Blood-pressure-lowering treatment.
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Adrenergic beta-Antagonists↗
Biomedical subjects
W B Applegate
Publications and source records attributed to W B Applegate.
Dementia and disability outcomes in large hypertension trials: lessons learned from the systolic hypertension in the elderly program (SHEP) trial.
In the Systolic Hypertension in the Elderly Program (SHEP) trial (1985-1990), active treatment reduced the incidence of cardiovascular events, but not that of dementia and disability, as compared with placebo. This study aims to evaluate if assessment of cognitive and functional outcomes was biased by differential dropout. Characteristics of subjects who did or did not participate in follow-up cognitive and functional evaluations were compared. The relative risks of incident cognitive impairment and disability were assessed in the two treatment groups, with the use of the reported findings and under the assumption that the proportions of cognitive and functional impairment among dropouts increased. Assignment to the placebo group and the occurrence of cardiovascular events independently predicted missed assessments. From the reported findings, the risk of cognitive and functional impairment was similar between the two treatment groups. However, when 20-30% and 40-80% of the subjects who missed the assessment were assumed to be cognitively and, respectively, functionally impaired, assignment to active treatment reduced the risk of these outcomes. In the SHEP, the cognitive and functional evaluations were biased toward the null effect by differential dropout. This might have obscured the appraisal of a protective effect of treatment on the cognitive and functional decline of older hypertensive adults.
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Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials.
BACKGROUND: Several observational studies and individual randomised trials in hypertension have suggested that, compared with other drugs, calcium antagonists may be associated with a higher risk of coronary events, despite similar blood-pressure control. The aim of this meta-analysis was to compare the effects of calcium antagonists and other antihypertensive drugs on major cardiovascular events. METHODS: We undertook a meta-analysis of trials in hypertension that assessed cardiovascular events and included at least 100 patients, who were randomly assigned intermediate-acting or long-acting calcium antagonists or other antihypertensive drugs and who were followed up for at least 2 years. FINDINGS: The nine eligible trials included 27,743 participants. Calcium antagonists and other drugs achieved similar control of both systolic and diastolic blood pressure. Compared with patients assigned diuretics, beta-blockers, angiotensin-converting-enzyme inhibitors, or clonidine (n=15,044), those assigned calcium antagonists (n=12,699) had a significantly higher risk of acute myocardial infarction (odds ratio 1.26 [95% CI 1.11-1.43], p=0.0003), congestive heart failure (1.25 [1.07-1.46], p=0.005), and major cardiovascular events (1.10 [1.02-1.18], p=0.018). The treatment differences were within the play of chance for the outcomes of stroke (0.90 [0.80-1.02], p=0.10) and all-cause mortality (1.03 [0.94-1.13], p=0.54). INTERPRETATION: In randomised controlled trials, the large available database suggests that calcium antagonists are inferior to other types of antihypertensive drugs as first-line agents in reducing the risks of several major complications of hypertension. On the basis of these data, the longer-acting calcium antagonists cannot be recommended as first-line therapy for hypertension.
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Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study.
BACKGROUND: Postmenopausal estrogen use has been associated with reduced carotid atherosclerosis in observational studies, but this relationship has not been confirmed in a clinical trial. The impact of estrogen on atherosclerotic disease in other peripheral arteries is unknown. METHODS AND RESULTS: Postmenopausal women with coronary heart disease (CHD) and an intact uterus (n=2763) were randomly assigned to conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) daily or to placebo in a secondary CHD prevention trial. This analysis focuses on incident peripheral arterial procedures and deaths in the 2 treatment groups; peripheral vascular disease was a predefined secondary outcome. During a mean of 4.1 years of follow-up, 311 peripheral arterial events were reported in 213 women, an annual incidence of 2.9%. The number of women who had peripheral arterial events was 99 among those assigned to active estrogen/progestin and 114 among those assigned to placebo, a nonsignificant difference (relative hazard 0. 87, 95% CI 0.66 to 1.14). In the placebo group, hypertension and diabetes mellitus were independently associated with higher rates of peripheral arterial events, and plasma HDL cholesterol and body mass index were associated with lower rates of peripheral arterial events. In the estrogen/progestin group, current smoking and diabetes were independent predictors of peripheral arterial events. Incident peripheral arterial disease was not a significant predictor of coronary, cardiovascular, or total mortality. CONCLUSIONS: Treatment with oral conjugated estrogen plus medroxyprogesterone acetate was not associated with a significant reduction in incident peripheral arterial events in postmenopausal women with preexisting CHD.
