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Table 3 Outcome/endpoint definitions for effectiveness objectives

From: Statistical analysis plan for management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: the SingHypertension pragmatic cluster randomized controlled trial

Outcome/endpoint

Measurement and definition

Systolic and diastolic blood pressure (SBP/DBP)

Measured using a calibrated automated device (Omron HEM- 7130 Blood Pressure Monitor) with the individual in the sitting position. Three readings taken at least 3 min apart. Mean of last two readings is used as the final measurement

SBP at 1-year (mmHg)

SBP is measured at the baseline, 1-year, and 2-year clinic visits by the clinical research coordinator. At each visit, three readings are taken at least 3 min apart following a standardized protocol. The mean of the last two readings will be used as the final SBP measurement for the visit. The SBP measurements at 1-year visit will be analyzed.

DBP (mmHg)

DBP is measured at the baseline, 1-year, and 2-year clinic visits by the clinical research coordinator. At each visit, three readings are taken at least 3 min apart following a standardized protocol. The mean of the last two readings will be used as the final DBP measurement for the visit.

Blood pressure controlled to conventional goal

SBP (mean of last 2 of 3 readings) is < 140 mmHg and DBP (mean of last 2 of 3 readings) is < 90 mmHg.

Blood pressure controlled to target per study algorithm

SBP (mean of the last 2 of 3 readings) is < 140 mmHg and DBP (mean of the last 2 of 3 readings) is < 90 mmHg, low to medium risk of CVD (Framingham risk score at < 20% risk of developing a CVD event during the next 10 years, no diabetes, no pre-existing CVD, no target organ damage like LVH, retinopathy, proteinuria ≥ 300 mg/day or clinical CKD [estimated GFR < 60 ml/min/1.73 m2 or UACR indicating 24 h albumin excretion of 300 mg/day or higher]), or < 130 mmHg systolic and < 80 mmHg diastolic if high risk of CVD (Framingham risk score at ≥ 20% risk of developing a CVD event during the next 10 years, or with diabetes or with pre-existing CVD, or with target organ damage like LVH, retinopathy, proteinuria ≥ 300 mg/day or clinical CKD)

Blood pressure controlled to target as per study algorithm or ≥ 5 mmHg reduction in SBP

BP controlled to target as explained above or reduction of SBP (mean of the last 2 of 3 readings) > 5 mmHg from baseline to the follow-up

Uncontrolled blood pressure

SBP (mean of last 2 of 3 readings) is ≥ 140 mmHg or DBP (mean of last 2 of 3 readings) ≥ 90 mmHg

Poorly controlled blood pressure

SBP (mean of last 2 of 3 readings) is ≥ 160 mmHg or DBP (mean of last 2 of 3 readings) ≥ 100 mmHg

Antihypertensive percentage of time adherent

Antihypertensive percent adherence is defined as the percentage of time hypertensive individuals followed their prescribed antihypertensive medication schedules. Percentage antihypertensive adherence will be obtained by dividing the number of days during follow-up for which a patient had pills available (based on 120-day intervals) by the total number of follow-up days. 120-day intervals are consistent with time between medication refills in the polyclinics [13, 14].

Serum LDL cholesterol (mmol/L)

Serum LDL cholesterol is collected as part of routine hypertension/diabetes lab panel in the polyclinics. Measurements will be recorded by CRC at baseline, year 1, year 2 follow-up visits, measured as total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides.

Hypertensive individuals with reduction in LDL cholesterol > 0.4 mmol/L (> 15 mg/dl)

Serum LDL cholesterol is collected as part of routine hypertension/diabetes lab panel in the polyclinics. Measurements will be recorded by CRC at baseline, year 1, and year 2 follow-up visits. The proportion of individuals experiencing a > 0.4 mmol/L decrease in LDL cholesterol at 1-year and 2-years follow-up

Composite outcome of death or hospital admission during the 2-year follow-up period

Information on the events of death or hospital admissions will be captured on study adverse event reporting forms and will be used to derive the composite outcome of death or hospitalizations caused by any condition.

Composite outcome of death or hospital admission due to CHD, heart failure, or stroke.

Information on the events of death or hospital admission due to CHD, heart failure, or stroke will be captured on study adverse event reporting forms and will be used to derive the composite outcome of death or cause-specific hospitalizations due to CHD, heart failure, or stroke.

Individual outcomes of all-cause mortality, CVD deaths, and hospital admission due to CHD, heart failure, or stroke.

Information on the events of death or hospital admission due to CHD, heart failure, or stroke will be captured on study adverse event reporting forms and will be used to derive the individual outcomes of all-cause mortality or cause-specific hospitalizations of CHD, heart failure, or stroke.

Diabetic hypertensive individuals with a reduction of ≥ 0.5% in glycated hemoglobin or a reduction of glycated % hemoglobin to < 7% in those with baseline glycated hemoglobin of ≥ 7%

Glycated hemoglobin measurements are performed in patients with diabetes as part of the routine diabetes lab panel in the polyclinics. These measurements will be recorded for participants with diabetes by the CRC at baseline, year 1, and year 2 follow-ups.

