Todd McDiarmid, MD

BACKGROUND: Hypertension is associated with an increased risk of morbidity and mortality. This study was undertaken to evaluate if newer classes of antihypertensive medications reduce the risk of cardiovascular events compared with an active control (diuretics) that has demonstrated a reduction in long-term clinical trials.

POPULATION STUDIED: The Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT) includes a total of 42,448 participants recruited from 625 centers in the United States, Canada, Puerto Rico, and the US Virgin Islands. Participants in the trial were men and women 55 years or older with hypertension (systolic blood pressure [SBP] Ž140 mm Hg or diastolic blood pressure [DBP] Ž90 mm Hg, or took medication for hypertension) and at least 1 additional risk factor for coronary heart disease (CHD). Follow-up was scheduled for 6 years. The doxazosin and chlorthalidone groups included 24,335 patients (mean age=67 years; 53% men; 47% non-Hispanic white) who were followed for a median of 3.3 years.

STUDY DESIGN AND VALIDITY: Eligible patients were initially randomized (allocation assignment concealed) to one of the 4 drugs (chlorthalidone, amlodipine, lisinopril, or doxazosin) as a first-line agent and then other drugs (atenolol, reserpine, clonidine, or hydralazine) were added in an open-label fashion, if necessary. The treatment goals were a DBP < 90 mm Hg and an SBP < 140 mm Hg. Following the initial titration visits, participants were seen every 3 months during the first year, and every 4 months thereafter. The randomization process provided an equal percentage of patients previously treated for hypertension, atherosclerotic cardiovascular disease, type 2 diabetes, smoking, low high-density lipoprotein, low ventricular hypertrophy (LVH) by electrocardiogram, and LVH by echocardiogram. The chlorthalidone group and the doxazosin group lost similar percentages of patients to follow-up, 3.2% and 3.7%, respectively, at the time of this analysis. The percentage of patients at years 3 and 4 who were still taking chlorthalidone (or another diuretic) was 87% and 86%, respectively. Of the patients taking doxazosin, only 76% were taking the drug at year 3 and 75% at year 4. By year 4, 40% of the chlorthalidone group was receiving step-up therapy, while 47% of the patients taking doxazosin required additional medications. All of these efforts to provide fair comparisons and use of the intention-to-treat analysis make this a valid comparative study.

OUTCOMES MEASURED: Primary outcome measures were fatal CHD and nonfatal myocardial infarction (MI). Secondary outcome measures included all-cause mortality, stroke, and combined cardiovascular disease (CHD death, nonfatal MI, stroke, angina, coronary revascularization, congestive heart failure [CHF], and peripheral arterial disease).

RESULTS: There was no difference between the doxazosin and chlorthalidone groups in the primary outcomes of fatal CHD or nonfatal MI or the secondary outcome of all-cause mortality. The doxazosin group did, however, have a higher risk of stroke than those patients treated with chlorthalidone (4.2% vs 3.6%; relative risk [RR]=1.19; 95% confidence interval [CI], 1.01-1.40; P=.04; number needed to harm [NNH]=167) and an increased risk of combined cardiovascular disease (25.5% vs 21.8%; RR = 1.25; 95% CI, 1.17-1.33; P <.001; NNH=27). Cardiovascular disease subset analysis demonstrated statistically significant differences in angina, coronary revascularization, and CHF. The difference between the groups was most remarkable for CHF, because a doubling of events occurred with doxazosin compared with chlorthalidone (8.1% vs 4.4%; RR=2.04; 95% CI, 1.79-2.32; P <.001; NNH=27).

BACKGROUND: Hypertension is associated with an increased risk of morbidity and mortality. This study was undertaken to evaluate if newer classes of antihypertensive medications reduce the risk of cardiovascular events compared with an active control (diuretics) that has demonstrated a reduction in long-term clinical trials.

POPULATION STUDIED: The Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT) includes a total of 42,448 participants recruited from 625 centers in the United States, Canada, Puerto Rico, and the US Virgin Islands. Participants in the trial were men and women 55 years or older with hypertension (systolic blood pressure [SBP] Ž140 mm Hg or diastolic blood pressure [DBP] Ž90 mm Hg, or took medication for hypertension) and at least 1 additional risk factor for coronary heart disease (CHD). Follow-up was scheduled for 6 years. The doxazosin and chlorthalidone groups included 24,335 patients (mean age=67 years; 53% men; 47% non-Hispanic white) who were followed for a median of 3.3 years.

STUDY DESIGN AND VALIDITY: Eligible patients were initially randomized (allocation assignment concealed) to one of the 4 drugs (chlorthalidone, amlodipine, lisinopril, or doxazosin) as a first-line agent and then other drugs (atenolol, reserpine, clonidine, or hydralazine) were added in an open-label fashion, if necessary. The treatment goals were a DBP < 90 mm Hg and an SBP < 140 mm Hg. Following the initial titration visits, participants were seen every 3 months during the first year, and every 4 months thereafter. The randomization process provided an equal percentage of patients previously treated for hypertension, atherosclerotic cardiovascular disease, type 2 diabetes, smoking, low high-density lipoprotein, low ventricular hypertrophy (LVH) by electrocardiogram, and LVH by echocardiogram. The chlorthalidone group and the doxazosin group lost similar percentages of patients to follow-up, 3.2% and 3.7%, respectively, at the time of this analysis. The percentage of patients at years 3 and 4 who were still taking chlorthalidone (or another diuretic) was 87% and 86%, respectively. Of the patients taking doxazosin, only 76% were taking the drug at year 3 and 75% at year 4. By year 4, 40% of the chlorthalidone group was receiving step-up therapy, while 47% of the patients taking doxazosin required additional medications. All of these efforts to provide fair comparisons and use of the intention-to-treat analysis make this a valid comparative study.

