Latin American guidelines on hypertension

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Review 905

Latin American guidelines on

hypertensionM

Ramiro A. Sanchez, Miryam Ayala, Hugo Baglivo, Carlos Velazquez,Guillermo Burlando, Oswaldo Kohlmann, Jorge Jimenez,Patricio Lopez Jaramillo, Ayrton Brandao, Gloria Valdes, Luis Alcocer,Mario Bendersky, Agustın Jose Ramirez, Alberto Zanchetti,on behalf of the Latin America Expert Group

Hypertension is a highly prevalent cardiovascular risk factor

in the world and particularly overwhelming in low and

middle-income countries. Recent reports from the WHO and

the World Bank highlight the importance of chronic

diseases such as hypertension as an obstacle to the

achievement of good health status. It must be added that for

most low and middle-income countries, deficient strategies

of primary healthcare are the major obstacles for blood

pressure control. Furthermore, the epidemiology of

hypertension and related diseases, healthcare resources

and priorities, the socioeconomic status of the population

vary considerably in different countries and in different

regions of individual countries. Considering the low rates of

blood pressure control achieved in Latin America and the

benefits that can be expected from an improved control, it

was decided to invite specialists from different Latin

American countries to analyze the regional situation and to

provide a consensus document on detection, evaluation and

treatment of hypertension that may prove to be cost-utility

adequate. The recommendations here included are the

result of preparatory documents by invited experts and a

subsequent very active debate by different discussion

panels, held during a 2-day sessions in Asuncion, Paraguay,

in May 2008. Finally, in order to improve clinical practice, the

opyright © Lippincott Williams & Wilkins. Unauth

�Endorsed by the Latin America Society of Hypertension.

0263-6352 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

publication of the guidelines should be followed by

implementation of effective interventions capable of

overcoming barriers (cognitive, behavioral and affective)

preventing attitude changes in both physicians and patients.

J Hypertens 27:905–922 Q 2009 Wolters Kluwer Health |

Lippincott Williams & Wilkins.

Journal of Hypertension 2009, 27:905–922

Keywords: diabetes, diagnosis, epidemiology, hypertension, specialpopulations, treatment

Abbreviations: ABPM, ambulatory blood pressure monitoring; ACEI,angiotensin-converting enzyme inhibitor; ADMA, asymmetricdimethylarginine; ARB, angiotensin receptor blocker; BP, blood pressure;CHD, coronary heart disease; CVD, cardiovascular disease; DALYs,disability-adjusted life years; DBP, diastolic blood pressure; DM, diabetesmellitus; ESRD, end-stage renal disease; GFR, glomerular filtration rate;HbA1c, glycosylated hemaglobin A1c; HDL, high-density lipoprotein; IMT,intima–media thickness; LDL, low-density lipoprotein; MS, metabolicsyndrome; OGTT, oral glucose tolerance test; PKC, proteinkinase C; ROS,reactive oxygen species; SBP, systolic blood pressure; TIA, transientischemic attack; TOD, target organ damage

Correspondence to Professor Ramiro Sanchez, Seccion Hipertension Arterial yUnidad Metabolica, Fundacion Favaloro. Belgrano 1782 P: 4, Buenos Aires(1093) ArgentinaTel/fax: +54 11 4378 1337; e-mail: [email protected]

Received 6 February 2009 Accepted 19 February 2009

IntroductionHypertension is a highly prevalent cardiovascular risk

factor in the world and particularly overwhelming in low

and middle-income countries. Recent reports from the

WHO [1] and the World Bank [2] highlight the importance

of chronic diseases such as hypertension as an obstacle to

the achievement of good health status. It must be added

that for most low and middle-income countries, deficient

strategies of primary healthcare are the major obstacles for

blood pressure control [3]. Furthermore, the epidemiology

of hypertension and related diseases, healthcare resources

and priorities, the socioeconomic status of the population

vary considerably in different countries and in different

regions of individual countries. Because of this, the docu-

ments from the World Health Organization-International

Society of Hypertension [4] and European Society of

Hypertension-European Society of Cardiology [5] encou-

rage the development of local guidelines taking into

account the above-mentioned conditions.

Considering the low rates of blood pressure control

achieved in Latin America and the benefits that can be

expected from an improved control, it was decided to

invite specialists from different Latin American countries

to analyze the regional situation and to provide a con-

sensus document on detection, evaluation and treatment

of hypertension that may prove to be cost-utility ade-

quate. That is why members of Hypertension, Cardiology

and Diabetes Societies from Latin American countries

met to discuss these new recommendations for preven-

tion and management of hypertension and related dis-

eases, and prepare a consensus document in which

special attention has been paid to the metabolic syn-

drome in order to alert physicians about this higher-risk

condition, particularly prominent in Latin America but

usually underestimated and undertreated. The resulting

orized reproduction of this article is prohibited.

DOI:10.1097/HJH.0b013e32832aa6d2

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906 Journal of Hypertension 2009, Vol 27 No 5

Table 2 Prevalence of risk factors associated with hypertension

Overweight(%)

Sedentarylife (%)

Smoking(%)

Dyslipidemia(%)

Argentina 19,7 nd 38.6 18,7Brazil 13 nd 20 13Chile 23.2 90.8 42 35.4Colombia 47 61 23 61Ecuador 41 34.9 24.8 –Mexico 31 30.8 36.6 36.5Paraguay 54 38 34 –Peru – – – 10Uruguay 59.7 64.3 15.7 18Venezuela 25.1 – 30 5.7

nd, Not determined.

document is designed to serve as a guide to physicians

assisting patients with hypertension and comorbidities.

The recommendations here included are the result of

preparatory documents by invited experts and a sub-

sequent very active debate by different discussion panels,

held during a 2-day session in Asuncion, Paraguay, in May

2008. After a formal presentation of the final conclusions

reached by each discussion panel, and their approval by

all participants, this final document was prepared by an

appointed Writing Committee. In order to improve

clinical practice, the publication of the guidelines should

be followed by implementation of effective interventions

capable of overcoming barriers (cognitive, behavioral and

affective) preventing attitude changes in both physicians

and patients.

Epidemiology, health economics, educationPrevalenceDiabetes mellitus and hypertension are frequently

associated, thereby increasing their negative impact on

the cardiovascular system [6,7]. More than 80% of the

attributed world burden of these diseases is in low and

middle-income countries. In Latin America, 13% of

deaths and 5.1% disability-adjusted life years (DALYs)

can be attributed to hypertension [1]. The age-adjusted

prevalence of hypertension in the adult general popu-

lation in different countries of Latin America (national

surveys or systematic randomized samplings) ranges from

26 to 42% [6–9]. In diabetic populations, the prevalence

of hypertension is 1.5–3-fold higher that in nondiabetic

populations in the same age segment [6]. In type 2

diabetes, hypertension may already be present at the

time of diagnosis or may even precede overt hypergly-

cemia [6].

The following tables show the prevalence, awareness,

treatment and control of hypertension, together with

cardiovascular mortality attributed to hypertension

(Table 1), and the prevalence of the major risk factors

associated with hypertension (Table 2) in various Latin

American countries.

opyright © Lippincott Williams & Wilkins. Unautho

Table 1 Arterial hypertension, sex and cardiovascular mortality

CountriesHypertension

prevalence (%)Hypertension

awareness (%)Treated

hypertension (%)

Argentina 28.1 54 42Brazil 25–35 50.8 40.5Chile 33.7 59.8 36.3Colombia 23 41 46Ecuador 28.7 41 23Mexico 30.5 56,4 23Paraguay 35 31 27Peru 24 39 14.7Uruguay 33 68 48Venezuela 33 55 30

Columns 2, 3, and 4 percentage values refer to the corresponding hypertensive popu

Medical economicsHypertension imposes a huge worldwide economic and

social burden because of the associated comorbidities and

chronic complications that impair survival and quality of

life. Thus, a recent analysis of an international data bank

[1] has shown that a very substantial proportion of car-

diovascular disease is attributable to high blood pressure.

The global expenditure on antihypertensive treatment is

about 50 billion dollars each year [10], more than 90% of

which is spent in high-income countries, whereas middle

and low-income countries, having a five times greater

burden of disease than the corresponding high-income

countries, have only access to less than 10% of the global

treatment resources. Hush cost-effectiveness, cost-

benefit and cost-utility of the treatment of hypertension

in the general population are strongly influenced by the

presence of comorbidities and complications [11–13].

