title: A dose escalation trial comparing the combination of diltiazem SR and hydrochlorothiazide with the monotherapies in patients with essential hypertension. Platelet alpha 2-adrenoceptor modifications induced by long-term treatment with indapamide in essential hypertension. Quantitative effects of timolol and hydrochlorothiazide on blood pressure, heart rate and plasma renin activity: results of a double-blind factorial trial in patients with essential hypertension. Ticrynafen and hydrochlorothiazide in hypertension Effects of atenolol and hydrochlorothiazide on blood pressure and plasma catecholamines in essential hypertension. Comparative study of once-daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Treatment of ambulatory hypertensives with nebivolol or hydrochlorothiazide alone and in combination. A randomized, double-blind, placebo-controlled, factorial-design trial. Fixed low‐dose combination therapy in hypertension ‐ a dose response study of perindopril and indapamide Long-Term Antihypertensive Efficacy and Safety of the Oral Direct Renin Inhibitor Aliskiren: A 12-Month Randomized, Double-Blind Comparator Trial With Hydrochlorothiazide Serum Lipoproteins During Treatment with the Antihypertensive Agent Indapamide Loss to follow-up Amlodipine versus chlorthalidone versus placebo in the treatment of stage I isolated systolic hypertension. Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Results of the Treatment of Mild Hypertension Study. Conclusions and implications of the systolic hypertension in the elderly program. Effect of hydrochlorothiazide, enalapril, and propranolol on quality of life and cognitive and motor function in hypertensive patients. Isolated systolic hypertension in the elderly. A placebo-controlled, dose-response evaluation of chlorthalidone. Long-acting and short-acting diuretics in mild essential hypertension. Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy Dopamine beta-hydroxylase and plasma renin activity in patients with low-, normal-, and high-renin essential hypertension. Short report: Ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design Changes in left ventricular mass during a double-blind study with chlorthalidone and slow-release nifedipine Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension. Low‐dose antihypertensive therapy with 1.5 mg sustained‐ release indapamide: Results of randomised double‐blind controlled studies Multicenter dose-response study of the effect of indapamide in the treatment of patients with mild to moderate hypertension. Renin predicts diastolic blood pressure response to nonpharmacologic and pharmacologic therapy. Glucose and insulin levels during diuretic therapy in hypertensive men. Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) Study Group. Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Nifedipine GITS and hydrochlorothiazide in essential hypertension. An assessment of diltiazem and hydrochlorothiazide in hypertension. Application of factorial trial design to a multicenter clinical trial of combination therapy. Evaluation of Indapamide in the Treatment of Hypertension Effect of Spirapril and Hydrochlorothiazide on Platelet Function and Euglobulin Clot Lysis Time in Patients with Mild Hypertension Practolol and bendrofluazide in treatment of hypertension. Compliance to treatment for hypertension in elderly patients: the SHEP pilot study. Systolic Hypertension in the Elderly Program. Effects of once daily indapamide and pindolol on blood pressure, plasma aldosterone concentration and plasma renin activity in a general practice setting Combination treatment with telmisartan and hydrochlorothiazide in black patients with mild to moderate hypertension Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects Dose response to chlorthalidone in patients with mild hypertension; Efficacy of a lower dose Randomized Prospective Study of a Nonthiazide Diuretic, Indapamide, in Preventing Calcium Stone Recurrences Low-dose bisoprolol/hydrochlorothiazide: an option in first-line, antihypertensive treatment. Chlorthalidone does not increase the hypotensive effect of nifedipine in essential hypertensives: a crossover multicentre study. Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects. Chlorthalidone in mild hypertension — Dose response relationship Use of Diuretics in Treatment of Hypertension in the Elderly Antihypertensive efficacy and tolerability of captopril in the elderly: comparison with hydrochlorothiazide and placebo in a multicentre, double-blind study. Evaluation of the antihypertensive efficacy and tolerability of moexipril, a new ACE inhibitor, compared to hydrochlorothiazide in elderly patients A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. The Trial of Antihypertensive Interventions and Management (TAIM) Study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Antihypertensive effect of hydrochlorothiazide administered once or twice daily. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Prospective study on the treatment of mild hypertension in the aged. Losartan with hydrochlorothiazide in the treatment of hypertension Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients: a double-blind controlled trial. A randomized, controlled trial comparing diltiazem, hydrochlorothiazide, and their combination in the therapy of essential hypertension. Nocturnal reduction of blood pressure and the antihypertensive response to a diuretic or angiotensin converting enzyme inhibitor in obese hypertensive patients. TROPHY Study Group. Quinapril and hydrochlorothiazide combination for control of hypertension: assessment by factorial design. Quinapril Investigator Group. Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension. Bendrofluazide Fails to Reduce Elevated Blood Pressure Levels in the Immediate Post-Stroke Period Antihypertensive efficacy of alpha-methyldopa, chlorothiazide and Supres-150 (alpha-methyldopa-chlorothiazide). Clinical evaluation of labetalol alone and combined with chlorthalidone in essential hypertension: A double-blind multicentre controlled study Dose‐effect and concentration‐effect relationships of pinacidil and hydrochlorothiazide in hypertension Serum lipoprotein levels during chlorthalidone therapy. A Veterans Administration-National Heart, Lung, and Blood Institute cooperative study on antihypertensive therapy: mild hypertension. Lower dose diuretic therapy in the treatment of patients with mild to moderate hypertension. [The optimal dose of bendroflumethiazide in hypertension. A randomized double-blind dose-response study]. Effect of indapamide on serum and red cell cations, with and without magnesium supplementation, in subjects with mild hypertension. Combined Versus Single Effect of Fosinopril and Hydrochlorothiazide in Hypertensive Patients Chlorthalidone attenuates the reduction in total cholesterol and small, dense LDL cholesterol subclass associated with weight loss. Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. Evaluation of indapamide 1.25 mg once daily in elderly patients with mild to moderate hypertension Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia. Unnecessary diuretic therapy in the elderly. A double-blind trial in hypertension comparing Baycaron (FBA 1500), hydrochlorothiazide and placebo. Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination. Once daily treatment of mild to moderate hypertension with xipamid: a controlled study. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Randomised study of six beta-blockers and a thiazide diuretic in essential hypertension EFFECTS OF NATURAL ESTROGEN/GESTAGEN AND THIAZIDE ON CORONARY RISK FACTORS IN NORMAL POSTMENOPAUSAL WOMEN Labetalol and bendrofluazide: comparison of their antihypertensive effects. