ORIGINAL ARTICLE

Intensive Cardiovascular Examination regarding Blood pressure levels:Evaluation of Risk Groups. ICEBERG study

KEMALETTIN BUYUKOZTURK1, BARIS ILERIGELEN2, GIRAY KABAKCI3,

NEVRES KOYLAN1 & OMER KOZAN4

1Cardiology Department, Istanbul Medical School, Istanbul University, Istanbul, Turkey, 2Cardiology Department,

Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey, 3Cardiology Department, Hacettepe Medical School,

Hacettepe University, Ankara, Turkey, and 4Cardiology Department, Dokuz Eylul Medical School, Dokuz Eylul University,

Izmir, Turkey

AbstractObjective. Assessment of total cardiovascular risk level is crucial for approaching hypertensive patients. Therefore, the aim ofthe Intensive/Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG)study is to determine cardiovascular risk evaluation and stratification of subjects with high normal and high blood pressure(BP>130/85 mmHg), and to evaluate the impact of laboratory tests on this stratification. Methods. ICEBERG was anepidemiological study conducted at 20 university hospitals and 197 primary healthcare centers. A total of 10,313 patients,who were diagnosed with high BP and under antihypertensive treatment or not antihypertensive under treatment at least forthe last 3 months were selected. Besides routine clinical evaluation, microalbuminuria (MAU) and high sensitive C-reactiveprotein (hs-CRP) tests, echocardiography (Echo) and carotid ultrasonography (USG) were performed in selected arms.The patients were stratified into low, moderate, high and very high added risk groups as described by the European Societyof Hypertension/European Society of Cardiology Guidelines Committee (2003). Results. Upon routine evaluation, thepercentage of ‘‘high and very high added cardiovascular risk’’ groups was between 51.2% and 60.7% in different studyarms. This percentage increased to 62.9% by subsequent serum biochemistry assessment and to 76.2% by hs-CRP testresults. Switching upwards to ‘‘high and very high added risk’’ groups was around 6% when MAU results were used, with a4.9% upwards switch to ‘‘high and very high added risk’’ groups when Echo was performed; this proportion increased by6.8%, when carotid USG was taken into account. Conclusion. Cardiovascular risk evaluation by intensive cardiovascularexamination including Echo and carotid USG provided more accurate risk stratification. Furthermore, a simple test todemonstrate presence of MAU usable at primary healthcare level will also help to evaluate the patient’s risk profile betterthan routine assessment methods alone.

Key Words: Blood pressure, cardiovascular system, hypertension

Introduction

The primary goal of the management of hyper-

tension is to achieve the maximum reduction in the

long-term total risk of cardiovascular morbidity and

mortality. However, despite a rising number of new

antihypertensive agents and an increasing awareness

of the debilitating consequences of uncontrolled

hypertension, the global burden of disease remains

high (1–3). The most important factor determining

the approach to hypertensive patients is the assess-

ment of the total cardiovascular risk level of the

patient. According to the European Society of

Hypertension/European Society of Cardiology

(ESH-ECG) Guidelines Committee, the patients

are classified into low, moderate, high and very high

added risk groups (4). An approximate absolute 10-

year risk of cardiovascular disease is v15%, 15–

20%, 20–30% and w30%, respectively, according to

Framingham criteria (5) and approximate absolute

Correspondence: Kemalettin Buyukozturk, Taksim, Lamartin Cad. 49/3, Beyoglu, 34437 Istanbul, Turkey. Tel: +90 (212) 250 7081. Fax: +90 (212) 297

2424. E-mail: buyukozturk@gediknet.com; kbuyukozturk@gmail.com

(Received 1 June 2006; accepted 6 September 2006)

Blood Pressure. 2006; 15: 291–301

ISSN 0803-7051 print/ISSN 1651-1999 online # 2006 Taylor & Francis

DOI: 10.1080/08037050600996644

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risk of fatal cardiovascular disease is v4%, 4–4.9%, 5–

8%andw8% according to the SCORE chart (6).Asan

example, coexisting dyslipidemia is counted as an

additional risk factor for future cardiovascular events

in hypertensive patients; thus, in the presence of

dyslipidemia, both antihypertensive and lipid-lowering

treatments should be given more aggressively.

The association between arterial hypertension and

organ damage at cardiac, vascular and renal levels

identifies a condition of high risk of future cardio-

vascular events in hypertensive patients. Therefore,

accurate detection of organ damage poses a problem

in the management of hypertensive patients, and an

important part of the patient’s status remains hidden

like the underwater part of an iceberg. Since it has

already been demonstrated that one of the very

important indicators in the cardiovascular risk in

hypertension is microalbuminuria (MAU), in addi-

tion to routine screening for cardiovascular risks,

MAU and high sensitive C-reactive protein (hs-

CRP) tests for screening might improve risk classi-

fication (7–9). Although MAU determined by

quantitative methods seems to be more accurate,

using a dipstick is simpler and cheaper, thus making

this qualitative method more suitable for screening

in primary healthcare settings for hypertensive

patients.

