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Objective: Optimal initial antihypertensive drug therapy in people with the metabolic syndrome is unknown., Research Design and Methods: We conducted a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) to compare metabolic, cardiovascular, and renal outcomes in individuals assigned to initial hypertension treatment with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (CCB; amlodipine), or an ACE inhibitor (lisinopril) in nondiabetic individuals with or without metabolic syndrome., Results: In participants with metabolic syndrome, at 4 years of follow-up, the incidence of newly diagnosed diabetes (fasting glucose >or=126 mg/dl) was 17.1% for chlorthalidone, 16.0% for amlodipine (P = 0.49, chlorthalidone vs. amlodipine) and 12.6% for lisinopril (P < 0.05, lisinopril vs. chlorthalidone). For those without metabolic syndrome, the rate of newly diagnosed diabetes was 7.7% for chlorthalidone, 4.2% for amlodipine, and 4.7% for lisinopril (P < 0.05 for both comparisons). There were no differences in relative risks (RRs) for outcomes with amlodipine compared with chlorthalidone in those with metabolic syndrome; in those without metabolic syndrome, there was a higher risk for heart failure (RR 1.55 [95% CI 1.25-1.35]). In comparison with lisinopril, chlorthalidone was superior in those with metabolic syndrome with respect to heart failure (1.31 [1.04-1.64]) and combined cardiovascular disease (CVD) (1.19 [1.07-1.32]). No significant treatment group-metabolic syndrome interaction was noted., Conclusions: Despite a less favorable metabolic profile, thiazide-like diuretic initial therapy for hypertension offers similar, and in some instances possibly superior, CVD outcomes in older hypertensive adults with metabolic syndrome, as compared with treatment with CCBs and ACE inhibitors.

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.

Angioedema is a rare, potentially life-threatening condition that has been associated with angiotensin-converting enzyme inhibitors since their introduction in the 1980s. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive study conducted to date, randomized 42,418 participants to a diuretic (chlorthalidone), a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-blocker (doxazosin). Patients who developed angioedema were compared for baseline characteristics and changes in antihypertensive drug administration. Fifty-three participants developed angioedema during active follow-up: 55% were black, 60% men, and 70% were assigned to lisinopril (including 62% of black participants with angioedema), 15% to chlorthalidone, 9% to doxazosin, and 6% to amlodipine. Six percent occurred within a day of randomization and 23% within the first week. Over half did not have an increase in their assigned (blinded) antihypertensive drug before angioedema onset; 3 (6%) had a dose increase within a week before onset. One patient died following an angioedema episode. The occurrence of angioedema in the angiotensin-converting enzyme inhibitor arm corresponds with previously reported angioedema-angiotensin-converting enzyme inhibitor associations.

Background: Optimal first-step antihypertensive drug therapy in type 2 diabetes mellitus (DM) or impaired fasting glucose levels (IFG) is uncertain. We wished to determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor decreases clinical complications compared with treatment with a thiazide-type diuretic in DM, IFG, and normoglycemia (NG)., Methods: Active-controlled trial in 31 512 adults, 55 years or older, with hypertension and at least 1 other risk factor for coronary heart disease, stratified into DM (n = 13 101), IFG (n = 1399), and NG (n = 17 012) groups on the basis of national guidelines. Participants were randomly assigned to double-blind first-step treatment with chlorthalidone, 12.5 to 25 mg/d, amlodipine besylate, 2.5 to 10 mg/d, or lisinopril, 10 to 40 mg/d. We conducted an intention-to-treat analysis of fatal coronary heart disease or nonfatal myocardial infarction (primary outcome), total mortality, and other clinical complications., Results: There was no significant difference in relative risk (RR) for the primary outcome in DM or NG participants assigned to amlodipine or lisinopril vs chlorthalidone or in IFG participants assigned to lisinopril vs chlorthalidone. A significantly higher RR (95% confidence interval) was noted for the primary outcome in IFG participants assigned to amlodipine vs chlorthalidone (1.73 [1.10-2.72]). Stroke was more common in NG participants assigned to lisinopril vs chlorthalidone (1.31 [1.10-1.57]). Heart failure was more common in DM and NG participants assigned to amlodipine (1.39 [1.22-1.59] and 1.30 [1.12-1.51], respectively) or lisinopril (1.15 [1.00-1.32] and 1.19 [1.02-1.39], respectively) vs chlorthalidone., Conclusion: Our results provide no evidence of superiority for treatment with calcium channel blockers or angiotensin-converting enzyme inhibitors compared with a thiazide-type diuretic during first-step antihypertensive therapy in DM, IFG, or NG.

