High Blood Press Cardiovasc Prev 2008; 15 (4): 217-224REVIEW ARTICLE 1120-9879/08/0004-0217/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Overview of the i-SEARCH Global StudyCardiovascular Risk Factors and Microalbuminuria inHypertensive Individuals

Michael Bohm,1 Martin Thoenes,2 Nicolas Danchin,3 Jan C. Reil1 and Massimo Volpe4

1 Cardiology, Angiology and Intensive Care Medicine, University of the Saarland, Homburg, Saar, Germany2 Sanofi-Aventis, Global Medical Affairs, Paris, France3 Department of Cardiology, Hospital Europeen Georges Pompidou, Paris, France4 Division of Cardiology, II Faculty of Medicine, University of Roma “La Sapienza”, Sant’Andrea Hospital, Rome, Italy

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2171. Study Methodology and Population in i-SEARCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2182. General Characteristics of the Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2193. The Prevalence of Microalbuminuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

3.1 The Overall Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2193.2 Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2193.3 Heart Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2193.4 Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

4. Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2224.1 Microalbuminuria and Cardiovascular Risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2224.2 The i-SEARCH Trial Programme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Microalbuminuria (MAU) is a highly predictive, sensitive, inexpensive and easily repeatable marker ofAbstractcardiovascular risk and all-cause mortality in hypertensive patients. The international, observational, practice-based study i-SEARCH (Survey for Evaluating Microalbuminuria Routinely by Cardiologists in patients withHypertension) was designed to assess the frequency with which MAU occurred in a large outpatient populationwho were currently treated or newly diagnosed with hypertension and were under professional care. The primaryaim of the study was to define the prevalence of MAU in hypertensive outpatients attending a cardiologist orinternist (i-SEARCH A) and to compare hypertensive outpatients with or without coronary artery disease (i-SEARCH B). A secondary objective was to establish a correlation between MAU and known cardiovascular riskfactors. A total of 21 050 patients from 26 countries were included in the primary analysis. Overall, this studydemonstrated a very high worldwide prevalence (58.4%) of MAU in high-risk cardiovascular patients, but with aconsiderable variation across countries. MAU was more prevalent in patients with coronary artery disease than inthose without. It was also significantly related to the presence of specific predictors, including male gender,abnormally high waist circumference, increased blood pressure levels (systolic ≥120 mmHg, diastolic ≥100mmHg), creatinine clearance ≥50 mL/min, or clinical conditions such as diabetes mellitus, congestive heartfailure, history of cerebral pathology, and peripheral arterial disease. Since the presence of MAU reflects long-term detrimental effects on the cardiovascular system, these results indicate the high, and in many cases hidden,burden of cardiovascular diseases among the hypertensive patients seen by cardiologists. This article discussesthe main results of the study and the potential implications of ongoing analyses included in the core clinical studyprogramme.

218 Bohm et al.

Received for publication 24 October 2008; accepted for publication 20 November 2008.

Key words: microalbuminuria, hypertension, coronary artery disease, cardiovascular risk, cardiovascularmortality.

Although the importance of microalbuminuria (MAU) as a lysis of data from the LIFE study (Losartan Intervention Formarker of cardiovascular risk and all-cause mortality in the hyper- Endpoint reduction in hypertension) showed that a reduction intensive population is now well established,[1,2] less is known about MAU was associated with a significantly reduced risk of non-fatalits true prevalence in high cardiovascular risk patients.[3] myocardial infarction (MI), stroke and cardiovascular death.[31,33]

Epidemiological and clinical data clearly illustrate the impor- This article discusses the main results of the i-SEARCH (Sur-tance of MAU as a strong predictive factor for future cardio- vey Evaluating Microalbuminuria Routinely by Cardiologists invascular risk, not only in the general population, but mostly in patients with Hypertension) study.[34]

patients with essential hypertension and additional risk factors orconcomitant diabetes mellitus or coronary artery disease

1. Study Methodology and Population in i-SEARCH(CAD).[4-7] In particular, in hypertensive patients, MAU has beenidentified as a strong, independent predictor of risk of major

The global i-SEARCH was an international, observationalcardiovascular events, mostly myocardial infarction, stroke andstudy performed from September 2005 to March 2006 in a total ofcardiovascular death.[8-11] The relationship between MAU and the1750 sites in 26 countries worldwide, in a population of 21 050development of cardiovascular diseases is also strengthened by itspatients followed by professional physicians in a cardiology orpresence in obesity, diabetes, CAD, diastolic dysfunction, conges-internal medicine practice setting.[34] The methodology of thetive heart failure, acute stroke, peripheral arterial disease (PAD),study has been previously described.[34] The primary objective wascarotid atherosclerosis and arterial hypertension.[8-11]

to define the prevalence of MAU in hypertensive outpatientsOn the basis of these considerations, the detection of MAU mayattending a cardiology or internal medicine outpatient setting (i-be considered as a useful diagnostic tool in the clinical manage-SEARCH A) and to compare its prevalence in hypertensive outpa-ment of high cardiovascular risk patients, and not simply as atients with or without CAD (i-SEARCH B).[34] Secondary objec-marker of impaired renal function.[12,13] Screening for MAU is, intives were to establish a correlation between the prevalence offact, currently recommended by international guidelines for hyper-MAU and known cardiovascular risk factors in the study popula-tension diagnosis and treatment.[14]

