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. Double-blind, parallel, comparative multicentre study of a new combination of diltiazem and hydrochlorothiazide with individual components in patients with mild or moderate hypertension. Effects of thiazide diuretic therapy on bone mass, fractures, and falls. The Study of Osteoporotic Fractures Research Group. The effects of mandatory prescribing of thiazides for newly treated, uncomplicated hypertension: interrupted time-series analysis. Patients compliance in hypertension--the importance of number of tablets. A randomized, controlled trial comparing diltiazem, hydrochlorothiazide, and their combination in the therapy of essential hypertension. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy. A 3-month double-blind cross-over study of the effect of benazepril and hydrochlorothiazide on functional class in symptomatic mild heart failure. Long-term use of thiazide diuretics and risk of hip fracture. Sodium restriction in hypertensive patients treated with a converting enzyme inhibitor and a thiazide. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term therapy. Veterans Administration Cooperative Study Group on Antihypertensive Agents. The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects. Antihypertensive efficacy and safety of fixed-dose combination therapy with losartan plus hydrochlorothiazide in Japanese patients with essential hypertension. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Influences of educational interventions and adverse news about calcium-channel blockers on first-line prescribing of antihypertensive drugs to elderly people in British Columbia. Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Comparative study of once-daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension. Losartan with hydrochlorothiazide in the treatment of hypertension. The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study. Treatment of hypertension by enalapril and hydrochlorothiazide separately and together: a multicenter study. Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension. Quinapril, hydrochlorothiazide, and combination in patients with moderate to severe hypertension. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Double-blind comparison of the efficacy and safety of trandolapril 2 mg and hydrochlorothiazide 25 mg in patients with mild-to-moderate essential hypertension. Investigator Study Group. Comparison of low doses of hydrochlorothiazide plus amiloride and hydrochlorothiazide alone in hypertension in elderly patients. Oslo Hypertension Study. Combined versus single effect of fosinopril and hydrochlorothiazide in hypertensive patients. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. A dose escalation trial comparing the combination of diltiazem SR and hydrochlorothiazide with the monotherapies in patients with essential hypertension. Diuretic drug use and the risk for hip fracture. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.
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. To compare the antihypertensive efficacy and tolerability of a new combination preparation of diltiazem (150 mg) and hydrochlorothiazide (12.5 mg) with the individual constituents in patients with mild/moderate hypertension.
                Multi-centre, double-blind, randomised parallel group study.
                Seventy-one patients with essential hypertension were recruited to the study.
                Following completion of the placebo run-in period 63 patients fulfilled the prerandomisation criteria and entered the 10 week treatment period. Patients were randomised to receive either the combination preparation (D 150 mg/H 12.5 mg), diltiazem (150 mg) or hydrochlorthiazide (12.5 mg). The dosage was increased in three patients who had not attained target blood pressure (BP) control after 6 weeks.
                Response to treatment assessed by change from baseline in clinic and 24 h ambulatory BP.
                The proportion of patients achieving target BP (a reduction in resting supine diastolic blood pressure (DBP) to below 90 mm Hg or a reduction of 10 mm Hg from baseline) was 80% in the combination group, 55% in the diltiazem group, and 38% in the hydrochlorothiazide group. The respective figures for reduction in supine DBP from baseline were 13.5 mm Hg, 11.2 mm Hg and 5.9 mm Hg. A similar treatment order appeared throughout each of the efficacy variables. BP control throughout the 24 h dosing interval was demonstrated by ambulatory BP monitoring. Each treatment was well tolerated.
                This study provides clear evidence of the efficacy of combination therapy with diltiazem and hydrochlorothiazide in the management of patients with hypertension. To determine the relation between the use of thiazide diuretics and bone mass, fractures, and falls in older women.
                Cross-sectional study of thiazide diuretics, bone mass, and prevalent vertebral deformities; cohort analysis of thiazide diuretics and nonspinal fractures and falls.
                Four clinical centers located in Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania.
                A total of 9704 ambulatory, nonblack women who were 65 years or older.
                Information on thiazide use, demographic data, medical history, and anthropometric measurements were obtained by questionnaire, interview, and examination. Appendicular bone mass was measured by single-photon absorptiometry. Incident falls and fractures were ascertained every 4 months.
                Women using thiazide diuretics for more than 10 years had significantly higher bone mass than women who had never used thiazide diuretics (for example, 0.381 g/cm2 compared with 0.355 g/cm2 for the distal radius [P < 0.001]). Current users of thiazide diuretics had an incidence of falls (relative risk, 1.06; 95% CI, 0.90 to 1.25) that was similar to that of those who had never used these drugs. After adjusting for age, body weight, functional status, total calcium intake, duration of estrogen replacement therapy, and self-reported health status, we found that current users of thiazide diuretics who had taken these drugs for more than 10 years had a risk for nonspinal (relative risk, 0.99; CI, 0.81 to 1.20) and osteoporotic (relative risk, 0.98; CI, 0.79 to 1.22) fractures that was similar to that of women who had never used thiazides; however, thiazide users did have a lower risk for fractures of the hip (relative risk, 0.63; CI, 0.34 to 1.16) and wrist (relative risk, 0.66; CI, 0.40 to 1.08), neither of which was significant.
