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Detection and follow-up of
cardiovascular disease and risk factors in
the Southern Cone of Latin America: the
CESCAS I study
Adolfo Luis Rubinstein,
1
Vilma Edith Irazola,
1
Rosana Poggio,
1
Lydia Bazzano,
2
Matı
´as Calandrelli,
3
Fernando Tomas Lanas Zanetti,
4
Jose Anibal Manfredi,
5
He
´ctor Olivera,
6
Pamela Seron,
5
Jacqueline Ponzo,
7
Jiang He
2
ABSTRACT
Introduction: Cardiovascular diseases (CVD) are
increasing throughout the world and cause 16.7
million deaths each year, 80% of which occur in
low and middle income countries. In Argentina,
Chile and Uruguay, the available data on
cardiovascular risk factors come predominantly from
cross-sectional studies that are principally based on
self-report or studies conducted with small
convenience samples. The CESCAS I study will
generate reliable estimates of the prevalence and
distribution of and secular trends in CVD and its risk
factors in this region.
Methods and analysis: CESCAS I is an
observational prospective cohort study with
a multistage probabilistic sample of 8000 participants
aged 35e74 years from four mid-sized cities
representing the Southern Cone of Latin America:
Bariloche and Marcos Paz in Argentina, Temuco in
Chile and Pando-Barros Blancos in Uruguay. In the
first phase, baseline data regarding exposure to risk
factors and prevalence of CVD will be collected in two
stages: (1) in homes and (2) in health centres.
Information will be gathered on medical history, risk
factors, lifestyles and health utilisation through
specific questionnaires, physical measurements, an
ECG and an overnight, fasting blood sample to
measure levels of serum lipids, glucose and
creatinine. In the second phase, annual follow-up
data will be obtained on the incidence rate of CVD
events and the association between exposure and
events.
Ethics and dissemination: The protocol has
obtained formal ethics approval from institutional
review boards in Argentina, Chile, Uruguay and the
USA. The lack of follow-up studies has prevented
Argentina, Chile and Uruguay from implementing
risk factor stratification and management strategies
at a population level. However, the CESCAS I study
data will help the development of public health
strategies based on primary care intervention, thus
helping to improve cardiovascular health in this
region.
INTRODUCTION
Cardiovascular diseases (CVD) are increasing
throughout the developing world and cause
almost 16.7 million deaths each year, 80% of
which occur in low and middle-income
countries.
1
Indeed, 34% of annual deaths are
due to CVD.
2
It has been projected that 41
million people world-wide will die in 2015 of
chronic CVD unless effective concerted
action is taken now.
3
In low and middle-
income countries, almost half of these deaths
will occur in people below 70 years of age
compared with only 27% in high-income
countries.
4
Furthermore, although in recent
To cite: Rubinstein AL,
Irazola VE, Poggio R, et al.
Detection and follow-up of
cardiovascular disease and
risk factors in the Southern
Cone of Latin America: the
CESCAS I study. BMJ Open
2011;1:e000126.
doi:10.1136/bmjopen-2011-
000126
<Prepublication history for
this paper is available online.
To view these files please
visit the journal online (http://
bmjopen.bmj.com).
Received 24 March 2011
Accepted 4 April 2011
This final article is available
for use under the terms of
the Creative Commons
Attribution Non-Commercial
2.0 Licence; see
http://bmjopen.bmj.com
For numbered affiliations see
end of article.
Correspondence to
Adolfo Luis Rubinstein;
arubinstein@iecs.org.ar
ARTICLE SUMMARY
Article focus
-To estimate the prevalence and distribution of and
secular trends in major cardiovascular disease
(CVD) events and risk factors in four cities in
Argentina, Chile and Uruguay.
Key messages
-Lack of follow-up studies prevents Argentina,
Chile and Uruguay from assessing local risk
estimates, obtaining reliable data on CVD burden
and implementing risk factor stratification and
management strategies at a population level.
-There is a strong need in the region to build the
capacity and infrastructure to undertake a
population-based cohort study to address knowl-
edge gaps and to inform policymakers of the
impact of CVD in the Southern Cone of Latin
America.