Considering the above-mentioned data, the proposal

for an intensive treatment of hypertension can be

expected to reduce costs and improve survival and quality

of life.

EducationIn the context of the large and growing disease burden,

strategies to improve population health require consist-

ent and comprehensive management of the major risk

factors contributing to premature mortality and disability.

rized reproduction of this article is prohibited.

Controlledhypertension (%) , (%) < (%)

Cardiovascularmortality (%)

18 – – 23.510.2 27.511.8 30.8 36.7 28.415 28

6.7 27.5 30.9 2819.2 26.3 34.2 –

7 2814 –11 56.9 43.1 29.512 20.6

lation (column 1).

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Latin American guidelines on hypertension Sanchez et al. 907

Education should be considered an important tool for

improving hypertension treatment strategies. To this

scope, the recently published WHO/ISH guidelines on

preventive cardiology are greatly helping general prac-

titioners in the management of global risk strategies, by

the use of pocket guidelines that can be easily obtained in

different languages (http://www.who.int/cardiovascular_

diseases/guidelines/Pocket_GL_information/en/index.

html). Systematic education of hypertensive patients is

strongly recommended. Such educational effort should

involve patients in their own environment, and provide

training in patient education to health teams. Some

educational programs for Latin America have been

proposed [14]. The promotion of education in the general

population and, particularly, among high-risk patients, is

greatly advisable. Formal education for children and

adolescents should include information about healthy

lifestyles.

The following strategies are strongly recommended:

(1) C

op

Table

OptimNormHigh-Hype

GrGrGr

Isolat

ommunity educational programs,

(2) O

perational strategies to promote lifestyle changes

especially in children, teen-agers and young adults,

(3) E

ducational programs for practitioners and health

teams (nurses, nutritionists, etc.),

(4) H

ypertension early detection programs, and

(5) G

uidelines for optimal control of blood pressure

values.

Clinical characteristicsDefinitionEstablished hypertension is a medical condition implying

a higher risk for cardiovascular events and impairment of

different organ functions in which the blood pressure is

chronically elevated above values considered in the

optimal or normal range. Hypertension is frequently

associated with comorbidities such as diabetes mellitus,

coronary heart disease (CHD), chronic heart failure,

stroke, transient ischemic attack (TIA), peripheral vas-

cular disease, chronic renal impairment. Persistent hy-

pertension is considered one of the risk factors for stroke,

heart attack, heart failure and arterial aneurysm, and is

one of the leading causes of chronic renal failure and

dialysis. Even moderate elevation of arterial blood pres-

sure leads to shortened life expectancy. When blood

yright © Lippincott Williams & Wilkins. Unauth

3 Classification of blood pressure

Blood pressure

al <120/80 mmHgal 120/80–129/84 mmHgnormal 130/85–139/89 mmHgrtensionade 1 140–159/90–99 mmHgade 2 160–179/100–109 mmHgade 3 �180/110 mmHged systolic hypertension �140/<90 mmHg

pressure is markedly elevated (mean arterial pressure

50% or more above average) life expectancy is reduced

by 30–40%, unless hypertension is appropriately treated

[15].

Blood pressure classificationAfter considering the classifications proposed by the

Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of

High Blood Pressure [16], the 2007 European Guidelines

for the Management of Hypertension [5], and the

previous Latin American Consensus on Arterial Hyper-

tension [17], it was decided, as shown in Table 3, to

maintain the concept that hypertension is diagnosed

when blood pressure values are at least 140/90 mmHg.

Above this value, hypertension can be subdivided in

grade 1, 2 or 3. This classification also applies to isolated

systolic hypertension, which must be diagnosed and

treated especially in older patients.

Considering that blood pressure is a continuous variable,

and that higher are the blood pressure values higher is

cardiovascular risk [18,19], it was decided that the

patients with blood pressure values between 120/80

and 129/84 mmHg can be considered as normal blood

pressure, whereas those with values between 130/85 and

139/89 mmHg as high-normal blood pressure. Blood pres-

sure values lower than 120/80 mmHg are considered as

optimal values. However, it should be emphasized that

high-normal and normal blood pressure are of a higher

risk than optimal blood pressure despite of being in the

normal range. By this way, blood pressure values lower

than 120/80 mmHg are considered as optimal values.

Arterial hypertension is actually classified as: primary,

essential or idiopathic when blood pressure is consist-

ently higher than normal with no known underlying

cause. It represents 85–90% of all cases of hypertension.

Hypertension is defined as secondary when blood pres-

sure is elevated as a result from an underlying, identifi-

able, often correctable cause (the remaining 10–15% of

the total hypertensive patients).

Resistant or refractory to treatment hypertension

Resistant or refractory to treatment hypertension is when

blood pressure remains above target values despite

institution of nonpharmacological treatment and pharma-

cological treatment including full doses of three or more

medications, one of these being a diuretic. These patients

must be referred to a specialist or a hypertension center

because this type of hypertension is often associated with

subclinical organ damage, and has high added cardiovas-

cular risk [20].

White-coat hypertension

Also known as isolated office hypertension it is the

condition in which blood pressure, measured in the office,

is consistently in the hypertensive range, whereas either

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908 Journal of Hypertension 2009, Vol 27 No 5

the ambulatory blood pressure monitoring (ABPM) mean

values [21] or home values [22] are always in the normo-

tensive range. Its prevalence is around 10%. Its overall

risk is not clearly established [23], but it appears to be

associated with more cardiac, renal and metabolic func-

tional and/or structural abnormalities than full normoten-

sion [24,25].

Hidden or masked hypertension

Also known as isolated ambulatory hypertension, it

represents the opposite condition to white-coat hyper-

tension, that is patients have normal office blood pres-

sure, whereas mean ABPM or home blood pressure

values are in the hypertensive range. It is found in every

one out of seven to eight patients with office normoten-

sive values [25]. The cardiovascular risk in these patients

seems to be similar to that of established hypertensive

patients [26,27]. Thus, care must be taken to avoid that

these patients remain undiagnosed if ABPM or home

blood pressure are not measured.

Isolated systolic hypertension

Is sustained systolic blood pressure (SBP) at least

140 mmHg with diastolic blood pressure (DBP) less than

90 mmHg. As SBP tends to rise with age, the prevalence

of systolic hypertension increases with age and, above the

age of 60 years, systolic hypertension represents a com-

mon form of hypertension. Impressive evidence has been

accumulated on the importance of SBP as a major risk

factor for cardiovascular diseases [28].

Risk stratificationTo manage a hypertensive patient not only blood pres-

sure levels should be considered but also total cardiovas-

cular risk. In order to stratify total cardiovascular risk, the

number of risk factors, the presence of target organ

damage and of previous or concurrent clinical conditions

or outcomes (Table 4) in association with blood pressure

grading should be taken into account, as shown in Fig. 1.

Among traditional risk factors, socioeconomic conditions

should be given particular attention in Latin America.

opyright © Lippincott Williams & Wilkins. Unautho

Table 4 Factors to be taken into account to quantify cardiovascular ris

Risk factors Subcli

Age, sex (male) Left veHypertension MicroaHigh total cholesterol CreatiTobacco smoking, impaired glucose tolerance, diabetesM IncreaFamily history of cardiovascular events HyperLow HDL cholesterol IncreaHigh LDL cholesterolHigh triglyceridesOverweight/obesity (BMI>25 kg/m2),MenopauseSocial/economic positionMM

Education

BMI, body mass index; HDL, high-density lipoprotein; IMT, intima–media thickness; LDLDiabetes Association, International Diabetes Federation. MM Homeless, primary degree

Similar emphasis should be given to a low educational

level, because of the high percentage of the native popu-

lation with low opportunities of an adequate education.

Figure 1 does not only include blood pressure values above

the conventional 140/90 mmHg cut-off values, but also

those considered optimal or normal, or high-normal. At all

blood pressure levels, including optimal ones, the total risk

increase progressively with the addition of other risk

factors, organ damage, diabetes and previous outcomes.

Diagnostic evaluation of the hypertensive patientThe time required for the initial evaluation of a hyper-

tensive patient is of at least 30 min. The main objectives

of diagnosis are:

(1) C

riz

k

nic TO

ntriculbum

nine>sed ctensivsed va

, low-educ

onfirming the existence of high blood values,

(2) D

etermining the grade of hypertension and the

existence of target organ damage,

(3) E

valuating the presence of comorbidities,

(4) I

dentifying treatments previously received or cur-

rently in use,

(5) Q

uantifying the global risk including its social

components,

(6) D

iagnosing or excluding possible secondary causes

of hypertension.