                Thiazide diuretics have no effect on a women's risk for falling or for experiencing nonspinal fractures. The trend toward a lower risk for hip and wrist fractures is consistent with findings in previous cohort studies but may reflect selection factors for the use of thiazide diuretics. A randomized trial is needed to determine the effect ot thiazide diuretics on the incidence of fractures. The purpose of our study was to evaluate the effects of a new reimbursement rule for antihypertensive medication that made thiazides mandatory first-line drugs for newly treated, uncomplicated hypertension. The objective of the new regulation was to reduce drug expenditures.
                We conducted an interrupted time-series analysis on prescribing data before and after the new reimbursement rule for antihypertensive medication was put into effect. All patients started on antihypertensive medication in 61 general practices in Norway were included in the analysis. The new rule was put forward by the Ministry of Health and was approved by parliament. Adherence to the rule was monitored only minimally, and there were no penalties for non-adherence. Our primary outcome was the proportion of thiazide prescriptions among all prescriptions made for persons started on antihypertensive medication. Secondary outcomes included the proportion of patients who, within 4 mo, reached recommended blood-pressure goals and the proportion of patients who, within 4 mo, were not started on a second antihypertensive drug. We also compared drug costs before and after the intervention. During the baseline period, 10% of patients started on antihypertensive medication were given a thiazide prescription. This proportion rose steadily during the transition period, after which it remained stable at 25%. For other outcomes, no statistically significant differences were demonstrated. Achievement of treatment goals was slightly higher (56.6% versus 58.4%) after the new rule was introduced, and the prescribing of a second drug was slightly lower (24.0% versus 21.8%). Drug costs were reduced by an estimated Norwegian kroner 4.8 million (0.58 million Euros, US$0.72 million) in the first year, which is equivalent to Norwegian kroner 1.06 per inhabitant (0.13 Euros, US$0.16).
                Prescribing of thiazides in Norway for uncomplicated hypertension more than doubled after a reimbursement rule requiring the use of thiazides as the first-choice therapy was put into effect. However, the resulting savings on drug expenditures were modest. There were no significant changes in the achievement of treatment goals or in the prescribing of a second antihypertensive drug. The importance of number of tablets for patient compliance was investigated in 160 patients with mild-moderate essential hypertension treated with a beta-adrenoceptor blocker and a thiazide diuretic. Mean BP at entry 146 +/- 16/92 +/- 8 mm Hg. All patients were given pindolol 10 mg and clopamide 5 mg in one combination tablet or in separate tablets for 4 months respectively. Approximately 90% of the patients took greater than 90% of the prescribed dose throughout the study. Mean BP decreased progressively and heart rate increased slightly. Side effects were more frequently reported during the first month of the study than previously, and 30 patients discontinued the treatment. No differences in this respect were seen between 1 and 2 tablets daily. Approximately 75% of the patients preferred 1 tablet daily, but combining two drugs in one tablet had no effect upon compliance. To compare the efficacy of combination therapy with sustained-release diltiazem and hydrochlorothiazide (DTZ SR-HCTZ) with that of monotherapy with DTZ SR, HCTZ, or placebo in the treatment of essential hypertension; and to determine whether the addition of a diuretic to diltiazem at apparent optimum doses of each agent significantly enhances their antihypertensive effects.
                Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial with a 6-week treatment phase.
                Private and university-based clinics.
                Subjects of either sex, ranging in age from 18-70 years, with a diagnosis of stable essential hypertension made from two consecutive weekly mean supine diastolic blood pressure (DBP) readings of 95 mm Hg or above to 110 mm Hg or less that varied 7 mm Hg or less after 4-6 weeks in the baseline phase. Of the patients enrolled, 298 met the inclusion criteria.
                Combination therapy with DTZ SR-HCTZ 120 mg-12.5 mg, or monotherapy with DTZ SR 120 mg or HCTZ 12.5 mg, or placebo was administered twice daily.
                Combination therapy with DTZ SR-HCTZ lowered both supine DBP and SBP significantly (p < 0.005) more than either single agent. The combination also lowered DBP and SBP significantly more than either monotherapy. During a 12-hour in-clinic monitoring period spanning a dosing interval, both the combination and DTZ SR therapies maintained efficacy, whereas the antihypertensive effects of HCTZ dissipated after 8 hours. Treatment-related adverse events for the combination and HCTZ were similar but slightly greater than those for DTZ SR and placebo.
                The addition of a diuretic to sustained-release diltiazem produced an enhanced antihypertensive effect compared with monotherapy with either individual agent. Angiotensin II acts at the cellular level through specific angiotensin II subtype I, AT-1 receptors. Losartan is the first of a new class of antihypertensive agents that specifically block angiotensin II at AT-1 receptors. By acting on complementary and different pharmacologic mechanisms, the concomitant use of low doses of hydrochlorothiazide with losartan may offer an additive antihypertensive activity with fewer adverse experiences.
                This double-blind study evaluated losartan concomitantly administered with hydrochlorothiazide as initial therapy in 703 patients with essential hypertension.
