Diuretic-Based Treatment and Cardiovascular Events
in Patients With Mild Renal Dysfunction Enrolled in
the Systolic Hypertension in the Elderly Program
Marco Pahor, MD; Ronald I. Shorr, MD; Grant W. Somes, PhD; William C. Cushman, MD; Luigi Ferrucci, MD; James E. Bailey, MD, MPH; Janet T. Elam, BS; William B. Applegate, MDBackground:It is expected that the treatment of
hy-pertension in patients with renal disease decreases the risk of cardiovascular events, but the evidence in these patients is lacking.
Objective:To assess the effect of diuretic-based treat-ment on cardiovascular events in patients with isolated systolic hypertension and renal dysfunction.
Methods:A total of 4336 persons aged 60 years and
older with systolic blood pressuresof 160 mm Hg and higher and diastolic blood pressures of less than 90 mm Hg were randomly assigned to receive either pla-cebo or chlorthalidone (12.5-25.0 mg/d), with the addition of atenolol (25-50 mg/d) or reserpine (0.05-0.10 mg/d) if needed, and observed for 5 years. The risk of first-occurring cardiovascular events, including stroke, transient ischemic attack, myocardial infarction, heart failure, coronary artery bypass surgery, angio-plasty, aneurysm, endarterectomy, sudden death, or rapid death, was stratified according to baseline serum creatinine levels (35.4-84.0, 84.1-101.6, 101.7-119.3,
and 119.4-212.2 µmol/L [0.4-0.9, 1.0-1.1, 1.2-1.3, and 1.4-2.4 mg/dL]).
Results:Systolic blood pressure reduction was not af-fected by baseline serum creatinine levels. Active treat-ment did not affect the risk of serum creatinine levels becoming elevated during follow-up. The risk of hypo-kalemia with active treatment decreased significantly with increasing baseline serum creatinine levels. In the 4 baseline serum creatinine groups, the relative risk (95% confidence interval) of cardiovascular events develop-ing with active treatment was 0.73 (0.54-0.97), 0.63 (0.49-0.82), 0.62 (0.44-0.87), and 0.59 (0.38-0.91). The results were similar for the outcomes of stroke or coro-nary artery events and in analyses stratified by sex or age. Conclusion:Diuretic-based treatment of patients with isolated systolic hypertension prevents the develop-ment of cardiovascular events in older persons with mild renal dysfunction.
Arch Intern Med. 1998;158:1340-1345
I
NCREASED SERUMcreatininelev-els, a marker of renal dysfunc-tion, are an independent predic-tor of cardiovascular events such as stroke and coronary artery events. Hypertension can accelerate re-nal dysfunction, and rere-nal dysfunction can cause or worsen hypertension. Both in-crease the risk of cardiovascular compli-cations.1In about 1 of 3 patients with hy-pertension, renal dysfunction develops that is characterized by abnormal serum cre-atinine levels,2and hypertension is a ma-jor cause of renal failure, second only to diabetes mellitus.3
Several studies of patients with re-nal dysfunction have investigated the ef-fects of antihypertensive treatment on sur-rogate outcomes such as serum creatinine levels, urine protein concentrations, and glomerular filtration rate.4-7 In such
pa-tients, however, the available evidence from studies that examine the effects of treatment on the incidence of major mor-bid events is extremely limited.1,8-11It is ex-pected that lowering the blood pressure (BP) in hypertensive patients with renal dysfunction produces the same benefits on cardiovascular outcomes as in those with normal renal function. Although such evi-dence is lacking, 2 trials provided contro-versial results. In the Hypertension De-tection and Follow-up Program,1there was a 16% reduction in mortality with op-timal BP control with mainly diuretic therapy among patients who had base-line serum creatinine levels of less than 150.3 µmol/L (,1.70 mg/dL) and only an 8% reduction among those who had higher creatinine levels. Although this differ-ence in effect was not statistically signifi-cant, the findings of the Hypertension De-ORIGINAL INVESTIGATION
From the Department of Preventive Medicine, University of Tennessee, College of Medicine, Memphis (Drs Pahor, Shorr, Somes, Cushman, Bailey, and Applegate and Ms Elam), and the Geriatric Department, I Fraticini, Istituto Nazionale di Ricerca e Cura per gli Anziani, Florence, Italy (Dr Ferrucci). Dr Cushman has received an honorarium for giving Grand Rounds sponsored by Monarch Pharmaceuticals Inc, Bristol, Tenn, who make a brand of chlorthalidone different from that used in this study.
tection and Follow-up Program may raise questions about the efficacy of diuretic-based antihypertensive treat-ment in patients with renal dysfunction. In another trial of patients with renal failure,9the use of angiotensin-converting enzyme inhibitor benazepril improved renal function and BP, but was associated with a significant in-crease in the risk of all-cause mortality. To our knowl-edge, no randomized study has examined whether di-uretic-based treatment of isolated systolic hypertension in patients with renal dysfunction decreases the risk of major cardiovascular events. The aim of this secondary analysis is to determine whether antihypertensive treat-ment as used in the Systolic Hypertension in the Elderly Program (SHEP) is as effective in preventing cardiovas-cular events among persons with increased baseline se-rum creatinine levels as it is among those with normal or low serum creatinine levels.
RESULTS
BASELINE CHARACTERISTICS
The baseline characteristics of the participants stratified according to treatment and serum creatinine levels are shown inTable 1. The participants with higher creati-nine levels were older, more likely to be men, of the black race, and more likely to have a history of heart attack.
Among the baseline serum creatinine strata, there were no significant differences in baseline BP, body mass in-dex, or percentage of participants who were using anti-hypertensive medications at the initial contact visit or who had a history of stroke or diabetes mellitus. In all creati-nine subgroups, the baseline characteristics of the pa-tients randomly allocated to receive placebo were simi-lar to those assigned to active treatment.
BP CONTROL
The reduction of systolic BPs achieved with active treat-ment was similar across serum creatinine levels (Figure 1). In a series of general linear models that tested the effect of baseline serum creatinine levels and treat-ment on changes of systolic BPs during follow-up, only the effect of treatment was statistically significant (P,.001). Although the baseline mean diastolic BP was similar in all creatinine subgroups, a slightly greater di-astolic BP reduction with active treatment was achieved in participants who had lower creatinine levels than in those who had higher creatinine levels (Figure 1). For example, on average, the diastolic BPs during follow-up of the active treatment group with baseline serum cre-atinine levels of 35.4 to 84.0 µmol/L (0.40-0.95 mg/dL) were 2 mm Hg lower than the diastolic BPs of the active treatment group with baseline serum creatinine levels of
PATIENTS AND METHODS
DESIGN AND PARTICIPANTS
The SHEP was a randomized, double-blind, placebo-controlled clinical trial jointly funded by the National Heart, Lung, and Blood Institute and the National Institute on Aging, Bethesda, Md.11The methods of the SHEP have been described in detail elsewhere.11The primary end point of the trial was the combined incidence of fatal and nonfatal stroke during a 5-year period. Secondary end points were the incidences of myocardial infarction, fatal coronary ar-tery disease, and major cardiovascular morbidity and mor-tality. The events were adjudicated independently by mem-bers of an end-point adjudication committee who used predetermined standardized adjudication criteria and who were unaware of the treatment and BP status. Beginning in 1985, 447 921 persons aged 60 years and older were screened from the community in 16 clinical centers, and among them, 4736 participants with isolated systolic hy-pertension were recruited. The medical history and the re-sults of an electrocardiogram and a physical examination were assessed at baseline. The seated BP was measured by trained technicians according to a standardized protocol. The BP inclusion criteria were a systolic BP of 160 to 219 mm Hg and a diastolic BP of less than 90 mm Hg assessed as the average of 4 measurements (2 measurements were obtained at each of the 2 baseline visits).
Exclusion criteria were a systolic BP of 220 mm Hg or higher, a recent myocardial infarction or stroke, or the pres-ence of a major illness such as cancer, alcoholic liver dis-ease, renal failure, insulin-treated diabetes mellitus, and de-pression. Participants who were receiving an antihypertensive
antihypertensive treatment were considered potentially eli-gible if they had a systolic BP between 130 and 219 mm Hg and a diastolic BP of less than 85 mm Hg and were free of ma-jor illnesses. They were asked to obtain permission from their physician and to sign an informed consent for withdrawal from current antihypertensive therapy to determine BP eligibility. They were monitored 2 to 8 weeks after drug withdrawal.
For this study, only the 4336 patients who had a valid measurement of serum creatinine levels by the day of ran-domization were included in the analyses. A total of 400 pa-tients who had been randomly assigned into the SHEP but for whom serum creatinine levels were not available on the day of randomization were excluded. The 400 patients who were excluded had baseline age, sex, race, smoking status, and comorbidity characteristics similar to the patients who were included in the analysis. We report primarily on the first-occurring major cardiovascular event, which included stroke, transient ischemic attack, myocardial infarction, heart fail-ure, coronary artery bypass surgery, angioplasty, aneurysm, endarterectomy, sudden death, or rapid cardiac death (within 1-24 hours of the onset of severe cardiac symptoms unre-lated to other known causes). In addition, the incidences of fatal and nonfatal stroke, fatal and nonfatal coronary heart disease, and all-cause mortality were analyzed separately.
INTERVENTION
The participants were randomly assigned to receive active treatment or placebo. A stepped-care treatment approach was used. The treatment goal was a systolic BP of less than 160 mm Hg or at least a 20–mm Hg reduction in the sys-tolic BP. In the active treatment group, the first step was Continued on next page
119.4 to 212.2 µmol/L (1.35-2.40 mg/dL). In a series of general linear models that tested the effect of baseline se-rum creatinine levels and treatment on changes of
dias-tolic BPs during follow-up, the effects of serum creati-nine levels and treatment were statistically significant (P=.03 andP,.001, respectively).
Table 1. Baseline Characteristics of the Participants According to Treatment and Baseline Serum Creatinine Levels*
Patient Characteristics
Baseline Serum Creatinine, µmol/L†
35.4-84.0 84.1-101.6 101.7-119.3 119.4-212.2 Placebo (n = 790) Active Treatment (n = 805) Placebo (n = 778) Active Treatment (n = 858) Placebo (n = 411) Active Treatment (n = 401) Placebo (n = 177) Active Treatment (n = 216) Age, y 70.8 ± 6.7 71.0 ± 6.5 71.4 ± 6.5 71.4 ± 6.7 72.3 ± 6.5 72.2 ± 6.7 74.1 ± 7.0 73.9 ± 6.7 Male sex, % 16.2 16.9 46.9 48.0 70.3 66.3 80.2 82.4 Ethnic origin, % White 81.8 82.2 78.3 78.4 77.6 74.8 77.4 75.0 Black 9.6 9.1 15.2 14.0 16.1 20.9 19.2 20.4 Asian 5.7 6.6 3.6 3.8 4.1 2.0 2.8 2.8
Body mass index, kg/m2 27.2 ± 5.3 27.3 ± 5.4 27.9 ± 5.0 27.9 ± 4.7 27.4 ± 4.7 27.7 ± 4.5 27.0 ± 4.1 27.4 ± 4.7
Systolic blood pressure, mm Hg 170 ± 9 171 ± 9 170 ± 10 170 ± 9 170 ± 8 171 ± 10 172 ± 10 172 ± 1
Diastolic blood pressure, mm Hg 76 ± 9 77 ± 10 77 ± 9 77 ± 9 77 ± 10 77 ± 11 77 ± 10 77 ± 9
Antihypertensive medication at
initial contact, % 31.4 35.4 35.5 31.8 35.0 31.9 38.4 33.8
History of myocardial infarction, % 2.5 1.7 1.3 1.1 6.3 5.0 5.1 5.6
History of stroke, % 1.3 2.2 2.1 2.4 1.5 2.2 3.4 4.2
History of diabetes mellitus, % 9.1 9.0 11.7 9.5 9.7 12.0 12.5 11.1
*Values are mean ± SD unless otherwise indicated.