Advanced diagnostic techniques are also advised

today in the accurate classification of the hyperten-

sive patients regarding added cardiovascular risks

(10,11). The detection of left ventricular hypertro-

phy (LVH) atherosclerotic plaques of large arteries

by echocardiography (Echo) and carotid ultrasono-

graphy (USG) might provide a more accurate risk

classification of the patients. It was reported that the

presence of LVH demonstrated by Echo has changed

cardiovascular risk stratification in 29% of the patients

(12). Furthermore, Cuspidi et al. (13) have shown that

when Echo and USG applied to 1074 untreated

patients of a low-risk group, it was understood that

50% of them were in fact in higher-risk groups.

The aim of the Intensive/Initial Cardiovascular

Examination regarding Blood pressure levels:

Evaluation of Risk Groups (ICEBERG) study was

to determine cardiovascular risk evaluation and

stratification of subjects with high normal and high

BP (>130/85 mmHg), and to evaluate the impact of

different laboratory tests on this stratification.

Materials and methods

Patients and study design

The ICEBERG study was designed as a cross-

sectional, non-interventional observational study

aiming to collect demographic and medical informa-

tion of study subjects who fulfilled the study

inclusion criteria described below. The study had

two subprotocols: ICEBERG-1 was conducted at 20

university hospitals where advanced tests were

available and ICEBERG-2 was conducted at 197

primary healthcare centers with basic diagnostic

capability.

Each substudy (ICEBERG-1 and ICEBERG-2)

had two profiles of patients defined: risk profile A

and B. Risk profile A consisted of patients who have

been previously diagnosed with primary hyperten-

sion and are under antihypertensive drug treatment

(treated patients), whereas risk profile B consisted of

patients with high normal and high blood pressure

[systolic BP (SBP) >130 mmHg or diastolic BP

(DBP) >85 mmHg] (14), and had not received any

antihypertensive drugs over the past 3 months

(untreated patients). The exclusion criteria were

secondary hypertension, pregnancy, being younger

than 18 years of age, and being enrolled in this study

previously.

ICEBERG-1 subprotocol. In 20 cardiologic centers

participating in the study, patients underwent

routine clinical evaluation including electro-

cardiogram (ECG) as detailed below. Diagnostic

tests performed for cardiovascular risk stratification

are listed in Table I. Initial risk assessment was

performed according to ESC-ESH 2003 guidelines

and reassessment was done by using quantitative

MAU (urinary albumin/creatinine ratio >22 mg/g

for male and 31 mg/g for female) and hs-CRP levels

(>1 mg/l) in all subjects. Additionally, the subjects

in the ICEBERG-1 untreated group were evaluated

for the presence of LVH, not only by ECG, but also

by Echo, and for vascular end organ damage by

carotid USG.

ICEBERG-2 subprotocol. A total of 197 physicians

working at primary healthcare centers participated in

this arm. Patients underwent routine clinical

evaluation as detailed below. Diagnostic tests

performed for cardiovascular risk stratification are

listed in Table I. Briefly, in the ICEBERG-2 treated

group, MAU was measured by urine strips (Micral-

test MicroalbuminuriaH, Roche Diagnostics GmBh;

qualitative method), whereas in the ICEBERG-2

untreated group, it was calculated as urinary

albumin/creatinine ratio in random urine samples

(quantitative method). Other tests (serum

creatinine, lipid profile, potassium, fasting blood

glucose, hs-CRP level measurements, complete

urine test and ECG) were performed in the

ICEBERG-2 untreated group, whereas the results

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of those if done within the last 12 months were

recorded in the ICEBERG-2 treated group.

Written informed consent was signed by every

patient that fulfilled the inclusion criteria and

accepted to participate in the study before enroll-

ment. The study was approved by the Ethics

Committee of Istanbul University, School of

Medicine.

Routine clinical evaluation

The initial evaluations of all participants included a

clinical interview (including concomitant disease

history) and complete physical examination. At least

two sitting BP measurements were performed as

described elsewhere (15). Waist circumference

measurement and body mass index (BMI) calcula-

tion were performed in every patient. Waist circum-

ference was measured at the level of umbilicus, at

mid-expiration, while the patient is erect and

balanced on her/his feet. BMI was calculated

according to the formula BMI (kg/m2)5(body

weight, in kg)/(height, in meters)2. Besides demo-

graphic data and anti-hypertensive drugs history,

hypertension risk profile, concomitant diseases and

target organ injury data as described in the ESH-

ESC guidelines (4) were collected (Table I).