                The greatest reduction in blood pressure was observed in the 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide group (17.2 mm Hg in sitting systolic blood pressure and 13.2 mm Hg in sitting diastolic blood pressure [P < or = .001]), and the effects of the two components appeared to be additive. Seventy-eight percent of the patients treated with 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide had an excellent or good antihypertensive response (sitting diastolic blood pressure < 90 mm Hg or > or = 90 mm Hg with a reduction of 10 mm Hg or more). Peak (6 hours after dosing) and trough placebo-adjusted ratios for the losartan-hydrochlorothiazide groups ranged from 62% to 85%, indicating that there was a smooth reduction in sitting diastolic blood pressure that was sustained over 24 hours. The most common clinical adverse experiences (> or = 4%) that occurred with an incidence slightly greater than that reported by the placebo-treated patients were headache, asthenia or fatigue, dizziness, sinusitis, and upper respiratory infection.
                The concomitant administration of losartan potassium, 50 mg, with 12.5 mg of hydrochlorothiazide once daily produced an additive reduction in trough sitting systolic and diastolic blood pressure and was well tolerated. This study compares the antihypertensive efficacy and tolerability of valsartan, a novel angiotensin II antagonist, given with hydrochlorothiazide (HCTZ) vs placebo or vs valsartan or HCTZ alone.
                871 adult out-patients with essential hypertension participated in this double-blind study. Patients were randomised in equal number to receive either combination therapy of valsartan (80 mg or 160 mg) and HCTZ (12.5 mg or 25 mg), or valsartan (80 mg or 160 mg) or HCTZ (12.5 mg or 25 mg) alone, or placebo. Patients were treated once daily for 8 weeks and assessed at 2, 4 and 8 weeks after randomisation.
                The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure (MSDBP) at end-point. The secondary variable was change in mean sitting systolic blood pressure (MSSBP) from baseline to end-point.
                All active treatments produced a statistically significant difference in MSDBP (P < 0.001) from baseline to end-point compared with placebo. Similar results were obtained for MSSBP. All combination regimens produced a statistically significantly greater reduction in MSDPB and MSSBP than the corresponding monotherapies. Dizziness and headache were the most common treatment-related adverse experiences reported. Hypokalaemia, associated with the use of thiazide diuretics, was more commonly reported in the higher dose HCTZ 25 mg groups.
                Valsartan 80 mg and 160 mg act additively with HCTZ 12.5 mg or 25 mg to lower MSDBP and MSSBP in patients with essential hypertension. The addition of HCTZ to valsartan 80 mg or 160 mg was well tolerated. The non-sulfhydryl selective angiotensin-converting enzyme inhibitor benazepril (20 mg daily) was compared with hydrochlorothiazide (50 mg daily) in post-infarction (6-24 months) patients with symptomatic (NYHA functional class 2) mild heart failure. No concomitant drug therapy was given. The study had a double-blind cross-over design with 3-month treatment periods. Both drugs were well tolerated, and both caused a similar reduction in systolic blood pressure. Heart rate was higher with the diuretic. Benazepril improved the NYHA functional class in 17 out of 29 (59%) patients, whereas one patient improved with hydrochlorothiazide (P = 0.0004). With regard to global efficacy score, benazepril was also superior. Thus, angiotensin-converting enzyme inhibitors may be superior to diuretics as first-choice therapy in symptomatic mild heart failure. To assess whether long-term thiazide use is associated with a decreased risk of hip fracture, a nested case-control study was done in the Canadian province of Saskatchewan between 1984 and 1985 among residents who were 65 years of age or older and who were not receiving other drugs thought to affect bone mass. There were 905 hip fractures identified from hospital discharge records and 5137 population controls matched for age, sex, and calendar year. Drug use was ascertained from computerised pharmacy records. Risk of hip fracture decreased significantly with increasing duration of current thiazide use: relative risk (95% confidence interval) of 1.2 (0.9-1.5) for less than 2 years use, 0.8 (0.7-1.0) for use of 2-5 years, and 0.5 (0.3-0.7) for 6 or more years. In contrast, there was no such trend for use of other antihypertensive-diuretic drugs (relative risk 0.9 [0.6-1.3] for use of 6 or more years). This protective effect was not altered by age, sex, nursing home residence, previous hospital admission, or use of other antihypertensive-diuretic drugs or psychotropic drugs. Medical record review for a sample of 235 cases suggested this finding was not due to confounding by body mass, ambulatory status, functional status, or dementia. These results support the hypothesis that thiazides protect against osteoporosis in elderly people. When the function of the renin system is inhibited, blood pressure becomes more dependent on changes in sodium and water balance. Diuretics alone and sodium restriction alone are additive to converting enzyme inhibitor therapy. However, it is not known if these two ways of reducing sodium balance are additive in the presence of established converting enzyme inhibition. We therefore performed a double-blind crossover study of the effects of moderate sodium restriction in 21 patients with essential hypertension who were already being treated with the combination of a converting enzyme inhibitor and a diuretic. After 1 month of captopril (50 mg twice daily) and hydrochlorothiazide (25 mg once daily) therapy, with their usual sodium intake, average supine blood pressure was 147/96 +/- 5/3 (SEM) mm Hg 2 hours after treatment. Patients then reduced their sodium intake to around 80-100 mmol/day for the remainder of the study. After 2 weeks of sodium restriction, they entered a double-blind, randomized, crossover study of Slow Sodium (100 mmol sodium/day) compared with Slow Sodium placebo, while continuing sodium restriction and the above treatment. During the double-blind study, after 1 month of treatment with captopril (50 mg twice daily), hydrochlorothiazide (25 mg once daily), and Slow Sodium placebo, supine blood pressure 2 hours after treatment was 138/88 +/- 4/2 mm Hg (24-hour urinary sodium 104 +/- 11 mmol). After 1 month of captopril (50 mg twice daily), hydrochlorothiazide (25 mg once daily), and Slow Sodium tablets, supine blood pressure 2 hours after treatment was 147/91 +/- 5/2 mm Hg (p less than 0.05; 24-hour urinary sodium 195 +/- 14 mmol).