Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. Pharmaceutical care program for patients with uncontrolled hypertension. Report of a double-blind clinical trial with ambulatory blood pressure monitoring. Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Bendrofluazide fails to reduce elevated blood pressure levels in the immediate post-stroke period. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Thiazide diuretic agents and the incidence of hip fracture. Effects of benazepril and hydrochlorothiazide, given alone and in low- and high-dose combinations, on blood pressure in patients with hypertension.
Blood pressure (BP) and metabolic variables were determined initially and after 1, 2, 4, 6 and 10 years' treatment in two groups of hypertensive men (n = 53 each) randomized to bendroflumethiazide 2.5-5 mg/day or propranolol 160-320 mg daily. There was no significant differences in BP or metabolic variables between the two groups at entry. BP was reduced to the same degree by both treatments. Five men in the propranolol group and one man in the thiazide group developed clinically overt diabetes during follow-up. Fasting blood sugar increased slightly but significantly though equally in both groups. Oral glucose tolerance was initially impaired to the same degree in both groups but improved significantly during treatment with both drugs. Fasting insulin increased slightly but to the same degree. While serum potassium decreased significantly in the thiazide group, the total body potassium was unchanged in this group. In the propranolol group, serum potassium rose, while total body potassium decreased significantly. Serum urate increased in both groups, though slightly more during thiazide treatment. One case of gout was found in each group. There was no difference in serum lipids between the two groups. The finding in this long-term trial indicate that in middle-aged men with mild to moderate hypertension a low-dose thiazide diuretic like bendroflumethiazide is as effective and safe an antihypertensive agent as the beta-blocker propranolol is and that it does not induce diabetes. The total clinical picture favors the retention of thiazide diuretics as a first choice drug in hypertension. Men aged 40-64 years with mild to moderate hypertension [diastolic blood pressure (DBP) 100-130 mmHg] were randomized to treatment with a diuretic (n = 3272) or a beta-blocker (n = 3297), with additional drugs if necessary, to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease (CHD) events and death. Patients with previous CHD, stroke or other serious diseases, or with contraindications to diuretics or beta-blockers were excluded. If normotension (DBP less than 95 mmHg) was not achieved by monotherapy, other antihypertensive drugs were added, but the two basic drugs were not crossed over. Patients were assessed at 6-monthly intervals. The mean follow-up for end-points was 45.1 months. Blood pressure (BP) side effects and end-points were recorded in a standardized manner. Entry characteristics and the BP reduction achieved were very similar in both treatment groups. All analyses were made on an intention-to-treat basis. The incidence of CHD did not differ between the two treatment groups. The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group. Total mortality and the total number of end-points were similar in both groups. The percentage of patients withdrawn due to side effects was similar, whereas the number of reported symptoms, according to a questionnaire, was higher for patients on beta-blockers. The incidence of diabetes did not differ between the two groups. Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers, and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD. Beta-blockers and thiazide diuretics were approximately equally well tolerated. The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group. Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications, including CHD, to a different extent. Pharmaceutical care programs may be an option to improve blood pressure (BP) control in patients with uncontrolled hypertension. The aim of this study was to evaluate the efficacy of pharmaceutical care programs in treating patients with resistant hypertension.
                In a double-blind randomized clinical trial, 71 patients with uncontrolled BP were enrolled in a pharmaceutical care program or in a control group and underwent a series of cognitive tests. The primary outcome was change in ambulatory BP (ABP) between the baseline evaluation and the final visit 6 months later. The secondary outcomes were the frequency of drug-related problems and adherence as determined by plasma levels of hydrochlorothiazide.
                The delta-values between the intervention and control groups for ABP in the different daily periods, with the corresponding 95% confidence limits, adjusted for age and baseline BP were: 3 (-1 to 5), 2 (-2 to 4), and 5 (-1 to 6) mm Hg for 24 h, daily and nightly systolic BP, respectively. The corresponding values for diastolic BP were 1 (-1 to 3), 0 (-2 to 2), and 3 (-1 to 4) mm Hg, respectively. Hydrochlorothiazide was detected in the plasma in 21 of 27 patients in the intervention group that attended to all appointments and 24 of 30 patients in the control group (P = .904).
                The pharmaceutical care program tested in this trial was feasible and showed a trend for better BP control in patients with uncontrolled hypertension. 1 A placebo-controlled, randomised double-blind comparison of captopril 25 mg three times a day, hydrochlorothiazide 15 mg three times a day, and the combination was conducted in 207 patients with essential hypertension with supine diastolic blood pressures of 92-110 mm Hg. Significant decreases in blood pressure were seen in all three groups; the magnitude of decrease seen with captopril and hydrochlorothiazide was similar, while the combination produced an additive response greater (p less than 0.001) than captopril or hydrochlorothiazide alone. 2 The major side effect reported was a rash in fewer than 6% of patients taking captopril alone or in combination. Loss of taste or proteinuria was not observed. 3 The addition of captopril of hydrochlorothiazide blunted the hypokalaemia and hyperuricaemia observed with hydrochlorothiazide alone in addition to its antihypertensive synergy. These observations indicate that this relatively low dose of captopril is safe and efficacious in the treatment of mild to moderate hypertension alone and particularly when combined with a thiazide diuretic. The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide.
                A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial.
                The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo.