Electrocardiography, Echo and carotid USG

All ECG, Echo and carotid USG recordings were

evaluated centrally by two blinded experienced

observers. ECG criteria for LVH were the presence

of Sokolow–Lyons indices (w38 mm) or Cornell

indices (w2440 mm?ms). LVH was defined as left

ventricular mass index (LVMI) >125 g/m2 for males

(M) and >110 g/m2 for females (F) by Echo.

Vascular end organ damage was defined as carotid

intima media thickness (CIMT) >0.9 mm and/or

atherosclerotic plaque presence determined by car-

otid USG.

Urinary albumin excretion and serum hs-CRP

measurement

All samples were analyzed in a central laboratory

(Duzen Laboratory accredited by Turkish Accredi-

tation Institute, NCCLS and Biologie Prospective).

Urinary albumin excretion was calculated as urinary

albumin/creatinine ratio in random urine samples

(quantitative method) in the ICEBERG-1 treated

and untreated groups, and the ICEBERG-2

untreated group, or determined by means of urine

strips (Micral-test MicroalbuminuriaH; qualitative

method) in the ICEBERG-2 treated group. Urine

albumin level of 30–300 mg/24 h and albumin/

creatinine ratio >22 mg/g in men and >31 mg/g in

women were accepted as MAU.

C-reactive protein (CRP) levels >1 mg/l, assayed

by particle-enhanced turbidimetric method were

considered high.

Stratification of patients by absolute cardiovascular risk

factor

Regarding overall absolute cardiovascular disease

risk assessment, the ESH-ESC Guidelines

Committee classified the patients into low, moder-

ate, high and very high added risk groups (4). In

the present study, the target organ damage was

Table I. The laboratory tests performed in the study groups.

Risk profile

Study protocol

ICEBERG-1 ICEBERG-2

Treated (n5765) Untreated (n5164) Treated (n58496) Untreated (n5888)

MAU (quantitative) + + 2 +MAU (qualitative) 2 2 + 2

Urine creatinine + + 2 +Serum creatinine + + * +Complete urine test + + * +Lipid profile + + * +Serum potassium + + * +Fasting blood glucose + + * +hs-CRP + + * +ECG + + * +Echo 2 +Carotid USG 2 +

Measurements of the last 12 months. MAU, microalbuminuria; hs-CRP, high sensitivity C-reactive protein; ECG, electrocardiography;

Echo, echocardiography; USG, ultrasonography.

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accomplished by the following approaches: (i)

routine procedures (interview, physical examination,

ECG, serum creatinine and urine analysis; in all

groups except that in the ICEBERG-2 treated

group, the laboratory data were recorded if done

within the last 12 months); (ii) routine procedures

along with subsequent reassessment by Echo and

carotid USG, serum CRP levels and urinary albumin

excretion. Patient stratification was done separately

and cumulatively by using data on the following: (i)

interview; (ii) BP; (iii) presence of MAU; (iv)

presence of LVH by ECG; (v) presence of LVH by

Echo; (vi) high CRP levels; (vii) presence of vascular

end organ damage by carotid USG.

Statistical analysis

The statistical analyses presented the demographic,

physical and laboratory findings, the presence of risk

factors, concomitant diseases, target organ damage

and the degrees of hypertension in the study groups

descriptively, using mean and standard deviation for

the numeric variables and percentage distributions

for the categorical ones. The contribution of inclu-

sion of various tests hierarchically as per the

stratification described above, while classifying

patients into several risk categories, was assessed

by providing percentages of patients in ‘‘high and

very high added risk’’ groups.

Results

Study population profile

A total of 10,313 subjects of 10,382 screened met

the inclusion criteria and were included in the study.

The mean age was 57.6¡11.6 years and 64.2% were

females. The number of patients in the ICEBERG-1

and ICEBERG-2 arms was 929 and 9384, respec-

tively. Table II summarizes demographic data of the

study population in both subprotocols, and physical

examination (BP, heart rate, BMI and waist cir-

cumference) and laboratory findings (lipid profile,

serum and urine analysis).

The distribution of patients to subgroups accord-

ing to the presence of risk factors such as age (w55

years for men and w65 year for women), smoking,

alcohol consumption, sedentary lifestyle, family

history of early onset cardiovascular disease, dysli-

pidemia, abdominal obesity and high CRP levels are

Table II. Demographic, physical and laboratory findings in the study groups.