Objective: To evaluate the cost-effectiveness of first-line treatments for hypertension.Background: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that first-line treatment with lisinopril or amlodipine was not significantly superior to chlorthalidone in terms of the primary endpoint, so differences in costs may be critical for optimizing decision-making.Methods: Cost-effectiveness analysis was performed using bootstrap resampling to evaluate uncertainty.Results: Over a patient's lifetime, chlorthalidone was always least expensive (mean $4,802 less than amlodipine, $3,700 less than lisinopril). Amlodipine provided more life-years (LYs) than chlorthalidone in 84% of bootstrap samples (mean 37 days) at an incremental cost-effectiveness ratio of $48,400 per LY gained. Lisinopril provided fewer LYs than chlorthalidone in 55% of bootstrap samples (mean 7-day loss) despite a higher cost. At a threshold of $50,000 per LY gained, amlodipine was preferred in 50%, chlorthalidone in 40%, and lisinopril in 10% of bootstrap samples, but these findings were highly sensitive to the cost of amlodipine and the cost-effectiveness threshold chosen. Incorporating quality of life did not appreciably alter the results. Overall, no reasonable combination of assumptions led to 1 treatment being preferred in over 90% of bootstrap samples.Conclusions: Initial treatment with chlorthalidone is less expensive than lisinopril or amlodipine, but amlodipine provided a nonsignificantly greater survival benefit and may be a cost-effective alternative. A randomized trial with power to exclude "clinically important" differences in survival will often have inadequate power to determine the most cost-effective treatment. [ABSTRACT FROM AUTHOR]

Background This study was performed to determine whether, in high-risk hypertensive patients with a reduced glomerular filtration rate (GFR), treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of renal disease outcomes compared with treatment with a diuretic. Methods We conducted post hoc analyses of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertensive participants 55 years or older with at least 1 other coronary heart disease risk factor were randomized to receive chlorthalidone, amlodipine, or lisinopril for a mean of 4.9 years. Renal outcomes were incidence of end-stage renal disease (ESRD) and/or a decrement in GFR of 50% or more from baseline. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease equation, was stratified into normal or increased (≥90 mL /min per 1.73m2, n = 8126), mild reduction (60-89 mL /min per 1.73 m2, n = 18 109), or moderate-severe reduction (<60 mL /min per 1.73 m2, n = 5662) in GFR. Each stratum was analyzed for effects of the treatments on outcomes. Results In 448 participants, ESRD developed. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking amlodipine in the mild (relative risk [RR], 1.47; 95% confidence interval [CI], 0.97-2.23) or moderate-severe (RR, 0.92; 95% CI, 0.68-1.24) reduction in GFR groups. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking lisinopril in the mild (RR, 1.34; 95% CI, 0.87-2.06) or moderate-severe (RR, 0.98; 95% CI, 0.73-1.31) reduction in GFR groups. In patients with mild and moderate-severe reduction in GFR, the incidence of ESRD or 50% or greater decrement in GFR was not significantly different in patients treated with chlorthalidone compared with those treated with amlodipine (odds ratios, 0.96 [P = .74] and 0.85 [P = .23], respectively) and lisinopril (odds ratios, 1.13 [P = .31] and 1.00 [P = .98], respectively). No difference in treatment effects occurred for either end point for patients taking amlodipine or lisinopril compared with those taking chlorthalidone across the 3 GFR subgroups, either for the total group or for participants with diabetes at baseline. At 4 years of follow-up, estimated GFR was 3 to 6 mL /min per 1.73 m2 higher in patients assigned to receive amlodipine compared with chlorthalidone, depending on baseline GFR stratum. Conclusions In hypertensive patients with reduced GFR, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Participants assigned to receive amlodipine had a higher GFR than those assigned to receive chlorthalidone, but rates of development of ESRD were not different between the groups. [ABSTRACT FROM AUTHOR]