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*Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands; Studiecoördinatiecentrum, Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement Moleculair en Cardiovasculair Onderzoek, Katholieke Universiteit, Leuven, Belgium; Erasmus University, Rotterdam, The Netherlands; Department of Internal Medicine and Hypertension Unit, General Hospital of Athens, Athens, Greece; ¶Istituto Auxologico Italiano and the Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore, Universitá di Milano, Milan, Italy; ||Department of Internal Medicine, Alexandrov’s University Hospital, Sofia, Bulgaria; #Department of Medicine and Therapeutics, University of Aberdeen, Abderdeen, Scotland; **Unidad de Hypertensión, Hospital 12 de Octubre, Madrid, Spain; Sackler School of Medicine, Tel Aviv, Israel; and National Public Health Institute, Helsinki, Finland.
Correspondence to Dr. Peter W. de Leeuw, Department of Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31-43-387-7005; Fax: 31-43-387-5006; E-mail: p.deleeuw{at}intmed.unimaas.nl
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Introduction |
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Materials and Methods |
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176.8 µmol/L (2.0 mg/dl) were excluded, but diabetic patients could be enrolled. Eligible patients were randomized to double-blind treatment with active medication or placebo. The study medications were stepwise titrated and combined to reduce the sitting systolic BP (mean of two readings at each follow-up visit) by 20 mmHg to <150 mmHg. Active treatment was initiated with nitrendipine (10 to 40 mg/d). If necessary, the dihydropyridine was combined with or replaced by enalapril (5 to 20 mg/d), hydrochlorothiazide (12.5 to 25 mg/d), or both drugs. Identical placebos were employed in the same way in the control group. At randomization and at yearly intervals thereafter, serum creatinine and uric acid concentrations were measured by standard laboratory techniques, and fresh urine samples were examined for proteinuria (>300 mg/L) by using a semiquantitative dipstick method. Protein excretion was classified as none (negative dipstick reaction, i.e., protein excretion less than 150 mg/L), trace amounts (150 to 300 mg/L), or overt (>300 mg/L). Serum creatinine levels were converted to GFR using Cockcroft-Gault formula (6).
We used SAS software, version 6.12 (SAS Institute Inc., Cary, NC) for database management and statistical analysis. The significance of mean unadjusted differences between groups was determined from the normal z distribution. To examine the relationship between initial renal function and subsequent morbidity and mortality, the total group of patients was divided into quintiles according to baseline levels of serum creatinine or serum uric acid. To analyze the association between protein excretion and cardiovascular complications, patients were divided according to the level of proteinuria, i.e., none, trace, or overt. Incidence rates in quintiles of serum creatinine and uric acid or in categories of proteinuria were calculated with adjustments for age and gender. Relative hazard rates with 95% confidence intervals (CI) were estimated by single and multiple Cox regression, adjusted for treatment group and significant covariates (7). For each calculation, we first tested whether the proportional hazards assumption was satisfied (8). Results have been reported only when this was the case.
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Results |
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Baseline measurements of serum creatinine were available in 4688 patients, baseline uric acid levels in 4552 patients, and data on urinary protein excretion in 4658 patients. These patients form the basis of the present report.
Treatment and BP during Follow-Up
The median follow-up in the 4695 patients was 2.0 yr. Because the patients had been recruited over 8 yr and because the trial stopped early, follow-up of the individual patients ranged from 1 to 97 mo. The number of patient-years in the placebo and active-treatment groups amounted to 5844 and 6140, respectively.
At the time of the last BP measurement, 1896 patients of the active treatment group and 1601 patients of the placebo group were still on double-blind treatment. Of the actively treated patients, 1624 were taking nitrendipine (mean daily dose, 28.2 mg), 613 enalapril (13.8 mg), and 269 hydrochlorothiazide (21.6 mg); for the matching placebos in the control group, these numbers were 1445, 839, and 472, respectively.
In the intention-to-treat analysis with adjustment for baseline BP, the BP differences between the two treatment groups at the last evaluation averaged 11 mmHg systolic and 4 mmHg diastolic.
Serum Creatinine at Baseline and Incidence of Endpoints
Baseline data on serum creatinine were available for 4688 patients. Table 1 lists the clinical characteristics of those patients when stratified by quintiles of serum creatinine. These quintiles did not differ with respect to the percentage of patients on active treatment. Also, the proportion of diabetic patients was similar. Creatinine levels were positively correlated with age, male gender, the proportion of patients with previous cardiovascular complications, and systolic BP. In women, a higher creatinine was also associated with a lower diastolic BP. No differences between quintiles were observed, either in men or in women, with respect to body mass index, serum cholesterol levels, and percentage of patients who smoked or used alcohol. The same was true when GFR rather than measured creatinine concentration was taken as the dividing variable.