Risk profile

Study protocol

ICEBERG-1 ICEBERG-2

Treated (n5765) Untreated (n5164) Treated (n58496) Untreated (n5888)

Age (yrs) 58.4¡10.4 50.1¡11.3 58.3¡11.4 51.1¡12.1

Gender (F/M) 464/298 92/71 5469/2860 485/398

Physical findings

SBP (mmHg) 142.5¡21.1 154.6¡18.4 150.1¡23.4 158.0¡19.9

DBP (mmHg) 86.1¡11.1 93.9¡10.6 89.9¡12.7 96.3¡10.7

Heart rate (beats/min) 75.2¡10.1 76.0¡8.9 79.6¡10.4 80.9¡10.1

BMI (kg/m2) 29.3¡4.9 28.4¡4.4 29.5¡5.0 29.1¡4.9

Waist circumference (cm) 99.1¡13.4 96.1¡13.5 99.8¡13.7 99.0¡13.3

Microalbumin

Urine albumin (mg/dl) 34.0¡73.1 37.6¡90.1 NA 30.3¡56.2

Urine creatinine (mg/dl) 117.6¡73.7 126.6¡77.0 NA 124.5¡74.4

Albumin/creatinine (mg/g) 49.9¡181.9 46.8¡189.3 NA 35.6¡88.0

Lipid profile

Total cholesterol (mg/dl) 195.3¡40.7 202.6¡42.4 214.1¡52.9 203.7¡46.2

HDL-cholesterol (mg/dl) 49.2¡12.7 51.6¡13.3 48.7¡19.1 48.2¡12.4

LDL-cholesterol (mg/dl) 115.7¡32.7 120.7¡33.3 127.2¡42.8 119.2¡35.0

Triglycerides (mg/dl) 157.3¡99.2 152.5¡97.7 174.7¡108.4 175.2¡120.1

Others

Potassium (mEq/l) 4.44¡0.79 4.44¡0.70 4.36¡0.57 4.40¡0.63

Fasting blood glucose (mg/dl) 109.8¡39.8 102.9¡30.5 124.2¡56.9 109.2¡48.6

Creatinine (mg/dl) 0.99¡0.35 0.99¡0.40 0.97¡0.56 1.00¡0.58

Creatinine clearance (ml/min) 86.9¡31.9 95.0¡34.3 95.4¡44.3 98.9¡32.0

CRP (mg/dl) 8.6¡20.9 5.7¡11.0 3.1¡14.1 2.7¡9.2

Data are given as mean¡standard deviation. CRP, C-reactive protein; HDL, high-density lipoproteins; LDL, low-density lipoproteins;

SBP, systolic blood pressure; DBP, diastolic blood pressure.

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summarized in Table III. Regarding concomitant

diseases, cerebrovascular diseases include stroke,

cerebral hemorrhage, and transient ischemic attack.

The history of myocardial infarction, angina pectoris

or coronary revascularization was evaluated as

concomitant cardiovascular disease. The presence

of diabetic nephropathy, renal dysfunction or pro-

teinuria was regarded as concomitant renal disease

and the presence of retinal hemorrhage or papilla

edema was considered concomitant advanced reti-

nopathy. As shown in Table III, metabolic syn-

drome which defined as in the National Cholesterol

Education Program (NCEP) Adult Treatment Panel

III (NCEP-ATP III) (14) is the most common

comorbidity in all subgroups with the following

percentages: 59.7%, 49.7%, 69.8% and 57.9%, in

the ICEBERG-1 treated and untreated groups and

ICEBERG-2 treated and untreated groups, respec-

tively.

The patients were stratified according to the

degree of hypertension as described in ESH-ECG

guidelines (4). As expected, none of the patients was

in the normal BP group in untreated patients

(Figure 1A). On the other hand, although they were

under antihypertensive therapy, only 20.3% and

12.4% of treated patients, respectively, were under

control (Figure 1A).

Evaluation of end organ damage (Table IV)

When the patients were evaluated for end organ

damage, LVH was found in 4.8%, 3.4% and 4.0% of

the ICEBERG-1 treated and untreated groups and

the ICEBERG-2 untreated groups, respectively, by

ECG. However, in subsequent reassessment by

Echo in the ICEBERG-1 untreated group, the

percentage of patients with LVH increased from

3.4% to 42.4%. Vascular end organ damage was

revealed in 25.0% of these patients (ICEBERG-1

untreated) with carotid USG. Renal injury was

shown in a minority of patients via serum creatinine

measurements, whereas urinary albumin excretion

revealed that a quarter of all groups in fact had renal

injury.

Influence of intensive cardiovascular examination in

addition to routine evaluation on cardiovascular risk

stratification

The patients were stratified according to different

risk groups according to ESH-ECG guidelines (4)

regarding existing risk factors in history and con-

comitant diseases (routine clinical evaluation) before

additional testing (Figure 1B). The percentage of

patients in ‘‘high and very high added risk’’ groups

was 51.3%, 60.7%, 53.0% and 54.1% in the

Table III. The presence of risk factors and concomitant diseases (%) in the study groups.