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Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP).
CONTEXT: The Systolic Hypertension in the Elderly Program (SHEP) demonstrated that treating isolated systolic hypertension in older patients decreased incidence of total stroke, but whether all types of stroke were reduced was not evaluated. OBJECTIVE: To investigate antihypertensive drug treatment effects on incidence of stroke by type and subtype, timing of strokes, case-fatality rates, stroke residual effects, and relationship of attained systolic blood pressure to stroke incidence. DESIGN: The SHEP study, a randomized, double-blind, placebo-controlled trial began March 1, 1985, and had an average follow-up of 4.5 years. SETTING AND PARTICIPANTS: A total of 4736 men and women aged 60 years or older with isolated systolic hypertension at 16 clinical centers in the United States. INTERVENTIONS: Patients were randomly assigned to receive treatment with 12.5 mg/d of chlorthalidone (step 1); either 25 mg/d of atenolol or 0.05 mg/d of reserpine (step 2) could be added (n = 2365); or placebo (n = 2371). MAIN OUTCOME MEASURES: Occurrence, type and subtype, and timing of first strokes and stroke fatalities; and change in stroke incidence for participants (whether in active treatment or placebo groups) reaching study-specific systolic blood pressure goal (decrease of at least 20 mm Hg from baseline to below 160 mm Hg) compared with participants not reaching goal. RESULTS: A total of 85 and 132 participants in the active treatment and placebo groups, respectively, had ischemic strokes (adjusted relative risk [RR], 0.63; 95% confidence interval [CI], 0.48-0.82); 9 and 19 had hemorrhagic strokes (adjusted RR, 0.46; 95% CI, 0.21-1.02); and 9 and 8 had strokes of unknown type (adjusted RR, 1.05; 95% CI, 0.40-2. 73), respectively. Four subtypes of ischemic stroke were observed in active treatment and placebo group participants, respectively, as follows: for lacunar, n = 23 and n = 43 (adjusted RR, 0.53; 95% CI, 0.32-0.88); for embolic, n = 9 and n = 16 (adjusted RR, 0.56; 95% CI, 0.25-1.27); for atherosclerotic, n = 13 and n = 13 (adjusted RR, 0. 99; 95% CI, 0.46-2.15); and for unknown subtype, n = 40 and n = 60 (adjusted RR, 0.64; 95% CI, 0.43-0.96). Treatment effect was observed within 1 year for hemorrhagic strokes but was not seen until the second year for ischemic strokes. Stroke incidence significantly decreased in participants attaining study-specific systolic blood pressure goals. CONCLUSIONS: In this study, antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained. JAMA. 2000;284:465-471
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Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT).