Clinical history and physical examination

Not only the grade of hypertension should be defined but

also the time at which hypertension was diagnosed. Infor-

mation on age, sex and race should be recorded. The physi-

cal exam must include measurement of height, weight,

waist, hipandcalculationof waist tohip ratio andbody mass

index (BMI), the evaluation of pulses, heart rate, blood

pressure values, heart auscultation, search of carotid, thor-

acic or periumbilical bruits and a funduscopic examination.

Search should be made for associated risk factors and

possible complications such as peripheral edema, angina

pectoris, dyspnea, headache, ectopic heart beats.

Blood pressure measurements must be performed

in accordance with the American Heart Association

ed reproduction of this article is prohibited.

D Clinical events

lar hypertrophy Coronary heart diseaseinuria Myocardial infarction1.3 mg/dl Stroke

arotid IMT Peripheral arterial diseasee retinopathy (grades III/IV) Chronic heart failurescular stiffness Chronic renal disease

density lipoprotein; TOD, target organ damage. M According to the Americanation, jobless.

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Latin American guidelines on hypertension Sanchez et al. 909

Fig. 1

Risk related to blood pressure values. DM, diabetes mellitus; MS, metabolic syndrome; RF, risk factor; TOD, target organ damage.

recommendations, in two different positions (sitting and

standing), with the aim to discover orthostatic hypoten-

sion (decreases greater than 20 mmHg in SBP and/or

10 mmHg in DBP), especially frequent in older patients

[29]. When SBP and DBP values correspond to different

grades, the higher grade should be used to define the

patient’s hypertension.

Home blood pressure measurements, performed by

instructed persons with either a mercury sphygmoman-

ometer or preferably by automatic or semiautomatic

validated devices, are an important tool for the control

and follow-up of hypertensive patients. Upper normal

values are similar for home and day-time ABPM, that is

135/85 mmHg [30].

Laboratory examinations

The main objectives are to detect other cardiovascular

risk factors, to assess target organ damage and to identify

secondary causes of hypertension. A complete blood

count, fasting plasma glucose, blood urea nitrogen, serum

and urinary creatinine, serum electrolytes, uric acid, total

high-density lipoprotein (HDL) and low-density lipopro-

tein (LDL) cholesterol, triglycerides, liver function tests,

T3, T4 and TSH, added to a complete urinanalysis,

estimated glomerular filtration rate [from serum creati-

nine with the Modification of Diet in Renal Disease

Study Equation for Estimating Glomerular Filtration

Rate with Standardized Serum Creatinine Values

opyright © Lippincott Williams & Wilkins. Unauth

(MDRD) formula], and an electrocardiogram must

always be performed at the first visit.

Recommended examinations

Vascular, cardiac and renal ultrasound and Doppler exam-

inations are recommended to evaluate left ventricular

mass and to identify subclinic atherosclerosis in different

vascular territories, renal arterial stenosis or kidney altera-

tions. Measurement of the pulse wave velocity is helpful

to assess large artery stiffness. Microalbuminuria (in a 24-

h urine collection or as albumin/creatinine ratio) is

highly recommended.

Ambulatory blood pressure monitoring

The method, which does not replace conventional

measurements, gives more detailed information on mean

24-h, daytime or night-time values [31,32]. The 24-h

mean values are more closely related to target organ

damage and outcomes than office values. ABPM is indi-

cated when:

(1) W

ori

hite coat hypertension is suspected,

(2) H

idden (masked) hypertension is suspected,

(3) N

ormal blood pressure is accompanied by total high

risk,

(4) E

valuation of the 24-h blood pressure profile

(dipping, nondipping, etc.) is desirable,

(5) R

efractory hypertension is suspected,

(6) H

ypotensive or hypertensive episodic events are

looked for,

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910 Journal of Hypertension 2009, Vol 27 No 5

Fig. 2

Blood pressure evaluation algorithm. TOD, target organ damage.

(7) A

opy

utonomic dysfunction is present,

(8) T

arget organ damage progresses or does not regress

despite apparently good control of blood pressure.

Finally, the flowchart of Fig. 2 can be followed to evalu-

ate hypertensive patients in whom possible causes of

secondary hypertension are searched for.

Metabolic syndrome, diabetes mellitus 1 or 2and hypertensionDefinition of metabolic syndromeThe metabolic syndrome is an entity with easily detect-

able features and prognostic relevance, yet largely under-

recognized, that may become a diagnostic target to identify

subjects at increased cardiovascular risk [33–36]. The

International Diabetes Federation (IDF, https://www.idf.

org/webdata/docs/IDF_Meta_def_final.pdf) considers

abdominal obesity as one of the major cardiovascular risk

predictor. However, since there are no data on normal

cut-offs for abdominal circumference and visceral fat in

Latin American populations, the use of the South Asian

data is suggested until more specific data become avail-

able. Some small studies support this proposal [37–39].

Cooperative studies are under way and the new infor-

mation may give more reliable information in this regard.

Although evidence about cardiovascular benefits of inter-

vention is still lacking [40], it makes sense, from a clinical

and epidemiological standpoint, to focus on this popu-

lation for the primary prevention of diabetes mellitus.

Definitions of metabolic syndrome range from the more

stringent definition based on insulin resistance (World

right © Lippincott Williams & Wilkins. Unautho

Health Organization) to that only based on clinical

criteria [National Cholesterol Education Program

(NCEP) [41]]. The NCEP definition has been adopted

in hypertension guidelines [5], presumably favoring a

higher sensitivity to identify populations at risk but at

the cost of decreased specificity in detecting true insulin

resistance [5,6]. An additional asset of the NCEP defi-

nition is clinical simplicity, as it may be applied almost

anywhere despite the limited resources available in Latin

America. However, the IDF classification seems to be

more appropriate for Latin America populations than the

other classifications in terms of the ethnic differences

[37,38]. The prevalence of metabolic syndrome varies in

terms of the classification criteria, age, sex, race and

socioeconomic status, but it is approximately 25–50%

in Latin America according to IDF criteria [37]. Recent

estimates of the prognostic value of metabolic syndrome

showed relative risk ratios for cardiovascular events or

mortality ranging from 2.0 to 3.3, whether or not diabetes

mellitus is included [36,42].

Definition of diabetes mellitus in Latin AmericaA growing body of evidence support the view that, like

blood pressure, fasting plasma glucose is a continuous

variable increasing the risk of cardiovascular disease,

independent of the fact that plasma levels reach or do

not reach the cut-off point used to establish the diagnosis

of diabetes [43,44]. The diagnostic criteria for diabetes

(confirmed fasting plasma glucose of at least 126 mg/dl or

plasma glucose of at least 200 mg/dl 2 h after an oral

glucose load) were chosen because they identified indi-

viduals at high risk of retinopathy. Recently, the terms of

rized reproduction of this article is prohibited.

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Latin American guidelines on hypertension Sanchez et al. 911

dysglicemia or prediabetes have been proposed to define

a condition in which the levels of fasting glucose range

between 100 and 125.9 mg/dl or the value of plasma

glucose 2 h after an oral glucose load of 75 g is between

140 and 199.9 mg/dl. It has been demonstrated that

the risk of developing diabetes mellitus and CVD is

increased in patients with prediabetes [45], especially

in populations of developing countries [14,46], who are

prone to develop insulin resistance associated with epi-

genetic adaptations to the rapid economic transition and

with changes in the lifestyle experienced by these popu-

lations [14,47].

The population prevalence of diabetes mellitus in Latin

America is 5–9%, being lower in rural areas and higher in

areas over an altitude of 3000 m, where around 100 000

individuals live. Prevalence of prediabetes is similar to

that of diabetes mellitus. The prevalence of hypertension

in the diabetic population is 1.5-fold to 3-fold higher than

among nondiabetic patients in the same age segment [6].

Prevalence of hypertension in diabetes is close to 30%; it

develops many years after the onset of diabetes, usually

as a consequence of diabetic nephropathy [48,49]. On the

contrary, in type 2 diabetes, hypertension may be present

at the time of diagnosis or may even precede overt

hyperglycemia [50]. In newly diagnosed type 2 diabetics,

the prevalence of hypertension is around 60%. In type 2

diabetes, it is difficult to determine whether hypertension

is secondary to diabetes, since patients are usually older

and more frequently obese than nondiabetic patients.

Because in western populations the prevalence of dia-

betes increases with age and degree of obesity [51], a

higher frequency of hypertension could be expected.