(ABSTRACT TRUNCATED AT 250 WORDS) As described in the preceding communication, either propranolol hydrochloride or hydrochlorothiazide were randomly allocated in a double-blind manner to 683 patients with initial diastolic BP in the range of 95 to 114 mm Hg. Of this number, 394 entered the long-term treatment phase. During the subsequent 12 months of long-term treatment, hydrochlorothiazide was more effective than propranolol in controlling BP (mean reductions, -17.5/-13.1 mm Hg with hydrochlorothiazide compared with -8.3/-11.3 with propranolol. After treatment with hydrochlorothiazide, a greater percentage of patients achieved the goal diastolic BP of less than 90 mm Hg (65.5% compared with 52.8% taking propranolol). Also during treatment, fewer patients receiving hydrochlorothiazide required termination as compared with those receiving propranolol; comparative dosage requirements were lower; additional titration during long-term treatment was required less often, and BP remained lower after withdrawal of the active drugs. However, biochemical abnormalities were greater with hydrochlorothiazide. Although not statistically significant, the antihypertensive effects of hydrochlorothiazide were greater in blacks than in whites. Whites, on the other hand, had a greater response to propranolol than blacks, although it was still less than the response of the whites to hydrochlorothiazide. The pharmacodynamic effects and acceptability of perindopril (4 mg daily) and hydrochlorothiazide (25 mg daily) given alone or in combination for 1 month were investigated in a double-blind, placebo controlled, parallel group study. The pharmacokinetics of perindopril and its active metabolite perindoprilat and the time course of angiotensin converting enzyme inhibition were studied for 72 h following the last dose of treatment in the two appropriate groups. Similar decreases in blood pressure were seen 24 h after the last dose of perindopril or hydrochlorothiazide (11/7 mm Hg supine) given alone at these doses. The effect of these drugs given together was additive on diastolic blood pressure and synergistic on systolic blood pressure (24.5/12.6 mm Hg supine) taking into account the placebo response. The significant increase in plasma renin activity produced by perindopril alone was potentiated by concurrent administration of hydrochlorothiazide. The formation of perindoprilat was slightly reduced in the group also receiving hydrochlorothiazide and there was a very small reduction in ACE inhibition in this group. Perindopril, whether given alone or in combination with hydrochlorothiazide, was well tolerated and produced no clinically significant change in routine haematology or serum biochemistry. The additive or synergistic effects of perindopril and hydrochlorothiazide on blood pressure must be due to their complementary physiological actions and not to a pharmacokinetic interaction. A randomized, double-blind, placebo-controlled, parallel-group multicenter study was conducted to evaluate the antihypertensive efficacy and safety of 8-week treatment with one of three fixed-dose combinations-losartan 50 mg plus hydrochlorothiazide 12.5 mg, losartan 50 mg plus hydrochlorothiazide 6.25 mg, or losartan 25 mg plus hydrochlorothiazide 6.25 mg-in comparison with those of hydrochlorothiazide 12.5 mg alone, losartan 50 mg alone, or placebo in Japanese patients with essential hypertension. Significant reductions in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were seen in all three combination groups compared with the placebo group (each p<0.001). The greatest reductions in DBP and SBP were observed in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group (12.7 and 18.0 mmHg, respectively). The reductions in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group were significantly greater (each p<0.001) than those in the placebo group and each of the monotherapy groups. There were no significant differences in the incidences of clinical and laboratory drug-related adverse events between any of the combination groups and the placebo group. All combination groups showed improved hypokalemia and hyperuricemia compared to the hydrochlorothiazide 12.5 mg group. These results demonstrated that once-daily, fixed-dose combination therapy with losartan 50 mg plus hydrochlorothiazide 12.5 mg is well tolerated and more efficacious in lowering DBP and SBP than monotherapy in Japanese hypertensive patients. Calcium antagonists are a first-line treatment for hypertension. The effectiveness of diltiazem, a non-dihydropyridine calcium antagonist, in reducing cardiovascular morbidity or mortality is unclear. We compared the effects of diltiazem with that of diuretics, beta-blockers, or both on cardiovascular morbidity and mortality in hypertensive patients.
                In a prospective, randomised, open, blinded endpoint study, we enrolled 10,881 patients, aged 50-74 years, at health centres in Norway and Sweden, who had diastolic blood pressure of 100 mm Hg or more. We randomly assigned patients diltiazem, or diuretics, beta-blockers, or both. The combined primary endpoint was fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death. Analysis was done by intention to treat.
                Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups (reduction 20.3/18.7 vs 23.3/18.7 mm Hg; difference in systolic reduction p<0.001). A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group (16.6 vs 16.2 events per 1000 patient-years; relative risk 1.00 [95% CI 0.87-1.15], p=0.97). Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group (6.4 vs 7.9 events per 1000 patient-years; 0.80 [0.65-0.99], p=0.04) and fatal and non-fatal myocardial infarction in 183 and 157 patients (7.4 vs 6.3 events per 1000 patient-years; 1.16 [0.94-1.44], p=0.17).
