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Background: Chronic kidney disease is common in older patients with hypertension. Objective: To compare rates of coronary heart disease (CHD) and end-stage renal disease (ESRD) events; to determine whether glomerular filtration rate (GFR) independently predicts risk for CHD; and to report the efficacy of first-step treatment with a calcium-channel blocker (amlodipine) or an angiotensin-converting enzyme inhibitor (lisinopril), each compared with a diuretic (chlorthalidone), in modifying cardiovascular disease (CVD) outcomes in high-risk patients with hypertension stratified by GFR. Design: Post hoc subgroup analysis. Setting: Multicenter randomized, double-blind, controlled trial. Participants: Persons with hypertension who were 55 years of age or older with 1 or more risk factors for CHD and who were stratified into 3 baseline GFR groups: normal or increased ([greater than or equal to] 90 mL/min per 1.73 [m.sup.2]; n 8126 patients), mild reduction (60 to 89 mL/min per 1.73 [m.sup.2]: n- 18 109 patients), and moderate or severe reduction (< 60 mL/min per 1.73 [m.sup.2]; n = 5662 patients). Interventions: Random assignment to chlorthalidone, amlodipine, or lisinopril. Measurements: Rates of ESRD, CHD, stroke, and combined CVD (CHD, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease). Results: In participants with a moderate to severe reduction in GFR, 6-year rates were higher for CHD than for ESRD (15.4% vs. 6.0%, respectively). A baseline GFR of less than 53 mL/min per 1.73 [m.sup.2] (compared with >104 mL/min per 1.73 [m.sup.2]) was independently associated with a 32% higher risk for CHD Amlodipine was similar to chlorthalidone in reducing CHD (16.0% vs. 15.2%, respectively; hazard ratio, 1.06 [95% Cl, 0.89 to 1.27]), stroke, and combined CVD (CHD, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease), but less effective in preventing heart failure. Lisinopril was similar to chlorthalidone in preventing CHD (15.1% vs. 15.2%, respectively; hazard ratio, 1.00 [Cl, 0.84 to 1.20]), but was less effective in reducing stroke, combined CVD events, and heart failure. Limitations: Proteinuria data were not available, and combination therapies were not tested. Conclusions: Older high-risk patients with hypertension and reduced GFR are more likely to develop CHD than to develop ESRD. A low GFR independently predicts increased risk for CHD. Neither amlodipine nor lisinopril is superior to chlorthalidone in preventing CHD, stroke, or combined CVD, and chlorthalidone is superior to both for preventing heart failure, independent of level of renal function.

The findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have generated worldwide reaction from clinicians and researchers, including a recent commentary in this journal. Such response was expected for a trial of ALLHAT's size and scope, especially since its results challenged some widely held beliefs. This paper reviews key aspects of the ALLHAT design, analyses, findings, and conclusions to provide a perspective on the commentary about the trial's results and implications for clinical practice. Several of the most frequent comments regarding the study's results are addressed, particularly with respect to heart failure and diabetes outcomes. Responses to these comments reinforce the investigators' original conclusion that thiazide-type diuretics should remain the preferred first-step drug class for treating hypertension and should generally be a part of any multidrug regimen.

Background: The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial reported that treatment initiated with doxazosin compared with chlorthalidone doubled the risk for heart failure in high-risk hypertensive patients (relative risk, 2.04 [95% CI, 1.79 to 2.32]). Patients assigned to doxazosin therapy had a mean in-trial systolic/diastolic blood pressure 3/0 mm Hg higher than that in patients assigned to chlorthalidone. Sixty-eight percent (6167 to 9061) of the former patients and 59% (9081 of 15 256) of the latter patients were given additional medications to achieve a target blood pressure of less than 140/90 mm Hg. Objective: To ascertain the influence of open-label antihypertensive drugs and subsequent blood pressure on relative risk for heart failure. Design: Randomized, double-blind, active-controlled clinical trial. Setting: 623 sites in the United States and Canada. Patients: Hypertensive patients 55 years of age or older with at least one additional risk factor for cardiovascular disease. Intervention: Chlorthalidone (12.5 to 25 mg/d) or doxazosin (2 to 8 mg/d) for a planned follow-up of 4 to 8 years. Measurements: Data on blood pressure, medication, and incident heart failure (treated outside hospital, hospitalized, of fatal) from February 1994 through December 1999. Results: After the treatment groups were categorized as having no exposure to open-label medications (monotherapy) or exposure to open-label therapy, the relative risk for heart failure with doxazosin versus chlorthalidone was 3.10 (CI, 2.51 to 3.82) and 1.42 (CI, 1.20 to 1.69), respectively. After adjustment for follow-up systolic/diastolic blood pressure, the overall relative risk was 2.00 (CI, 1.72 to 2.32). Conclusion: In high-risk patients with hypertension, the higher risk for heart failure while taking doxazosin compared with chlorthalidone is attenuated but not eliminated by adding other antihypertensive drugs. The small observed difference in systolic blood pressure does not explain this increased risk.