Risk profile

Study protocol

ICEBERG-1 ICEBERG-2

Treated

(n5765)

Untreated

(n5164)

Treated

(n58496)

Untreated

(n5888)

Risk factors

Age (w55 for men, w65 for women) 40.2% 25.6% 40.1% 22.7%

Smoking 15.4% 20.1% 14.7% 23.9%

Alcohol consumption 7.5% 10.4% 6.4% 12.2%

No physical activity 61.4% 59.8% 70.2% 64.6%

Family history of early onset cardiovascular disease 29.4% 27.4% 31.1% 30.9%

Dyslipidemia (history) 39.9% 18.9% 29.4% 19.4%

Dyslipidemia (laboratory results; total cholesterol w250 mg/dl;

LDL w155 mg/dl; HDL v40 mg/dl in men, v48 mg/dl in women)

45.8% 42.5% 49.6% 47.6%

High CRP (laboratory results; >1 mg/dl) 86.9% 85.3% 75.7% 83.4%

Abdominal obesity (waist circumference >102 cm in men,

>88 cm in women)

74.5% 61.3% 76.5% 72.3%

Concomitant diseases

Cerebrovascular disease 3.9% 0.6% 4.2% 1.6%

Heart disease 26.4% 7.9% 14.7% 4.3%

Renal disease 2.5% 0.0% 2.2% 0.5%

Peripheral vessel disease 2.0% 0.6% 2.8% 1.2%

Advanced retinopathy (if evaluated) 0.9% 32.9% 2.4% 17.2%

DM (history) 17.0% 8.5% 22.8% 11.9%

DM (laboratory results; fasting blood glucose w126 mg/dl) 16.2% 12.5% 27.3% 15.1%

Metabolic syndrome 59.7% 49.7% 69.8% 57.9%

CRP, C-reactive protein; DM, diabetes mellitus.

Evaluating risk groups in hypertension 295

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ICEBERG-1 treated and untreated groups, and the

ICEBERG-2 treated and untreated groups, respec-

tively (Figure 1B).

Upward switches were observed when laboratory

findings were taken into consideration in all groups

(Figures 2 and 3). For example, in the ICEBERG-1

treated group, the percentage of patients in ‘‘high

and very high added risk’’ strata increased to 59.2%

by subsequent assessment of serum biochemistry

test results, and to 72.7% by hs-CRP test results.

Switching upwards to ‘‘high and very high added

risk’’ groups was 6.2% and 6.6%, when quantitative

and qualitative MAU tests were taken into account,

respectively. When MAU plus hs-CRP tests were

taken into account, 15.6%, 14.7% and 16.5%

switched from lesser to ‘‘high and very high added

risk’’ groups in the ICEBERG-1 treated and

untreated groups and the ICEBERG-2 untreated

arms.

Intensive cardiovascular examination in the

ICEBERG-1 subprotocol provided a more accurate

stratification (Figures 2 and 3). While 82.2% of the

Figure 1. Distribution of patients in study groups into different degree of hypertension (A) and into risk groups according to existing risk

factors before additional tests (B). HT, hypertension.

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Table IV. Presence of target organ damage (%) in study groups.

Risk profile

Study protocol

ICEBERG-1 ICEBERG-2

Treated

(n5765)

Untreated

(n5164)

Treated

(n58496)

Untreated

(n5888)

LVH (ECG) 4.8% 3.4% NA 4.0%

LVH (Echo) NA 42.4% NA NA

Arterial wall thickening (carotid USG) NA 25.0% NA NA

Increased serum creatinine levels (1.3–1.5 mg/dl in men and 1.2–

1.4 mg/dl in women)

5.6% 1.3% 6.0% 3.4%

MAU (urine albumin 30–300 mg/24 h and albumin/creatinine

>22 mg/g in men, >31 mg/g in women)

21.3% 22.3% 24.3% 23.5%

LVH, left ventricular hypertrophy; USG, ultrasonography; MAU, microalbuminuria.

Figure 2. Percentage of ICEBERG-1 treated (A) and ICEBERG-1 untreated (B) patients in ‘‘high and very high added risk’’ groups

according to various tests. SB, serum biochemistry; MA, microalbuminuria; ECG, electrocardiography; hs-CRP, high sensitivity C-reactive

protein; Echo, echocardiography; USG, carotid ultrasonography.

Evaluating risk groups in hypertension 297

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subjects were classified into ‘‘high and very high

added risk’’ groups, initially; further 4.9% switched

upwards from lesser risk groups to ‘‘high and very

high added risk’’ groups, when Echo was performed;

and this proportion increased by 6.8%, when carotid

USG was taken into account.

Discussion

The ICEBERG study was a cross-sectional, non-

interventional epidemiologic study which included a

total of 10313 patients with high normal and high BP

of which 9384 were being managed and followed-up at

primary healthcare settings (ICEBERG-2). The dis-

tribution of patients regarding demographics, physical

examination and laboratory findings did not show a

markedly different profile in treated ICEBERG-1 and

ICEBERG-2, and also in the untreated ICEBERG-1

and ICEBERG-2 groups. On the other hand, the

distribution of patients with higher degrees of hyper-

tension in the ICEBERG-1 subgroups compared with

those in ICEBERG-2 indicates that patients with

higher BP levels, who most probably could not have

been well controlled at primary healthcare settings,

have been referred to the well-equipped reference

centers.

