Cardiovascular and Renal Risk Assessment as a Guide for Treatment in Primary Hypertension
Roberto Pontremoli,
Giovanna Leoncini,
Francesca Viazzi,
Denise Parodi,
Elena Ratto,
Simone Vettoretti,
Maura Ravera,
Cinzia Tomolillo and
Giacomo Deferrari
Department of Internal Medicine, University of Genoa, Genoa, Italy
Correspondence to Dr. Roberto Pontremoli, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6-16132 Genoa, Italy. Phone: +39-010-353-8932; Fax: +39-02-700-509-259; E-mail rpontrem{at}medicina.unige.it
ABSTRACT. BP levels per se may be an unreliable indicator ofrisk in the individual patient. In fact, the global cardiovascularprofile, including the presence and degree of target organ damage,is a better predictor of future events and, therefore, shouldbe used to choose both treatment and BP goals. However, theprevalence of target organ damage and therefore the percentageof patients who are at risk very much depends on the diagnostictechniques used. However, as a result of the high prevalenceof hypertension and its financial impact on public health systems,limiting unnecessary and extensive diagnostic tests also shouldbe a priority. The routine search for microalbuminuria may leadto the detection of a significantly greater percentage of patientswho are at high risk while contributing the optimization ofthe cost-effectiveness of diagnostic workup in hypertensivepatients.
Hypertension is the most important modifiable risk factor forcardiovascular disease, and its prevention and treatment currentlyrepresent a public health challenge in Western countries (1).Among the large number of hypertensive patients, however, onlya subgroup actually develops acute morbid complications. Earlyidentification of those who are at risk is of paramount importancebecause it could set the stage for a more rational therapeuticapproach by allowing direct additional measures to those whoneed them the most. Unfortunately, the height of BP per se isoften an unreliable indicator of risk in the individual patient.In fact, it has recently been suggested that global cardiovascularrisk, rather than the severity of hypertension, should be usedto guide the decision of whether to begin treatment and itsgoals (2,3). Accordingly, several factors, such as age, gender,family history, obesity, smoking habits, lipid status, and thepresence of diabetes or other comorbid conditions, should betaken into consideration together with BP load to individualizetreatment. In particular, the presence and degree of subclinicaltarget organ damage, namely left ventricular hypertrophy, carotidatherosclerosis, and renal dysfunction, may turn out to be extremelyuseful in guiding the choice of first drug as well as the goalBP level.
Such therapeutic strategy has proved to be beneficial in termsof cost-effectiveness. Data from the National Health and NutritionExamination Survey, for example, indicate that, with a similar12-mmHg reduction in systolic BP, a significantly lower numberof patients had to be treated to prevent a single fatal eventduring a 10-yr follow-up in the subgroup of patients at highrisk as compared with those at low risk (4). Thus, the higherthe risk, the greater the benefit achieved from a given amountof BP reduction. It is interesting that the relationship betweenglobal risk and BP reduction holds true also in the range ofnormal and high-normal BP values. These considerations providethe rationale for performing a thorough evaluation of risk profile,including subclinical organ damage, before starting treatmentin all hypertensive patients. However, the sensitivity of riskassessment in detecting high-risk patients very much dependson the diagnostic approach used in the clinical setting (5).
Prognostic and Therapeutic Implications of Target Organ Damage
Identifying target organ damage may vary significantly, dependingon the techniques used. Noninvasive assessment of cardiac andperipheral arterial structures and function by ultrasound (US)techniques is a reliable and accurate way to detect hypertensiveorgan damage. Routine application of this procedure, however,is not currently recommended by international guidelines, andit is performed only on a small number of hypertensive patients.An overly restrictive diagnostic approach to risk stratificationcould lead to significant misclassification of patients andto underestimation of the actual absolute risk, with unfavorablepractical and financial consequences.
Subclinical organ damage often precedes and predicts the developmentof morbid events. Thus, patients with left ventricular hypertrophy,especially the concentric type, show a higher risk of developinga coronary event or a stroke as compared with those with normalleft ventricular geometry (6). Similarly, carotid atherosclerosishas been associated with a worse prognosis regardless of othertraditional risk factors (7). What is even more important isthat under effective antihypertensive treatment, changes insubclinical organ damage over time are paralleled by modificationof risk status (8). Thus, by noninvasively detecting the presenceof left ventricular hypertrophy and/or carotid atherosclerosis,not only can we gather important information to help individualizetreatment but also we are able to monitor the effectivenessof treatment. Furthermore, in the presence of renal damage (renaldysfunction or proteinuria), lower BP goals (<130/80 mmHg)are recommended.