OUTCOMES MEASURED: Primary outcome measures were fatal CHD and nonfatal myocardial infarction (MI). Secondary outcome measures included all-cause mortality, stroke, and combined cardiovascular disease (CHD death, nonfatal MI, stroke, angina, coronary revascularization, congestive heart failure [CHF], and peripheral arterial disease).

RESULTS: There was no difference between the doxazosin and chlorthalidone groups in the primary outcomes of fatal CHD or nonfatal MI or the secondary outcome of all-cause mortality. The doxazosin group did, however, have a higher risk of stroke than those patients treated with chlorthalidone (4.2% vs 3.6%; relative risk [RR]=1.19; 95% confidence interval [CI], 1.01-1.40; P=.04; number needed to harm [NNH]=167) and an increased risk of combined cardiovascular disease (25.5% vs 21.8%; RR = 1.25; 95% CI, 1.17-1.33; P <.001; NNH=27). Cardiovascular disease subset analysis demonstrated statistically significant differences in angina, coronary revascularization, and CHF. The difference between the groups was most remarkable for CHF, because a doubling of events occurred with doxazosin compared with chlorthalidone (8.1% vs 4.4%; RR=2.04; 95% CI, 1.79-2.32; P <.001; NNH=27).

BACKGROUND: Hypertension is associated with an increased risk of morbidity and mortality. This study was undertaken to evaluate if newer classes of antihypertensive medications reduce the risk of cardiovascular events compared with an active control (diuretics) that has demonstrated a reduction in long-term clinical trials.

POPULATION STUDIED: The Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT) includes a total of 42,448 participants recruited from 625 centers in the United States, Canada, Puerto Rico, and the US Virgin Islands. Participants in the trial were men and women 55 years or older with hypertension (systolic blood pressure [SBP] Ž140 mm Hg or diastolic blood pressure [DBP] Ž90 mm Hg, or took medication for hypertension) and at least 1 additional risk factor for coronary heart disease (CHD). Follow-up was scheduled for 6 years. The doxazosin and chlorthalidone groups included 24,335 patients (mean age=67 years; 53% men; 47% non-Hispanic white) who were followed for a median of 3.3 years.

STUDY DESIGN AND VALIDITY: Eligible patients were initially randomized (allocation assignment concealed) to one of the 4 drugs (chlorthalidone, amlodipine, lisinopril, or doxazosin) as a first-line agent and then other drugs (atenolol, reserpine, clonidine, or hydralazine) were added in an open-label fashion, if necessary. The treatment goals were a DBP < 90 mm Hg and an SBP < 140 mm Hg. Following the initial titration visits, participants were seen every 3 months during the first year, and every 4 months thereafter. The randomization process provided an equal percentage of patients previously treated for hypertension, atherosclerotic cardiovascular disease, type 2 diabetes, smoking, low high-density lipoprotein, low ventricular hypertrophy (LVH) by electrocardiogram, and LVH by echocardiogram. The chlorthalidone group and the doxazosin group lost similar percentages of patients to follow-up, 3.2% and 3.7%, respectively, at the time of this analysis. The percentage of patients at years 3 and 4 who were still taking chlorthalidone (or another diuretic) was 87% and 86%, respectively. Of the patients taking doxazosin, only 76% were taking the drug at year 3 and 75% at year 4. By year 4, 40% of the chlorthalidone group was receiving step-up therapy, while 47% of the patients taking doxazosin required additional medications. All of these efforts to provide fair comparisons and use of the intention-to-treat analysis make this a valid comparative study.

OUTCOMES MEASURED: Primary outcome measures were fatal CHD and nonfatal myocardial infarction (MI). Secondary outcome measures included all-cause mortality, stroke, and combined cardiovascular disease (CHD death, nonfatal MI, stroke, angina, coronary revascularization, congestive heart failure [CHF], and peripheral arterial disease).

RESULTS: There was no difference between the doxazosin and chlorthalidone groups in the primary outcomes of fatal CHD or nonfatal MI or the secondary outcome of all-cause mortality. The doxazosin group did, however, have a higher risk of stroke than those patients treated with chlorthalidone (4.2% vs 3.6%; relative risk [RR]=1.19; 95% confidence interval [CI], 1.01-1.40; P=.04; number needed to harm [NNH]=167) and an increased risk of combined cardiovascular disease (25.5% vs 21.8%; RR = 1.25; 95% CI, 1.17-1.33; P <.001; NNH=27). Cardiovascular disease subset analysis demonstrated statistically significant differences in angina, coronary revascularization, and CHF. The difference between the groups was most remarkable for CHF, because a doubling of events occurred with doxazosin compared with chlorthalidone (8.1% vs 4.4%; RR=2.04; 95% CI, 1.79-2.32; P <.001; NNH=27).