                The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension. Blood pressure (BP) levels, beat-to-beat blood pressure variability, dynamic cerebral autoregulation and cardiac baroreceptor sensitivity are frequently abnormal following acute stroke and are associated with an adverse short- and long-term prognosis. Thiazide diuretics are effective antihypertensive agents in preventing primary and secondary stroke, but their hypotensive and cerebral autoregulatory effects in the immediate post-stroke period have not been studied.
                Thirty-seven hypertensive neuroradiologically proven ischaemic stroke patients were randomized in a double-blind, placebo controlled, parallel group study to bendrofluazide 2.5 mg daily or matching placebo, within 96 h of stroke onset, for a 7-day period. Casual and non-invasive beat-to-beat arterial BP levels, cerebral blood flow velocity, ECG and transcutaneous carbon dioxide levels were measured within 70 +/- 20 h of cerebral infarction and again 7 days later. Dynamic cerebral autoregulatory indices, pulse interval, BP variability and cardiac baroreceptor sensitivity were also calculated.
                Small, non-significant falls were seen in casual and beat-to-beat BP levels over the 7-day period in both active and placebo-treated patients with no differences between treatments. No significant changes were seen in dynamic cerebral autoregulation or in cardiac baroreceptor sensitivity during the follow-up in either group.
                Following acute ischaemic stroke, the standard dose of bendrofluazide at 2.5 mg daily in this study sample did not lower systemic BP levels over the subsequent 7-day period. There was no evidence that bendrofluazide significantly altered cerebral autoregulation or improved cardiac baroreceptor sensitivity post-ictus. Bendrofluazide appears to be an ineffective hypotensive agent at the standard dosage in the initial post-stroke period.
                Copyright 2005 S. Karger AG, Basel. Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension.
                After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (-20.3/-14.2 versus -18.6/-13.0 mm Hg; P<0.05) and were also greater at week 52 (-22.1/-16.0 versus -21.2/-15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (-17.4/-12.2 versus -14.7/-10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001).
                Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension. Thiazide diuretic agents lower the urinary excretion of calcium. Their use has been associated with increased bone density, but their role in preventing hip fracture has not been established. We prospectively studied the effect of thiazide diuretic agents on the incidence of hip fracture among 9518 men and women 65 years of age or older residing in three communities. At base line, 24 to 30 percent of the subjects were thiazide users. In the subsequent four years, 242 subjects had hip fractures. The incidence rates of hip fracture were lower among thiazide users than nonusers in each community; the Mantel-Haenszel relative risk of hip fracture, adjusted for community and age, was 0.63 (95 percent confidence interval, 0.46 to 0.86). The protective effect of the use of thiazides was independent of sex, age, impaired mobility, body-mass index, and current and former smoking status; the multivariate adjusted relative risk of hip fracture was 0.68 (95 percent confidence interval, 0.49 to 0.94). Furthermore, the protective effect was specific to thiazide diuretic agents, since there was no association between the use of antihypertensive medications other than thiazides and the risk of hip fracture. These prospective data suggest that in older men and women the use of thiazide diuretic agents is associated with a reduction of approximately one third in the risk of hip fracture. To assess the efficacy and safety of several combinations of benazepril, an angiotensin-converting enzyme inhibitor, and hydrochlorothiazide, as compared with placebo, in the treatment of patients with essential hypertension.
                A 6-week, randomized, double-blind, parallel study conducted at 24 centers. A placebo run-in period of 1 to 4 weeks preceded the double-blind phase.
                Male and female outpatients, aged 18 years and older, were eligible to participate if their sitting diastolic blood pressure was between 95 and 114 mm Hg at the last two consecutive visits during the placebo phase. Among the 334 patients who entered the double-blind phase, 17% were aged 65 years or older and 26% were black. Eleven patients withdrew because of adverse experiences, including two patients receiving placebo.
                Patients received placebo; benazepril, 20 mg; hydrochlorothiazide, 25 mg; or combination therapy with benazepril/hydrochlorothiazide, 5/6.25 mg, 10/12.5 mg, 20/25 mg, 20/6.25 mg, or 5/25 mg, once daily for 6 weeks.
                The mean change from baseline in sitting diastolic blood pressure at end point (last postrandomization measurement carried forward) in the double-blind phase. Combination therapy with benazepril/hydrochlorothiazide, 20/25 mg, was compared with benazepril, 20 mg alone, and hydrochlorothiazide, 25 mg alone. Sitting systolic blood pressure and the effect of race and age on treatment efficacy were also evaluated.
                Compared with placebo, all benazepril/hydrochlorothiazide combinations produced statistically significant reductions from baseline in sitting diastolic and systolic blood pressures at study end point. In the benazepril/hydrochlorothiazide, 20/25 mg, group, the adjusted mean changes in sitting diastolic blood pressure at end point were statistically significantly greater than those in the monotherapy treatment groups (benazepril, 20 mg, P < or = .05; hydrochlorothiazide, 25 mg, P < or = .001) alone. All therapies were generally well tolerated. Decreases in mean serum potassium level with hydrochlorothiazide monotherapy were reduced or eliminated with combination therapy.
                Benazepril in combination with hydrochlorothiazide, including a low-dose combination of 5/6.25 mg, is effective in reducing sitting diastolic and systolic blood pressure in patients with hypertension.
Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug. This means that the BP lowering effect of thiazides is additive. Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose. Because of the short duration of the trials and lack of reporting of adverse events, this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug.