Section of Nephrology, Department of Internal Medicine, University of Genoa, Genoa, Italy
Address correspondence to: Dr. Roberto Pontremoli, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6-16132 Genoa, Italy. Phone and Fax: +39-010-353-8932; E-mail roberto.pontremoli{at}unige.it
Accurate assessment of cardiovascular risk is a key step towardoptimizing the treatment of hypertensive patients. We analyzedthe impact and cost-effectiveness of routine, thorough assessmentof target organ damage (TOD) in evaluating risk profile in hypertension.A total of 380 never-treated patients with essential hypertensionunderwent routine work-up plus evaluation of albuminuria andultrasonography of cardiac and vascular structures. The impactof these tests on risk stratification, as indicated by EuropeanSociety of Hypertension-European Society of Cardiology guidelines,was assessed in light of their cost and sensitivity. The combineduse of all of these tests greatly improved the detection ofTOD, therefore leading to the identification of a higher percentageof patients who were at high/very high risk, as compared withthose who were detected by routine clinical work-up (73% insteadof 42%; P < 0.0001). Different signs of TOD only partly clusterwithin the same subgroup of patients; thus, all three testsshould be performed to maximize the sensitivity of the evaluationprocess. The diagnostic algorithm yielding the lowest cost perdetected case of TOD is the search for microalbuminuria, followedby echocardiography and then carotid ultrasonography. Adoptinglower cut-off values to define microalbuminuria allows us tooptimize further the cost-effectiveness of diagnostic algorithms.In conclusion, because of its low cost and widespread availability,measuring albuminuria is an attractive and cost-effective screeningtest that is especially suitable as the first step in the large-scalediagnostic work-up of hypertensive patients.
Accurate and sensitive stratification of cardiovascular riskhas an important practical impact on devising treatment strategies.In fact, the presence of a high or very high risk profile mandatesimmediate initiation of antihypertensive drug treatment andmay be an indication for more aggressive intervention on associatedrisk factors and comorbidities (1,2). Furthermore, it has beenproved that identifying and targeting the subset of patientswho are at highest risk improves the cost-effectiveness of antihypertensivetreatment, for any degree of BP reduction (3).
European Society of Hypertension-European Society of Cardiology(ESH-ESC) guidelines indicate several approaches for the evaluationof global cardiovascular risk, depending on resource availabilityand local know-how (1). However, the minimum work-up recommendedby the guidelines is a highly insensitive approach for detectingpatients with organ damage (4). In fact, it has been shown thatthe more extensive the diagnostic work-up, the higher the percentageof correctly identified patients at risk (5). Microalbuminuriahas recently been included among the signs of target organ damage(TOD) in patients with essential hypertension, even in the absenceof diabetes (1,6). Unfortunately, this test is not yet performedroutinely in clinical practice, and its usefulness has recentlybeen challenged (7), even though a growing body of evidencepoints to an association between this abnormality and a higherincidence of cardiovascular events (8).
Influence of Thorough Evaluation of TOD on Global Risk Profile
To assess the relative role of microalbuminuria and cardiacand vascular ultrasonography in the process of risk stratification,we compared the sensitivity and cost of these three diagnostictechniques, both alone and in various combinations, in the searchfor TOD in a group of 380 untreated, nondiabetic patients withessential hypertension. None of the patients had experiencedprevious cardiovascular and/or cerebrovascular events or presentedgrades III or IV hypertensive retinopathy at funduscopy.
According to the 2003 ESH-ESC guidelines classification (1),80 patients had grade 1 hypertension (21%), 194 had grade 2(51%), and 106 had grade 3 (28%) hypertension. With regard toother risk factors, 44% of the patients had dyslipidemia, and28% were smokers. Sixty-one (16%) patients had electrocardiographicsigns of left ventricular hypertrophy (LVH). The prevalenceof microalbuminuria, carotid thickening or plaque, and LVH atechocardiogram was 13, 32, and 49%, respectively. Overall, 232(61%) patients showed early signs of TOD (microalbuminuria,carotid abnormalities, echo-LVH). As a result of the routineclinical work-up, 19 (5%) of the 380 patients were classifiedat low risk, 201 (53%) at medium, 91 (24%) at high, and theremaining 69 (18%) at very high risk. Performing one additionaldiagnostic test for TOD led to a substantial reclassificationof risk for many patients. In fact, by measuring albuminuria,left ventricular mass index, and carotid thickness, we wereable to shift 7, 17, and 22% of the patients, respectively,from low/medium to high/very high risk strata. The combineduse of all of these tests led to the detection of a significantlyhigher percentage of patients at high/very high risk (as comparedwith the routine clinical screening; 73% instead of 42%; 2 =73.6, P < 0.0001).