Strengths and limitations of this study
-CESCAS I will be the first longitudinal study to
estimate the CVD trend and risk factors in
Argentina, Chile and Uruguay.
Rubinstein AL, Irazola VE, Poggio R, et al.BMJ Open 2011;1:e000126. doi:10.1136/bmjopen-2011-000126 1
Open Access Protocol
decades age-adjusted rates for cardiovascular mortality
have decreased in developed countries, rates have
increased in low and middle-income countries.
15
In Latin America, it is estimated that between 1990
and 2020, deaths from CVD, including coronary heart
disease (CHD), will increase by approximately 145% in
both men and women compared with an increase of
28% in women and an increase of 50% in men in
developed countries during the same period.
6
Moreover, at least 75% of CVD can be explained by risk
factors such as an unhealthy diet, low physical activity and
tobacco use.
7
In the World Health Report 2002, 26 risk
factors were evaluated and ranked by their importance.
Major risk factors identified for most Latin American
countries were hypertension, increased body mass index
(BMI), and alcohol and tobacco use.
8
The Latin American
INTERHEARTstudy showed that most cardiovascular risk
in the Southern Cone could be explained by tobacco use,
abnormal lipids, abdominal obesity and high blood pres-
sure.
9
In Argentina, recent estimates showed that in 2005
there were more than 600 000 disability adjusted life years
(DALYs) and almost 400 000 years of potential life lost
due to CHD and stroke, where modifiable risk factors
explained 75% of fatal and non-fatal acute CHD and
stroke events, 82% of acute CHD events and 62% of
strokes. Similarly, modifiable risk factors explained 76%
of costs due to acute events and 71% of DALYs lost.
10
In
Argentina, Chile and Uruguay, the available data on CVD
risk factors come mainly from cross-sectional studies that
are principally based on self-report or studies conducted
with small convenience samples, which do not give reli-
able estimates.
11e13
None of the studies mentioned above
included a prospective follow-up study. While the ongoing
ELSA study, a recently established cohort study in Brazil,
will provide data on cardiovascular events, its population
is composed of employee volunteers from six Brazilian
universities and thus will not be able to offer population-
based estimates of the impact of CVD risk factors on the
incidence of CVD.
14
The CESCAS I study will generate reliable estimates of
the prevalence and distribution of and secular trends in
CVD and its risk factors in this region. These data will
contribute to the development of public health strate-
gies, thus helping to improve cardiovascular health in
Latin America.
METHODS
Study design
CESCAS I is an observational, prospective cohort study
initiated in November 2010 and is composed of two
phases. In the first phase, baseline data will be collected
regarding exposure to risk factors and prevalence of
CVD. In the second phase, annual follow-up data will be
obtained on the CVD incidence rate and the association
between exposure and the event.
Study population
This study entails a probabilistic sample of 8000 non-
institutionalised mainly urban men and women between
the ages of 35 and 74 years representing the general
adult population in Argentina, Chile and Uruguay. Four
mid-sized cities have been selected: two in Argentina
(Bariloche and Marcos Paz), one in Chile (Temuco) and
one in Uruguay (Pando-Barros Blancos).
Sampling method
As the prevalence of CVD risk factors was considered
likely to vary by age, gender and geographical area, the
sampling method was stratified accordingly, following
a complex sampling design that consisted of four strati-
fied stages to obtain a representative sample from each
of the four locations (figure 1). The first stage consisted
of randomly sampling census radii from each location,
stratified by socio-economic level. In the second stage
a number of blocks proportional to the radius size were
randomly selected. The third stage sampled households
from each block using systematic sampling. If the
selected house did not include a permanent residence
(eg, offices/weekend residences, abandoned or demol-
ished dwellings, those under construction, or addresses
which were not identified), it was replaced with another
house. In the selected households all members between
35 and 74 years of age were recorded to create the final
sampling frame. In the fourth stage, one recorded
member per household was randomly selected. The final
sampling frame was composed of one subject per
household, stratified by gender (50% women and 50%
men) and age category (35e44, 45e54, 55e64 and
65e74 years old) constituting a total of 2000 subjects per
site, all of them meeting the following criteria: a perma-
nent resident at the location for at least 6 months per
year, willing to sign a consent form to participate, not
intending to relocate within the next 2 years, and able to
respond autonomously to the questionnaire (without
cognitive impairment or language problems). Replace-
ment of selected participants because of refusal to
participate or inability to be located was not allowed.