Arterial hypertension is a well-established risk

factor for both coronary artery disease and stroke.

The decision to treat hypertension and prevent

cardiovascular complications has, for many years,

Figure 3. Percentage of ICEBERG-2 treated (A) and ICEBERG-2 untreated (B) patients in ‘‘high and very high added risk’’ groups

according to various tests. SB, serum biochemistry; MA, microalbuminuria; ECG, electrocardiography; hs-CRP, high sensitivity C-reactive

protein.

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been based on the level of BP. However, careful

analysis of major trials emphasizes the need to assess

the global cardiovascular risk for each patient in

order to make appropriate treatment decisions.

Thus, current hypertension guidelines recommend

targeting BP goals according to a risk stratification

encompassing additional cardiovascular risk factors,

target organ damage and concomitant diseases.

In the present study, the subgroups of the study

population were stratified into cardiovascular risk

groups as described by the ESH/ESC Guidelines

Committee (4). As expected, treated patients of both

ICEBERG-1 and ICEBERG-2 groups had lower

risk compared with the corresponding untreated

subgroups when assessed based on both medical

history and routine physical examination only and

on additional test results. However, the treated

ICEBERG-1 and ICEBERG-2 subgroups consisted

of almost a decade younger patients than the treated

ones and this might contribute to the lower risk in

ICEBERG-1A and ICEBERG-2A patients.

LVH, diagnosed by ECG, is a potent marker of

cardiovascular risk (16,17). Although recommended

in all hypertensive subjects, the use of ECG as a tool

for LVH is limited by its poor sensitivity (16). Most

ECG indexes are poorly sensitive, with inability to

correctly identify many subjects with true LVH,

especially when it is mild or moderate (18), whereas

Echo is more sensitive and specific for identifying

LVH than ECG. Indeed, in the present study, the

percentage of patients in ‘‘high and very high added

risk’’ groups according to ECG data shifted from

82.2% to 87.1% by the addition of Echo findings.

Therefore, Echo, by providing a more accurate

assessment of cardiovascular damage related to

hypertension, may lead to a more precise stratifica-

tion of the global cardiovascular risk.

Indeed, WHO/ISH guidelines do suggest that

Echo should be performed when the clinical

examination shows the presence of target organ

damage, or suggests the presence of LVH and/or

other cardiac diseases. In clinical practice, an

echocardiographic study probably should be per-

formed in the presence of (i) grade 3 hypertension,

(ii) albuminuria w25 mg/24 h, (iii) LVH by ECG,

(iv) BMI w27 kg/m2 or (v) when it is necessary to

better identify the global cardiovascular risk in both

low- and high-risk patients or treatment-resistant

patients. In particular, in low-risk patients, the

presence of increased LV mass is an indicator for

the initiation of pharmacological treatment. At this

time, the echocardiographic instrumentation for LV

mass measurements is largely available in most

western countries, and hopefully with reduction of

price its use will be worldwide expanded. However,

unlike Echo, carotid USG evaluation alone did not

seem to change the percentage of patients’ level

(84.7%) compared with ECG alone (82.2%) in

untreated hypertensive ICEBERG patients.

On the other hand, changes in renal function

related with primary hypertension are associated

with an elevated cardiovascular morbidity and

mortality. The diagnosis of renal dysfunction in

patients with different forms of cardiovascular

disease is usually determined by glomerular filtration

rate or creatinine clearance, and/or the detection of

MAU.

MAU has been shown to correlate with the

presence of nephrosclerosis (19). Thus, attention

has recently been drawn to MAU and its relevance

as a predictor of cardiovascular disease. It has been

shown very recently that the presence of MAU in

primary hypertension is associated with an elevated

cardiovascular risk (20–22). It seems that the

presence of albuminuria is a powerful way of

identifying those patients that require an integrated

intervention on multiple cardiovascular risk factors.

Another important point is that a failure to reduce

albumin excretion in urine may indicate an inade-

quacy of the intervention (23). Mann et al. have

described that in subjects with high cardiovascular

risk, MAU predicts the development of proteinuria

in non-diabetic and in diabetic people (24). The

HOPE trial has shown progression in one of three

patients with diabetes and in one to seven without

diabetes (25). In this study, we measured MAU

qualitatively in the ICEBERG-2 treated study and

quantitatively in other study arms and observed that

switching upwards to a higher-risk group was 3.8%

and 0.9% in the ICEBERG-1 treated group and

6.1% and 0.2% in the ICEBERG-2 treated group.

These data reveal that both methods have similar

sensitivity and that qualitative measurement simply

by dipstick is useful in the primary care setting.