BACKGROUND: Patients with peripheral arterial disease (PAD) have high rates of cardiovascular morbidity and mortality, including that caused by associated coronary heart disease and cerebrovascular disease. Previous studies have shown that coagulation parameters are altered in PAD and that altered coagulation may play a critical role in the susceptibility to cardiovascular complications in PAD. It is therefore important to assess the effect of secondary prevention measures on coagulation in patients with PAD. The Arterial Disease Multiple Intervention Trial (ADMIT), a multicenter, randomized, placebo-controlled trial, was conducted to determine the feasibility of a combined lipid-modifying, antioxidant, and antithrombotic treatment regimen in patients with PAD. The objective of this study was to assess the effect of the ADMIT interventions on coagulation. METHODS: ADMIT participants were randomly assigned to low-dose warfarin, niacin, and antioxidant vitamin cocktail or corresponding placebos in a 2 x 2 x 2 factorial design. Specialized coagulation studies were performed in a subset of 80 ADMIT participants at baseline and after 12 months of treatment. RESULTS: Low-dose warfarin (1 to 4 mg/d) resulted in a significant decrease in factor VIIc (P <.001) and in plasma F1.2 (P =.001). Unexpectedly, niacin treatment also resulted in significant decrease in both fibrinogen (48 mg/dL; P <.001) and F1.2 (P =.04). von Willebrand factor increased after antioxidant vitamin treatment (P =.04). CONCLUSIONS: A regimen of low-dose warfarin effectively modifies coagulation in patients with PAD. Niacin also favorably modifies fibrinogen and plasma F1.2. Niacin, in addition to its lipid effects, modifies abnormal coagulation factors that accompany PAD.
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Effective and safe modification of multiple atherosclerotic risk factors in patients with peripheral arterial disease.
BACKGROUND: Patients with peripheral arterial disease (PAD) are at an increased risk of cardiovascular mortality and morbidity and thus are an excellent group in whom to evaluate the feasibility and the effect of an aggressive multifactorial intervention on atherosclerotic vascular disease risk factors. The Arterial Disease Multiple Intervention Trial (ADMIT) was designed to determine the efficacy, safety, and compliance of an multifactorial therapy on selected atherosclerotic disease risk factors in patients with PAD. METHODS: By a 2 x 2 x 2 factorial design, eligible participants (N = 468) were randomly assigned to low-dose warfarin, antioxidant vitamins, and niacin or its corresponding placebo, and followed up for 1 year. All participants were encouraged to use aspirin. Pravastatin was added to the drug regimen for those who needed to reduce LDL cholesterol to recommended levels. RESULTS: Niacin increased HDL cholesterol levels by 30%, with the majority of effect achieved at a dosage of 500 mg twice daily. Warfarin had an anticoagulant effect. The antioxidant vitamins resulted in a significant increase in vitamin E, C, and beta-carotene plasma levels. Overall, compliance was high and few adverse effects were reported. CONCLUSIONS: ADMIT demonstrates that it is both feasible and safe to modify multiple atherosclerotic disease risk factors effectively with intensive combination therapy in patients with PAD.
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Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP).
OBJECTIVE: To assess longitudinally the association of serum uric acid and its change due to diuretic treatment with cardiovascular events in hypertensive patients. DESIGN: Cohort study in a randomized trial. SETTING: Cohort of hypertensive patients. PARTICIPANTS: A total of 4327 men and women, aged > or = 60 years, with isolated systolic hypertension, randomized to placebo or chlorthalidone, with the addition of atenolol or reserpine if needed, were observed for 5 years. MAIN OUTCOME MEASURES: Major cardiovascular events, coronary events, stroke and all-cause mortality. RESULTS: Cardiovascular event rates for quartiles of baseline serum uric acid were: I, 32.7 per 1000 person-years; II, 34.5 per 1000 person-years; III, 38.1 per 1000 person-years; and IV, 41.4 per 1000 person-years (P for trend = 0.02). The adjusted hazard ratio (HR), of cardiovascular events for the highest quartile of serum uric acid versus the lowest quartile was 1.32 (95% CI, 1.03-1.69). The benefit of active treatment was not affected by baseline serum uric acid. After randomization, an increase of serum uric acid < 0.06 mmol/l (median change) in the active treatment group was associated with a HR of 0.58 (0.37-0.92) for coronary events compared with those with a serum uric acid increase > or = 0.06 mmol/l. This difference was not explained by blood pressure effects. Those with a serum uric acid increase > or = 0.06 mmol/l in the active treatment group had a similar risk of coronary events as the placebo group. CONCLUSIONS: Serum uric acid independently predicts cardiovascular events in older persons with isolated systolic hypertension. Monitoring serum uric acid change during diuretic treatment may help to identify patients who will most benefit from treatment.