However, after adjusting for age and overweight/obesity,

the prevalence of hypertension was still 1.5-fold higher in

diabetic patients relative to nondiabetic patients [52]. In

certain ethnic groups [53], diabetic nephropathy could be

the primary cause of hypertension in type 2 diabetes, as is

the case among Pima Indians and African-American

individuals. Patients with diabetes and hypertension

are at a high risk for both macrovascular disease (coronary

artery, cerebrovascular and peripheral vascular disease),

and microvascular (renal failure, retinopathy). Although

the relation between diabetic neuropathy and high blood

pressure remains unclear, some epidemiologic evidence

suggests that hypertension may facilitate the develop-

ment of neuropathy [6].

Complications of diabetesDiabetic nephropathy

The prevalence of nephropathy is 20–30% in patients

with type 1 diabetes mellitus, and 30–50% in those with

type 2 diabetes mellitus [54]. Three stages are described.

Incipient nephropathy

Incipient nephropathy features a supranormal glomerular

filtration rate (GFR) for about 10 years, followed by an

opyright © Lippincott Williams & Wilkins. Unauth

increased urinary albumin excretion (30–300 mg/day) for

about 5 years. Presence of increased urinary albumin

excretion in both type 1 and type 2 diabetes mellitus

identifies patients at risk for progressive renal disease,

and is considered an independent predictor of cardiovas-

cular disease. Twenty to forty percent of individuals with

abnormal microalbuminuria are reported to progress to

frank albuminuria, and 20% of them to end-stage renal

disease (ESRD).

Clinical nephropathy

Clinical nephropathy is characterized by more than

300 mg/day urinary albumin excretion and hypertension

in almost 100% of patients. In type 1 diabetes mellitus,

80% of patients may develop albuminuria greater than

300 mg/day within 10–15 years, and many of them will

progress to ESRD. Without intervention, progression to

this condition may be faster; in fact, 50% of patients will

have developed ESRD in 10 years and 75% in 20 years

[55]. On the contrary, therapeutic interventions in both

types of diabetes mellitus can slow down GFR decline.

Progressive renal insufficiency

Progressive renal insufficiency may be defined as

macroalbuminuria (�300 mg/day) and a reduced GFR

(<30 ml/min per 1.73 m2). Macroalbuminuria identifies

diabetic patients with substantial histological damage

and predicts a linear decline in GFR. Newly diagnosed

type 2 diabetes mellitus patients should be screened

for albuminuria on a yearly basis. In type 1 diabetes

mellitus patients, albuminuria should be searched for

after 5–7 years from diagnosis, since increased urinary

albumin excretion rarely occurs earlier in the course of

the disease.

The management of diabetes and hypertension in

patients with nephropathy mandates strict glucose and

blood pressure control. The target for glycosylated hema-

globin A1c (HbA1c) should be less than 6.5–7%, since

this has been shown to delay progression from micro-

albuminuria to macroalbuminuria [5]. The recommended

blood pressure goal is less than 130/80 mmHg, and less

than 120/75 mmHg in patients with proteinuria more than

1 g and/or reduced GFR.

Randomized intervention trials have demonstrated

that the management of hypertension in patients with

diabetic nephropathy should include blockade of the

renin–angiotensin system [56–58] with agents such as

angiotensin-converting enzyme inhibitors (ACEIs,

greater evidence in type 1 diabetes mellitus) or angio-

tensin receptor blockers (ARBs, greater evidence in

type 2 diabetes mellitus). If the blood pressure target

is not achieved, other drugs should be added, such as

diuretics (thiazides), calcium antagonists or b-blockers.

The combination of three or more drugs is often necess-

ary to meet blood pressure targets. Although there are

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912 Journal of Hypertension 2009, Vol 27 No 5

data favoring the combined use of ACEIs and ARBs in

patients with type 2 diabetes mellitus and proteinuria,

the recently published results of this combination in the

large ONTARGET trial [59] call for caution, and require

a careful reappraisal of this approach.

Patients with diabetic nephropathy require dietary protein

restriction in addition to the pharmacological treatment

since a reduced dietary protein intake (0.6 g/kg per day)

may delay the progression to ESRD [60].

Cardiovascular complicationsPatients with diabetes and hypertension are at increased

risk for cardiovascular diseases such as CHD, heart fail-

ure, stroke, peripheral vascular disease. Comorbidities,

including dyslipidemia, prothrombotic state and auto-

nomic dysfunction, may contribute to poorer outcomes,

thereby increasing morbidity and mortality. The inci-

dence of cardiovascular disease in men and women with

diabetes mellitus 2 is up to three to four times higher

that in unaffected individuals. Furthermore, diabetes

mellitus is associated with a cardiovascular disease

mortality rate that exceeds 70%, and people with diabetes

mellitus 2 are two to three times more likely to die from

cardiovascular disease than people with no history of

diabetes mellitus, even after controlling for other cardio-

vascular risk factors [61,62]. They are also at high risk

of renal failure, limb amputation, cognitive decline, pre-

mature death, retinal disease leading to blindness and

erectile dysfunction.

Coronary heart disease

Several factors account for the increased risk, including

increased fibrinogen levels (particularly during poor gly-

cemic control), increased levels of plasminogen activator

inhibitor-1, and increased platelet aggregation [63].

Screening for CHD should include exercise stress testing

and myocardial perfusion single-photon emission com-

puted tomography imaging, when necessary.

The management of CHD is similar for hypertensive

patients with or without diabetes mellitus. Smoking

cessation should be strongly encouraged. Treatment

targets include re-establishment of coronary flow and

myocardial perfusion, plaque stabilization, prevention

of recurrent ischemia, limitation of left ventricular

(LV) remodeling, suppression of arrhythmias and sec-

ondary prevention. Treatment should include b-block-

ers. Antiplatelet therapy with aspirin [64] is the mainstay

of treatment for diabetic patients with CHD, and is also

recommended during and after acute myocardial infarc-

tion. It is important to achieve an adequate glycemic

control as early as possible, since blood glucose levels on

admission are an independent predictor of early and late

mortality of patients with myocardial infarction [65].

Statins should be administered to protect vulnerable

plaques even in patients with a normal lipid profile [65].

opyright © Lippincott Williams & Wilkins. Unautho

Left ventricular dysfunction and heart failure

Diabetes is a major risk factor for LV dysfunction and

heart failure. In the Glasgow Monica study, the incidence

of LV dysfunction was higher in diabetic patients (29%)

compared with nondiabetic patients (7%) [66]. In the

Framingham study [67], the relative risk for clinical heart

failure in patients with diabetes was 3.8 in men and 5.5 in

women, relative to nondiabetic patients. The prevalence

of heart failure in elderly diabetic patients has been

recently reported to be 39% [68]. The rate of heart failure

was found to be 4.2/1000 patients/year for diabetic

patients with HbA1c less than 7.0%, and to increase to

9.2/1000 patients/year for those with HbA1c greater than

10% [69]. Diabetic and hypertensive patients often

develop the so-called ‘diastolic heart failure’, that is, heart

failure with preserved systolic ejection fraction [70]. The

high prevalence of heart failure and the significant mor-

bidity and mortality associated with it mandate the early

identification of risk factors and clinical signs to allow the

appropriate treatment. Although an electrocardiogram

and X-rays may be helpful, two-dimensional and pulsed

Doppler echocardiography is recommended whenever

heart failure is suspected in order to visualize the changes

in heart structure and function that underlie heart failure. A

24-h electrocardiographic monitoring is also important to

screen for arrhythmias, since heart failure is a proven

predictor of sudden cardiac death.

Large clinical trials have documented the benefits of

drugs blocking enhanced neuro-hormonal systems (sym-

pathetic and renin–angiotensin) in attenuating cardiac

remodeling, improving ventricular function, and redu-

cing morbidity and mortality. Treatment should include a

diuretic (furosemide), an ACEI or ARB and a b-blocker,

unless contraindicated. Spironolactone can also be con-

sidered in absence of severe renal dysfunction.

Stroke

The rates of stroke-related disability are higher in dia-

betic than in nondiabetic patients [71]. The risk of fatal

vs. nonfatal stroke is associated with higher levels of

HbA1c many years before the event [72]. Hence, blood

pressure and glycemic control, together with other pro-

ven therapies such as aspirin and statins [73], are war-

ranted for stroke prevention.