There is a body of increasing interest in new

biochemical markers of risk and the most promising

would appear to be the hepatic acute-phase reactant

CRP (26). CRP has been added among risk factors

because of the mounting evidence that it is a

predictor of cardiovascular events at least as strong

as LDL-cholesterol and because of its association

with metabolic syndrome (27,28). An interesting

finding of the study was that increased CRP levels

had an important impact on re-stratification of the

patients. In the ICEBERG-1 treated subprotocol,

the percentage of patients in ‘‘high and very high

added risk’’ groups with standard biochemical tests

(59.2%) shifted to 72.7% with increased CRP. This

increase (13.5%) was similar to those of the

ICEBERG-1 untreated and ICEBERG-2 untreated

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groups (11.0% and 12.1%, respectively). Therefore,

approximately 12% of the patients switched to

higher risk groups with CRP measurement.

Moreover, we observed a significant correlation

between the increased hs-CRP and the SBP level

in non-treated hypertensive patients (pv0.001),

although there was no correlation between increased

CRP and the duration of hypertension (data not

shown). Thus, risk screening of both new onset and

previously diagnosed hypertensive patients should

include hs-CRP testing as an indicator of target

organ damage.

In conclusion, our results suggest that cardiovas-

cular risk evaluation based only on simple routine

work-up, ignoring the information provided by

additional tests (i.e. determination of MAU and

hs-CRP and Echo), may underestimate the level of

absolute risk and that they help to obtain a more

valid assessment of global cardiovascular risk in

hypertensive patients after routine examination.

Furthermore, a simple test to demonstrate the

presence of MAU, which may be used at primary

healthcare level, will also help to evaluate the

patient’s risk profile better than routine assessment

methods alone.

Acknowledgments

This study was presented, in part, at the American

Society of Hypertension’s 20th Annual Scientific

Meeting, San Francisco Marriott, 14–18 May 2005.

This study was sponsored by Sanofi-Aventis,

Turkey.

We would like to acknowledge the collaboration

and commitment of all local investigators and their

staff, without whom present study would not have

been possible.

The ICEBERG 1 trial was performed in cardiology

departments of Akdeniz University, Ankara Numune

Hospital; Ankara University, Ataturk Research and

Education Hospital, Cukurova University, Dokuz

Eylul University, Ege University, Erciyes University,

Gazi University, Hacettepe University, Istanbul

University Cerrahpasa Medical Faculty, Istanbul

University Istanbul Medical Faculty, Kadir Has

University, Kocaeli University, Mersin University,

Ondokuz Mayıs University, Trakya University,

Yuksek Ihtisas Hospital and the nephrology depart-

ment of Hacettepe University.

References

1. Joffres MR, Ghadirian P, Fodor JG, Petrasovits A,

Chockalingam A, Hamet P. Awareness, treatment and control

of hypertension in Canada. Am J Hypertens.

1997;10:1097–1102.

2. Colhoun HM, Dong W, Poulter NR. Blood pressure screen-

ing, management and control in England: Results from the

health survey for England 1994. J Hypertens.

1998;16:747–752.

3. Chamontin B, Poggi L, Lang T, Menard J, Chevalier H,

Gallois H, et al. Prevalence, treatment, and control of

hypertension in the French population: Data from a survey

on high blood pressure in general practice, 1994. Am J

Hypertens. 1998;11:759–762.

4. European Society of Hypertension–European Society of

Cardiology Guidelines Committee. 2003 European Society

of Hypertension-European Society of Cardiology guidelines

for the management of arterial hypertension. J Hypertens.

2003;21:1011–1053.

5. Anderson KM, Wilson PW, Odell PM, Kannel WB. An

updated coronary risk profile. A statement of health profes-

sionals. Circulation. 1991;83:356–362.

6. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A,

De Backer G, et al. Estimation of ten-year risk of fatal

cardiovascular disease in Europe: The SCORE project. Eur

Heart J. 2003;24:987–1003.

7. Leoncini G, Ravera M, Parodi D, Ratto E, Vettoretti S,

Tomolillo C, et al. Microalbuminuria identifies overall

cardiovascular risk in essential hypertension: An artificial

neural network-based approach. J Hypertens. 2002;20:

1315–1321.

8. Pedrinelli R, Dell’Omo G, Penno G, Di Bello V, Giorgi D,

Pellegrini G, et al. Microalbuminuria, a parameter indepen-

dent of metabolic influences in hypertensive men. J

Hypertens. 2003;21:1163–1169.

9. Stuveling EM, Bakker SJ, Hillege HL, Burgerhof JG,

de Jong PE, Gans RO, et al. C-reactive protein modifies the

relationship between blood pressure and microalbuminuria.

Hypertension. 2004;43:791–796.