†To convert serum creatinine values from micromoles per liter to milligrams per deciliter, divide micromoles per liter by 88.4. the administration of chlorthalidone, 12.5 mg/d. The
dos-age was doubled if the goal BP was not achieved. If the goal BP was not reached at the first step, atenolol, 25 mg/d, was added (second step). If atenolol therapy was not tolerated, reserpine, 0.05 mg/d, could be substituted. The dosage of the second-step drugs could be doubled if the goal BP was not reached. No active antihypertensive agent was given to the participants randomly allocated to receive placebo. An open-label potassium supplement was given to the par-ticipants in both treatment arms who had serum potas-sium concentrations below 3.5 mmol/L.
FOLLOW-UP
All participants were observed monthly until the BP goal was reached and quarterly thereafter until the end of follow-up. Blood specimens were drawn routinely at baseline and at each annual clinic follow-up visit. The blood specimens were centrifuged and sent by overnight mail to a central laboratory for analysis (MetPath, Teterboro, NJ). Serum cre-atinine, uric acid, urea nitrogen, sodium, and potassium levels were part of the blood test battery.
DATA ANALYSIS
The patients allocated to active treatment were compared with those receiving placebo. Their characteristics were com-pared by means of thex2test and analysis of variance as appropriate. For analysis, the participants were stratified according to tertiles and values above normal of the base-line serum creatinine as follows: 35.4 to 84.0 µmol/L (0.4-0.9 mg/dL) (lowest tertile, n=1595), 84.1 to 101.6 µmol/L (1.0-1.1 mg/dL) (median tertile, n=1536), 101.7 to 119.3 µmol/L (1.2-1.3 mg/dL) (upper tertile less values above
normal, n=812), and 119.4 to 212.2 µmol/L (1.4-2.4 mg/ dL) (values above normal in the general population corre-sponding to the upper decile, n=393). These cutoff points have been chosen to obtain a sufficient number of partici-pants and events in each stratum and a sufficient number of strata to allow analyses of trend. No participants had baseline serum creatinine levels of less than 35.4 µmol/L or greater than 212.2 µmol/L (,0.40 or.2.40 mg/dL). In separate analyses, the participants were stratified accord-ing to 4 similar levels (3 tertiles and the lower decile) of creatinine clearances. For men, the creatinine clearance (milliliters per minute) was calculated with the following formula: ([140 − age]3weight in kilograms)/(723 serum creatinine level in milligrams per deciliter).12For women, the value was reduced to 85% of that estimated with this equation.
The Kaplan-Meier method was used to plot survival free of cardiovascular events, and the log-rank test was used to compare treatments.13Cox proportional hazards regres-sion models were used to estimate the hazard ratio and 95% confidence intervals for the effect of treatment on the out-comes of interest.14The assumption of proportionality of hazards was assessed with log−log plots and by testing the interaction of exposure with time.15To test the trend of drug effect with increasing baseline serum creatinine levels, the interaction of treatment with baseline serum creatinine lev-els as a continuous variable was assessed in separate pro-portional hazards models after adjusting for the main ef-fect of treatment, baseline serum creatinine levels, age, sex, ethnicity, systolic and diastolic BPs, body mass index, and history of stroke, heart attack, and diabetes mellitus. Gen-eral linear models for repeated measures were used to ana-lyze the variation of BP and serum creatinine levels accord-ing to treatment.
SERUM CREATININE AND POTASSIUM VARIATIONS
The active treatment group when compared with the placebo group had a small but statistically significant (P,.001) increase in mean serum creatinine levels fol-lowing randomization, but all the differences had oc-curred by 1 year and were stable thereafter (Figure 2). A similar pattern was observed when the data were stratified according to the 4 baseline serum creatinine groups and for the outcome of serum urea nitrogen and uric acid concentrations (data not shown). There were no significant differences between the placebo and ac-tive treatment groups in the number of patients who had elevated serum creatinine values during follow-up. During follow-up, 9 patients receiving placebo and 5 patients receiving active treatment had 1 or more serum creatinine values of greater than 265.2 µmol/L (.3.0
mg/dL), and 44 patients in each group had 1 or more se-rum creatinine values of greater than 176.8 µmol/L (.2.0 mg/dL).