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide Relative value of beta blockers and thiazides for initiating antihypertensive therapy. Beta blockers or thiazides in hypertension. Antihypertensive activity of a new agent, indapamide: a double-blind study. Arterial compliance and baroreceptor sensitivity after chronic treatment with indapamide. The effects of benazepril, a new angiotensin‐converting enzyme inhibitor, in mild to moderate essential hypertension: A multicenter study Low-dose diuretic and/or dietary sodium restriction when blood pressure is resistant to ACE inhibitor. [Treatment of hypertension with indapamide 1.5 mg sustained-release form: synthesis of results]. Atenolol and chlorthalidone in combination for hypertension. Results of combination anti-hypertensive therapy after failure of each of the components. Department of Veterans Affairs Cooperative Study Group on Anti-hypertensive Agents. Indapamide SR versus candesartan and amlodipine in hypertension: the X-CELLENT Study. Reduction in long-term antihypertensive medication requirements. Effects of weight reduction by dietary intervention in overweight persons with mild hypertension. ACE Inhibition with Spirapril Improves Diastolic Function at Rest Independent of Vasodilation During Treatment with Spirapril in Mild to Moderate Hypertension Low-dose diuretic therapy for hypertension. Effects of benazepril and hydrochlorothiazide, given alone and in low- and high-dose combinations, on blood pressure in patients with hypertension. Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. Efficacious response with lower dose indapamide therapy in the treatment of elderly patients with mild to moderate hypertension. Low dose bendrofluazide (1.25 mg) effectively lowers blood pressure over 24 h: results of a randomized, double-blind, placebo-controlled crossover study. Beta blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial. Clonidine and guanfacine in hypertension Antihypertensive Efficacy and Safety of Fixed-Dose Combination Therapy with Losartan plus Hydrochlorothiazide in Japanese Patients with Essential Hypertension Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Circulating prostacyclin concentrations may be increased by bendrofluazide in patients with essential hypertension. Antihypertensive action of bendroflumethiazide: Increased prostacyclin production? Twenty-four hour antihypertensive efficacy of indapamide, 1.5-mg sustained release: results of two randomized double-blind controlled studies. First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension. Effects of enalapril and hydrochlorothiazide on blood pressure, renin-angiotensin system, and atrial natriuretic factor in essential hypertension: a double blind factorial cross-over study. Placebo-controlled comparison of the effects of nebivolol and low-dose hydrochlorothiazide as monotherapies and in combination on blood pressure and lipid profile in hypertensive patients. Double-blind comparison of indapamide with a placebo in hypertensive patients treated by practicing physicians. EFFECTS OF TIMOLOL AND HYDROCHLOROTHIAZIDE ON BLOOD-PRESSURE AND PLASMA RENIN ACTIVITY Double-blind Factorial Trial Duration of antihypertensive effect of a single daily dose of hydrochlorothiazide The Combination of Chlorthalidone with Nifedipine Does Not Exert an Additive Antihypertensive Effect in Essential Hypertensives: A Crossover Multicenter Study Clinical studies of a new, low-dose formulation of metolazone for the treatment of hypertension. Risk of ventricular arrhythmias in hypertensive men with left ventricular hypertrophy. Lacidipine, hydrochlorothiazide and their combination in systolic hypertension in the elderly Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. A double-blind study of tienilic acid with two year follow-up of patients with mild to moderate essential hypertension. The effects of thiazide diuretics upon plasma lipoproteins. Comparative effects of two beta‐blockers on cardiovascular reactivity and type A behavior in hypertensives. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension. Antihypertensive effects of low doses of hydrochlorothiazide in hypertensive black Zimbabweans. THE ANTIHYPERTENSIVE PROPERTIES OF THE ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR MOEXIPRIL GIVEN ALONE OR IN COMBINATION WITH A LOW DOSE OF A DIURETIC Placebo-controlled comparison of captopril, metoprolol, and hydrochlorothiazide therapy in non-insulin-dependent diabetic patients with primary hypertension. [Comparison of the clinical usefulness of diuretics in elderly and younger essential hypertension--double blind trial using tripamide]. The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide. Moxonidine and hydrochlorothiazide in combination: a synergistic antihypertensive effect. Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone. Cilazapril plus hydrochlorothiazide: improved efficacy without reduced safety in mild to moderate hypertension. A double-blind placebo-controlled multicenter study of factorial design. GLUCOSE INTOLERANCE DURING DIURETIC THERAPY: Results of Trial by the European Working Party on Hypertension in the Elderly
abstract: A multicentre , r and omised , 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 r and omised 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 The effect of long-term treatment with indapamide in platelet alpha 2-adrenoceptors has been evaluated in 10 patients with essential hypertension , in a double-blind , cross-over study with placebo . After three months of therapy , indapamide significantly reduced mean blood pressure ( from 137 + /- 12 to 116 + /- 6 mm Hg , p less than 0.001 ) , whereas heart rate did not change ( from 72 + /- 8 to 73 + /- 7 beats/minute ) . At the same time , platelet alpha 2-adrenoceptor number increased ( from 168.2 + /- 48.4 to 256.8 + /- 14.5 fmol/mg protein , p less than 0.02 ) , whereas the dissociation constant did not change ( from 3.79 + /- 2.9 to 4.97 + /- 4.48 ) . The plasma norepinephrine level was significantly reduced after long-term treatment with indapamide ( from 275 + /- 118 to 210 + /- 56 pg/ml , p less than 0.02 ) . These results bring about an inhibition of norepinephrine release from sympathetic nerve endings with a likely secondary increase of the number of platelet alpha 2-adrenoceptors 1 . The anti-hypertensive actions of timolol and hydrochlorothiazide were analysed in a double-blind 2 x 2 factorial trial in twenty patients with essential hypertension . Each patient went through four phases of 8 weeks in r and omized order , receiving timolol alone , hydrochlorothiazide alone , timolol plus hydrochlorothiazide , and placebo . 2 . Supine mean arterial pressure fell from 119 mmHg in the placebo phase , to 110 mmHg during the thiazide phase , 106 mmHg during the timolol phase , and to 101 mmHg during the combined timolol plus hydrochlorothiazide phase . 3 . Factorial analysis revealed that the hypotensive actions of the beta-receptor-blocking drug and the diuretic were additive , without any synergism or antagonism . 4 . Plasma renin activity measured in ng 3 h-1 ml-1 rose from 5 - 02 in the placebo phase to 9 - 54 in the diuretic phase , but fell to 1 - 79 in the beta-receptor blockade . It was unchanged in the combined therapy phase , despite the greater drop in blood pressure . These results suggest that the fall in plasma renin activity during beta-receptor blockade is of little importance in the hypotensive action of beta-receptor-blocking drugs In a double‐blind study , 28 patients having mild to moderate essential hypertension were r and omly assigned to a 6‐week regimen of ticrynafen , hydrochlorothiazide , or placebo .  Blood pressure fell after ticrynafen and hydrochlorothiazide .  Serum uric acid fell strikingly with ticrynafen whereas it rose with hydrochlorothiazide .  