Adrenergic beta-Antagonists↗
Do sweat calcium losses affect bone mass during firefighter training?
Although participation in vigorous exercise is associated with increased bone mass, recent evidence suggests that loss of calcium in sweat may result in a negative calcium balance and, ultimately, a decrease in bone mass. Anthropometric characteristics, habitual physical activity levels, dietary calcium intake, bone mineral content, and bone turnover markers were measured in 42 male recruits before and after 4 months of firefighter training. During two strenuous mid-training sessions, sweat calcium concentrations were measured; they averaged 1.1 mM. Whole body and total hip bone mineral content increased significantly, as did one marker of bone formation, and were not associated with sweat calcium concentration. This study demonstrates that intense physical training sessions that produce high sweat rates do not have an adverse effect on the bone mineral content of healthy young men.
Absorptiometry, Photon↗
Effect of voluntary weight loss on bone mineral density in older overweight women.
OBJECTIVES: To examine the effect of diet and exercise-induced weight loss on bone mineral density in overweight postmenopausal women DESIGN: A 1-year prospective, randomized clinical trial. SETTING: Two university medical school research centers. PARTICIPANTS: Sixty-seven overweight postmenopausal women, a subset of the women who participated in the Trial of Nonpharmacological Interventions in the Elderly (TONE) to control hypertension. The participants were assigned randomly to one of four groups: usual care, weight loss only, sodium restriction only, or combined weight loss/sodium restriction. INTERVENTION: All TONE participants in the treatment groups attended regular dietary intervention sessions to lose weight, reduce sodium intake, or both that they might refrain from using antihypertensive medications for a period of 15 to 36 months (median = 29 months). MEASUREMENTS: Bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DXA), serum and urine markers of bone metabolism, and other demographic and clinical data were collected at baseline, 6 months, and 12 months. RESULTS: Women assigned to the weight loss interventions lost 9.2 +/- 1.2 lbs (mean +/- SE) at 6 months and 7.7 +/- 2.0 lbs at 12 months compared with 1.8 +/- 1.0 lbs at 6 months and 1.9 +/- 1.6 lbs at 12 months for those assigned to no weight loss intervention (P < .0001). Weight loss was correlated with a decrease in total body BMD (P = .004) and an increase in osteocalcin (P = .004) after controlling for baseline bone measures, intervention assignment, and other baseline covariates. Regression analyses indicated that total body BMD decreased by 6.25 +/- 2.06 g/cm2 x 10-4 for each pound of weight loss. CONCLUSIONS: Voluntary weight loss in overweight postmenopausal women is associated with modest decrease in total body BMD. Clinicians recommending weight loss for older postmenopausal women may need to include recommendations for reducing the risk of bone loss.
Absorptiometry, Photon↗
Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program.
The treatment of hypertension with high-dose thiazide diuretics results in potassium depletion and a limited benefit for preventing coronary events. The clinical relevance of hypokalemia associated with low-dose diuretics has not been assessed. To determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events, we analyzed data of 4126 participants in the Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons. After 1 year of treatment, 7.2% of the participants randomized to active treatment had a serum potassium <3.5 mmol/L compared with 1% of the participants randomized to placebo (P<0.001). During the 4 years after the first annual visit, 451 participants experienced a cardiovascular event, 215 experienced a coronary event, 177 experienced stroke, and 323 died. After adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. Within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia (P<0.05). The participants who had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.
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Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes.