It has been previously described in SHEP that the patients receiving active treatment had significantly lower serum potassium levels during follow-up than those re-ceiving placebo and that the patients rere-ceiving active treat-ment were significantly more likely to have hypokale-mia any time during follow-up (serum potassium level ,3.2 mmol/L).11In the present stratified analyses, the proportion of actively treated participants having hypo-kalemia decreased progressively with increasing base-line serum creatinine levels (Figure 3) (P,.001 for trend). The proportion of patients having hypokalemia in the placebo group did not vary significantly accord-ing to baseline serum creatinine levels. Consequently, the difference in the risk of hypokalemia between the active treatment group and the placebo group decreased with increasing baseline creatinine levels.
CARDIOVASCULAR EVENTS
As expected, the proportion of participants having ei-ther any cardiovascular event, stroke, coronary events, or death increased with increasing creatinine level (P,.001,P=.002,P,.001, andP,.001, respectively, with the Mantel-Haenszel test for linear association) (Table 2). In all baseline serum creatinine subgroups, the partici-pants receiving active treatment were significantly less likely to have cardiovascular events than those receiv-ing placebo (Figure 4). The beneficial effect of active treatment on cardiovascular events was significant in each baseline serum creatinine stratum and tended to in-crease progressively with increasing baseline serum cre-atinine level. ThePvalue for trend, however, did not reach statistical significance after adjustment for the main
ef-Blood Pressure, mm Hg 110 Follow-up, y 190 0 1 2 3 4 90 170 70 150 50 130 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 Serum Creatinine Levels, µmol/L
Systolic: Active Treatment Diastolic: Placebo Diastolic: Active Treatment Systolic: Placebo 35.4-84.0 84.1-101.6 101.7-119.3 119.4-212.2
BP Groups
Figure 1.Variations of mean systolic and diastolic blood pressures (BP) during follow-up according to treatment and baseline serum creatinine levels. The graph has been truncated after 4 years.
100 70 30 50 20 0 40 10 0 1 2 3 4
Serum Creatinine Level,
µ
mol/L
Follow-up, y
Placebo Group Active Treatment Group 90
60 80
Figure 2.Variations of mean serum creatinine levels during follow-up according to treatment. The graph has been truncated after 4 years. In a general linear model that tested the effect of treatment on repeated measures of serum creatinine during follow-up, the effect of treatment was statistically
significant ( P,.001). 7 3 5 2 0 4 1
Persons With Hypokalemia, %
Serum Creatinine Categories, µmol/L Placebo Active Treatment 6 35.4-84.0 84.1-101.6 101.7-119.3 119.4-212.2 P<.001 P=.57 P=.04 P<.001
Figure 3.Risk of having hypokalemia (serum potassium level,3.2 mmol/L) during follow-up according to treatment and baseline serum creatinine levels. The P values above each column are for the comparison of placebo vs active treatment. The trend for a decreasing risk of hypokalemia with increasing baseline serum creatinine level in the active treatment group is significant ( P=.003); the trend for a decreasing risk of hypokalemia with increasing baseline serum creatinine level in the placebo group is not significant ( P=.62).
fect of treatment, baseline serum creatinine level, age, sex, race, baseline systolic and diastolic BPs, body mass in-dex, and history of stroke, myocardial infarction, and dia-betes mellitus (Table 2) (P=.96 for trend). In separate analyses that used 4 levels of estimated baseline creati-nine clearance instead of 4 levels of serum creaticreati-nine to stratify the participants, the results were unchanged. Simi-lar results were found when the incidences of stroke and coronary artery events were analyzed according to treat-ment and serum creatinine levels (Table 2) and when the data of men, women, participants aged 60 to 69 years, and those aged 70 years and older were analyzed sepa-rately (data not shown). The findings remained un-changed when the participants were stratified accord-ing to quartiles of baseline serum creatinine levels or according to levels of serum creatinine of less than 115 and 115 µmol/L and higher, instead of the 4 groups
pre-sented in Table 2. The reduction in all-cause mortality with active treatment was significant only in the group with baseline serum creatinine levels of 101.7 to 119.3 µmol/L (1.2-1.3 mg/dL). Three persons died of renal dis-ease—1 in the placebo group among the patients with creatinine levels of 101.7 to 119.3 µmol/L and 2 in the treated group in the highest creatinine stratum.