Prevention of cardiovascular disease in diabetic patients

To prevent cardiovascular disease in patients with dia-

betes mellitus and hypertension, strict control of glycemia

[74,75] and blood pressure is fundamental. The Diabetes

Control and Complications Trial (DCCT) in people with

type 1 diabetes found that a 6-year period of intensive

glycemic control (HbA1C 7.2 vs. 9.0%) led to a 42%

reduction in cardiovascular outcomes after 11 more years

of passive follow-up. Interestingly, during passive follow-

up, glycemic control was not different between the groups

[74]. In type 2 diabetes mellitus the evidence is less clear:

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Latin American guidelines on hypertension Sanchez et al. 913

the UK Prospective Diabetes Study (UKPDS) [75]

showed only benefit in preventing microvascular disease

by reducing HbA1C to 7.0 vs. 7.9%, and three recent trials

(ACCORD [76], ADVANCE [77] and DIGAM 1–2 [78])

lowering HbA1C to below 7% failed to reduce macrovas-

cular disease significantly, although ADVANCE reported

a small but significant improvement in microvascular out-

comes. However, these studies indicated that the cardio-

vascular risk of a diabetic patient is directly related to the

duration of diabetes, and the efficacy of hypoglycemic

therapy in reducing cardiovascular risk might be affected

by the duration of diabetes [79]. Early intensive treatment

should be encouraged in diabetic patients, especially in

those at high risk of developing cardiovascular disease, as

are the hypertensive diabetic patients.

Risk of diabetes in hypertensionEpidemiologic evidence suggests that hypertension is a

risk factor for the development of diabetes. One pro-

spective study found that people with hypertension had a

2.4 higher incidence of diabetes than people without

hypertension [80]. One explanation for the increased risk

of diabetes in hypertension is activation of the renin–

angiotensin system. Both angiotensin II-mediated pan-

creatic vasoconstriction [81] and aldosterone-mediated

hypokalemia [82] inhibit glucose-induced insulin release

from the beta cell. In addition, angiotensin II and insulin

share signal transduction pathways. Thus, insulin acti-

vates proteinkinase C (PKC) through the tyrosine phos-

phorylation of insulin receptor substrate type 1 and 2

(IRS-1 and IRS-2) and stimulates the mitogen-activated

protein (MAP)-kinase pathway signaling, whereas angio-

tensin II inhibits PKC signaling that alters the intracellu-

lar signaling of insulin, producing insulin resistance [83].

Blockade of the renin–angiotensin system reduces the

contraregulatory hormone norepinephrine [84], improves

peripheral insulin sensitivity [85], and prevents the

development of diabetes in people with hypertension,

heart disease, or heart failure, and reduces glucose levels

[86–88]. For these reasons the recommendation of the

2007 European Guidelines for the Management of Arter-

ial Hypertension recommend that in hypertensive

patients with metabolic syndrome and type 2 diabetes

ARB or ACE inhibitors [5] should be used as first anti-

hypertensive drugs. In Latin American populations

similar recommendations should be given for this kind

of patients, especially in face of their higher proneness to

develop insulin resistance at lower levels of abdominal

obesity [89,90], a condition with epidemic characteristics

in Latin America [91], and associated with changes in

vascular function independently of other cardiovascular

risk factors [92].

Treatment of hypertensionGeneral principlesMiddle-income and low-income regions, such as most of

the Latin American countries, have a five times greater

opyright © Lippincott Williams & Wilkins. Unauth

burden of disease than do high-income countries, with

access to less than 10% of the global treatment resource.

Therefore, priority should be given to those at the highest

risk of fatal events, because most hypertensive patients

receive no treatment whatsoever. Particular attention

should be given to those individuals with social risk

conditions such as homelessness, poverty, lack of edu-

cation, or unemployment.

In hypertensive patients, the primary goal of treatment is

to achieve maximum reduction in the long-term total risk

of cardiovascular disease with maintenance of good qual-

ity of life. This requires treatment of the elevated blood

pressure values per se as well as all associated reversible

risk factors in order to reduce the associated cardiovas-

cular risk. In this way, any reduction in blood pressure,

even if not optimal, helps toward total risk reduction.

However, blood pressure should be reduced to at least

below 140/90 mmHg (systolic/diastolic), and to lower

values, if tolerated, in all hypertensive patients. Target

blood pressure should be at least less than 130/80 mmHg

in patients with diabetes and in high or very-high-risk

patients such as those with associated clinical conditions

(stroke, myocardial infarction, renal dysfunction, protei-

nuria) [5,73].

Systolic blood pressure is a better predictor of risk in

elderly patients, and also in these patients the goal of

treatment should be achieving less than 140 mmHg,

although in no-intervention trial these low values have

been achieved. In very elderly hypertensive patients

important cardiovascular risk reduction was found in

the HYVET study with a blood pressure target of 150/

80 mmHg [93]. Despite the use of combination treat-

ment, reducing SBP to less than 140 mmHg may be

difficult and more so if the target is a reduction to less

than 130 mmHg. Additional difficulties should be

expected in the elderly, in patients with diabetes, and

in general, in patients with cardiovascular damage.

In order to more easily achieve goal blood pressure,

antihypertensive treatment should be initiated before

significant cardiovascular damage develops. 24-h ABPM

is a useful tool that should be recommended, when

available, to reinforce or correct treatment [94–97].

Lifestyle changesLifestyle measures should be instituted, whenever

appropriate, in all hypertensive patients, including those

who require drug treatment. The purpose is to lower

blood pressure, to control other risk factors, and to reduce

the number or the doses of antihypertensive drugs.

Lifestyle measures are also advisable in patients with

normal and high-normal blood pressure to reduce the risk

of developing hypertension. Lifestyle recommendations

should not be given as lip service but instituted with

adequate behavioral and expert support, and reinforced

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914 Journal of Hypertension 2009, Vol 27 No 5

periodically. The lifestyle measures that are widely

recognized to lower blood pressure and/or cardiovascular

risk, and that should be considered are:

(1) S

opy

moking cessation

(2) W

eight reduction (and weight stabilization)

(3) R

eduction of excessive alcohol intake

(4) P

hysical exercise

(5) R

eduction of salt intake (<6 g NaCl)

(6) I

ncrease of Kþ intake (>6 g)

(7) I

ncrease in fruit and vegetable intake and decrease in

saturated and total fat intake.

Body mass index and abdominal circumference are

reliable clinical markers in cardiovascular prevention.

Optimal BMI for the hypertensive population is between

18.5 and 25 kg/m2. Likewise, an adequate abdominal

circumference is less than 90 cm in male and less than

80 cm in women [37–39,98], but no tables of normality

values based on epidemiological studies of sufficient

power are available in Latin America.

Aerobic exercise is an important complement of diet

for weight and blood pressure reduction. It should be

implemented in all hypertensive patients and particularly

in those with additional risk factors for at least 30 min daily.

Because long-term compliance with lifestyle measures is

low and the blood pressure response highly variable,

patients under nonpharmacological treatment should

be followed up closely.

Initiation of blood pressure-lowering therapyInitiation of blood pressure-lowering therapy should be

decided on two criteria: the level of SBP and DBP and the

level of total cardiovascular risk. Drug treatment should

be initiated promptly in grade 3 hypertension as well as in

grade 1 and 2, when total cardiovascular risk is high or

very high. In grade 1 or 2 hypertensive patients with

moderate total cardiovascular risk drug treatment may be

delayed for a few weeks and in grade 1 hypertensive

patients without any other risk factor for several months.

However, it is important to pay particular attention to

those individuals who are at risk because of their social

environment (homeless, poor, the uneducated, or the

unemployed), in whom a prompter initiation of therapy

should be considered and a close monitoring of health is

mandatory. When initial blood pressure is in the high-

normal range the decision on drug intervention heavily

depends on the individual clinical condition. In the case

of diabetes, history of cerebrovascular, coronary, or peri-

pheral artery disease, the recommendation to start blood

pressure-lowering drugs finds some support in the results

of controlled trials. Patients in the normal blood pressure

range but at very high cardiovascular risk because of

associated clinical disease should be advised to imple-

ment intense lifestyle measures. In these patients blood

right © Lippincott Williams & Wilkins. Unautho

pressure should be closely monitored and drug treatment

considered in the presence of increasing blood pressure or

worsening of the clinical condition.