Our data further support the role of increased urinary albuminexcretion as an integrated marker of TOD. In fact, the subgroupof patients with microalbuminuria was much more likely to showeither one or both of the other signs of TOD (odds ratio [OR],20; P < 0.0001) as compared with patients with LVH (OR, 3;P < 0.0001) or carotid abnormalities (OR, 3; P < 0.0001).Further improvement in the cost-effectiveness of measuring albuminuriato evaluate cardiovascular risk could be obtained by adoptinga cut-off value for albumin to creatinine ratio (ACR) that islower than what is indicated by the ESH-ESC guidelines (9,10).As a matter of fact, it was shown recently that the relationshipbetween urinary albumin excretion and cardiovascular risk holdstrue well below the threshold of 2.5 mg/mmol in women and 3.5mg/mmol in men. Thus, by using a value of 1.8 mg/mmol of ACR(corresponding to the upper quintile of our study population),we were able to identify a significantly greater percentageof patients with TOD (n = 77 [20%] instead of n = 49 [13%]).A similar approach increased the sensitivity of albuminuriato 30% in detecting patients with either one or both the othersigns of TOD (P < 0.0001, 2 = 30.27). In fact, patients inthe upper quintile of albuminuria had a six times greater riskfor showing echo-LVH and/or carotid abnormalities (OR, 6.7;95% confidence interval, 3.20 to 13.84).
Because the various signs of TOD cluster only in part withinthe same subgroup of patients, all three tests should be performedto maximize the sensitivity of the evaluation process. Takinginto account a cost of 100 per echocardiogram (11) or carotidultrasound examination and a cost of 10 per albuminuria evaluation(mean of two determinations on different days), we calculatedthe cost of screening for the presence of TOD (cost = numberof patients x price per examination) by various approaches (Figure 1).The actual cost per detected case of TOD is the ratio betweenthe cost of screening and the number of TOD cases that wereidentified. We chose the more rational approach of carryingout in-depth evaluation for TOD only in the subgroup of patientswho were found to be at low to medium risk after minimum traditionalwork-up. Therefore, a considerably lower number of patientsneeded to be screened, resulting in a significant decrease intotal cost (40%). Along these lines, the most cost-effectivediagnostic algorithm is the search for microalbuminuria, followedby echocardiography, and then carotid ultrasound. Moreover,by adopting a lower cut-off value (1.8 mg/mmol) for ACR, wewere able to reduce the cost per detected case by approximately30% for albuminuria (from 84 to 59). Overall, this approachallowed for savings between 13 and 41 (i.e., 5 and 16% of thetotal cost of screening) for each patient we detected with TOD(Figure 1).
Figure 1. Algorithm to optimize cost-effectiveness in the diagnosis of target organ damage (TOD). Mi+, patients with albuminuria >1.8 mm/mmol; LVH, patients with left ventricular hypertrophy (LVMI 25 g/m2 in men and 110 g/m2); IMT+, patients with intima-media thickness 10.90 mm, or plaque. The actual cost per detected case of TOD (n = 127) is expressed for each algorithm. Estimated total cost of various strategies takes into account the price of all tests performed in each sequence of tests (A1: 221 albumin tests, 184 echocardiograms, 125 carotid ultrasound (US) scans; A2: 221 albumin tests, 184 carotid US scans, 142 echocardiograms; B1: 221 echocardiograms, 137 albumin tests, 125 carotid US scans; B2: 221 echocardiograms, 137 carotid US scans, 101 albumin tests; C1: 221 carotid US scans, 153 albumin tests, 141 echocardiograms; C2: 221 carotid US scans, 153 echocardiograms, 101 albumin tests.
In conclusion, routine evaluation of risk profile can lead tounderestimating the presence of TOD and, therefore, to misclassificationof a substantial number of patients. Ultrasonographic evaluationof cardiac and vascular structures is a sensitive tool for detectinghigh-risk patients and may have a significant impact on riskprofile. Thanks to its low cost and widespread availability,measuring albuminuria is an attractive and cost-effective screeningtest that is especially suitable as the first step in the large-scalediagnostic work-up of hypertensive patients. In the near future,the increasing prevalence of hypertension likely will not beparalleled by the availability of financial resources for primaryprevention in the cardiovascular and renal field (12), and ourfindings therefore could have useful, practical implicationsfor developing diagnostic-therapeutic strategies at the communitylevel.
Acknowledgments
This work was partly supported by grants from Ministero Universitàe Ricerca Scientifica (FIRB2001) and from the Ministero dellaSalute (ex art.12 D.Lgs 502/92-Esercizio 2003) of Italy.
We thank Drs. Massimo Del Sette and Gian Paolo Bezante for performingcardiovascular ultrasound scans.
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Abstract
Introduction
2 = 73.6, P < 0.0001). 
100 per echocardiogram (11) or carotid ultrasound examination and a cost of 
25 g/m2 in men and