Background: Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and [Beta]-blockers adversely alters levels of other cardiovascular disease risk factors. Methods: The Systolic Hypertension in the Elderly Program was a community-based, multicenter, randomized, double-blind, placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older. This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program, including changes in serum chemistry test results in a subgroup for 3 years. Patients were randomized to receive placebo or treatment with active drugs, with the dose increased in stepwise fashion if blood pressure control goals were not attained: step 1, 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. Results: After 3 years, the active treatment group had a 13/4 min Hg greater reduction in systolic and diastolic blood pressure than the placebo group (both groups, P [is less than] 001). New cases of diabetes were reported by 8.6% of the participants in the active treatment group and 7.5% of the participants in the placebo group (P = .25). Small effects of active treatment compared with placebo were observed with fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P [is less than] 01), total cholesterol (+0.09 mmol/L [+3.5 mg/dL]; P [is less than] .01), high-density lipoprotein cholesterol (0.02 mmol/L [-0.77 mg/dL]; P [is less than] 01) and creatinine (+2.8 [micro]mol/L [+0.03 mg/dL]; P [is less than] 001). Larger effects were seen with fasting levels of triglycerides (+0.9 mmol/L [+17 mg/dL]; P [is less than] 001), uric acid (+35 [micro]mol/L [+.06 mg/dL]; P [is less than] 001), and potassium (-0.3 mmol/L; P [is less than] 001). No evidence was found for a subgroup at higher risk of risk factor changes with active treatment. Conclusions: Antihypertensive therapy with low-dose chlorthalidone (supplemented if necessary) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels. Arch Intern Med. 1998;158:741-751

Objective: To determine the relationship between increasing depressive symptoms and cardiovascular events or mortality. Design: Cohort analytic study of data from randomized placebo-controlled double-blind clinical trial of antihypertensive therapy. Depressive symptoms were assessed semiannually with the Center for Epidemiological Studies-Depression (CES-D) scale during an average follow-up of 4.5 years. Setting: Ambulatory patients in 16 clinical centers of the Systolic Hypertension in the Elderly Program. Patients: Generally healthy men and women aged 60 years or older randomized to active antihypertensive drug therapy or placebo who were.79% white and 53% women and had follow-up CES-D scores and no outcome events during the first 6 months (N=4367). Main Outcome Measures: All-cause mortality, fatal or nonfatal stroke, or myocardial infarction. Results: Baseline depressive symptoms were not related to subsequent events; however, an increase in depression was prognostic. Cox-proportional hazards regression analyses with the CES-D scale as a time-dependent variable, controlling for multiple covariates, indicated a 25% increased risk of death per 5-unit increase in the CES-D score (relative risk [RR], 1.25; 95% confidence interval [CI], 1.15 to 1.36). The RR for stroke or myocardial infarction was 1. 18 (95% CI, 1.08 to 1.30). Increase in CES-D store was an independent predictor in both placebo and active drug groups, and it was strongest as a risk factor for stroke among women (RR, 1.29; 95% CI, 1.07 to 1.34). Conclusions: Among elderly persons, a significant and substantial excess risk of death and stroke or myocardial infarction was associated with. an increase in depressive symptoms over time, which may be a marker for subsequent major disease events and warrants the attention of physicians to such mood changes. However, further studies of causal pathways are needed before widespread screening for depression in clinical practice is to be recommended. (Arch Intern Med. 1996,156:553-561)