tion, and to increase physicians’ awareness of the importance ofThe presence of MAU, however, is often under-diagnosed orMAU screening to identify patients ‘at high cardiovascularunder-managed in the general adult population.[15-24] In a studyrisk’.[34]

conducted in hypertension centres in Italy, detection of MAU wasSample size estimation, defined at the country level, was basedonly attempted in 2% of the patients.[15] An e-mail survey reported

on the 95% confidence interval of the prevalence of MAU. Preva-that <5% of professional cardiologists routinely prescribe detec-lence was estimated to be approximately 25% in this patienttion of MAU in their outpatient clinical practice in Italy, and aboutpopulation, although with a wide range of values, between7% consider it when prescribing antihypertensive drugs. More-10–50%.[15-24] A reasonable precision for estimation of MAUover, surprisingly little is known about the true prevalence ofprevalence appeared to be 3–4%; therefore, to assess the trueMAU within the hypertensive patient population, and highly vari-prevalence rate of MAU at 25% with a precision of ±4%, aable prevalence rates from as low as 4% to as high as 46% haveminimum of 450 patients were needed per country.[34]been reported in a large series of independent studies, mostly due

to the heterogeneity of populations and methods applied in these According to the inclusion criteria,[34] eligible patients wereclinical studies.[15-24] male and female outpatients, aged ≥18 years, with currently treat-

At the same time, the lack of information on MAU prevalence ed or newly diagnosed arterial hypertension, defined according tois disappointing and even surprising, especially when considering current guidelines.[14] Patients with potential confounding factorsthat evidence is available demonstrating that a reduction in urinary with regard to MAU determination, including acute fever (bodyalbumin excretion rate translates into a reduction in cardiovascular temperature >38°C), renal disease (serum creatinine >20 mg/L),events in hypertensive patients,[25-31] particularly when they are concomitant urinary tract infection, pharmacological treatmenttreated with antihypertensive agents that may counteract the renin- (cimetidine), or having undertaken strenuous physical activity inangiotensin system (RAS).[32] For example, a retrospective ana- the preceding 24 hours, as well as female participants who were

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Overview of the i-SEARCH Global Study 219

either pregnant or menstruating, were ineligible due to the likely of patients. Among hypertensive patients with concomitant diabe-presence of false-positive results.[34] tes, 71.7% of patients were receiving oral hypoglycaemic drugs

and/or insulin.At each site, consecutive patients fulfilling the eligibility crite-ria were invited to participate in the study. Once enrolled, the

3. The Prevalence of Microalbuminuriafollowing measurements were carried out on each patient during asingle clinic visit: heart rate, urine albumin and creatinine concen-tration, and waist and hip circumference.[34] To ensure consistency 3.1 The Overall Populationbetween study sites, all centres performed dipstick screening for

Within the primary analysis population, relatively few patientsMAU with sponsor-provided reagent strips (Microalbustix®),1had impaired renal function.[34] Only 6.7% had previously knownwhich have a sensitivity of 82.6% and followed a standardizedMAU; however, urinalysis with a one-time dipstick test revealedsample collection and testing procedure.[34] Possible urine albuminthat 58.4% of the total study population had evidence of MAU,levels were 10, 30, 80 or 150 mg/L.[34] Results from these assess-with prevalence rates higher in men (61.6%) than in womenments were entered on each patient’s case report form (CRF),(54.9%).[34] Consistently, high MAU prevalence was seen acrosstogether with demographic data, cardiovascular history, cardio-the 26 countries from which the study population was drawn.vascular risk factors, co-morbidities, symptoms and signs ofPrevalence ranged from 53% to 71%, with some of the highestcardiovascular disease, and current chronic drug therapy. Whenrates seen in Middle Eastern and Asian countries (figure 1).[34]

available (<12 months previously), levels of cholesterol, triglycer-Using a logistic regression model with a stepwise selectionide, high-density lipoprotein, low-density lipoprotein, C-reactive

method, some specific factors were found to be significantlyprotein and serum creatinine were also reported in CRFs. Theassociated with the presence of MAU: male gender, high waistSokolow index, used to assess the presence of left ventricularcircumference, sitting systolic blood pressure (SBP) and diastolichypertrophy, calculated from the last available electrocardiogram,blood pressure (DBP) levels (SBP ≥120 mmHg, DBP ≥100and left ventricular function (ejection fraction) were also bothmmHg), creatinine clearance ≥50 mL/min, and the presence ofincluded on each patient’s CRF.diabetes, congestive heart failure, CAD, history of cerebral patho-logy, PAD, dyspnoea and palpitations.[34] The prescription of2. General Characteristics of the Study Populationcardiovascular and antidiabetic drug therapy was also associated