10. Bots ML, Dijk JM, Oren A, Grobbee DE. Carotid intima-

media thickness, arterial stiffness and risk of cardiovascular

disease: Current evidence. J Hypertens. 2002;20:2317–2325.

11. Yikona J, Wallis EJ, Ramsay LE, Jackson PR. Coronary and

cardiovascular risk estimation in uncomplicated mild hyper-

tension. A comparison of risk assessment methods.

J Hypertens. 2002;20:2173–2182.

12. Schillaci G, Simone G, Reboldi G, Porcellati C, Devereux RB,

Verdecchia P. Change in cardiovascular risk profile by

echocardiography in low- or medium-risk hypertension.

J Hypertens. 2002;20:1519–1525.

13. Cuspidi C, Ambrosioni E, Mancia G, Pessina AC,

Trimarco B, Zanchetti A, on behalf of the APROS

Investigators. Role of echocardiography and carotid ultra-

sonography in stratifying risk in patients with essential

hypertension: The Assessment of Prognostic Risk

Observational Survey. J Hypertens. 2002;20:1307–1314.

14. Expert Panel on Detection, Evaluation, and Treatment of

High Blood Cholesterol in Adults. Executive Summary of

Third Report of the National Cholesterol Education Program

(NCEP) Expert Panel on Detection, Evaluation, and

Treatment of High Blood Cholesterol in Adults (Adult

Treatment Panel III). JAMA. 2001;285:2486–2497.

15. O’Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G,

et al., European Society of Hypertension Working Group on

Blood Pressure Monitoring. European Society of

Hypertension recommendations for conventional, ambulatory

and home blood pressure measurement. J Hypertens.

2003;21:821–848.

300 K. Buyukozturk et al.

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mem

oria

l Uni

vers

ity o

f N

ewfo

undl

and

on 0

7/18

/14

For

pers

onal

use

onl

y.

16. Kannel WB, Gordon T, Offutt D. Left ventricular hyper-

trophy by electrocardiogram: Prevalence, incidence and

mortality in the Framingham Study. Ann Intern Med.

1969;71:89–105.

17. Sokolow M, Perloff D. The prognosis of essential hyperten-

sion treated conservatively. Circulation. 1961;23:697.

18. Martinez MA, Sancho T, Armada E, Rubio JM, Anton JL,

Torre A, et al., Vascular Risk Working Group Grupo

Monitorizacion Ambulatoria de la Presion Arterial

(MAPA)–Madrid. Prevalence of left ventricular hypertrophy

in patients with mild hypertension in primary care: Impact of

echocardiography on cardiovascular risk stratification. AJH.

2003;16:556–563.

19. Mimran A, Ribstein J, DuCailar G. Is microalbuminuria a

marker of early intrarenal vascular dysfunction in essential

hypertension? Hypertension. 1994;23:1018–1021.

20. Rosa TT, Palatini P. Clinical value of microalbuminuria in

hypertension. J Hypertens. 2000;18:645–654.

21. Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I,

Wedel H, Zanchetti A. Renal function and intensive lowering

of blood pressure in hypertensive participants of the

Hypertension Optimal Treatment (HOT) study. J Am Soc

Nephrol. 2001;12:218–225.

22. De Leeuw PW, Thijs L, Birkenhager WH, Voyaki SM,

Efstratopoulos AD, Fagard RH, et al., Systolic Hypertension

in Europe (Syst-Eur) Trial Investigators. Prognostic signifi-

cance of renal function in elderly patients with isolated

systolic hypertension: Results from the Syst-Eur trial. J Am

Soc Nephrol. 2002;13:2213–2222.

23. Redon J, Williams B. Microalbuminuria in essential hyper-

tension: Redefining the threshold. J Hypertens.

2002;20:353–355.

24. Mann JF, Gerstein HC, Yi QL, Lonn EM, Hoogwerf BJ,

Rashkow A, et al. Development of renal disease in people at

high cardiovascular risk: Results of the HOPE randomized

study. J Am Soc Nephrol. 2003;14:641–647.

25. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF,

Hoogwerf B, et al., HOPE Study Investigators. Albuminuria

and risk of cardiovascular events, death, and heart failure in

diabetic and nondiabetic individuals. JAMA. 2001;286:

421–426.

26. Ridker PM. Role of inflammatory biomarkers in prediction of

coronary heart disease. Lancet. 2001;358:946–948.

27. Ridker PM. Clinical application of C-reactive protein for

cardiovascular disease detection and prevention. Circulation.

2003;107:363–359.

28. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein,

the metabolic syndrome and risk of incident cardiovascular

events: An 8-year follow-up of 14719 initially healthy

American women. Circulation. 2003;107:391–397.

Evaluating risk groups in hypertension 301

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mem

oria

l Uni

vers

ity o

f N

ewfo

undl

and

on 0

7/18

/14

For

pers

onal

use

onl

y.