15 16
Recruitment plan
Participants are invited to participate through a letter
from the site institution. The interviewer makes the first
contact with the household and arranges an appoint-
ment for a home visit to collect questionnaire data and
schedule a follow-up clinic visit. A clinic visit is scheduled
Figure 1 Sampling procedure in the CESCAS I study.
2Rubinstein AL, Irazola VE, Poggio R, et al.BMJ Open 2011;1:e000126. doi:10.1136/bmjopen-2011-000126
A longitudinal study of cardiovascular disease and risk factors in Latin America
to obtain physical measurements, an ECG and overnight
fasting blood samples. To minimise non-participation
and the potential for bias, the following measures will be
taken to facilitate and encourage participation:
<Travel assistance or home assessment for those unable
to travel to the examination centres
<Variety of appointment times to suit all members of
the community
<Feedback of blood test and examination results to
participants.
Data collection
Baseline data collection is conducted in two stages: at
home and in the health centre. In the home, an inter-
viewer administers specific questionnaires to collect the
required information. Once the survey is complete, the
interviewer proceeds to arrange a visit to a health centre
where the physical measurements, ECG and blood
sample will be obtained.
Questionnaires
A trained interviewer will gather information regarding
participant characteristics including demographic,
socioeconomic and healthcare utilisation data, personal
and family history of CVD, and risk factors such as high
blood pressure, dyslipidaemia and diabetes, as well as
current pharmacological and non-pharmacological
treatment. Data will also be collected regarding inter-
mittent claudication, cancer, respiratory disease, alcohol
consumption and weight history using cross-culturally
adapted questionnaires from the Hispanic Community
Health Study/Study of Latinos (HCHS/SOL).
17
Physical
activity will be assessed through the HCHS/SOL study
questionnaire adapted from the International Physical
Activity Questionnaire.
18
Information about current and
former cigarette smoking, including age at which
smoking was initiated, years of smoking, number of
cigarettes smoked per day, cessation attempts and
treatments, will be assessed using the Global Adult
Tobacco Survey.
19
Use of other forms of tobacco, expo-
sure to passive cigarette smoking and indoor pollution
will also be assessed. Nutritional information will be
collected using a semi-quantitative food frequency
questionnaire adapted from the National Cancer Insti-
tute Diet History Questionnaire, which has been vali-
dated by our research team for use in Argentina, Chile
and Uruguay (N Elorriaga, personal communication,
2011). Depression and anxiety will be assessed by the
nine-item Patient Health Questionnaire (PHQ-9),
20
which has been validated in Argentina.
21
Stressful
events and spirituality will be assessed through a cross-
culturally adapted version of the HCHS/SOL study
questionnaire.
17
Locally validated versions of the SF-12 and EQ-5D will
be used to measure health-related quality of life and
social utilities and preferences, respectively.
22 23
All
questionnaires used in the study and their sources are
listed in table 1.
Blood pressure and anthropometric measurements
Trained and certified observers will measure blood
pressure during the health centre visit following the
recommendations of the American Heart Association.
24
According to the study protocol, before blood pressure is
measured, the participant should remain seated and at
rest for 5 min. Tea, mate or coffee consumption, as well
as smoking or exercising, in the 30 min before testing is
not permitted. A standardised mercury or aneroid
sphygmomanometer with an adequate cuff size will be
used. The cuff will be placed on the right arm of the
participant, inflated to 10 mm Hg, and then inflated
again until it reaches a pressure 30 mm Hg above the
level at which the radial pulse can no longer be palpated.
Three measurements will be obtained, with 30 s intervals
between them. Korotkoff sounds will be recorded, and
used to identify systolic and diastolic blood pressure.
Weight will be measured with the subject wearing
undergarments but not shoes. Weight will be recorded in
kilograms to one decimal place using standing scales
supported on a steady surface. Height will be measured
without shoes, in centimetres to one decimal place, on
the Frankfort plane positioned at a 908angle against
a metallic metric tape measure mounted on a wall.
Abdominal circumference will be measured in centi-
metres to one decimal place, on a horizontal plane 1 cm
above the belly button which generally coincides with
the narrowest waist circumference.
Laboratory measurements
Overnight fasting blood samples will be drawn by veni-
puncture to measure levels of serum lipids, glucose and
creatinine. Samples will be processed and temporarily
stored at the extraction site to be sent later for analysis
and storage (in ultra freezers at 808C) in the central
laboratory at the Hospital Italiano of Buenos Aires. LDL
cholesterol levels will be calculated using the
Friedewald equation for participants with triglyceride
levels <400 mg/dl. According to this equation, total
LDL cholesterol is equal to: total cholesterolHDL
cholesteroltriglycerides/5.
Electrocardiogram
The study will employ a 12-lead electrocardiogram
standardised at 25 mm/s and at 1 mV of amplitude.
Study outcomes
Hypertension is defined as a mean systolic blood pres-
sure $140 mm Hg and/or diastolic blood pressure
$90 mm Hg, and/or self-report of current use of anti-
hypertensive medications.
25
Obesity is defined as BMI
$30 kg/m
2
and overweight as BMI $25 kg/m
2
.
26e29
Dyslipidaemia is defined as total cholesterol $200 mg/dl
or 11.1 mmol/l, LDL cholesterol $130 mg/dl or
7.2 mmol/l, or HDL cholesterol <40 mg/dl or
2.2 mmol/l.
30
Diabetes mellitus is defined as fasting
glucose $126 mg/dl or 7 mmol/l. Glucose intolerance is
defined as a fasting glucose level of 110e125 mg/dl or
6.1e6.9 mmol/l.
31
Current smoking is defined as
Rubinstein AL, Irazola VE, Poggio R, et al.BMJ Open 2011;1:e000126. doi:10.1136/bmjopen-2011-000126 3
A longitudinal study of cardiovascular disease and risk factors in Latin America
smoking at least one cigarette per day at the time of
the survey. Former smoking is defined as a person who
has been a smoker but does not smoke at the time of the
survey. Passive smoking is defined as involuntarily
breathing air that is contaminated by tobacco smoke.
27 32
During the follow-up a person will be categorised as
having CVD if it is self-reported or their self-assigned proxy
has reported any of the following conditions diagnosed by
a physician: CVD death, acute myocardial infarction,
angina, heart failure, cerebrovascular events, peripheral
vascular disease or coronary or peripheral revascularisa-
tion. The study outcome committee will review the
collected source documents related to the reported event
and adjudicate on all CVD outcomes independently.
Training and quality assurance
Field work quality assurance
Data collection will be conducted according to the
standardised operations manual. Between 5% and 10%
of participants will have repeated measurements of
arterial pressure, height, weight and waist circumference
to adjust for the effect of measurement error on selected
variables. All the equipment used will be certified to
international standardisation norms. Periodic moni-
toring of data collection procedures will be performed
by the coordinating centre.
Laboratory quality control
All laboratory measurements (total cholesterol, HDL,
LDL, triglycerides, glucose and plasma creatinine) will
be carried out by the central laboratory. Each laboratory
technician will have to complete a training program.
Processing of data
The database was designed using the OpenClinica
system.
33
This is a computerised system of related
databases with web interface. The data will be entered
from each site, via the web, into electronic forms.
Double data entry with independent operators will be
performed to eliminate data entry errors. The data will
be stored on a central server. Validation rules will be
generated in accordance with the nature of the variables.
Automatic queries will be generated in response to out-
of-range entries to be investigated by study personnel at
each site.