Serum potassium declined very little with ticrynafen ; much less than with hydrochlorothiazide . Serum creatinine and blood urea nitrogen rose slightly more with ticrynafen than with hydrochlorothiazide . There were no clinical adverse effects to either of the medications . Ticrynafen appears to be an effective antihypertensive with a substantial hypouricemic effect The antihypertensive effects of atenolol and hydrochlorothiazide were compared with placebo in a r and omized , double-blind crossover study , with the blood pressure responses related to sympathetic nervous system activity . Twelve patients with essential hypertension were given atenolol ( 100 mg ) , hydrochlorothiazide ( 50 mg ) , and placebo as single daily doses , each for 6 weeks . Mean supine , st and ing , and post-exercise blood pressures ( mm Hg ) on atenolol ( 155/94 , 152/95 , 177/93 , respectively ) and hydrochlorothiazide ( 154/99 , 150/103 , 172/96 ) were lower ( p less than 0.01 ) than corresponding placebo values ( 172/109 , 166/113 , 204/111 ) at 6 weeks . The role of the sympathetic nervous system in the antihypertensive actions of atenolol and hydrochlorothiazide was examined . The supine plasma norepinephrine on placebo was used as an index of sympathetic activity to categorize each patient 's " adrenergic status . " The six " hyperadrenergic " patients with high resting norepinephrine values ( mean , 302 pg/ml ) exhibited a greater ( p = 0.05 ) decrease in BP ( -30/-20 mm Hg ) on atenolol compared with the BP fall of -9/-11 mm Hg observed in the lower norepinephrine group ( mean , 211 pg/ml ) . Resting plasma norepinephrine values did not predict the BP fall on hydrochlorothiazide . The " adrenergic status " of each patient as measured by the plasma norepinephrine concentration tended to be relatively constant regardless of therapy or the state of activity . In this study , atenolol was an effective antihypertensive agent comparable to hydrochlorothiazide in potency . Adrenergic status tended to predict the BP response to atenolol and was a relatively constant feature of the patients in all treatment phases Two hundred and eleven patients with mild or moderate hypertension , mean age 53.5 + /- 9.5 years ( range 24 - 70 ) were r and omised 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 BACKGROUND Most patients with hypertension require more than one agent to control blood pressure ( BP ) . The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide ( HCTZ ) . METHODS This was a r and omized , double-blind , factorial design study . After a placebo run-in period , eligible patients ( n = 502 ) with a baseline mean seated diastolic blood pressure ( SeDBP ) of 100 to 115 mm Hg were r and omized to one of 12 groups :  placebo , olmesartan medoxomil monotherapy ( 10 , 20 , or 40 mg/day , HCTZ monotherapy ( 12.5 or 25 mg/day ) , or one of six groups of olmesartan medoxomil/HCTZ combination therapy . The primary endpoint was the change in mean trough SeDBP from baseline at week 8 . Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses , but did not compare BP reductions with different combination doses . RESULTS Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure ( SeSBP ) at week 8 than did monotherapy with either component . All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner . Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg , 20.1/16.4 mm Hg , and 26.8/21.9 mm Hg with placebo , olmesartan medoxomil/HCTZ 20/12.5 mg , and olmesartan medoxomil/HCTZ 40/25 mg , respectively . All treatments were well tolerated . CONCLUSIONS Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated This placebo-controlled multifactorial design trial assessed the antihypertensive efficacy of nebivolol , a novel cardioselective beta 1-blocker with vasodilating properties , and hydrochlorothiazide monotherapy and in combination . After a 4-week placebo period , 240 white patients with a mean daytime ambulatory blood pressure of > or = 90 mm Hg were r and omized to receive either placebo , nebivolol ( 1 , 5 , or 10 mg ) , hydrochlorothiazide ( 12.5 or 25 mg ) , or one of the six possible combinations of nebivolol and hydrochlorothiazide for 12 weeks . A dose-related reduction in clinic and ambulatory blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination . Nebivolol , 5- and 10-mg doses , showed a larger effect than hydrochlorothiazide doses on clinic blood pressure and over the 24-h interval . Moreover , the combination doses had substantial antihypertensive effects that were sustained over the entire 24-h profile with a greater effect observed with the higher dose combinations . The reduction in ambulatory blood pressure was further substantiated by the reduction of blood pressure loads ( % of BP > 140/90 mm Hg awake and > 120/80 mm Hg asleep ) to as low as 11.5 % with 10 mg of nebivolol combined with 25 mg of hydrochlorothiazide . Nebivolol and hydrochlorothiazide were well tolerated . We provided evidence that nebivolol , given as monotherapy or in combination with low dose of hydrochlorothiazide , is effective in reducing clinic and 24-h ambulatory blood pressure in patients with ambulatory hypertension . The results provided further evidence for the use of ambulatory blood pressure monitoring and factorial design s when investigating new antihypertensive agents Objective To establish the optimal dose of the perindopril/indapamide combination ( Per/Ind ) in the treatment of mild or moderate hypertension . Design This was a r and omized , double-blind , placebo-controlled , seven-way parallel-group , dose-ranging study , set in multicenter , outpatient offices/clinics in Europe and Canada . Patients A total of 438 patients aged between 18 and 75 years whose supine diastolic blood pressure was between 95 and 114 mmHg were r and omly assigned to an 8-week double-blind treatment with either placebo , Per 2/Ind 0.625 , Per 4/Ind 1.25 , Per 8/Ind 2.5 , Per 0/Ind 1.25 , Per 2/Ind 1.25 or Per 8/Ind 1.25 mg . Main outcome measures Systolic and diastolic blood pressure measured in the clinic approximately 24 h after dosing . Results There was a linear dose – response relationship ( P = 0.001 ) for doubling the dose of Per 2/Ind 0.625 mg up to Per 8/Ind 2.5 mg with a progressive fall in supine diastolic blood pressure ( −9.3 to −15.0 mmHg ) . Combining 1.25 mg Ind with increasing doses of Per ( 0 , 2 , 4 and 8 mg ) also showed a linear dose – response relationship ( P < 0.001 ) , with supine diastolic blood pressure falling by −8.0 to −12.0 mmHg compared with a fall of −5.2 mmHg for the placebo group . Similar findings were noted for supine systolic blood pressure , st and ing blood pressure and ambulatory blood pressure . Hypokalemia was more common ( 9.7 % ) in the Per 8/Ind 2.5 mg group than in the groups receiving other doses ( 0–4.6 % ) . Conclusion The combinations of Per 2/Ind 0.625 mg and Per 4/Ind 1.25 mg were effective in reducing blood pressure without producing clinical ly important side effects Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , 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 . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized 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 ) . Conclusions — 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 Considering the documented , potentially undesirable influence of various thiazide-type or loop diuretics on serum lipoproteins , we prospect ively investigated in 69 men(mean age ± SEM , 32 ± 1 years ) the metabolic effects of the new diuretic-antihypertensive compound indapamide . Compared to placebo , indapamide ( 2.5 mg/day ) given for 6 to 8 weeks lowered ( p < 0.02 to < 0.001 ) blood pressure(supine values from 148/98 ± 3/2 to 137/93 ± 3/2 ) in 29 men with mild to moderate essential hypertension , but not in 40 healthy men . In both groups , significant ( p < 0.05 to < 0.001 ) decreases in body weight ( −0.8 kg ) and plasma potassium ( −0.6 mmol/L ) , and increases in plasma uric acid (= 20 % ) , renin activity (= 200 % ) , and aldosterone documented good compliance . There were no significant changes hi total cholesterol(in all subjects , from 208 ± 6 to 213 ± 6 mg/dl ) , low- or very low-density lipoprotein(VLDL ) cholesterol ( 127 ± 6 to 129 ± 6 and 21 ± 1 to 21 ± 2 respectively ) , high-density lipoprotein cholesterol ( 50 ± 1 to 51 ± 1 mg/dl ) , total triglycerides(Tg ) ( 108 ± 5 to 112 ± 6 mg/dl ) , VLDL-Tg , apoproteins Al and A2 , plasma glucose , epinephrine , norepinephrine , sodium , calcium , magnesium , and creatinine ; apoprotein B ( 84 ± 2 to 88 ± 3 mg/dl ) and plasma insulin after glucose loading dose tended to be increased minimally . The absence of distinct lipoprotein alterations after short-term indapamide treatment may be of clinical and epidemiological interest.