                Diltiazem was as effective as treatment based on diuretics, beta-blockers, or both in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death. The way in which dissemination of evidence changes medical practice needs to be better understood. Controversy about calcium-channel blockers (CCB) in the past 3 years has provided a natural experiment, enabling assessment of the impact of media stories, a national warning letter, a teleconference, small group workshops, and newsletters on first-line prescribing of antihypertensive drugs.
                We included all physicians (4403) in British Columbia who prescribed a thiazide diuretic, beta-blocker, inhibitor of angiotensin-converting enzyme (ACE), or CCB as the first antihypertensive agent for 36,507 residents aged 66 years and over, with no previous or concurrent sign of underlying cardiovascular disease. We used a database covering all prescriptions to elderly people to measure the change in proportion of newly treated patients who received each class of drug as first-line therapy. We used a matched cohort design for assessment of the teleconference and workshops, a randomised community design for the newsletters, and time-series analysis for the media impacts.
                The proportion of patients who received a CCB as first-line therapy declined gradually from 22% in early 1994 to 15% in late 1996. This proportion was not affected by two waves of adverse news about CCBs in 1995, but fell by 5% for 5 months and by 3% for 1 month after two waves in 1996. The proportion of patients who received either a CCB or an ACE inhibitor as first-line therapy, contrary to guidelines, was still 42% overall in 1996. The workshops and newsletters were followed by shifts from first-line CCB to first-line thiazide prescribing.
                Changes in prescribing practices occur gradually with the accumulation of small impacts from educational interventions and lay media attention. The purpose of this study was to assess the safety and antihypertensive dose-response effects of irbesartan and hydrochlorothiazide (HCTZ) in patients with mild-to-moderate hypertension. After a 4- to 5-week single-blind placebo lead-in period, 683 patients with seated diastolic blood pressure (SeDBP) between 95 and 110 mm Hg were randomized to receive once-daily dosing with one of 16 different double-blind, fixed combinations of irbesartan (0, 37.5, 100, and 300 mg irbesartan) and HCTZ (0, 6.25, 12.5, and 25 mg HCTZ) for 8 weeks. The primary efficacy variable was the change from baseline in trough SeDBP after 8 weeks of therapy. Data were analyzed by response surface modeling. At Week 8, mean changes from baseline in trough SeDBP (mm Hg) ranged from -3.5 for placebo, -7.1 to -10.2 for the irbesartan monotherapy groups, -5.1 to -8.3 for the HCTZ monotherapy groups, and -8.1 to -15.0 for the combination groups. Irbesartan plus HCTZ produced additive reductions in both SeDBP and seated systolic BP, with at least one combination producing greater BP reduction than either drug alone (P < .001). All treatments were well tolerated; there were no treatment-related serious adverse events. Irbesartan tended to ameliorate the dose-related biochemical abnormalities associated with HCTZ alone. In conclusion, the combination of HCTZ in doses up to 25 mg with irbesartan, in doses up to 300 mg, is safe and produces dose-dependent reductions in BP. Two hundred and eleven patients with mild or moderate hypertension, mean age 53.5 +/- 9.5 years (range 24-70) were randomised double-blind to treatment with either captopril 50 mg (C50), hydrochlorothiazide 25 mg (HCTZ 25), the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg (C50/HCTZ 25) or placebo. Blood pressure, heart rate, body weight and side effects were assessed at the end of the run-in period on placebo and after 4, 6, 8 weeks treatment at the same time, 20-24 h after the last dosing. Routine biochemical examinations were carried out on all patients after the placebo period as well as after 4 and 8 weeks. Blood pressure significantly decreased in all groups, but the mean percentage change from baseline was highly statistically significant at 8 weeks, for C50 and C50/HCTZ 25 groups. The incidence of clinical side effects was low and not statistically different for the four groups with few specific adverse effects (one transient alteration of taste in captopril group). No patient was withdrawn from the study due to side effects. A better anti-hypertensive efficacy was obtained with the fixed combination captopril 50 mg/hydrochlorothiazide 25 mg once daily compared to placebo or each component alone, and without any difference in side effects. To review the efficacy and safety of losartan and hydrochlorothiazide compared to losartan alone, hydrochlorothiazide alone or placebo in the treatment of mild to moderate hypertension in a clinical trial.
                A randomly allocated, placebo-controlled, double-blind parallel study was performed in 40 clinical centers throughout the United States. A total of 703 males and females aged 18-75 years with a sitting diastolic blood pressure of 95-115 mmHg entered the trial and 604 completed the 12-week protocol. The participants were randomly assigned to concomitant therapy once a day with: (1) 50 mg losartan and 6.25 mg hydrochlorothiazide, (2) 50 mg losartan and 12.5 mg hydrochlorothiazide, (3) 50 mg losartan alone, (4) 12.5 mg hydrochlorothiazide alone or (5) placebo. All participants were followed for 12 weeks.