Statistical investigation
Sample size
The calculated sample size is 8000 participants (2000 per
site) which is consistent with the recommended
requirements for precision for complex surveys. This
sample will be sufficient to provide precise estimates of
the prevalence of major CVD risk factors by gender and
site, in four age-defined categories (35e44, 45e54,
55e64 and 65e74 years old) as well as their association
with the development of CVD.
34e36
The proposed
sample size is sufficient to comply with the precision
requirements of a complex sample that assumes that the
design effect is 1.5 and the prevalence of the risk factors
of interest is 5% or greater (table 2).
For analysis, the capacity to detect risk factors was
calculated using a statistically significant
a
level of 0.05
and a statistical power of 85%, which will permit
detection of moderate and large relative risks.
Statistical analysis
The general characteristics of the population will be
described. For continuous variables, mean and median,
range, standard deviation and/or quartile range will be
calculated according to the distribution of each variable.
In the case of categorical variables, absolute and relative
frequencies will be calculated.
Table 1 Data collection in the CESCAS I study
Type of data Components Instrument
General information Socio-demographic and economic data, and type of health services
utilisation
HCHS/SOL*
Claudication Location, functional class HCHS/SOL*
History Cardiovascular, respiratory, hypertension, dyslipidaemia, diabetes,
pharmacological and non-pharmacological treatment and cancer
HCHS/SOL*
Alcohol Level of consumption (daily quantity, frequency, type of alcoholic
beverage)
HCHS/SOL*
Physical activity Type of activity, frequency and intensity, in free time and during work IPAQ
Spirituality Importance, religious practice HCHS/SOL*
Nutrition Types of foods, quantity and frequency FFQ
Smoking Current, former and passive smoker; other types of tobacco use
(pipe, cigar)
GATS
Mental health Depression, traumatic events, anxiety PHQ-9/HCHS/SOL*
Global health SF-12
Quality of life EQ-5D
Physical examination Blood pressure, weight, height and waist circumference
Laboratory Total cholesterol, HDL cholesterol, triglycerides, glucose and creatinine
ECG 25 mm/s and at 1 mV of amplitude
*Forms from the Hispanic Community Health Study/Study of Latinos, cross-culturally adapted for use in Argentina, Chile and Uruguay.
FFQ, Food Frequency Questionnaire; GATS, Global Adult Tobacco Survey; IPAQ, International Physical Activity Questionnaire; PHQ-9, Patient
Health Questionnaire depression scale.
4Rubinstein AL, Irazola VE, Poggio R, et al.BMJ Open 2011;1:e000126. doi:10.1136/bmjopen-2011-000126
A longitudinal study of cardiovascular disease and risk factors in Latin America
In order to determine the prevalence and incidence of
risk factors, CVD events and the association between risk
factors and CVD events, the design effect of the first stage
unit of sampling will be considered. Weighting will be
based on the relationship between the number of indi-
viduals finally included in the study and the population
size and composition of each site according to the most
recent census data. Likewise, the analysis will be carried out
by socioeconomic strata, according to gender and four age
categories (35e44, 45e54, 55e64 and 65e74 years old).
To assess associations between risk factors and CVD
events, linear regression and simple and multiple logistic
regressions will be used according to the nature of the
response variables. Continuous variables that are
not normally distributed will be evaluated by the appli-
cation of transformations and categorisations wherever
applicable.
37
The secular trends in risk factors over time will be
evaluated with statistical analysis methods that take
account of the correlation between repeated measures.
To evaluate the changes in risk factors over time by sub-
groups of interest, generalised estimation equations will
be used. To estimate the rate of accumulated cardiovas-
cular incidents, the KaplaneMeier method will be used.
The log rank test will be used to compare the differences
between the curves of accumulated incidence events. In
order to quantify the relationship between risk factors
and the incidence of CVD events, the Cox proportional
hazards method will be used. Potential confounders and
interactions will be explored. Appropriate diagnostics
will be carried out to test goodness of fit, collinearity and
atypical observations in each model. In all cases,
fulfilment of assumptions in the model by means of
exploration of residual behaviour will be verified.