(Hypertension 7 [ Suppl II ] : II-164–II-169 , 1985 In this issue , we answer three questions with respect to loss to follow-up in a clinical trial : How important is loss to follow-up ? How is loss to follow-up calculated ? How many patients can be lost to follow-up without mistrusting the results ? 1 . How important is loss to follow-up ? The simple answer to this question is “ very important ” because loss to follow-up can severely compromise a study 's validity . Incomplete follow-up biases the results when either : The dropout rates are different between study groups ; or The patients who drop out are different from those who do not drop out . Why do these situations make a difference ? Because in each situation , those lost to follow-up often have a different prognosis than those who complete the study . For example , patients who receive treatment for cervical myelopathy may not return for follow-up because they became asymptomatic and felt no need to return to see the surgeon . Conversely , some patients may not return because they had a particularly bad outcome ( worse pain or function ) or complication , or because they died . In either case , bias can affect the validity of the inferences drawn from the study . 2 . How is loss to follow-up calculated ? There is much confusion about how to determine the proportion of patients lost to follow-up . In order to correctly calculate the follow-up rate , one needs to know the denominator . In a r and omized controlled trial ( RCT ) , the denominator for each group is the number of patients who were r and omized , not the number who received the treatment . For example , suppose we have an RCT comparing two treatment groups , Group A and Group B. The investigators evaluate 178 patients and r and omize 120 ; 61 to Group A and 59 to Group B ( Fig 1 ) . Following the figure , we note that 49 patients received treatment A and 52 received treatment B. At the final follow-up 40 were analyzed in Group A and 41 in Group B. How many were considered lost to follow-up ? Many would consider the loss to follow-up rate to be 9 ( 18 % ) of 49 in treatment A and 11 ( 21 % ) of 52 in treatment B using as the denominator only those that were treated . However , the real proportion lost to follow-up must consider those who were r and omly assigned , even if they did not receive treatment . In the present example , this is calculated as 21 ( 34 % ) of 61 for treatment A and 18 ( 31 % ) of 59 for treatment B. Fig 1 Hypothetical example of patients lost to follow-up in a r and omized controlled trial . When calculating loss to follow-up in a retrospective cohort study , all individuals receiving treatment during the study period should be used as the denominator , not just those with complete data . For example , let 's say you want to compare decompression plus lumbar fusion with decompression alone in disc herniation and the data available are all patients receiving either treatment in the last 5 years ( N = 275 ) . However , the data base from which the data are obtained is incomplete and only 190 have the necessary data available . Since the investigators stated as part of the inclusion criteria that only those patients with complete data are included , they consider the follow-up to be 100 % ( 190/190 ) . This conclusion is wrong . The denominator should include all patients who underwent the surgery irrespective of completeness of data . The follow-up rate for this example is 69 % ( 190/275 ) . 3 . How many patients can be lost to follow-up without mistrusting the results ? Some have suggested that 20 % poses serious threats to validity 1 . This may be a good rule of thumb , but keep in mind that even small proportions of patients lost to follow-up can cause significant bias 2 . One way to determine if loss to follow-up can seriously affect results is to assume a worst-case scenario with the missing data and look to see if the results would change . Here is an example : Let 's assume a multicenter study enrolled 500 patients into each arm of a study comparing artificial disc replacement ( ADR ) with fusion , and the end point is adjacent segment disease ( ASD ) . The trial numbers are found in Fig 2 . Fig 2 Hypothetical example of the effect of loss to follow-up considering a worst-case scenario . ADR indicates artificial disc replacement ; ASD , adjacent segment disease . The proportion of patients with ASD in the ADR group is half as much versus the fusion group , 25 % ( 100/400 ) compared with 50 % ( 200/400 ) . If we assume that the 100 lost to follow-up in the ADR group had ASD and the 100 lost to follow-up in the fusion group did not , then the rate of ASD in each group would be 40 % ( 200/500 ) . In this case , adopting the worst-case scenario for the intervention group with respect to those lost to follow-up causes the results to change significantly from half the rate of ASD with ADR to the same rate . When this happens , loss to follow-up can threaten the internal validity of the trial . Only when the worst case does not change the inferences derived from the results is lost to follow-up not a problem The study was to compare the effects of amlodipine ( calcium channel antagonist ) , chlorthalidone ( diuretic ) , and placebo in adults more than 50 years of age with stage 1 isolated systolic hypertension ( ISH ) . After a 4-week placebo run-in phase , 150 patients were r and omly assigned in a double-blind fashion to treatment with 5 mg of amlodipine ( n = 48 ) , 15 mg of chlorthalidone ( n = 50 ) , or placebo ( n = 52 ) . Patients who failed to meet the systolic blood pressure ( BP ) reduction goal by week 4 had their dose increased to 10 mg of amlodipine or 30 mg of chlorthalidone , and maintained at this increased dose for 12 weeks . Results showed a mean reduction ( mean + /- SD ) in sitting systolic BP from baseline to the last treatment visit of -14.6+/-12.2 mm Hg ( 95 % confidence interval [ CI ] -18.2 , -11.0 ) , -14.0+/-13.46 mm Hg ( 95 % CI -17.8 , -10.2 ) , and -3.4+/-11.83 mm Hg ( 95 % CI -6.7 , -0.1 ) for the amlodipine , chlorthalidone , and the placebo treatment groups , respectively . Both active treatments showed significantly greater reductions than the placebo group ( P < or = .001 ) , but were not significantly different from each other . Sixty-seven percent of the amlodipine , 69 % of the chlorthalidone , and 25 % of the placebo-treated patients reached the protocol defined systolic BP goal ( P = .001 ) . Both active treatment groups showed a trend of better systolic BP response in older patients ( > or = 65 years ) . Secondary efficacy measures including pulse pressure , st and ing systolic , diastolic , and the 24-h ambulatory BP were also statistically significantly improved for both active treatments at the end of treatment , except for chlorthalidone in st and ing diastolic BP . Adverse events that occurred during the study were as expected and were well tolerated . The results of this study support the efficacy and safety of amlodipine and chlorthalidone for the treatment of stage 1 ISH during 20 weeks of treatment OBJECTIVE To explore the sex-specific benefits and risks of treatment of stage 1 diastolic hypertension . METHODS Participants were African-American and white hypertensive men ( n = 557 ) and women ( n = 345 ) ( age range , 45 to 69 years ) with