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When data were analyzed separately for the placebo and the active treatment group, relative hazard rates appeared to be greater in the former but the interaction between serum creatinine and treatment group was NS. Similarly, hazard rates tended to be higher in nondiabetic patients compared with diabetic patients, but again the interaction term between creatinine and diabetes was NS. Relative hazard rates for total mortality (P = 0.03), cardiovascular mortality (P = 0.04), and all cardiac endpoints (P = 0.02) were higher in women than in men.
Serum Uric Acid at Baseline and Incidence of Endpoints
Serum uric acid was measured at entry in 4552 patients. When broken down by quintiles of serum uric acid (Table 3), patients in the quintiles were comparable with respect to age, treatment status, and the proportion of patients with diabetes. In the highest quintile, there were more men and more patients with previous cardiovascular complications. Serum uric acid was positively associated with body mass index in both genders, with diastolic pressure in men, and with serum cholesterol in women. No differences between quintiles were observed, either in men or in women, with respect to systolic BP and percentage of patients who smoked or used alcohol.
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Urinary Protein Excretion at Baseline and Incidence of Endpoints
Data on protein excretion at the time of randomization were available for 4658 patients. These patients were divided into three groups depending on whether there was no proteinuria (n = 4225), trace proteinuria (n = 324), or overt proteinuria (n = 109) at entry. Groups were comparable with respect to age, gender, and treatment status. The proportion of patients with previous cardiovascular complications, however, was significantly higher in those with overt proteinuria compared with the group without proteinuria. The same was true for the percentage of patients with diabetes (Table 5). Both in men and in women, systolic BP was significantly higher in patients with overt proteinuria than in those without.
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Because serum creatinine and proteinuria both predicted outcome, we have also tested whether these two markers have an independent effect on prognosis. Forcing both variables in the Cox model showed, indeed, that serum creatinine and proteinuria were independent determinants for all cardiovascular endpoints, i.e., cardiovascular mortality, stroke mortality, and all types of fatal and nonfatal endpoints. With respect to total mortality a similar trend was found, although that was not statistically significant.
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Discussion |
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The observation that serum creatinine predicted cardiovascular morbidity and mortality in our population fits well with data from other studies, which have shown an independent association between serum creatinine and cardiovascular or overall prognosis. Probably, this association is least obvious in unselected populations. For instance, during a 15-yr follow-up in the community-based Framingham Heart Study, mild renal insufficiency (defined as a serum creatinine of 136 to 265 µmol/L in men and 120 to 265 µmol/L in women) was not associated with cardiovascular disease (fatal and nonfatal) in women when adjustments were made for coexisting risk factors (13). In men, however, the relationship between renal impairment and all-cause mortality remained significant, even after such adjustments (the reason that we found the opposite may be that most patients in our study still had serum creatinine concentrations within the normal range). In more selected populations, stronger relationships have been described between serum creatinine and cardiovascular outcome. This may be illustrated by the data from the Hypertension Detection and Follow-up Program (HDFP), which was a community-based randomized trial of stepped-care versus referred-care in hypertensive patients (14) and which showed that the 8-yr mortality risk rose progressively with increasing baseline serum creatinine concentrations. A serum creatinine concentration above 150 µmol/L appeared to be independently associated with a twofold higher mortality rate, mostly due to cardiac or cerebrovascular causes. Likewise, the investigators from the HOT trial recently reported that an elevation in serum creatinine and a reduction in estimated creatinine clearance in treated hypertensive patients are powerful predictors of cardiovascular events and death (3). Several other observations support such relationships. For instance, in the British Regional Heart Study, which is a prospective study on middle-aged men, a serum creatinine level 116 µmol/L significantly increased the risk of stroke, even after adjustment for a wide range of cardiovascular risk factors (15). At a serum creatinine level of 130 µmol/L, the risk for ischemic heart disease was significantly increased as well, but this did not hold after adjustment for potential confounders. Other studies found serum creatinine to be an independent predictor of mortality in healthy elderly subjects (16), in elderly patients with a recent stroke (17), in normotensive survivors of myocardial infarction (18), and in older Chinese patients with isolated systolic hypertension (10). Finally, in patients with asymptomatic or symptomatic heart failure, renal impairment is associated with an increased risk for all-cause mortality (19) and predicts mortality even better than left ventricular ejection fraction (20). Importantly, in hypertensive subjects, creatinine levels that are still in the normal range may already predict outcome (21).