Selection of antihypertensive drugsThe main benefits of antihypertensive therapy are due to

lowering of blood pressure per se. Five major classes of

antihypertensive agents – thiazide diuretics, calcium

antagonists, ACE inhibitors, angiotensin receptor block-

ers, and ß-blockers – are suitable for the initiation and

maintenance of antihypertensive treatment, alone or in

combination [5]. ß-blockers, especially in combination

with a thiazide diuretic, should not be used in patients

with the metabolic syndrome or at high risk of incident

diabetes. In these patients carvedilol, nebivolol, or slow-

release indapamide may be suitable [99–101]. Renin

inhibitors, such as aliskiren, although not yet available

in all countries, have been shown to be effective anti-

hypertensive agents [102]. However, results of outcome

trials are still waited, and the cost/benefit ratio of these

agents is still unknown. In many patients more than one

drug is needed, so fixed combinations might be useful in

order to improve compliance and increase successful

control of blood pressure [103].

The choice of a specific drug or drug combination, and

the avoidance of others should take into account the

following:

(1) T

riz

he previous favorable or unfavorable experience of

the individual patient with a given class of com-

pounds.

(2) T

he effect of drugs on cardiovascular risk factors in

relation to the cardiovascular risk profile of the

individual patient.

(3) T

he presence of subclinical organ damage, clinical

cardiovascular disease, renal disease or diabetes,

which may be more favorably treated by some drugs

than others.

(4) T

he presence of other disorders that may limit the

use of particular classes of antihypertensive drugs.

(5) T

he possibilities of interactions with drugs used for

other comorbidities.

(6) T

he cost of drugs, either to the individual patient or

to the health provider.

Cost considerations, however, should never predominate

over efficacy, tolerability, and protection for the indivi-

dual patient.

Continuing attention should be given to side-effects of

drugs, because these are the most important causes of

noncompliance. Drugs are not equal in terms of adverse

effects, particularly in individual patients. Drugs which

exert their antihypertensive effect over 24 h with a once-

a-day administration should be preferred because a

simple treatment schedule favors compliance [104].

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Latin American guidelines on hypertension Sanchez et al. 915

In hypertensive patients with moderate or high cardiovas-

cular risk and specific accompanying conditions, the fol-

lowing pharmacological interventions are recommended:

(1) A

opy

CE inhibitors or ARBs in patients with metabolic

syndrome or type 2 diabetes because metabolic

parameters are not affected or may even be

improved.

(2) A

CE inhibitors or ARBs in patients with renal

dysfunction and microalbuminuria or proteinuria

because these agents slow down progression to

chronic renal failure and dialysis.

(3) A

CE inhibitors or ARBs in patients with systolic and

diastolic left ventricular dysfunction even if asymp-

tomatic.

(4) A

CE inhibitors, ARBs, and calcium channel block-

ers in patients with left ventricular hypertrophy

because these agents facilitate left ventricular

regression.

(5) B

eta blockers in patients with CHD.

(6) C

alcium channel blockers (dyhydropyridines) in

elderly hypertensive patients and African Amer-

icans hypertensive patients.

(7) a

-Adrenergic blocking agents in patients with

prostatic hypertrophy.

(8) T

hiazides and chlortalidone in African American

hypertensive patients, elderly hypertensive patients,

or low-income people who cannot afford the cost of

other drugs.

(9) I

n hypertensive patients with heart failure diuretics,

ACE inhibitors, bisoprolol, carvedilol or nebivolol,

and spironolactone.

(10) I

n postmyocardial infarction patients ACE inhibi-

tors and beta blockers.

(11) R

ecurrency of stroke is better prevented with

diuretics (slow-release indapamide) and ACE

inhibitors.

(12) P

atients with peripheral vascular disease should be

encouraged to quit smoking and perform aerobic

exercise. Calcium channel blockers are suitable

to lower blood pressure without exacerbation of

symptoms.

(13) A

CE inhibitors or ARBs in patients with recurrent

atrial fibrillation. Beta blockers or verapamil in

sustained atrial fibrillation.

(14) S

tatins and antiplatelet agents in very-high-risk

hypertensive patients (secondary prevention).

Table 5 Recommended cuff length for blood pressuremeasurement

Inflatable bladder

Flexible cuff length (cm)Width (cm) Length (cm)

Newborn 4 8 23Breast feeding 8 13 30Child 10 18 40Adult 13 22 52Obese 16 34 65Thigh 20 40 76

Calculated to cover, al least 80% of the arm circumference.

Special populationsHypertension in children

Definition of hypertension in children

Hypertension in pediatrics is defined by percentile tables

related to sex, age, and height provided in the Report

from the Working Group on High Blood Pressure in

Children and Adolescents [105]. Normal blood pressure

is defined when blood pressure, depending on sex, age,

and height, is under the 90th percentile, high-normal

right © Lippincott Williams & Wilkins. Unauth

blood pressure when blood pressure is over the 90th and

under the 95th percentiles in three or more occasions.

Adolescents with blood pressure values at least 120/

80 mmHg should be considered as prehypertensive.

White-coat hypertension is defined when blood pressure

values are equal or over the 95th percentile and in the

normal range out of the office. For diagnosis confirmation,

ABPM or home blood pressure is required.

Blood pressure measurement The demonstrated link

between childhood blood pressure values and essential

hypertension in adult life supports the recommendation

that blood pressure must be routinely measured in the

pediatric physical evaluation. The old concept that hy-

pertension in children and adolescents is predominantly

secondary is untrue. Thus, it is recommended that blood

pressure must be measured since the first days of life and

at least once in a year even in children, especially in the

obese ones, as hypertension is closely related to obesity in

children [106–111].

Measurement of blood pressure is mandatory in diseases

or conditions accompanied by higher risk of arterial

hypertension, such as renal diseases, diabetes, insulin

resistance, long-term steroid therapy, nonsteroidal anti-

inflammatory drugs, oral contraceptives, cyclosporine,

neurofibromatosis, newborns with pathological umbilical

vessels, Turner syndrome, corrected aortic coarctation,

hemolytic–uremic syndrome, unexplained congestive

heart failure, dilated myocardiopathy, and seizures of

unknown cause.

Blood pressure measurements should follow these recom-

mendations:

(1) T

ori

he child must be sitting in a chair that enables him

to have the arm supported. If this is not possible, the

child must sit on mother’s lap.

(2) N

o measurement of blood pressure must be

performed if the child is crying or moving the arm

from which the measurement is to be performed.

(3) T

o choose the correct arm-cuff, the arm circumfer-

ence must be measured at mid distance between the

acromium and olecranon (Table 5). The air bladder,

not the cuff, must cover 80% of the arm circumfer-

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916 Journal of Hypertension 2009, Vol 27 No 5

ence and 2/3 of the olecranum–acromion distance. In

case of unavailability of the correct cuff, the next size

can be used. If only an adult cuff is available, the

thigh of the children can be used with the child lying,

performing the auscultation in the popliteal fossa.

From 6–7 years of age a small adult cuff can be used.

Diagnostic evaluation Children with marked and per-

sistent arterial hypertension should be evaluated for

secondary hypertension. Inquiry should be made about

newborn diseases and history of urinary infection, feeding

habits, energizer drinks, and illicit drugs. Physical exam

should include heart rate, peripheral pulses, vascular and

cardiac bruits, and blood pressure in both arms and legs.

ABPM or home blood pressure readings may help to

confirm the diagnosis and to discard white-coat hyper-

tension, which is frequent in adolescents [112,113], thus

avoiding unnecessary studies. The 24-h ABPM classifi-

cation related to sex and age could be performed by using

tables reported elsewhere [114].

Blood count, serum and urinary creatinine, serum uric

acid, serum and urinary electrolytes, acid–base evalu-

ation, plasma renin activity, serum aldosterone, fasting

glycemia, serum lipids, a full urine test with microalbu-

minuria, cardiac and renal Doppler ultrasound should be

performed whenever there is a consistent suspicion of

secondary hypertension.

Special tests according to type of suspected secondary

hypertension can be considered, such as renal scintigra-

phy before and after ACEI, magnetic angio-resonance

and/or aorto-renal arteriography (renovascular disease),

urinary catecholamines and metanephrine (pheochromo-

cytoma), aldosterone : renin ratio, cortisol plasma levels

(primary hyperaldosteronism or Cushing disease).