OBJECTIVE: To assess whether ACE inhibitors are superior to alternative agents for the prevention of cardiovascular events in patients with hypertension and type 2 diabetes. RESEARCH DESIGN AND METHODS: This study is a review and meta-analysis of randomized controlled trials that included patients with type 2 diabetes and hypertension who were randomized to an ACE inhibitor or an alternative drug, were followed for > or =2 years, and had adjudicated cardiovascular events. RESULTS: A total of 4 trials were eligible. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial (n = 470) compared enalapril with nisoldipine, the Captopril Prevention Project (CAPPP) (n = 572) compared captopril with diuretics or beta-blockers, the Fosinopril Versus Amlodipine Cardiovascular Events Trial (FACET) (n = 380) compared fosinopril with amlodipine, and the U.K. Prospective Diabetes Study (UKPDS) (n = 758) compared captopril with atenolol. The cumulative results of the first 3 trials showed a significant benefit of ACE inhibitors compared with alternative treatments on the outcomes of acute myocardial infarction (63% reduction, P < 0.001), cardiovascular events (51% reduction, P < 0.001), and all-cause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS. The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in any of the trials. None of the findings were explained by differences in blood pressure control. CONCLUSIONS: Compared with the alternative agents tested, ACE inhibitors may provide a special advantage in addition to blood pressure control. The question of whether atenolol is equivalent to captopril remains open. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials.
Angiotensin-Converting Enzyme Inhibitors↗
The role of diastolic blood pressure when treating isolated systolic hypertension.
OBJECTIVE: To assess the role of treated diastolic blood pressure (DBP) level in stroke, coronary heart disease (CHD), and cardiovascular disease (CVD) in patients with isolated systolic hypertension (ISH). DESIGN: An analysis of the 4736 participants in the Systolic Hypertension in the Elderly Program (SHEP) was undertaken. The SHEP was a randomized multicenter double-blind outpatient clinical trial of the impact of treating ISH in men and women aged 60 years and older. MAIN OUTCOME MEASURES: Cox proportional hazards regression analysis, with DBP and systolic blood pressure (SBP) as time-dependent covariables. RESULTS: After adjustment for the baseline risk factors of race (black vs other), sex, use of antihypertensive medication before the study, a composite variable (diabetes, previous heart attack, or stroke), age, and smoking history (ever vs never) and adjustment for the SBP as a time-dependent variable, we found, for the active treatment group only, that a decrease of 5 mm Hg in DBP increased the risk for stroke (relative risk, [RR], 1.14; 95% confidence interval [CI], 1.05-1.22), for CHD (RR, 1.08; 95% CI, 1.00-1.16), and for CVD (RR, 1.11; 95% CI, 1.05-1.16). CONCLUSIONS: Some patients with ISH may be treated to a level that uncovers subclinical disease, and some may be overtreated. Further studies need to determine whether excessively low DBP can be prevented by more careful titration of antihypertensive therapy while maintaining SBP control. It is reassuring that patients receiving treatment for ISH never perform worse than patients receiving placebo in terms of CVD events.
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Effects of lovastatin and warfarin on early carotid atherosclerosis: sex-specific analyses. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.
BACKGROUND: Few clinical trials have documented the efficacy of preventive treatment in asymptomatic women. METHODS AND RESULTS: Lovastatin and minidose warfarin were evaluated in a factorially designed, placebo-controlled, randomized trial. The primary outcome was 3-year change in the mean maximum intimal-medial thickness of the carotid arteries as measured by B-mode ultrasonography. Participants (n=919) were randomized to 1 of 4 treatment groups: lovastatin alone, warfarin alone, lovastatin+warfarin combination, or a double-placebo group. Eligible participants were asymptomatic for cardiovascular disease, with evidence of early carotid atherosclerosis and moderately elevated LDL cholesterol level. Almost half (n=445) of the participants were women. To avoid confounding, 117 women taking estrogen were excluded from analysis. Both sexes experienced reductions in disease progression with lovastatin; there was no evidence of an overall sex x treatment interaction (P=0.72). When estimates of the sex-specific results were examined post hoc, women experienced disease regression to the greatest extent with the lovastatin + warfarin combination (P=0.02), although the women on lovastatin alone also had a reduction in progression (P=0.09). Men experienced the greatest reduction with lovastatin alone (P=0.02), although there is a suggestion that warfarin may also reduce progression to some extent. CONCLUSIONS: Lovastatin is beneficial in reducing disease progression in women and men. Warfarin has no effect in women, although it may reduce progression in men. In men, warfarin does not add to the benefit of lovastatin and has no advantage over lovastatin alone.