a diastolic blood pressure less than 100 mm Hg . Participants were r and omized to treatment with placebo , chlorthalidone ( 15 mg/d ) , acebutolol hydrochloride ( 400 mg/d ) , doxazosin mesylate ( 2 mg/d ) , amlodipine besylate ( 5 mg/d ) , or enalapril maleate ( 5 mg/d ) ; all were given nutritional-hygienic intervention . RESULTS After 4 years , women who were r and omized to lifestyle intervention  only were less likely to be receiving  step 1 therapy alone ( placebo ) than men who were r and omized to placebo therapy ( 46 % vs 66 % , respectively , P < .01 ) . There were significantly greater decreases in the mean systolic blood pressure in both men and women who were assigned to treatment with active drugs compared with those participants who were receiving placebo therapy ; differences among treatments with active drugs were similar between men and women . Men experienced larger falls in their total and low-density lipoprotein cholesterol and triglyceride levels regardless of the treatment assignment than did women ; however , there were no significant sex-by-treatment interactions . Quality -of-life indexes were generally improved with active drug treatment compared with placebo therapy in both sexes ; there was a sex-by-treatment interaction for the general health index . The relative risk ( RR ) for combined clinical events was similar in women ( RR , 0.64 ; 95 % confidence interval [ CI ] , ( 0.36 to 1.16 ) and in men ( RR , 0.67 ; 95 % CI , 0.40 to 1.14 ) who were assigned to treatment with all active drugs combined , compared with those who were receiving placebo therapy . CONCLUSION In these exploratory analyses , men and women who were assigned to treatment with active drugs experienced greater and generally similar benefits from treatment than those participants who were assigned to lifestyle intervention only Isolated systolic hypertension has a higher prevalence with age and an associated excess cardiovascular risk . The Systolic Hypertension in the Elderly Program ( SHEP ) was a r and omized , prospect i ve , double blind clinical trial to assess the efficacy and safety of a antihypertensive regimen based on low dose diuretic therapy in reducing the five year combined incidence of fatal and nonfatal stroke . SHEP demonstrated a significant 36 % reduction in stroke incidence . Also , 27 % reduction in coronary heart disease incidence and a 32 % reduction in major cardiovascular disease incidence were achieved . The benefits accrued to all subgroups identified based on baseline age , race , sex , blood pressure , serum cholesterol levels , and ECG abnormalities . A low-dose diuretic regimen should be the initial treatment of choice for most hypertensive patients , based on demonstrated reduction in risk for major cardiovascular events , its safety , acceptance by patients , and low cost The effect of hydrochlorothiazide , propranolol , and enalapril on cognitive and motor function and quality of life ( QOL ) in hypertensive patients was studied . Patients > or = 55 years of age with asymptomatic essential hypertension were included in a r and omized , double-blind , placebo-controlled , crossover study . Subjects discontinued their previous antihypertensive agents and started hydrochlorothiazide 25 mg , extended-release propranolol hydrochloride 120 mg , enalapril maleate 10 mg , or placebo . One capsule was taken for three days and then the dosage was doubled for the remainder of a four-week period . Subsequent crossover treatments were begun without a washout period . In each treatment phase , a battery of psychometric tests was used to assess cognitive and motor function and quality of life ; all tests but one were self-administered via computer terminal . Pulse rate and blood pressure were recorded , and compliance was monitored by capsule count . Sixteen of 30 patients interviewed completed the trials ; one additional patient was evaluated after receiving all treatments except hydrochlorothiazide . Mean + /- S.D. age of the subjects was 66 + /- 6.1 years ; 10 were black and 7 white ; 9 were men . Except for the hydrochlorothiazide group , blood pressure in the active treatment groups did not differ significantly from placebo ; hydrochlorothiazide significantly reduced systolic but not diastolic blood pressure compared with placebo . Compared with placebo , hydrochlorothiazide was associated with fewer incorrect responses in a test of complex reaction time and with greater discriminant reaction time response rates ; otherwise , no difference between groups was noted in cognitive or motor performance . There were no significant differences between active treatments and placebo on individual QOL measures . ( ABSTRACT TRUNCATED AT 250 WORDS One hundred seventy-one patients , 60 years of age or older with isolated systolic hypertension , were r and omly assigned to receive chlorthalidone 12.5 , 25.0 , or 50.0 mg or placebo once daily for 12 weeks . The majority of the patients receiving chlorthalidone 12.5 mg achieved therapeutic success with no clinical ly significant biochemical changes or side effects . The 50.0-mg dose level enhanced efficacy only minimally over the 25.0-mg dose level . Drug-related side effects were significantly more prevalent in the chlorthalidone 50.0-mg group than in the placebo group . The data suggest that most elderly patients with isolated systolic hypertension , regardless of the severity , could be treated effectively and safely with chlorthalidone 12.5 mg per day A r and omised , placebo-controlled , double-blind crossover study was conducted in 14 patients with mild essential hypertension comparing different regimens of administration of the " short-acting " diuretic , chlorothiazide and the " long-acting " diuretic , chlorthalidone . There were 6 r and omised treatment phases each of 5 weeks duration . For blood pressure recorded both at the Clinic and at home the most prominent effects were seen with st and ing blood pressure , for which significant reductions of mean blood pressure compared to the placebo phase were observed with chlorthalidone 25 mg once daily ( -5 + /- 1 ( SE ) mm Hg - p less than 0.05 ) , chlorthalidone 50 mg once daily ( -7 + /- 1 mm Hg - p less than 0.01 ) and chlorothiazide 500 mg twice daily ( -4 + /- 1 mm Hg - p less than 0.05 ) . Blood pressure reductions with chlorothiazide 500 mg once daily and 1000 mg once daily were not significant . About half of the patients completing the trial could be described as " non-responders " . The observed biochemical changes ( reduced plasma potassium and chloride concentrations and increased plasma bicarbonate and urate concentrations ) were most marked in the phases with the most prominent blood pressure effects . The result support the suggestion that a sustained diuretic effect is desirable when diuretics are used in the treatment of hypertension . This can be obtained by selection of the appropriate dosage regimen for a particular diuretic , such as once daily administration for " long-acting " and twice daily for " short-acting " thiazide-type diuretics Objective : 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 . Design : 871 adult out- patients with essential hypertension participated in this double-blind study . Patients were r and omised 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 r and omisation . Main outcome measures : 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 . Results : 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 . Conclusions : 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 relationship of serum dopamine-beta-hydroxylase ( DBH ) , plasma renin activity ( PRA ) and urinary catecholamines ( IU catechols ) in various forms of essential hypertension ( EHT ) ( low , normal and high renin ) was evaluated . Eighty-four predominantly white , young ( 37 + / 8 years ( SD ) ) , mildly hypertensive patients ( diastolic pressure 93 + /- 4 mm Hg ( SD ) ) continued their regular diet and received no medications . Thirteen patients had low-renin , 64 had normal-renin , and seven had high-renin EHT .  