

Outcome Measures

Primary Outcome Measures

Burden and progression of atherosclerotic plaque assessed via coronary computed tomography angiography [5 years]
Burden and progession of atherosclerotic plaque will by measured by coronary computed tomographical angiography (CCTA). Participants will first undergo a non-contrast-enhanced cardiac CT for coronary artery calcium (CAC) scoring, followed by a contrast-enhanced CCTA. Toshiba Aquilion Multislice CT scanners and prospective ECG triggering will be used. Sublingual nitroglycerin will be administered as per standard protocols approximately 3 minutes before the CCTA scan, and intravenous contrast will be injected at a rate of 5.5-7 ml/s depending on the body habitus of the participant; for an average patient, the dose of contrast is expected to be approximately 60-80 mL. The non-contrast-enhanced images will be transferred to the Cardiology CT core lab at Tabba Heart Institute and evaluated by trained radiologists who will quantify CAC according to Agatston's method.

Secondary Outcome Measures

Incidence of diabetes measured by HbA1C [5 years]
Glycosylated hemoglobin (HbA1C) will be used to assess the incidence of diabetes. HbA1C of greater than or equal to 6.5% will be taken as diabetic
Risk factors of clinical cardiovascular disease [5 years]
Regression will be done to assess the association of multiple factors like age, gender, family history, medical history etc with cardiovascular disease
Incidence of hypertension in mm Hg measured by DINAMAP monitor [5 years]
Systolic and diastolic blood pressure will be measured in each participant using a DINAMAP monitor (General Electric). Field workers will measure each adult's blood pressure on the right arm while the person will be in a seated position. Blood pressure will be measured twice with at least one minute between measurements. We will use the average of the two blood pressure measurements in our study. Average Bp of greater than 140/90 will be taken as hypertensive.