Adult↗
Emerging noninvasive biochemical measures to predict cardiovascular risk.
New predictors of cardiovascular events are needed to improve the accuracy of risk stratification. Such predictors should be easily measurable in the population and potentially modifiable. This review reports on new biomarkers that are closely linked to the pathogenic mechanisms underlying the progression of the atherosclerotic plaque leading to rupture and thrombosis that ultimately precipitate acute clinical events, such as stroke and myocardial infarction. These risk factors have been associated with subclinical or clinical cardiovascular disease in large populations and include markers of lipoprotein and lipid metabolism, vitamin B12 metabolism, fibrinolysis, coagulation, inflammation, infection, endothelial dysfunction, the angiotensin system, and oxidative stress. For other key processes of atherosclerosis and cardiac disease, such as apoptosis or programmed cell death, there are currently no markers that can be measured noninvasively. Atherosclerosis is a multifactorial condition and possibly only a subset of factors are the main determinants of disease in a given patient. A better definition of the cardiovascular risk profile will help to better target primary and secondary prevention. Further epidemiological studies are needed to characterize the actual predictive and clinical value of these new emerging cardiovascular biomarkers.
Biomarkers↗
Prevention of dementia: Syst-Eur trial.
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Blood Pressure↗
Does syndrome X exist in hypertensive elderly persons with impaired glycemic control?
BACKGROUND: This report focuses on the glycemic state in relation to insulin and lipid levels of a cohort of elderly hypertensive persons to estimate the prevalence of syndrome X. METHODS: A cross-sectional study was performed at the University of Tennessee, Memphis, and the General Clinical Research Center (GCRC) on 95 participants in the Trial of Nonpharmacologic Interventions in the Elderly (TONE) study who agreed to participate in an ancillary study. A standard oral glucose tolerance test (OGTT) with insulin and C-peptide levels and a fasting lipid profile were obtained. RESULTS: In this sample of healthy elderly participants with hypertension who were taking an antihypertensive medication, 43 (45.3%) had normal glucose tolerance (NGT), 41 (43.2%) had impaired glucose tolerance (IGT), and 11 (11.6%) had undiagnosed non-insulin-dependent diabetes mellitus (NIDDM). Fasting hyperinsulinemia occurred in only one participant, who was in the IGT group. Hypertriglyceridemia and low high density lipoprotein (HDL) occurred in four persons, none of whom had hyperinsulinemia. Persons in the NIDDM and IGT groups had decreased beta cell function compared to persons in the NGT group, but did not have increased peripheral insulin resistance as estimated from the OGTT data. CONCLUSIONS: Our data demonstrated that in this cohort of elderly hypertensive participants with a high prevalence of central obesity, impaired glycemic control was common, but was not associated with fasting hyperinsulinemia or peripheral insulin resistance. Furthermore, we conclude that syndrome X essentially did not occur in these participants and postulate that the primary etiology for their impaired glycemic control is beta cell dysfunction. Further research is needed to elucidate these relationships.
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Diuretic-based treatment and cardiovascular events in patients with mild renal dysfunction enrolled in the systolic hypertension in the elderly program.
BACKGROUND: It is expected that the treatment of hypertension 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 treatment 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 pressures of 160 mm Hg and higher and diastolic blood pressures of less than 90 mm Hg were randomly assigned to receive either placebo 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, angioplasty, 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 micromol/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 affected by baseline serum creatinine levels. Active treatment did not affect the risk of serum creatinine levels becoming elevated during follow-up. The risk of hypokalemia 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 developing 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 coronary artery events and in analyses stratified by sex or age. CONCLUSION: Diuretic-based treatment of patients with isolated systolic hypertension prevents the development of cardiovascular events in older persons with mild renal dysfunction.
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