                At baseline, mean trough sitting diastolic blood pressure was 100.9-101.7 mmHg, with no significant difference between treatment groups. Sitting diastolic blood pressure fell 4.0 mmHg with placebo, 7.2 mmHg with 12.5 mg hydrochlorothiazide, 7.2 mmHg with 50 mg losartan, 9.3 mmHg with 50 mg losartan + 6.25 mg hydrochlorothiazide, and 13.2 mmHg with 50 mg losartan + 12.5 mg hydrochlorothiazide. The fall in mean trough sitting systolic blood pressure was 2.4, 9.3, 10.7, 12.0 and 17.9 mmHg for the respective groups. After subtracting the placebo effect, the reductions in blood pressure induced by losartan and hydrochlorothiazide were additive for both sitting diastolic and systolic blood pressures and approximately equaled the reduction seen with the combination of losartan and hydrochlorothiazide. There were no significant differences in adverse events between treatment groups.
                The concomitant administration of 50 mg losartan + 12.5 mg hydrochlorothiazide produced additive falls in sitting diastolic and systolic blood pressures which were greater than that achieved with either drug alone. On the basis of the adverse effects reported, the combination was well tolerated. Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study, 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2, 5, 10, or 20 mg, hydrochlorothiazide, 25 mg, or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg, respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2, 5, and 10 mg), blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks, the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril, hydrochlorothiazide, or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements, serum biochemistry test results, or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug. The efficacy and safety of enalapril and hydrochlorothiazide was investigated in a multicenter study of 81 patients with mild to moderate essential hypertension. The subjects were randomly assigned to one of three groups and, following a placebo period, given enalapril maleate (20 mg), hydrochlorothiazide (12.5 mg), or a combination of the two drugs (32.5 mg). A significant decrease in blood pressure was observed after only 2 weeks in the enalapril and enalapril-hydrochlorothiazide groups. A double dose was required to achieve a satisfactory response in one-third of the patients in both the enalapril (9 of 27) and the enalapril-hydrochlorothiazide groups (8 of 27). Adverse reactions included cough in one patient and mild hyperkalemia in another, both of whom received enalapril. Two patients on the drug combination developed side effects--symptomatic orthostatic hypotension in one and impotence in the second. Enalapril alone and in combination with hydrochlorothiazide appears to be effective and well tolerated. The combination of angiotensin converting enzyme (ACE) inhibitor and thiazide diuretic has advantages over monotherapy for the treatment of hypertension. Previous study designs have often been inadequate to demonstrate the details of interactions between these antihypertensive agents. This study used a modified 4 x 4 factorial randomized, double-blind, placebo-controlled, parallel group design to study the efficacy of 17 different doses of fosinopril (Fos), a phosphinic acid derived ACE inhibitor, and hydrochlorothiazide (HCTZ) in 550 patients with mild to moderate hypertension. Data from these variables were fit to quadratic response surface models (QRSM) using polynomial functions in the doses of the two components. Using QRSM, seated systolic (SeSBP) and diastolic blood pressure (SeDBP) responses at 8 weeks were predicted for actual doses and interpolated for intermediate doses not studied. Fos and HCTZ alone and in combination produced a dose-related reduction in SeSBP and SeDBP. Using 10 mg Fos + 12.5 mg HCTZ reduced the adjusted mean SeDBP 6.3 mm Hg and 20 mg Fos + 12.5 mg HCTZ lowered the same measure 9.1 mm Hg. Coadministration of Fos and HCTZ produced an additive antihypertensive effect. This study of combination agents for hypertension using a factorial design with QRSM accurately predicts dose responses and is a valuable clinical trial methodology. This 8-week, double-blind, multicentre study compared the efficacy and safety of the combination of quinapril and hydrochlorothiazide (HCTZ) with each drug as monotherapy. Outpatients with moderate to severe hypertension defined as supine diastolic blood pressure (DBP) > or = 105 mmHg and < or = 120 mmHg at the end of a 2 to 4-week placebo-baseline period were randomly assigned to one of the three treatments: once-daily 10 mg quinapril plus 12.5 mg HCTZ or monotherapy with these doses. After 4 weeks, the doses were to be doubled for the remaining 4 weeks. Three hundred and sixty-eight patients were randomized to double-blind medication; 346 completed the study. Seven patients withdrew due to lack of efficacy. Four patients withdrew due to side effects. In all three treatment groups, clinically significant reductions in DBP were achieved. Combination therapy was statistically more effective than each component taken as monotherapy. Adverse events were infrequent in all treatment groups. No patients experienced symptomatic hypotension or orthostatic hypotension. The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension.
                We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55-80 years with hypertension (blood pressure > or = 150/95 mm Hg, or > or = 160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 mg [corrected] plus amiloride 2.5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25-50 mg or enalapril 5-10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat.
                Primary outcomes occurred in 200 (6.3%) patients in the nifedipine group and in 182 (5.8%) in the co-amilozide group (18.2 vs 16.5 events per 1000 patient-years; relative risk 1.10 [95% CI 0.91-1.34], p=0.35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p<0.0001), but serious adverse events were more frequent in the co-amilozide group (880 vs 796, p=0.02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0.81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0.33% [-0.7 to 1.4]).
                Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy. This multicenter international trial recruited 205 patients from 16 investigators. After a 4-week, single-blind placebo run-in, patients were randomized to receive 16 weeks of trandolapril 2 mg/day (68 patients), hydrochlorothiazide (HCTZ) 25 mg/day (68 patients), or the combination (69 patients). Morning predosing supine diastolic blood pressure (DBP) was the primary efficacy measurement. Intention-to-treat analysis showed significant decreases in all three groups in mean (+/- SEM) supine DBP throughout the study, with no significant differences at week 16 between trandolapril (-10.6 +/- 1.3 mm Hg) and HCTZ (-10.9 +/- 1.3 mm Hg). The combination gave a significantly greater reduction than either drug alone (-15.1 +/- 1.13 mm Hg). Blood pressure was normalized in the combination group in 67% of patients, a significantly higher proportion than either trandolapril (63%) or HCTZ (60%; p = 0.04). Each treatment was well tolerated. The incidence of adverse events was similar in all three groups. Trandolapril 2 mg once daily is an effective antihypertensive agent, comparable to HCTZ. Furthermore, the combination of the two drugs was shown to enhance the antihypertensive effect of the two compounds alone. A randomised, double-blind study comparing 25 mg of hydrochlorothiazide plus 2.5 mg of amiloride with 25 mg of hydrochlorothiazide alone was conducted in 40 elderly patients with mild to moderate hypertension. After 8 weeks of treatment, the target blood pressure, supine diastolic blood pressure less than 90 mm Hg, was obtained in 73% of the hydrochlorothiazide plus amiloride treated patients (n = 17) and in 41% of the hydrochlorothiazide treated patients (n = 19; p less than 0.05). However, there was no statistically significant difference in blood pressure reduction between the 2 groups. Four patients dropped out, 3 of them due to side-effects. Serum potassium and magnesium concentrations were reduced in the hydrochlorothiazide group and serum sodium concentration in the hydrochlorothiazide plus amiloride group. Our results suggest that in elderly hypertensive subjects, a higher proportion of patients could be managed with the low dose hydrochlorothiazide plus amiloride regimen than with the low dose hydrochlorothiazide regimen. The Oslo Hypertension Study started in 1972 and lasted for 66 (range 60-78) months. A total of 785 healthy men, aged 40 to 49 years, with mild hypertension were randomised to a drug-treated group and to an untreated, control group. The drugs used for treatment were hydrochlorothiazide alone in 36%, hydrochlorothiazide and propranolol in 26%, hydrochlorothiazide and methyldopa in 20%, and other drugs in 18%. A total of 95% in the drug-treated group received hydrochlorothiazide. Pressure complications, such as stroke and aneurysms, only occurred in the control group. Coronary events were more numerous in the drug-treated group, so that the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups. After 5 and 10 years, total mortality was found to be the same in both groups. However, the 10-year coronary heart disease mortality was significantly higher in the drug-treated group than in the untreated controls (14 v 3, p less than 0.01). Possible reasons for the failing effect of drug treatment of hypertension on coronary heart disease is discussed, and attention is drawn to the adverse effect of diuretics and beta-adrenergic blockers, both on lipid and carbohydrate metabolism. This is in contrast to the alpha-adrenergic blocker, prazosin, which has been shown to improve the blood lipid profile. The antihypertensive effect and safety of fosinopril and hydrochlorothiazide combined were compared with each drug singly and placebo in a controlled manner. After a 4- to 5-week placebo lead-in period, 67 mild to moderate essential hypertensive patients (seated diastolic blood pressure > or = 95 and < or = 110 mm Hg) were randomized in a double-blind fashion into four parallel treatment groups: 20 mg fosinopril plus 12.5 mg hydrochlorothiazide, 20 mg fosinopril, 12.5 mg hydrochlorothiazide, and placebo during 8 weeks. Patients were seen biweekly. Sitting diastolic blood pressure was the outcome variable defining therapeutic response. The efficacy of fosinopril plus hydrochlorothiazide as a combined therapy was superior to any single drug (P < .05) and placebo (P < .01) in the treatment of mild to moderate essential hypertension. Mean adjusted systolic/diastolic blood pressure decrements at week 8 were -18.8/-13.7, -12.9/-11.8, -8.5/-9.3, and -2.7/-6.9 mm Hg for the fosinopril plus hydrochlorothiazide, fosinopril, hydrochlorothiazide, and placebo groups, respectively. Clinical adverse events and laboratory changes documented throughout the study were similar to placebo and were mild in severity in all groups. To test the antihypertensive and metabolic effects of lisinopril, 10 mg/d (L); hydrochlorothiazide, 12.5 and 25 mg/d (H12.5 and H25); and its combination with lisinopril (L/H12.5 and L/H25) against placebo in patients with mild to moderate (stage I and stage II) hypertension.
                Multicenter, double-blind, placebo-controlled outpatient study of 12 weeks' duration.
                After 4 weeks of single-blind placebo treatment, 505 patients whose sitting diastolic blood pressure was 100 to 114 mm Hg were randomized into the study--467 patients completed it (placebo, 71; L, 80; H12.5, 79; H25, 77; L/H12.5, 79; and L/H25, 81). The patients were seen in the clinic every 2 weeks, where measurements of their sitting and upright blood pressure and heart rate were taken 24 +/- 2 hours after drug administration. Complete blood cell counts with differential cell counts, blood chemistry studies, urinalyses, and electrocardiograms were done at baseline and during the study. Roentgenograms were done once at baseline.