As far as patients with isolated systolic hypertension are concerned, the SHEP trial has already shown that the proportion of any cardiovascular events, strokes, coronary events, and deaths increases with increasing serum creatinine levels in this population as well (11). In this regard, our data are consistent with those from SHEP and all the other studies that examined the relationship between serum creatinine and prognosis. It would seem, therefore, that this relationship is relatively independent of the type of treatment, suggesting that creatinine is a rather robust marker of the atherosclerotic process. Serum creatinine may not be an accurate indicator of renal function per se nor of the extent of nephrosclerosis (18); it is therefore possible that a rise in creatinine, or for that matter a reduction in GFR, reflects a critical fall in renal perfusion secondary to progression of left ventricular dysfunction (19).
Although we assessed the impact of serum uric acid on prognosis as well, our data indicate that this variable is a much weaker predictor of hypertension-related complications. At first sight, this may seem surprising because several studies in the past few years have shown an association between the level of uric acid and cardiovascular events. For instance, Fang and Alderman (22) evaluated the data of 5926 subjects from the community-based NHANES epidemiologic follow-up study and found that increased serum uric acid levels are independently and significantly associated with the risk of cardiovascular mortality. In fact, they showed that for each 60 µM increase in serum uric acid the adjusted relative hazard ratio for the risk of cardiovascular death was 1.09 in men and 1.26 in women after adjustment for age, race, body mass index, smoking status, alcohol consumption, cholesterol level, history of hypertension and diabetes, and diuretic use. Except for the smaller number of patients and shorter duration of follow-up in the Syst-Eur trial, the obvious difference in study design may well account for the discrepancies. On the other hand, it is by no means certain that uric acid acts as an independent cardiovascular risk factor because the data from the Framingham study do not support such a role for uric acid when appropriate adjustments are made for several confounding variables (23). But even when one compares the Syst-Eur data to other clinic-based studies on (treated and untreated) hypertensive patients (24), our results cannot confirm the alleged role of uric acid as a predictor of cardiovascular prognosis.
Unlike the three studies mentioned above, Syst-Eur was a prospective intervention trial that allowed patients to be followed in a standardized way. In this respect, the Systolic Hypertension in the Elderly Program (SHEP) trial (12) and the Syst-China trial (10) are the only studies that qualify for a meaningful comparison with Syst-Eur. Both studies were placebo-controlled and included approximately the same number of patients with isolated systolic hypertension. Recently, the SHEP investigators have reported that after adjustment for age, gender, race, body mass index, history of heart attack, stroke and diabetes, serum creatinine, glucose, cholesterol, HDL-cholesterol, and triglycerides, uric acid remained an independent risk factor for cardiovascular events (12). Thus, also in the SHEP trial uric acid appears to be far more powerful as a predictor of cardiovascular complications than in Syst-Eur. One of the major differences between the two studies was the type of treatment (diuretic-based in SHEP and calcium channel blocker–based in Syst-Eur); it is therefore tempting to speculate that the prognostic influence of uric acid is either enhanced by diuretic treatment or attenuated by calcium channel blocker treatment. The discrepancy with the results from the Syst-China trial, which also found a relationship between uric acid and complications, may be explained by the fact that other risk factors, such as elevated cholesterol, were less prominent in the Chinese patients (10). The reason that we found uric acid to be a less conspicuous indicator of cardiovascular risk could also be due to the limited increase in serum creatinine that we encountered in this study (25). Perhaps, a greater loss of renal function or a more pronounced fall in extracellular fluid volume (such as may occur during diuretic treatment) is necessary to unmask the role of uric acid as an independent marker of risk. Finally, we should consider the possibility that part of the discrepancies may be due to the fact that an U-shaped rather than a linear relationship exists between serum uric acid and risk. Indeed, evidence for such a U-shaped association was provided by the PIUMA study (26). Although the Syst-Eur data suggest a similar phenomenon, we found this to be statistically significant only for total mortality. Interestingly, though, event rates started to rise from a nadir of 308 µmol/L, a figure comparable to that described by the PIUMA investigators (26).