Although achieving BP targets remains the most important determinantof cardiovascular and renal protection, it has also been shownthat specific classes of drugs may exert additional organ protectionbeyond their BP-lowering effects (2,3). A recent meta-analysisof 50 randomized, controlled trials demonstrated that angiotensin-convertingenzyme inhibitors (ACEI) provide greater reduction of left ventricularmass as compared with other classes of drugs (9). More recently,results from the Losartan Intervention For Endpoint Reductionin Hypertension Study seem to add to the importance of renin-angiotensinsystem inhibition for cardiac protection. In fact, this studyshowed a significantly greater reduction of ECG-determined leftventricular hypertrophy by the use of the angiotensin receptorblocker (ARB) losartan as compared with the -blocker atenolol,with an almost identical BP reduction in the two arms of thestudy (10). However, the trials completed so far, comparingthe effect of various antihypertensive treatment on the regressionof carotid atherosclerosis, suggest the superiority of calciumchannel blockers over diuretics and -blockers at similar BPreductions (11–14).
Finally, there is undisputed evidence that pharmacologic disruptionof the renin-angiotensin system conveys superior renal protectionin the hypertensive patient with renal disease and proteinuria(15). Thus, ACEI are recommended in nondiabetic patients andin those with type 1 diabetes and any degree of albuminuria,whereas ARB are considered the treatment of choice in patientswith type 2 diabetes for preventing clinical nephropathy anddelaying its progression to ESRD (16–18). In addition,recent preliminary data indicate that a more complete inhibitionof the renin-angiotensin system obtained by the concomitantuse of an ACEI and an ARB is superior to either drug alone inretarding the progression of diabetic (19) and nondiabetic renaldiseases with proteinuria (20).
Usefulness of Microalbuminuria in the Treatment of Hypertensive Patients
During the past several years, an abnormal urinary albumin excretionlevel, below the threshold commonly used to define clinicalproteinuria (i.e., microalbuminuria), has been proposed as anintegrated marker of risk in patients with essential hypertension.A large number of studies have reported an association betweenmicroalbuminuria and several metabolic and nonmetabolic riskfactors (increased BP load and variability, insulin resistance,lipid abnormalities, and endothelial dysfunction) (21), as wellas with the presence of end organ damage, namely left ventricularhypertrophy and carotid atherosclerosis (22). Although the presenceof microalbuminuria seems to be a concomitant indicator of highrisk status rather than a risk factor per se, it has been shownto be a predictor of cardiovascular morbidity and mortalityin patients with essential hypertension in the presence or absenceof diabetes (23).
New evidence from the Losartan Intervention For Endpoint Reductionin Hypertension Study indicates that changes in urinary albuminexcretion under antihypertensive treatment parallel those ofECG-determined left ventricular mass (24). Thus, given its wideavailability and relatively low cost, determination of albuminuriacould become a useful tool in the evaluation of global cardiovascularrisk. We compared the sensitivity and costs of three differentapproaches to cardiovascular risk stratification in a groupof 346 untreated patients with essential hypertension. The percentageof patients at high or very high risk (according to EuropeanSociety of Hypertension–World Health Organization classification)as obtained by the standard approach alone, in combination withroutine US-based assessment of cardiovascular organ damage,and, last, in combination with the evaluation of urinary albuminexcretion varies significantly. Routine search for microalbuminurialeads to the detection of a significantly higher percentageof patients with organ damage and yields a stratification ofrisk almost superimposable to what is obtained by the routineuse of US, although at a significantly lower cost. On the basisof these findings, we extrapolated the cost of the three differentscreening approaches for the general population by calculatingan estimated 20% prevalence of hypertension (Figure 1). We concludedthat the routine evaluation of microalbuminuria could lead toa substantial improvement in the identification of high-riskpatients while optimizing the cost-effectiveness of cardiovascularrisk stratification.
Figure 1. Cost-effectiveness of measuring microalbuminuria in the evaluation of cardiovascular risk in primary hypertension. The sensitivity and costs of three different approaches to cardiovascular risk stratification are compared (see text for details). Calculation of costs are made on the basis of an estimated 20% prevalence of hypertension in the general population. Routine evaluation of microalbuminuria could lead to a substantial improvement in the identification of high-risk patients while optimizing the cost-effectiveness of cardiovascular risk stratification.