                Compared with placebo, all drug regimens decreased sitting and upright blood pressure (P < .001) and had no effect on sitting and upright heart rate. The greatest effect was obtained with the combinations of L/H12.5 and L/H25. There was no difference between L/H12.5 and L/H25 or between H12.5 and H25. There were no serious clinical side effects except cough, which was slightly higher with L, L/H12.5, and L/H25. The only metabolic side effects were in serum potassium level, which was lower with H25 (P < .01), and serum glucose level, which was higher with H25 and L/H25 (P < .01).
                The data suggest that (1) monotherapy of hypertension with L, H12.5, H25, L/H12.5, and L/H25 was effective and well tolerated; (2) the best results were achieved with L/H12.5 and L/H25; (3) lower doses of hydrochlorothiazide either alone or in combination with lisinopril were equipotent with higher doses and were free of metabolic side effects. A multicentre, randomised, placebo-controlled parallel group study comparing various doses of the combination diltiazem SR (DTZ SR)/hydrochlorothiazide (HCTZ) with the monotherapies was performed to delineate the optimal antihypertensive dosage of the two drug combinations. The study was carried out in 298 patients with mild to moderate essential hypertension (stable supine diastolic blood pressure, DBP, greater than or equal to 95 and less than or equal to 110 mmHg). After a single-blind placebo lead-in period lasting 4-6 weeks to establish stable baseline BP, the patients were randomised to receive either placebo (n = 75), HCTZ (n = 76), DTZ SR (n = 72), or the combination of DTZ SR/HCTZ (n = 75). There were three 4-week evaluation periods with forced escalation of therapy as follows: HCTZ (6.25, 6.25, 12.5 mg twice daily), DTZ SR (60, 90, 120 mg twice daily), and the combination of DTZ SR/HCTZ (60/6.25, 90/6.25, 120/12.5 mg twice daily). DTZ SR/HCTZ (120/12.5 mg) produced statistically significantly greater reductions in supine DBP compared with each monotherapy and placebo. The lower doses of DTZ SR/HCTZ (60/6.25 mg and 90/6.25 mg) produced statistically significantly greater supine DBP reductions compared with DTZ SR monotherapy and placebo, but not compared with HCTZ monotherapy. A comparison of reduction in supine DBP between evaluation periods demonstrated a dose-response relationship for the combination therapy in reducing BP over the dosage range studied. Adverse clinical and laboratory events were not significantly different between the therapies.(ABSTRACT TRUNCATED AT 250 WORDS) To test the hypothesis that use of thiazide diuretics prevents hip fracture and to study the risk for hip fracture associated with furosemide use.
                A case-control study.
                Hospitals owned by a health maintenance organization in Washington.
                Elderly patients (n = 462) hospitalized because of a hip fracture between 1977 and 1983 and an equal number of age- and sex-matched population-based control patients.
                Use of thiazide diuretics and furosemide was ascertained from medical records and computerized pharmacy records. The relative risk for hip fracture associated with diuretic use was calculated and adjusted for the potentially confounding effects of nursing home residence; previous hospitalizations; a history of stroke, alcoholism, or the organic brain syndrome; body weight; leg paralysis; and use of phenobarbital, corticosteroids, or other diuretics. Current and former users of diuretics were analyzed separately.
                The adjusted risk for hip fracture was 1.6 (95% CI, 1.0 to 2.5) for current thiazide users. The adjusted risk for hip fracture for current furosemide use was 3.9 (CI, 1.5 to 10.4).
                According to this study, use of thiazide diuretics did not protect against hip fracture and cannot be recommended for fracture prevention. Current furosemide use was also associated with hip fracture. Hypertension is a leading cause of end-stage renal disease (ESRD) in the United States, with no known treatment to prevent progressive declines leading to ESRD.
                To compare the effects of 2 levels of blood pressure (BP) control and 3 antihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension.
                Randomized 3 x 2 factorial trial with enrollment from February 1995 to September 1998.
                A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years.
                Participants were randomly assigned to 1 of 2 mean arterial pressure goals, 102 to 107 mm Hg (usual; n = 554) or 92 mm Hg or less (lower; n = 540), and to initial treatment with either a beta-blocker (metoprolol 50-200 mg/d; n = 441), an angiotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d; n = 436) or a dihydropyridine calcium channel blocker, (amlodipine 5-10 mg/d; n = 217). Open-label agents were added to achieve the assigned BP goals.
                Rate of change in GFR (GFR slope); clinical composite outcome of reduction in GFR by 50% or more (or > or =25 mL/min per 1.73 m2) from baseline, ESRD, or death. Three primary treatment comparisons were specified: lower vs usual BP goal; ramipril vs metoprolol; and amlodipine vs metoprolol.
                Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP group and 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from baseline through 4 years did not differ significantly between the lower BP group (-2.21 [0.17] mL/min per 1.73 m2 per year) and the usual BP group (-1.95 [0.17] mL/min per 1.73 m2 per year; P =.24), and the lower BP goal did not significantly reduce the rate of the clinical composite outcome (risk reduction for lower BP group = 2%; 95% confidence interval [CI], -22% to 21%; P =.85). None of the drug group comparisons showed consistent significant differences in the GFR slope. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in the clinical composite outcome of 22% (95% CI, 1%-38%; P =.04) and 38% (95% CI, 14%-56%; P =.004), respectively. There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups.
                No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal. Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline.
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.