General characteristics of the study population are listed in with the presence (or absence) of MAU. The logistic regressiontable I.[34] Overall, the gender distribution was broadly equal in model also revealed that the use of calcium-channel blockers, β-this predominantly elderly population. Almost two-thirds of the blockers, biguanides, sulfonylureas, insulin and anticoagulantspatients (60.7%) had an abnormally high waist circumference, and other than warfarin/coumadin were associated with an increasedover one-third (34.6%) had overweight or obesity (as defined by a risk for MAU.[34] Neither the use of ACE inhibitors nor ARBs wasbody mass index of ≥30 kg/m2). The majority of the study patients significantly associated with MAU in the multivariate model.[34]

(76.8%) had uncontrolled hypertension, 46.3% dyslipidaemia and27.5% concomitant diabetes. Over one-third of the patients 3.2 Coronary Artery Disease(35.7%) had evidence of cardiovascular-related co-morbidities,

In the overall analysis, a close relationship was seen betweenwith 22.9% of patients having documented CAD. Almost allincreasing urinary albumin excretion rate (UAER) and prevalencepatients (91.6%) had one or more risk factor for cardiovascularof CAD. As shown in figure 2, when comparing patients with anddiseases other than hypertension, which included a history of MIwithout CAD, a progressive shift towards higher MAU values inor CAD, diabetes, dyslipidaemia, a lack of physical exercise or aCAD patients with higher UAER was found compared with thosehistory of smoking.observed in patients with lower UAER.In the primary analysis population,[34] almost all patients

(91.1%) were prescribed cardiovascular drugs, while 56.2% were3.3 Heart Rate

also on a special diet for cardiovascular risk reduction. In particu-lar, antihypertensive drugs were the most widely prescribed drugs, Heart rate, as well as SBP and DBP levels, has been reported towhich in over one-third of the patients included treatment with have an impact on MAU in hypertensive patients with a highangiotensin II type 1 receptor antagonists (angiotensin receptor cardiovascular risk.[35,36] The occurrence of MAU might be relatedblockers [ARBs]) or ACE inhibitors. Statins were taken by 38.1% to an increased intraglomerular pressure in the presence of system-

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220 Bohm et al.

Table I. Demographics and cardiovascular history at study entry (primary analysis population) [reproduced from Bohm et al.,[34] with permission]

Category Parameter Patients

Demographics Male/female (%) 52.3/47.7

Mean age ± SD (y) 62.4 ± 11.7

Mean BMI ± SD (kg/m2) 28.9 ± 5.7

Mean waist circumference ± SD (cm) 99.4 ± 14.4

Mean waist/hip ratio ± SD 0.95 ± 0.12

Hypertension Mean duration ± SD (y) 8.1 ± 7.7

Mean SBP ± SD (mmHg) 149.242 ± 20.2

Mean DBP ± SD (mmHg) 87.4 ± 11.8

% Uncontrolled (≥140/90 mmHg) 76.8

Heart rate/sinus rhythm Mean heart rate ± SD (bpm) 74 ± 12

In sinus rhythm (%) 94.8

Behavioural risk factors for CVD Family history of MI/CAD (%) 27.8

Lack of regular physical exercise (%) 35.0

Current/former smoker (%) 14.2/20.5

Additional risk factors Mean total cholesterol ± SD (mmol/L) 5.3 ± 1.1

Mean HDL ± SD (mmol/L) 1.3 ± 0.5

Mean LDL ± SD (mmol/L) 3.2 ± 1.0

Mean triglycerides ± SD (mg/dL) 1.8 ± 1.0

Mean CRP ± SD (mg/dL) 0.93 ± 0.96

Current diabetes mellitus (%) 27.5

Type 1/type 2 diabetes (%) 4.9/95.1

Mean duration of diabetes ± SD (y) 7.9 ± 7.7

Mean serum creatinine ± SD (μmol/L) [n = 15 511] 89.9 ± 23.8

Mean creatinine clearance ± SD (mL/min) [n = 15 140] 87.9 ± 34.1

<30 mL/min (%) 0.6

30–60 mL/min (%) 19.3

60–80 mL/min (%) 26.5

80–120 mL/min (%) 38.8

>120 mL/min (%) 14.8

CAD (%) 22.9

Co-morbidities Congestive heart failure (%) 5.8

Atrial fibrillation (%) 8.3

History of ischaemic strokes (%) 4.8

History of TIA (%) 3.8

PAD (%) 4.2

Carotid endarterectomy (%) 19.7

Other CVD LVH (Solokow mm ± SD) [n = 8311] 24.8 ± 9.8

Ejection fraction ≤40% (%) 4.7

Cartoid stenosis (%) 2.9

Aortic aneurysm 1.4

BMI = body mass index; bpm = beats per minute; CAD = coronary artery disease; CRP = C-reactive protein; CVD = cardiovascular disease; DBP =diastolic blood pressure; HDL = high-density lipoprotein; LDL = low-density lipoprotein; LVH = left ventricular hypertrophy; MI = myocardial infarction; PAD= peripheral arterial disease; SBP = systolic blood pressure; TIA = transient ischaemic attack.

© 2008 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2008; 15 (4)