COMMENT
These analyses show that diuretic-based treatment of iso-lated systolic hypertension significantly decreases the risk of cardiovascular events in older persons with mild renal dysfunction. During follow-up, the average systolic BP in the placebo and the active treatment groups did not vary according to baseline serum creatinine levels, and dias-tolic BPs in the treatment group tended to be slightly higher in participants with higher baseline serum creatinine lev-els than in those with lower serum creatinine levlev-els.
Active treatment did not appear to adversely affect renal function. Although the serum creatinine levels of actively treated participants increased slightly following randomization, during follow-up, average serum creati-nine levels remained stable, and the small number of par-ticipants who had marked creatinine elevations during follow-up was similar in the active treatment and pla-cebo groups. If the diuretic-based treatment had had an adverse effect on renal function, a progressive increase in average serum creatinine levels and more partici-pants having elevated creatinine levels over time would be expected. The observed initial increase in serum cre-atinine levels was most likely related to the reduction of intravascular volume and consequent modest hemocon-centration caused by the diuretic therapy. This interpre-tation is supported by the corresponding initial increase in serum urea nitrogen and uric acid concentrations in the actively treated group.
Hypokalemia might partially offset the benefits of diuretic antihypertensive treatment. It has been sug-gested that hypokalemia may be responsible for the ad-Table 2. Hazard Ratio (HR) of Cardiovascular Events in Group With Active Treatment Compared
With Placebo Group According to Baseline Serum Creatinine Values*
Outcome
Treatment Group
Baseline Serum Creatinine, µmol/L* 35.4-84.0 (n = 1595) 84.1-101.6 (n = 1536) 101.7-119.3 (n = 812) 119.4-212.2 (n = 393)
Any cardiovascular event 0.73 (0.54-0.97) 0.63 (0.49-0.82) 0.62 (0.44-0.87) 0.59 (0.38-0.91)
Placebo 105 (13.3) 142 (18.3) 85 (20.7) 47 (26.6)
Active 80 (9.9) 92 (12.1) 52 (13.0) 36 (16.7)
Stroke 0.65 (0.41-1.03) 0.50 (0.32-0.80) 0.92 (0.53-1.61) 0.51 (0.26-1.00)
Placebo 46 (5.8) 53 (6.8) 26 (6.3) 22 (12.4)
Active 31 (3.9) 27 (3.6) 23 (5.7) 14 (6.5)
Any coronary event 0.80 (0.51-1.27) 0.73 (0.50-1.05) 0.55 (0.33-0.91) 0.62 (0.32-1.19)
Placebo 41 (5.2) 66 (8.5) 43 (10.5) 21 (11.9)
Active 34 (4.2) 48 (6.3) 23 (5.7) 16 (7.4)
All-cause mortality 0.92 (0.64-1.33) 0.77 (0.55-1.09) 0.64 (0.42-0.97) 1.18 (0.72-1.95)
Placebo 60 (7.6) 75 (9.6) 58 (14.1) 26 (14.7)
Active 57 (7.1) 58 (7.7) 35 (8.7) 37 (17.1)
*To convert serum creatinine values from micromoles per liter to milligrams per deciliter, divide micromoles per liter by 88.4. Data are given as HR (95%
confidence interval) and number (percentage) of events.