Proteinuria is another well-known marker of future cardiovascular complications, notably in patients with diabetes mellitus. It is increasingly recognized that proteinuria is also an indicator of risk in patients with hypertension and even in normotensives. For instance, Miettinen et al. (27) found that clinical proteinuria (defined as proteinuria of >300 mg/L) in nondiabetic subjects aged 45 to 64 yr is an independent predictor of stroke and other atherosclerotic vascular lesions. Similarly, the Framingham study showed that all-cause mortality in men and all-cause as well as cardiovascular mortality in women are also related to baseline proteinuria when elderly subjects (mean age, 68 yr) are classified into those with no, trace, or greater-than-trace proteinuria (28). The present study now extends such data to the elderly with isolated systolic hypertension. Although nowadays most studies focus on (micro-)albuminuria, the data from the Syst-Eur trial pertain only to proteinuria which was recorded as none, trace, or overt. Indeed, at the time the study started, it was not feasible to implement in all participating centers a reliable method for detecting microalbuminuria. However, even though our results may have been more complete if we had analyzed microalbuminuria, we can still conclude that there is a relationship between urinary protein excretion and outcome in elderly patients with isolated systolic hypertension. Whether microalbuminuria has similar predictive power in this population remains a matter of further investigation.
The three measurements (creatinine, uric acid, protein excretion) that we have used in this study are neither very sensitive nor very specific markers of renal function. Indeed, serum concentrations of creatinine and uric acid are dependent also on extrarenal factors and urinary protein excretion may well reflect the hydraulic consequence of an elevated (intrarenal) pressure rather than true glomerular damage. Despite this caveat, both serum creatinine and proteinuria turned out to be renal markers of future (cardiovascular) complications, suggesting that glomerular damage is somehow associated with the progression of atherosclerotic lesions. Although several investigators favor the opinion that proteinuria or a higher serum creatinine reflects generalized endothelial dysfunction or a prothrombotic state, others on equally reasonable grounds argue against these possibilities (15,18). Clearly, more work has to be done before the pathophysiologic connection between renal function and atherosclerotic complications will be elucidated.
One of the limitations of this study is that there may be unmeasured confounders that could have influenced our results. Although the observed relationships between renal function and cardiovascular prognosis remained statistically significant after correction for classical risk factors (including cholesterol status), we did not account for the more recently reported risk factors such as hyperhomocysteinemia or certain infections. Second, one should bear in mind that our results apply to elderly people with systolic hypertension only. Therefore, the data cannot be extrapolated to other patient populations.
In conclusion, we have shown in elderly patients with isolated systolic hypertension that both serum creatinine and proteinuria are (independent) indicators of future mortality and morbidity, whereas serum uric acid is not.
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Acknowledgments |
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Trial Coordinators
Robert Fagard, MD, and Jan A. Staessen, MD.
Regional Coordinators
Guramy G. Arabidze, MD (Bellorussia and the Russian Federation); Willem H. Birkenhäger, MD (the Netherlands); Christopher J. Bulpitt, MD (United Kingdom); Manuel Carrageta, MD (Portugal); Hilde Celis, MD (Belgium); Françoise Forette, MD (France); Jozef Kocemba, MD (Poland); Gastone Leonetti, MD (Italy); Choudomir Nachev, MD (Bulgaria); Eoin T. O’Brien, MD (Ireland); Eberhard Ritz, MD (Germany); José L. Rodicio, MD (Spain); Joseph Rosenfeld, MD (Israel); Jaakko Tuomilehto (Finland, Estonia and Lithuania).
Steering Committee
Guramy G. Arabidze, MD; Paul De Cort, MD; Robert Fagard, MD; Françoise Forette, MD; Kalina Kawecka-Jaszcz, MD; Gastone Leonetti, MD; Choudomir Nachev, MD; Eoin T. O’ Brien, MD; José L. Rodico, MD; Joseph Rosenfeld, MD; Jaakko Tuomilehto, MD; John Webster, MD; and Yair Yodfat, MD.
Data Monitoring Committee
Christopher J. Bulpitt, MD; Astrid E. Fletcher, PhD; Jan A. Staessen, MD; and Lutgarde Thijs, BSc.
Endpoint Committee
Peter W. de Leeuw, MD; Robert Fagard, MD; Gastone Leonetti, MD; and James C. Petrie, MD.
Ethics Committee
Willem H. Birkenhäger, MD; Colin T. Dollery, MD; and Robert Fagard, MD.
Publication Committee
Willem H. Birkenhäger, MD; Christopher J. Bulpitt, MD; Jan A. Staessen, MD; and Alberto Zanchetti, MD.
Coordinating Office
Nicole Ausloos; Hilde Celis, MD; Elly Den Hond, DSc; Lut De Pauw, RN; Paul Drent, RN; Dmitri Emelianov, MD; Jerzy Gasowski, MD; Heng Fan; Tatiana Kuznetsova, MD; Tim Nawrot, BSc; Yvette Piccart; Yvette Toremans; Lutgarde Thijs, BSc; Sylvia Van Hulle, RN; Ji G. Wang, MD; and Renilde Wolfs.
A complete list of the Syst-Eur investigators appears in references (4) and (5).
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Footnotes |
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