Background: Increasing concern over long-term drug treatment of mild hypertension has stimulated several studies of weight reduction. Phase I of the Trial of Antihypertensive Interventions and Management demonstrated a short-term effect of weight loss on blood pressure control in overweight persons with mild hypertension, who were either taking placebo or taking low-dose monotherapy. Phase II investigates the long-term benefit of weight loss on the ability to maintain blood pressure control. Methods: From 10 148 community-based screenees, 587 persons (5.8%), aged 21 to 65 years, entered a multicenter, randomized drug (double-blind, placebo-controlled) and diet trial. Participants had a diastolic blood pressure between 90 and 100 mm Hg and were at 110% to 160% of their ideal weight. They were randomized to a usual diet (n=296) or to a weight loss diet (n=291) and within each diet group to placebo, chlorthalidone, 25 mg/d, or atenolol, 50 mg/d. Treatment failure was defined as using additional antihypertensive medications if diastolic blood pressure rose above 90 mm Hg according to protocol-specified criteria. Results: At baseline, mean diastolic blood pressure was 93 mm Hg; systolic blood pressure, 143 mm Hg; weight, 88 kg; percent ideal weight, 137%; age, 48 years; 56% were men; and 33% were black. Mean follow-up was 4.5 years. There was a net loss of 2 to 3 kg with weight loss diet compared with usual diet over most of the follow-up period. The 5-year incidence of treatment failure was 56.7 per 100 participants with usual diet and 49.8 per 100 with weight loss. Long-term weight loss decreased failure of blood pressure control for those receiving placebo or low-dose diuretic or [Beta]-blocker by 23%. The results were similar in direction in each drug group. Conclusions: The Trial of Antihypertensive interventions and Management demonstrated that weight reduction is an effective long-term therapy for maintaining blood pressure in the normal range when used as monotherapy or in combination with either thiazide diuretics or [Beta]-blockers. Consequently, weight loss should be recommended for the management of obese individuals with mild hypertension. (Arch Intern Med. 1993;153:1773-1782)

The effects of diet and drug therapy on quality-of-life need to be taken into account when an antihypertensive regimen is chosen. In a recent clinical trial, weight reduction was shown to have a considerable positive effect on quality-of-life measures, and sodium restriction had a detrimental impact.

* This report examines the effect of weight loss, alone and in combination with drugs, on diastolic blood pressure change in the Trial of Antihypertensive Interventions and Management (TAIM), which is a randomized, multicenter, placebo-controlled clinical trial of drug and diet combinations in the treatment of mild hypertension among 787 patients. Diastolic blood pressure drop (11.6 mm Hg) at 6 months among those patients who were randomized to weight reduction and placebo drug treatment was greater among those who lost 4.5 kg or more, than the 7-mm Hg drop for those who lost less than 2.25 kg or for the placebo-treated control group, and it was statistically equivalent to the reduction achieved by 25 mg of chlorthalidone or 50 mg of atenolol (11.1- and 12.4-mm Hg drop, respectively). Weight loss potentiated effects of drugs, with reductions of 18.4 mm Hg, for those patients who were taking atenolol and had a 4.5-kg or more weight loss, and of 15.4 mm Hg, for those patients who were taking chlorthalidone and had at least a 2.25-kg weight loss. We concluded that effective weight loss ([Mathematical Expresssion Omitted] 4.5 kg) lowers blood pressure similarly to low-dose drug therapy and potentiates drug effects, with the apparent 4.5-kg threshold being lowered to 2.25 kg for those patients who receive chlorthalidone. (Arch Intern Med. 1992;152:131-136)