1.0
0.9
0 0.7 0.8
Probability of Remaining Free of CVD
Follow-up, y P=.03 P<.001 1.0 0.9 0 0.7 0.8 0 1 2 3 4 P=.006 0 1 2 3 4 P=.02 101.7-119.3 µmol/L 119.4-212.2 µmol/L 35.4-84.0 µmol/L
Serum Creatinine, Serum Creatinine, 84.1-101.6 µmol/L Act Plac Act Plac Act Plac Act Plac
Figure 4.Probability of remaining free of cardiovascular disease (CVD) according to treatment and baseline serum creatinine levels. The graph has been truncated after 4 years. The P values shown in each graph are for the comparison of placebo (Plac) vs active treatment (Act) calculated with the log-rank test.
verse outcomes associated with the use of high doses of diuretic agents.16The present analyses show that increas-ing baseline serum creatinine levels were associated with a lower risk of hypokalemia with diuretic therapy. The lower propensity for hypokalemia to develop among pa-tients with renal dysfunction could partially explain the enhanced efficacy of diuretic treatment in those with in-creased baseline serum creatinine levels.
This study has limitations. First, because the se-rum creatinine level might not be an accurate indicator of renal function in older persons who have a reduced muscle mass, some participants with reduced muscle mass and mild renal dysfunction might have been grouped with participants with normal renal function. Such misclas-sification is likely to be conservative because it would un-derestimate the proportion of participants with renal dys-function. Second, only a small proportion of screened persons have been ultimately randomly allocated. The SHEP protocol excluded participants with major mor-bidity and severe renal failure. Therefore, in this cohort, the highest value of the baseline serum creatinine was limited to 212.2 µmol/L (2.40 mg/dL). The results of this study cannot be generalized to patients with severe re-nal failure, congestive heart failure, unstable angina, or with recent stroke or myocardial infarction and to those who have contraindications to the use of diuretic agents orb-blockers. Finally, the post hoc design of the pre-sent analyses does not allow a definitive cause-and-effect statement.
Few randomized studies have examined the effects of antihypertensive agents on morbid or mortal events in patients with renal dysfunction. In the Hypertension De-tection and Follow-up Program trial, there was no signifi-cant difference in mortality reduction with optimal BP con-trol with mainly diuretic therapy among patients with baseline serum creatinine levels of less than 150.3 µmol/L (,1.70 mg/dL) compared with those with higher creati-nine levels.1In a trial of patients with insulin-dependent diabetic nephropathy,10the administration of captopril sig-nificantly decreased the combined end point of mortality or need of dialysis or renal transplantation. In another trial of patients with renal insufficiency caused by various dis-orders,9the administration of benazepril prevented the pro-gression of renal failure as assessed by serum creatinine levels and decreased BPs but was associated with a sig-nificant excess mortality. Compared with conventional treatment, in a 7-year extended follow-up of a trial of pa-tients with chronic nephropathy,17enalapril maleate treat-ment was associated with a significantly lower incidence in the combined end point of death or renal replacement therapy. Most of these studies have shown beneficial ef-fects of antihypertensive treatment on mortality or end-stage renal disease. They provide little information, however, on the efficacy of treatment in preventing car-diovascular events in patients with renal dysfunction.
The present findings have important clinical rel-evance. Serum creatinine levels tend to increase with creasing age in healthy persons, and even small in-creases in the serum creatinine level are associated with a significant increase in the risk of cardiovascular events.1
There is emerging evidence that diuretic-based treat-ment of isolated systolic hypertension is effective in preventing major cardiovascular events in subgroups of high-risk older patients such as those with type 2 diabe-tes mellitus18or renal dysfunction, as described herein. It is not known yet whether modern antihypertensive agents, such as angiotensin-converting enzyme inhibi-tors that are more effective than diuretic agents in improving secondary measures of renal function, are also more effective in preventing major morbid events in patients with mild renal dysfunction. The present findings are in agreement with the recommendations of the 1995 update of the Working Group Reports on Chronic Renal Failure and Renovascular Hypertension4 and strongly support the use of diuretics for the treat-ment of hypertension in patients with mild renal dys-function.
Accepted for publication October 2, 1997.
Reprints: Marco Pahor, MD, Department of Preven-tive Medicine, University of Tennessee, College of Medi-cine, 66 N Pauline, Suite 633, Memphis, TN 38105 (e-mail: [email protected]).
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