Albuminuria (measured as ACR) (mg/g)

Spot urinary albumin and creatinine tests are performed as study-specific tests for this study and will be used to calculate the urinary albumin to creatinine ratio (ACR) at the baseline and year 2 follow-up visits.

Estimated CKD-EPI GFR (ml/min/1.73m2)

Serum creatinine measurements are collected as part of the routine hypertension/diabetes lab panel in the polyclinics. These measurements will be recorded by the CRC at baseline, year 1, and year 2 follow-up visits and used to estimate eGFR using the CKD-EPI equation [17]

Cardiovascular risk score

The Framingham risk score with appropriate adjustments for the Singaporean population is calculated as part of routine practice in the polyclinics and will be collected by the CRC at baseline, 1-year, and 2-year follow-up visits. The original Framingham risk score without adjusting for Singaporean population [15] will be computed too. The INTERHEART “Cholesterol” modifiable risk score provides a comprehensive numeric assessment of risk factors for cardiovascular events. The score is the sum of points for questions corresponding to categories of these risk factors. In addition, Million Hearts Longitudinal ASCVD Risk Assessment Tool will be used to compute change in CVD risk [19].

Total cholesterol levels (mmol/L)

Measured in terms of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. (Chemistry analyzer: Roche Hitachi 912; Reagent: Roche reagents).

Lifestyle—diet

Diet: A dietary questionnaire is administered at baseline and the 1-year and 2-year follow-up visits to collection information on dietary habits. Frequency of intake per week will be considered as an indicator for each type of dietary intake.

Lifestyle—physical activity based on self-report International Physical Activity Questionnaire [16]

Physical activity: The International Physical Activity Questionnaire [16] is administered at baseline, 1-year, and 2-year follow-up visits to assess subjects’ physical activity level in their everyday life. It asks questions about the time spent being physically active in the last 7 days. It has three domains—vigorous, moderate, walking and sitting, with each having two questions. Total physical activity score (MET-min/week) and activity classification (inactive, minimally active, and highly active) are derived according to the IPAQ scoring guideline [15]. Domain score for vigorous, moderate, and walking are calculated using the following formulas. They represent volume of activity computed by weighting each type of activity by its energy requirements defined in METS (METs are multiples of the resting metabolic rate) to yield a score in MET-minutes.

Vigorous MET-minutes/week = 8.0 × vigorous-intensity activity minutes × vigorous-intensity days

Moderate MET-minutes/week = 4.0 × moderate-intensity activity minutes × moderate days

Walking MET-minutes/week = 3.3 × walking minutes × walking days

A combined total physical activity MET-min/week is computed as the sum of vigorous + moderate + walking MET-minutes/week scores.

(The IPAQ Sitting question is an additional indicator variable and is not included as part of any summary score of physical activity.)

Activity classifications are defined as follows:

Inactive—

• No activity reported, OR

• Some activity reported but insufficient for moderately active or highly active categories

Moderately active—any of the following 3 criteria:

• 3 or more days of vigorous activity of at least 20 min per day, OR

• 5 or more days of moderate-intensity activity or walking of at least 30 min per day, OR

• 5 or more days of any combination of walking, moderate-intensity, or vigorous-intensity activities achieving a minimum of at least 600 MET-min/week.

Highly active—any one of the following 2 criteria:

• Vigorously intense activity on at least 3 days and accumulating at least 1500 MET-minutes/week, OR

• 7 or more days of any combination of walking, moderate-intensity or vigorous intensity activities achieving a minimum of at least 3000 MET-minutes/week

Body mass index (BMI) (kg/m2)

BMI is calculated as weight (kg) divided by height2 (meters). Height is measured using standardized Portable Stadiometer available in polyclinics in cm with graduation of 1 mm. Weight is measured using standardized Tanita Digital Weight Scale (Tanita HS 302).

Current smokers*

Subjects smoking tobacco on a daily basis, including cigarette, pipes, cigars, cheroots, cigarillos, and water pipe smoking sessions are considered as current smokers. Modified from Global Adult Tobacco Survey Collaborative Group [20].

HRQoL/QALY

HRQoL is measured using the EQ-5D-5L questionnaire. It measures health status on the day of assessment and has five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each has one question with five levels of severity. In addition, it has a visual analog scale [15] measuring health on a scale of 0 (worst health) to 100 (best health). The EQ-5D index summarizing health profile of the subjects will be calculated using the EQ-5D-5L valuation set for England [21]. QALY will be estimated using the EQ-5D scale which provides a standard metric for comparing health effects of varied interventions across diverse diseases and conditions.

Waist circumference

Measured as per the WHO STEPS protocol [22]. The measurement of waist circumference is made at the approximate midpoint between the lower margin of the last palpable rib and the top of the iliac crest.

Fruits and vegetables intake (per week)

A dietary questionnaire is administered to collect information on dietary habits related to fruits and vegetables intake. At least one intake per week will be considered an indicator for each type of dietary intake.

Salt intake (g/day)

Measured in terms of urine spot sodium-to-creatinine ratio and 24-h urine sodium estimation by Kawasaki formula [23].

Incident diabetes

The use of hypoglycemic agents or fasting blood glucose ≥ 126 mg/dL at any time during the 2-year follow-up period for all participants without prevalent diabetes at enrolment.