DBH , total IU catechols and urinary norepinephrine were not different between these renin subgroups . DBH was significantly lower in all hypertensives ( 55.6 + /- 36 IU ) and in the low-renin subgroup ( 46 + /- 30 IU ) compared with normal subjects ( 68 + /- 35 IU ) ( p less than 0.01 ) . However , the DBH range was so broad that an individual DBH value did not distinguish EHT from normals . After a baseline period , patients were r and omly assigned to receive chlorthali done 50 mg q.a.m . or placebo in a double-blind study . In the chlorthalidone group 1 month after therapy , the diastolic pressure decreased , PRA increased , and total IU catechols and urinary norepinephrine increased . Serum DBH did not change during diuretic therapy . A significant correlation could not be shown between pretreatment DBH and the changes in PRA and IU catechols before and after diuretics for all treated EHT patients . However , within the normal PRA EHT subgroup receiving chlorthalidone , the one-third of patients with lowest pretreatment DBH levels ( n = 10 ) were compared with the one-third of patients with the highest pretreatment DBH values ( n = 10 ) . The lower DBH patients showed significantly less change in PRA ( delta PRA = 2.9 + /- 1.8 ng/ml/hr ) compared with the higher DBH patients ( delta PRA = 8.2 + /- 1.6 ; P less than 0.05 ) . In some EHT patients , DBH levels may be related to PRA response to diuretic therapy Objective To identify appropriate dosages of ramipril and hydrochlorothiazide ( HCT ) when given in combination once a day for the treatment of essential hypertension . Design A 2- or 4-week placebo run-in followed by 6-week , double-blind , parallel-group phase : 4 x 3 factorial ( 2.5 , 5 and 10 mg ramipril ; 12.5 and 25 mg HCT ; all six combinations ; placebo ) . Setting Office practice ( 21 centres ) . Patients and participants Patients with mild-to-moderate essential hypertension ( World Health Organization stage I — II ; supine diastolic blood pressure 100—115 mmHg in last 2 weeks of run-in ) : 581 enrolled , 534 r and omly assigned to double-blind therapy and 517 completed . Main outcome measures Reduction in supine and st and ing blood pressure . Results In pairwise comparisons , the combinations of 5 mg ramipril with 12.5 and 25 mg HCT and 10 mg ramipril with 12.5 mg HCT consistently produced significantly greater blood pressure reductions than their respective components . Response surface analyses were performed , and a stairstep model was constructed to characterize the shape of the dose-response surface . The combinations involving 5 and 10 mg ramipril with 12.5 and 25 mg HCT were again more effective than their components . Withdrawals and adverse effects were minimal for all treatments . A large drop in serum potassium was observed on 25 mg HCT , but not on combination therapy . Addition of ramipril appeared to reduce the hyperuricaemic effect of HCT . Conclusions Several dosage combinations of ramipril plus HCT produced significantly greater blood pressure reductions than the monotherapies at the same dosages . Overall , the combination of 5 mg ramipril and 25 mg HCT gave the best mean reduction . Combination therapy with ramipril plus HCT was safe and effective for patients with mild-to-moderate essential hypertension Summary The presence of a possible correlation between changes in left ventricular mass of hypertensive patients and the degree of blood pressure reduction with different antihypertensive drugs has been investigated in 40 out patients by M-mode echocardiography . Ten of these , with blood pressure in normal limits with different antihypertensive treatment had their therapy changed in chlorthalidone 25 mg/day without any run-in ( Group A ) ; other 30 patients , with a previously uncontrolled blood pressure , after a 14 day run-in , were r and omly allocated to chlorthalidone 25 mg/day ( Group B ) , slow release nifedipine 20 mg/day ( Group C ) or placebo ( Group D ) . At the end of the eight week treatment period a further decrease in systolic blood pressure was observed in Group A without changes in ventricular mass ; an highly significant decrease in both systolic and diastolic blood pressure was observed in B and C but only patients on chlorthalidone changed their ventricular mass ; no change in both blood pressure and ventricular mass was observed on placebo . As changes in ventricular mass are not correlated with blood pressure reduction , we conclude that other , not well defined factors , apart from the decrease in duration and degree of left ventricular systolic wall tension , may be responsable for reversal of left ventricular hypertrophy The combination of angiotensin converting enzyme ( ACE ) inhibitor and thiazide diuretic has advantages over monotherapy for the treatment of hypertension . Previous study design s have often been inadequate to demonstrate the details of interactions between these antihypertensive agents . This study used a modified 4 x 4 factorial r and omized , 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 Objective In accordance with international recommendations on the need to decrease doses of antihypertensive drugs , a low-dose ( 1.5 mg ) sustained-release ( SR ) formulation of indapamide was developed to optimize the drug 's efficacy : safety ratio . The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design . Patients and methods Clinical data were obtained in two European r and omized double-blind studies with 690 mild to moderate hypertensive patients ( 95 mmHg ≤ supine diastolic blood pressure ≤ 114 mmHg using a mercury sphygmomanometer ) treated respectively for 2 and 3 months , with a mean age of 53 and 57 years , 44 and 57 % males , mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg . Results The first study , a dose-finding study with indapamide SR at 1.5 , 2 and 2.5 mg versus placebo and the immediate-release ( IR ) formulation of indapamide , showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio . The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR , and better acceptability with 1.5 mg indapamide SR , particularly in the number of patients with serum potassium levels < 3.4 mmol/l , which was reduced by more than 50 % . The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study . Conclusion The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio , which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension This study , carried out in three centers in the United States , investigated the antihypertensive effect of three dosages of indapamide in 87 patients with mild to moderate hypertension . The dosages studied were 1 mg , 2.5 mg , and 5 mg daily . A double-blind , parallel study design was used with a six-week placebo run-in period followed by an eight-week treatment period and a two-week follow-up period . Compared with placebo , all dosages caused a significant decrease ( P less than 0.05 ) in blood pressure , with an average decrease of approximately 6 mmHg diastolic and 13 mmHg systolic . The antihypertensive effect seemed to be fully manifest after six weeks of treatment . At all dosage levels , indapamide produced markedly greater therapeutic success rates than did the placebo . Success was defined as either a st and ing phase-5 diastolic blood pressure of less than 90 mmHg or a decrease by at least 10 mmHg from baseline . Although the decrease in mean serum potassium concentration was dose-related , the decrease was not clinical ly significant with any dose . A reduction in serum chloride and increases in serum uric acid and glucose were also observed . These changes were slight and did not cause the discontinuation of treatment for any patient . The most frequently observed side effects were mild to moderately severe dizziness , weakness , and headaches OBJECTIVE Plasma renin activity was measured at baseline and 6 months in a trial of nonpharmacologic therapy of mild hypertension to determine whether plasma renin activity predicts the diastolic blood pressure ( DBP ) response to nonpharmacologic therapy . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of volunteers from the general community with mild hypertension ( DBP between 90 and 100 mm Hg ) , off all antihypertensive therapy at baseline , treated in special research clinics ( n = 593 ) . INTERVENTIONS Subjects were r and omly assigned to usual , weight loss , or low sodium/high potassium diet and then r and omly assigned to receive placebo , chlorthalidone , or atenolol . MAIN OUTCOME MEASURES Renin was analyzed as plasma renin activity and as a renin index ( logarithm of 24-hour urinary sodium excretion times logarithm of plasma renin activity ) ( 593 patients at baseline and 6 months ) to correct for varied sodium intakes . The DBP was measured using the r and om zero device . RESULTS Change in DBP at 6 months could be predicted from baseline plasma renin activity or renin index . The DBP was decreased after 6 months of therapy by 2 mm Hg for each unit increase in baseline plasma renin activity and by 0.16 mm Hg for each unit increase in baseline renin index . Patients in the highest renin index quartile had a greater DBP response to atenolol therapy , and patients in the lowest renin index quartile had a greater DBP response to chlorthalidone therapy . Weight loss diet achieved a greater reduction in DBP in patients with higher baseline renin index and had an additive effect on DBP response in both of the drug groups . Patients on a weight loss diet receiving placebo in the highest baseline renin index quartile had a reduction in DBP of 12.4 mm Hg , compared with 4.4 mm Hg in the lowest baseline renin index quartile ( P = .009 ) . A low sodium/high potassium diet had a lesser effect than a weight loss diet on pharmacologic therapy . As with the weight loss diet , patients on a low sodium/high potassium diet in the highest baseline renin index quartile had a greater reduction in DBP than patients in the lowest baseline renin index quartile . CONCLUSIONS These data suggest a significant relationship between baseline levels of plasma renin index and the likelihood of success of nonpharmacologic treatment of hypertension We investigated serum glucose and insulin levels result ing from thiazide or thiazide-like diuretic administration and determined whether they were associated with serum or intracellular potassium or magnesium values . We also explored the role of obesity both alone and with thiazides on serum insulin and glucose . Hypertensive men were withdrawn from  diuretics  and repleted with oral potassium and magnesium and then r and omized to 2 months of treatment with ( 1 ) hydrochlorothiazide , ( 2 ) hydrochlorothiazide with oral potassium , ( 3 ) hydrochlorothiazide with oral potassium and magnesium ( 4 ) hydrochlorothiazide and triamterene , ( 5 ) chlorthalidone , or ( 6 ) placebo . Serum was available from 202 participants for insulin and glucose determinations . Mean fasting serum glucose and insulin did not change significantly after 2 months of r and omized therapy with the exception of participants r and omized to chlorthalidone , who had significant increases in both serum insulin and glucose ( P < .05 and P < .01 , respectively ) . As body mass index increased , there was a corresponding increase in serum insulin and to a lesser degree in serum glucose . Also , as body mass index increased , participants taking hydrochlorothiazide had a corresponding increase of serum insulin ( P < .05 ) . After treatment , intracellular potassium and magnesium were both associated with higher serum insulin ( P < .001 for each ) , and serum potassium was associated with higher and serum magnesium with lower serum glucose ( P < .01 for each ) . In most hypertensive men , treatment with 50 mg chlorthalidone increases glucose and insulin levels , whereas administration of 50 mg hydrochlorothiazide , with or without potassium and /or magnesium conserving strategies , does not . ( ABSTRACT TRUNCATED AT 250 WORDS Because obesity-associated hypertension has unique hemodynamic and hormonal profiles , certain classes of antihypertensive agents may be more effective than others as monotherapy . Thus , we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week , multicenter , double-blind trial in 232 obese patients with hypertension . Patients with an office diastolic pressure between 90 and 109 mm Hg were r and omized to treatment with daily doses of lisinopril ( 10 , 20 , or 40 mg ) ,  hydrochlorothiazide  ( 12.5 , 25 , or 50 mg ) , or  placebo . Mean body mass indexes were similar for all patients . At week 12 , lisinopril and hydrochlorothiazide effectively lowered office diastolic ( -8.3 and -7.7 versus -3.3 mm Hg , respectively ; P<.005 ) and systolic ( -9.2 and -10.0 versus -4.6 mm Hg , respectively ; P<.05 ) pressures compared with placebo .  Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo ( P<.001 ) . Significant dose-response differences were observed between treatments . Sixty percent of patients treated with lisinopril had an office diastolic pressure < 90 mm Hg compared with 43 % of patients treated with hydrochlorothiazide ( P<.05 ) . Responses to therapies differed with both race and age . Neither treatment significantly affected insulin or lipid profiles ; however , plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril ( + 0.31 versus -0.21 mmol/L ; P<.001 ) . Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline . In conclusion , lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension . Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics , may have a more rapid rate of response , and may offer advantages in patients at high risk of metabolic disorders 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 r and omized 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 Twenty-nine subjects with mild to moderate essential hypertension completed this 13 week r and omized , double-blind , placebo-controlled study comparing the antihypertensive effects of nifedipine GITS ( N ) ( 30 - 60 mg/day ) , hydrochlorothiazide ( H ) ( 25 - 50 mg/day ) and placebo ( P ) . Nifedipine GITS is a new formulation design ed for once daily administration . N lowered blood pressure 15/10 mmHg ( p less than 0.0005/p less than 0.0001 ) , H 15/8 mmHg ( p less than 0.0005/p 0.05 ) , and P 4/0 mmHg ( p = NS ) . All patients required the larger dose of active drug to control BP . No drug affected the heart rate . For N , but not H , there was a positive correlation between age and the magnitude in reduction of SBP ( r = 0.79 ; p less than 0.005 ) , but not for DPB . N drug levels did not correlate with its antihypertensive effect . Epinephrine , norepinephrine , aldosterone , and plasma renin activity were not affected by N. No patients on N experienced immediate vasodilator side effects . N is a well tolerated and effective antihypertensive drug that can be given once daily . It does not cause reflex stimulation of the sympathetic nervous system This multicenter , factorial- design trial assessed the safety and additive antihypertensive efficacy of a slow-release ( SR ) formulation of diltiazem hydrochloride given alone or in combination with hydrochlorothiazide for treatment of mild to moderate hypertension . After a 4- to 6-week placebo run-in period , 297 qualifying patients were r and omized to receive placebo , 1 of 4 doses of diltiazem SR monotherapy , 1 of 3 doses of hydrochlorothiazide monotherapy , or 1 of 12 possible combinations of diltiazem SR and hydrochlorothiazide for 6 weeks . A dose-related reduction in blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination . Absolute blood pressures of patients who received combination therapy were lower by an overall mean