Prevention Pediatricians should measure blood pressure

as part of the physical examination in all children. Phys-

icians in charge of adult hypertensive patients or adult

cardiac patients should measure blood pressure in their

patients’ offspring also, since hypertension presents

familiar aggregation [115]. Lifestyle changes should be

elicited in the entire family, these greatly contributing to

the primary prevention of hypertension and cardiovascular

morbi-mortality. Healthy eating changes and increased

physical activities should be promoted in schools, in view

of actively antagonizing the overweight and obesity epi-

demics induced by trash food intake and sedentarism due

to the time spent at the computer and in front of the

television. Obesity is one of the major components of the

metabolic syndrome that also include other cardiovascular

risk factors like arterial hypertension, insulin resistance,

and dyslipidemia [107,116]. High salt intake through pro-

cessed foods and sugar intake in sweetened beverages also

contribute to weight gain [117]. A reduced salt intake is a

simple measure to prevent weight gain. A greater intake of

right © Lippincott Williams & Wilkins. Unautho

vegetables and fruits, foods with high potassium content,

may also help to prevent a blood pressure increase. Recom-

mendations should be given against active or passive

exposition to tobacco smoking, since there is a straight

relationship between parental and children’s smoking

habits. Childhood is a specific window in which prevention

of hypertension and cardiovascular risk factors should

be started.

Treatment Nonpharmacological treatment is the major

measure to lower blood pressure in children. It is similar

to that recommended above for prevention of hyper-

tension.

Pharmacological treatment should not start before

4–6 months of an unsatisfactory response to lifestyle

changes, when target organ damage is present and in

patients with secondary hypertension.

Clinical studies with antihypertensive drugs in children

are not numerous nor large, but they have provided some

information about doses and safety of drugs. Treatment

should be started with a single drug, all classes (ACEIs,

ARBs, beta blockers, calcium antagonists, and diuretics)

being suitable. Small doses should initially be used and

subsequently titrated until blood pressure control is

reached. In case of failure, a second drug can be added

in order to avoid too large doses of any single drug.

Cautions when treating hypertension in children Avoid

the use of ACEIs and ARBs in female adolescents at risk

of pregnancy (specific contraindication). Beta blockers

can cause some reduction in physical performance and

diuretics increase the risk of electrolyte disturbances.

Hypertension in pregnancyIn pregnancy hypertension has a prevalence of about 5–

10%, and is more prevalent in high-risk pregnancies, such

as those with a previous history of preeclampsia or chronic

severe hypertension, or in primiparous women. In Latin

America a higher prevalence of hypertension in pregnancy

has been documented than in high-income countries [118].

Therefore, special attention is given to this topic in the

present guidelines. Indeed, most of the complications of

hypertension in pregnant women are preventable, and the

best prevention is based on early detection of hypertension

through a careful measurement of blood pressure.

Definition and classification

Hypertension in pregnancy is defined as blood pressure

values of at least 140/90 mmHg in two or more readings at

a 4-h interval [119]. Proteinuria in pregnancy is defined as

urinary protein excretion of at least 300 mg/24 h. Among

the different hypertensive syndromes in pregnancy

particular attention is called to preeclampsia because

of its prevalence in Latin America.

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Latin American guidelines on hypertension Sanchez et al. 917

Preeclampsia is frequently associated with fetal compli-

cations. It starts through an anomalous placentation

before the 20th week [120], and usually presents clini-

cally after the 28th week, with an increase in blood

pressure, proteinuria, and hyperuricemia. Edema,

impaired renal function, hemolysis and platelet aggrega-

tion, attributed to endothelial dysfunction secondary to

placental ischemia, can also occur. Endothelial dysfunc-

tion may release different toxins into the maternal blood,

such as cytokines, reactive oxygen species (ROS), asym-

metric dimethylarginine (ADMA), antibodies against

angiotensin II receptors, and so on [121]. Factors favoring

the abnormal placentation are: first pregnancy before age

18 years or after 40 years age, previous history of pre-

eclampsia (especially if before the 32nd week [122]),

history of spontaneous abortion or severe intrauterine

growth retardation, pregnancy resulting from assisted

fertilization, multiple pregnancies, close familiar

(mother, sister) history of preeclampsia, Rh isoimmu-

nization, subclinical infections, chronic arterial hyper-

tension, renal failure, obesity, autoimmune diseases.

Differences between developed countries in the causes

of preeclampsia and in the strategies to prevent it have

been described [123]. Inflammation secondary to vaginal

and urinary subclinical infection [124,125], periodontal

disease [126], insulin resistance [127] are considered as

possible risk factors for the development of preeclampsia.

Therefore, it is important that pregnant women with

the above-mentioned risk factors be carefully followed

to detect hypertension and proteinuria early, prevent

severe complications requiring hospitalization, and, if

necessary, perform cesarean delivery to preserve mother

and child.

Prevention

Low-dose aspirin The efficacy is lower than initially

expected [128] and its use is still controversial. Never-

theless in patients at high risk of preeclampsia early

aspirin administration (100 mg/day from the 8th week

until 2 weeks before probable delivery) may delay onset

of preeclampsia.

Calcium supplementation An inverse relationship has

been shown between calcium intake and preeclampsia

[129]. Although a number of trials of calcium supple-

mentation have failed to consistently show benefits, some

low and middle-income populations of Latin America

have low calcium diets and in these groups beneficial

effects on preeclampsia and premature delivery have

been obtained by giving a 1 g daily supplement of

calcium [130–132].

Subclinical infections Because of the strong relation-

ship between urinary and periodontal infections and

preeclampsia [133], it is imperative to search for and

treat bacteriuria, urinary, and/or vaginal and periodontal

infections in pregnant women.

opyright © Lippincott Williams & Wilkins. Unauth

Diagnostic studies

Biochemical tests during pregnancy should include blood

count, glycemia, serum electrolytes, creatinine and uric

acid, urinalysis and 24-h proteinuria. These measure-

ments must be repeated at the 20th, 28th, 32nd, and

36th weeks and more frequently when hypertension or

complications are present. Pregnant women at high risk

of preeclampsia may be advised to have a uterine arterial

Doppler ultrasound at weeks 10–12 and 20–28.

In women with a history of preeclampsia before the 32nd

week, or of recurrent abortions, hematological abnorm-

alities are two to three times more frequent than in the

general population [134,135]. A search for anticardiolipin

antibodies, homocysteine, antithrombin III deficit, lupus

inhibitor, activated C protein resistance, protein S deficit,

helps in the identification of women that, in a future

pregnancy, may require aspirin or heparin to prevent

complications. Likewise, in any pregnant woman

with high fasting plasma glucose an OGTT should be

performed.

Treatment

Pharmacological treatment must be started when

blood pressure is at least 150/100 mmHg. Treatment

can be initiated orally, and the patient recontrolled after

48–72 h.

Based on 40 years experience and 7.5 years follow-up of

children of treated mothers, alpha methyl-DOPA (500–

2000 mg/day) is the drug of first choice. Second-line drugs

are labetalol (100–400 mg/day), long-acting nifedipine

(30–60 mg/day), and hydralazine (50–200 mg/day) [136].

Drugs with absolute contraindications are renin inhibi-

tors, ACE inhibitors, and ARBs [137,138]. Relative

contraindications are beta blockers (mostly atenolol),

because of reduced placental perfusion and untoward

effects in the newborn (reduction in weight, bradycardia,

and hypooglycemia) [139]. Diuretics are also relatively

contraindicated, unless when cardiac failure is present,

because pregnancy is characterized by reduced plasma

volume, which may be further reduced by diuretic

therapy.

Emergency hospitalization and treatment (often intrave-

nously) is required when DBP is at least 110 mmHg or

remains above 100 mmHg despite treatment, proteinuria

is greater than 1 g/24 h, there is the HELLP syndrome or

eclampsia. Even in emergency situations blood pressure

must be reduced gradually during the first 24 h. Recom-

mended drugs are: labetalol – initial dose 20 mg i.v., with

subsequent doses at 10-min intervals, if necessary, up to a

maximal dose of 220 mg; long-acting nifedipine – if the

patient is conscious, 10 mg every 30 min orally, with a

maximal dose of 40 mg (magnesium sulfate can be associ-

ated although some reduction in uterine contractility has

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918 Journal of Hypertension 2009, Vol 27 No 5

been reported); – 0.15 mg intravenously followed by

0.75 mg in 500 ml 5% dextrose solution (five drops per

min); nitroglycerine infusion if there is pulmonary

edema. Sodium nitroprussiate should be infused only

postpartum, due to the risk of thyocianate intoxication

of the fetus. Intravenous hydralazine is now discouraged

because it appears to be associated with more perinatal

adverse effects. In absence of an adequate therapeutic

response, decisions depend on gestational time: when

this is more than 36 weeks, pregnancy should be inter-

rupted. When gestational time is less than 36 weeks,

corticoids should be administered to induce pulmonary

maturation, and pregnancy interrupted after 48 h.