Patients with mild high blood pressure (hypertension) often have no symptoms (asymptomatic). As many antihypertensive drugs have recognized side effects, a common perception among physicians is that patients regard the treatment as worse than the disease. In recent years, studies of drugs and their side effects have included evaluations of effects on quality of life. A recent study, the Trial of Antihypertensive Interventions and Management (TAIM), was designed to assess the effects of various combinations of drug and diet therapies on blood pressure, cardiovascular risks and quality of life after six months of therapy. The drugs studied were chlorthalidone, atenolol, and a placebo; the diets were a usual diet, a low sodium, high potassium diet, and a weight-reducing regimen. Among the quality of life issues studied were sleep, depression, anxiety, fatigue, satisfaction with physical health, and sexual satisfaction. While there may have been some clinically relevant side effects, there were no statistically significant adverse effects attributed to either antihypertensive drug or the placebo. One exception was chlorthalidone, which caused problems with erection, orgasm, and sexual interest in men who maintained their usual diets. However, the patients on chlorthalidone and a weight-reducing diet had the least sexual dysfunction, as well as the greatest weight loss and blood pressure reduction. The weight-reducing diet seemed to enhance satisfaction with physical health, while the low sodium, low potassium diet caused sexual problems in men, and had more adverse effects on sleep and fatigue than did a usual diet. The weight-reducing diet enhanced the blood pressure reducing effect of both drugs, and reduced cardiovascular risks; the combinations of low sodium, low potassium diet and antihypertensive drug therapy did not. Thus, this study suggests that a weight-reducing diet can be a useful addition to drug therapy, as it seems to prevent problems with sexual function in asymptomatic male patients with mild hypertension. (Consumer Summary produced by Reliance Medical Information, Inc.)

Drugs used to treat hypertension, abnormally high blood pressure, may actually increase the risk of developing cardiovascular disease, which affects the major blood vessels supplying the heart. Adverse effects of antihypertensive agents on cardiovascular risk factors may be particularly important in patients with less severe hypertension, because most deaths due to hypertension occur among people with moderate hypertension. The effects of diet and drug therapy for mild hypertension on cardiovascular risk factors were assessed in 692 patients with mild hypertension and whose weight was between 110 and 160 percent of ideal. Nine different therapy regimens were developed using combinations of the usual, low sodium-high potassium weight loss diets and the antihypertensive agents, chlorthalidone and atenolol, or else a placebo or substance with no known therapeutic effect. The cardiovascular risk associated with each of the nine different treatment combinations was evaluated after a period of six months. A decrease in blood pressure was associated with a reduction in cardiovascular risk in all treatment groups except that in which the usual diet was combined with chlorthalidone, which produced increased cholesterol levels. Antihypertensive agents combined with a weight loss diet were associated with the lowest risk of cardiovascular disease. The findings show that diet and antihypertensive agents have different effects on cardiovascular risk, and dietary therapy, particularly weight reduction, helped to reduce cardiovascular risk. (Consumer Summary produced by Reliance Medical Information, Inc.)

JOSHUA I. BARZILAY [1] CHERYL L. JONES [2] BARRY R. DAVIS [2] JAN N. BASILE [3] DAVID C. GOFF JR. [4] JERRY O. CIOCON [5] MARY ELLEN SWEENEY [6] OTELIO [...]

Optimal first-step antihypertensive drug therapy in persons with type 2 diabetes mellitus (DM) or impaired fasting glucose (IFG) is uncertain. This randomized, double-blind, active-controlled clinical trial assessed efficacy of first-step [...]

Background: A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease. Objective: To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients. Design: Subset analysis of a randomized, controlled trial. Setting: 80 hospitals and affiliates in the United States and Canada. Patients: 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL). Intervention: Pravastatin, 40 mg/d, or placebo. Measurements: Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke. Results: Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% Cl, 4 to 13 percentage points]; relative risk reduction, 32%; P [is less than] 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [Cl, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [Cl, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (Cl, 8 to 24) to prevent a major coronary event and 22 (Cl, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients. Conclusions: In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial., Pravastatin appears to reduce the risk of heart attacks and stroke in older patients with average levels of blood cholesterol and a previous heart attack. Pravastatin is a cholesterol-lowering drug. Researchers treated 1,283 elderly patients, with average cholesterol levels of 240 mg/dL, with either pravastatin or a placebo. In five years of study, 19.7% of patients taking pravastatin, and 28.1% of patients taking a placebo, had a heart attack or other major coronary event. Pravastatin treatment lowered the risk of heart attack by 45% and the stroke risk by 40% in this group of elderly patients.