Thorough assessment of cardiovascular and renal risk, includingthe presence and degree of target organ damage, is a prerequisitefor devising effective therapeutic strategies and for individualizationof treatment goals. Clinical studies have shown that the higherthe risk status of an individual patient, the greater the benefitfor a given amount of BP reduction. Thus, patients with diabetesand/or renal disease, especially those with proteinuria, shouldbe treated to very low BP targets to achieve maximal cardiovascularand renal protection. Furthermore, the presence of target organdamage (e.g., left ventricular hypertrophy, carotid atherosclerosis,microalbuminuria) should also be taken into consideration whenchoosing the initial hypertensive drug.
Acknowledgments
We thank Dr. Gian Paolo Bezante and Dr. Massimo Del Sette forperforming ultrasound examinations.
Kaplan NM: Hypertension in the population at large. In: Kaplan’s Clinical Hypertension, 8th Ed., edited by Kaplan NM, Baltimore, Lippincott Williams & Wilkins, 2002, pp 1–24
The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Arch Intern Med 157: 2413–2446, 1997[Abstract]
1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens 17: 151–183, 1999[Medline]
Ogden LG, He J, Lydick E, Whelton PK: Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension 35: 539–543, 2000[Abstract/Free Full Text]
Leoncini G, Sacchi G, Viazzi F, Ravera M, Parodi D, Ratto E, Vettoretti S, Tomolillo C, Deferrari G, Pontremoli R: Microalbuminuria identifies global cardiovascular risk in essential hypertension: An artificial neural network-based approach. J Hypertens 20: 1315–1321, 2002[CrossRef][Medline]
Ghali JK, Liao Y, Cooper RS: Influence of left ventricular geometric patterns on prognosis in patients with or without coronary artery disease. J Am Coll Cardiol 31: 1635–640, 1998[Abstract/Free Full Text]
O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340: 14–22, 1999[Abstract/Free Full Text]
Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R, Zampi I, Reboldi G, Porcellati C: Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation 97: 48–54, 1998[Abstract/Free Full Text]
Schmieder RE, Schlaich MP, Klingbeil AU, Martus P: Update on reversal of left ventricular hypertrophy in essential hypertension (a meta-analysis of all randomized double-blind studies until December 1996). Nephrol Dial Transplant 13: 564–569, 1998[Abstract/Free Full Text]
Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 359: 995–1003, 2002[CrossRef][Medline]
Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR, Bond MG: Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 276: 785–791, 1996[Abstract]
Zanchetti A, Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A: The Verapamil in Hypertension and Atherosclerosis Study (VHAS): Results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens 16: 1667–1676, 1998[CrossRef][Medline]
Simon A, Gariepy J, Moyse D, Levenson J: Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation 103: 2949–2954, 2001[Abstract/Free Full Text]
Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palu C, Hansson L, Magnani B, Rahn KH, Reid JL, Rodicio J, Safar M, Eckes L, Rizzini P; European Lacidipine Study on Atherosclerosis investigators: Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: Principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 106: 2422–2427, 2002[Abstract/Free Full Text]
Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, de Jong PE, de Zeeuw D, Lau J, Levey AS: Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 135: 73–87, 2001[Abstract/Free Full Text]
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345: 870–878, 2001[Abstract/Free Full Text]
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001[Abstract/Free Full Text]
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869, 2001[Abstract/Free Full Text]
Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321: 1440–1444, 2000[Abstract/Free Full Text]
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet 361: 117–124, 2003[CrossRef][Medline]
Pontremoli R: Microalbuminuria in essential hypertension—Its relation to cardiovascular risk factors. Nephrol Dial Transplant 1: 2113–2115, 1996
Pontremoli R, Ravera M, Bezante GP, Viazzi F, Nicolella C, Berruti V, Leoncini G, Del Sette M, Brunelli C, Tomolillo C, Deferrari G: Left ventricular geometry and function in patients with essential hypertension and microalbuminuria. J Hypertens 17: 993–1000, 1999[CrossRef][Medline]
Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K: Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension 35: 898–903, 2000[Abstract/Free Full Text]
Olsen MH, Wachtell K, Borch-Johnsen K, Okin PM, Kjeldsen SE, Dahlof B, Devereux RB, Ibsen H: A blood pressure independent association between glomerular albumin leakage and electrocardiographic left ventricular hypertrophy. The LIFE Study. Losartan Intervention For Endpoint reduction. J Hum Hypertens 16: 591–595, 2002[CrossRef][Medline]
Top
Abstract
Introduction
-blocker atenolol, with an almost identical BP reduction in the two arms of the study (10). However, the trials completed so far, comparing the effect of various antihypertensive treatment on the regression of carotid atherosclerosis, suggest the superiority of calcium channel blockers over diuretics and 