Complications of hypertension in pregnancy

HELLP syndrome HELLP is an abbreviation of the

main findings [140]: hemolytic anemia, elevated liver

enzymes, and low platelet count. This, together with

eclampsia, is the most frequent cause of maternal death.

It can follow a severe preeclampsia or represent the first

manifestation of the disease. The three diagnostic criteria

are microangiopathic anemia with hyperbilirubinemia,

increased lactic acid dehydrogenase and hepatic

enzymes, and thrombocytopenia. The patient must be

hospitalized, possibly in an intensive care unit, and

interruption of pregnancy is recommended indepen-

dently of gestational time.

Eclampsia Eclampsia is characterized by seizures. It

generally follows preeclampsia when this is inadequately

treated. Hospitalization in an intensive care unit is

required to provide adequate therapy [141,142]. Magnes-

ium sulfate i.v. has been proved effective in the preven-

tion of eclampsia and treatment of seizures [143].

Recommendation for follow-up of women and children after

a hypertensive pregnancy

Breast feeding Blood pressure less than 150/100 mmHg

does not require treatment and salt restriction can be the

only measure to normalize blood pressure. If antihyper-

tensive drugs are needed, those with low breast milk

excretion should be used, such as methyldopa, nitrendi-

pine, captopril, or enalapril [144]. Special caution must be

taken with diuretics since a reduction in breast milk

production can be induced; diuretics are also excreted

in breast milk and can cause electrolytic alterations in

the newborn.

Long-term maternal blood pressure control All women

presenting hypertension during pregnancy should have

their blood pressure followed up subsequently, since they

are prone to show or develop continuing hypertension.

Furthermore, a number of retrospective studies have

shown an increased cardiovascular risk in women with

preeclampsia and intrauterine undernutrition [145–147].

opyright © Lippincott Williams & Wilkins. Unautho

Child blood pressure control Several epidemiological

studies have shown a strong association between low

birth weight and prevalence of hypertension and cardio-

vascular diseases in adulthood. These findings support

the concept that cardiovascular diseases may start in

intrauterine life [148]. Therefore, children of mothers

with a hypertensive pregnancy should have their blood

pressure controlled up to adulthood.

Hypertension in the elderlyHypertension is known to be one of the most important

treatable risk factors in patients older than 65 years.

Isolated systolic hypertension which is very frequent in

the elderly [149] carries an additional risk because the

increased pulse pressure (>65 mmHg) has been found to

be associated with increased cardiovascular morbidity

and mortality [150]. The elderly are prone to orthostatic

hypotension and pseudo hypertension due to a reduced

arterial compliance, therefore blood pressure measure-

ments must also be done with the patient in the erect

posture. Twenty-four hour ABPM may also be a valuable

adjunct to the clinical evaluation [151,152].

Diagnosis

In elderly hypertensive patients, especially those resist-

ant to treatment, renovascular hypertension due to

abdominal aorta atherosclerosis must be searched for.

Doppler ultrasound examinations of the renal artery

and abdominal aorta are a useful screening tool.

Treatment

In the elderly, blood pressure should be reduced to a

target similar to that recommended for younger people,

that is below 140/90 mmHg. This goal, however, is more

difficult to achieve. In the elderly, blood pressure

decrease must be gradual to ensure good tolerability

and guarantee a good quality of life.

A number of large trials (SHEP, STOP, MRC, Syst-Eur,

and Syst-China [153–157]) provided strong evidence of

the benefits of lowering blood pressure in older patients

either with systolic–diastolic or isolated systolic hyper-

tension, showing decreases in stroke (25–47%), coronary

events (13–30%), heart failure (29–55%), and cardiovas-

cular death (17–40%), in actively treated vs. placebo-

treated patients. The recent HYVET trial [93], which

included 3800 patients older than 80 years randomized to

either placebo or active treatment with indapamide and

perindopril, showed that even in these very elderly

patients blood pressure reduction is associated with a

significant reduction in fatal and nonfatal stroke (30%),

stroke deaths (39%), all-cause mortality (21%), cardio-

vascular deaths (23%), and heart failure deaths (64%).

Pharmacological treatment

When selecting antihypertensive drugs for older people,

the frequent presence of comorbidities and, consequently,

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Latin American guidelines on hypertension Sanchez et al. 919

of multiple drug intake, must be taken into account, and

the risk of pharmacological interactions considered. To

avoid excessive or sudden falls in blood pressure, due to

impaired pharmacokinetics, overestimation of blood pres-

sure values, the postprandial and orthostatic hypotension,

reduced blood flow autoregulation, and so on, agents must

be started at low doses, and doses adjusted every 4–6

weeks after evaluating side-effects. The first-step drugs in

older people without complications are diuretics and

calcium antagonists, as more frequently used in random-

ized trials, but favorable data are also available for other

agents (see HYVET results for the use of ACEI in com-

bination with a diuretic). In elderly hypertensive patients

with associated risk factors, hypertensive complications, or

comorbidities, drugs must be chosen depending on the

concomitant disease. Long-acting drugs are preferred due

to better patient compliance (an aspect particularly valu-

able in the elderly in whom a simplified drug delivery is

recommended) and a smoother antihypertensive effect.

Latin American Guidelines on HypertensionExpert GroupsChairpersons: Ramiro A Sanchez (Argentina); Miryam

Ayala (Paraguay).

Advisor: Professor Alberto Zanchetti (Istituto Auxologico

Italiano, Milan Italy).

Group 1: Epidemiology: Dr Oswaldo Kohlman (Brazil),

Dr Jose Ortellado (Paraguay), Dra Ximena Berrios

(Chile), Dra Maria Paniagua (Paraguay), Dr Angel Gon-

zalez Caamano (Mexico). Dr Carlos Ponte (Venezuela),

Dra Martha Sereday (Argentina), Dr Sano Masao (Para-

guay), Dr Fernando Montenegro (Ecuador), Dr Juan

Carlos Schettini (Uruguay).

Group 2: Diagnostic and Risk Stratification: Dr Hugo

Pascual Baglivo (Argentina), Dr Carlos J Velazquez (Para-

guay), Dr Javier Galeano (Paraguay), Dr Miguel Adorno

(Paraguay), Dr Ernesto Cardona (Mexico), Dr Dagomar

Aristizabal (Colombia), Dr Diego Garcıa Garcıa (Colom-

bia), Dr Alejandro Iriarte (Paraguay), Dr Ernesto Pena-

herrera (Ecuador), Dr Gabriel Waissman (Argentina).

Group 3: Treatment: Dr Mario Bendersky (Argentina), Dr

Luis Alcocer (Mexico), Dr Gustavo Olmedo (Paraguay),

Dr Jose A Manfredi (Uruguay), Dr Jose Parra Carrillo

(Mexico), Dr Rafael Hernandez Hernandez (Venezuela),

Dr Alfonso Bryce Moncloa (Peru), Dr Alberto Villamil

(Argentina), Dr Pablo Rodrıguez (Argentina), Dr Raul

Ortiz-Guerrero (Paraguay), Dr Walter N Nissen (Para-

guay), Dr Hernan Prat-Martorell (Chile).

Group 4: Special populations (Children and adolescents,

pregnancy, elderly): Dra Gloria Valdes (Chile), Dr Ayrton

Brandao (Brazil), Dra Leticia Gutierrez (Paraguay), Dr

Guillermo Fabregues (Argentina), Dr Roberto Ciciolli

opyright © Lippincott Williams & Wilkins. Unauth

(Paraguay), Dra Rosa Simsolo (Argentina), Dr Luis

Hernan Zarate (Chile).

Group 5: Metabolic syndrome and diabetes mellitus:

Dr Jorge Jimenez (Paraguay), Dr Guillermo Burlando

(Argentina), Dra Felizia Canete (Paraguay), Dr Pablo

Aschner (Colombia), Dr Luis Barriocanal (Praguay), Dr

Aldo Benıtez (Paraguay), Dra Gilda Benıtez (Paraguay),

Dra Susan Benıtez (Paraguay), Dr Manuel Garcıa de los

Rıos (Chile), Dr Patricio Lopez Jaramillo (Colombia),

Dra Ana Marıa Jorge (Uruguay), Dra Mafalda Palacios

(Paraguay), Dra Maricela Vidrio (Mexico).

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