Statistical analysis software STATA 10.0 and SAS 9.0 will
be used.
37e39
Ethical aspects
The study will be carried out following the guidelines for
the protection of the rights of human volunteers. All
investigators and personnel in the study have completed
a training course, certified by the National Institutes of
Health (NIH). All participants will sign an informed
consent form during the initial visit. To protect participant
confidentiality, the information included in the database
will not contain personal identifiers.
Timeline of the study
Baseline data collection is projected to be carried out
during 2011. The follow-up phase will begin in 2012 and
will consist of an annual telephone interview continuing
up to the fourth year with a second round of physical
and biochemical measurements and an ECG performed
2e3 years after the baseline measurements.
CONCLUSIONS
Despite the increasing burden of CVD in the Southern
Cone, which over the last decades has been ranked as the
main cause of mortality and morbidity, national health
programs and policies are still mostly focused on inter-
ventions aimed at tackling communicable diseases or
perinatal or childhood conditions. Therefore, new
programs should be targeted at modifying lifestyle and
nutritional risk factors to reduce CVD in high risk
subjects.
36
However, the lack of follow-up studies prevents
our countries not only from assessing local risk estimates
and obtaining more reliable data on the burden of CVD,
but also from implementing risk factor stratification and
management strategies at a population level. Accord-
ingly, and based on limited and imprecise evidence, there
is a strong need in the region to build the capacity and
infrastructure necessary to undertake a population-based
cohort study to address these remaining knowledge gaps
and to inform public health policymakers of the impact
of CVD in our countries. The CESCAS I study data will
help develop public health strategies based on the
application of primary care interventions, thus helping to
improve cardiovascular health in this region.
Author affiliations:
1
Southern Cone American Center for Cardiovascular Health
(CESCAS/SACECH), Institute for Clinical Effectiveness and Health Policy
(IECS), Buenos Aires, Argentina
2
Department of Epidemiology, School of Public Health and Tropical Medicine,
Tulane University, New Orleans, Louisiana, USA
3
Sanatorio San Carlos, Cardiologı
´a, Bariloche, Rio Negro, Argentina
4
Universidad de la Frontera, CIGES, Temuco, Chile
5
Department of Cardiology, Faculty of Medicine, Universidad de la Repu
´blica,
Montevideo, Uruguay
6
Municipalidad de Marco Paz, Secretarı
´a de Salud, Marcos Paz, Argentina
7
Department of Family Medicine, Faculty of Medicine, Universidad de la
Repu
´blica, Montevideo, Uruguay
Acknowledgements We thank Eiman Jahangir and Alisson Lee, fellows of
the Fogarty International Clinical Research Fellows Program (FICRF), for
careful revision of the manuscript.
Funding This work was supported by the National Heart, Lung, and Blood
Institute (NHLBI) grant number HHSN268200900029C.
Competing interests None.
Ethics approval Institutional review boards from Argentina (Hospital Italiano
de Buenos Aires), Chile (Universidad de la Frontera), Uruguay (Universidad de
la Repu
´blica) and the USA approved this study.
Contributors AR, JH, VI, RP, LB, FL, JM, MC, HO, PS and JP all contributed to
the conceptualisation and design of the study and all revised this manuscript
critically. All authors gave final approval of the version to be published.
Provenance and peer review Not commissioned; internally peer reviewed.
Data sharing statement Following the policy of the National Institutes of
Health (NIH), we reaffirm the practice of making data used for scholarly
research available to other investigators.
Table 2 Sample size required for different proportions and
design effects
Proportion
Design effect
1.0 1.5 2.0 2.5 3.0
0.26e0.50 30 45 60 75 90
0.25 32 48 64 80 96
0.20 40 60 80 100 120
0.15 53 80 107 133 160
0.10 80 120 160 200 240
0.05 160 240 320 400 480
Rubinstein AL, Irazola VE, Poggio R, et al.BMJ Open 2011;1:e000126. doi:10.1136/bmjopen-2011-000126 5
A longitudinal study of cardiovascular disease and risk factors in Latin America
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