of 3.0 mm Hg diastolic and 8.0 mm Hg systolic vs diltiazem SR used alone and 3.5 mm Hg diastolic and 4.0 mm Hg systolic vs hydrochlorothiazide used alone . At the largest doses used , 50 % of patients achieved goal blood pressure while taking hydrochlorothiazide , 57 % while taking diltiazem SR , and 75 % while taking combination therapy . Combination therapy was well tolerated . This trial clearly demonstrates that diltiazem SR and hydrochlorothiazide have additive antihypertensive effects A r and omized double-blind , crossover trial was carried out in twenty hypertensive patients to evaluate the hypotensive efficacy and safety of indapamide . Indapamide in doses of 2.5 mg per day in combination with other antihypertensive agents was as effective in reducing the blood pressure in hypertensive patients as one tablet of Moduretic ( 50 mg hydrochlorothiazide and 5 mg amiloride ) . Indapamide induced no changes in serum potassium or uric acid levels and there were no major side effects Thirteen patients with mild hypertension ( untreated diastolic blood pressure of 95 to 114 mmHg ) received , in r and om order , three successive treatments of four weeks with placebo , spirapril ( 6 mg daily ) , or hydrochlorothiazide ( HCT2 ) ( 24 mg daily ) . At the end of each treatment , blood sample s for assessment of platelet aggregation and platelet release of platelet factor 4 ( PF4 ) and for assessment of fibrinolysis , estimated by tissue plasminogen activator ( t-PA ) , plasminogen activator inhibitor-type 1 ( PAI-1 ) , and euglob ulin clot lysis time ( ECLT ) , were taken , first at rest , then immediately after five to ten minutes of vigorous exercise , and finally after the subsequent hour of recovery rest . Platelet aggregation induced in vitro by adrenaline significantly decreased during treatment with HCT2 , the threshold rising to 10 μM as compared with 1.0 with placebo ( P < 0.05 ) at rest , and the threshold for adenosine diphosphate ( ADP ) aggregation also rose , from 2 μM to 4 ( NS ) . The resting plasma PF4 value fell , although not significantly , during HCT2 treatment from the placebo value of 3.28 to 2.56 ng/mL. During spirapril treatment there was no change in the threshold of either adrenaline or ADP for aggregation of platelets sample d at rest , and the PF4 plasma levels showed no significant reductions at rest . However , during exercise PF4 showed an approximate doubling of the resting value irrespective of therapy . This exercise-induced increase in PF4 was significantly reduced by spirapril as compared with placebo ( P < 0.05 ) . ECLT and t-PA did not shift significantly from the placebo level during either therapy . PAI-1 did not change  during spirapril therapy , but during HCT2 treatment it fell , although not significantly , to 9.36 IU/mL from 15.91 with placebo ( NS ) . Spirapril and HCT2 did not produce any unwanted side effect on platelet function or fibrinolysis . HCT2 seems to decrease platelet activity at rest , whereas spirapril seems to some extent to decrease platelet activity at exercise comparison of practolol mg/day , bendrofluazide 5 mg/day , and combined therapy of practolol with bendrofluazide has been carried out in 24 patients with sustained hypertension ( mean supine blood pressure I67/104 mmHg ) . The effect of treatment on the supine , erect , and post-exercise blood pressure was studied . After four weeks of therapy , each of the active treatments was significantly superior to treatment with placebo . There was a trendfor treatment with practolol alone to reduce the blood pressure more than bendrofluazide alone in all positions but this was not statistically significant after four weeks of treatment . The maximum reduction in supine blood pressure was achieved with combined therapy of practolol with bendrofluazide ( mean blood pressure I38 9/90o5 mmHg ) . The combined therapy was significantly superior to bendrofluazide alone in allpositions but was superior to practolol alone onlyfor supine and erect systolic blood pressures . The reductions in blood pressure achieved during the period on combined therapy were not significantly greater than the sum of the reductions obtained in the periods when the individual drugs were given separately . This study shows that practolol either alone or in combination with bendrofluazide is a useful addition to the range of antihypertensive drugs Assessing the compliance of people over 60 years of age and older with an antihypertensive treatment regimen was a major objective of the Systolic Hypertension in the Elderly Program ( SHEP ) pilot study . The study r and omized 551 men and women over the age of 60 ( mean age = 72 years ) to a stepped care treatment that included chlorthalidone or placebo in a double-blind trial . Three measures of compliance to treatment protocol --pill count , self-report , and a urine chlorthalidone assay -- all indicated high levels of compliance in 80 to 90 % of participants at 3 months and 1 year after r and omization . Pill-taking compliance was similar in the active and placebo groups , although the rate of discontinuance from study medications at 1 year was higher in the placebo than in the active group . Compliance was high in all age categories , including those over age 80 . These data suggest that elderly patients can achieve high levels of compliance with antihypertensive medications Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide ( 2.5 mg daily ) and pindolol ( 10 mg daily ) on blood pressure , heart rate , plasma renin activity and plasma aldosterone concentration . There were four r and omised test phases of eight weeks each during which patients received indapamide alone , pindolol alone , indapamide plus pindolol and no active treatment ( placebo ) .  Blood pressure and heart rate were measured every two weeks . Supine mean arterial pressure fell from 117 mm Hg in the placebo phase to 111 mm Hg in the indapamide phase , 106 mm Hg in the pindolol phase and 103 mm Hg in the combined indapamide plus pindolol phase . Factorial analysis confirmed that the hypotensive effects of the two drugs were additive , without evidence of potentiation or antagonism . Indapamide caused significant reductions in plasma potassium and chloride , and increases in plasma bicarbonate and urate concentrations ; it also caused increases in plasma renin activity and aldosterone concentration . These changes are similar to those observed with thiazide diuretics Background : Hydrochlorothiazide ( HCTZ ) is commonly used to treat black patients with hypertension . To avoid the metabolic disturbances associated with high‐dose HCTZ , blood pressure control may be achieved by combining low doses with another antihypertensive OBJECTIVE --To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension . DESIGN --Double blind parallel group trial of patients who were given placebo for six weeks and then r and omly allocated to various doses of bendrofluazide ( 1.25 , 2.5 , 5 , or 10 mg daily ) or placebo for 12 weeks . SETTING --General practice s in Zeal and , Denmark . PATIENTS --257 Patients with newly diagnosed or previously treated hypertension , aged 25 - 70 , who had a mean diastolic blood pressure of 100 - 120 mm Hg after receiving placebo for six weeks . MAIN OUTCOME MEASURES --Reduction in diastolic blood pressure and changes in biochemical variables ( potassium , urate , glucose , fructosamine , total cholesterol , apolipoprotein A I , apolipoprotein B , and triglyceride concentrations ) . RESULTS --All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree ( 10 - 11 mm Hg ) . Clear relations between dose and effect were shown for potassium , urate , glucose , total cholesterol , and apolipoprotein B concentrations . The 1.25 mg dose increased only urate concentrations , whereas the 10 mg dose affected all the above biochemical variables . CONCLUSION --The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25 - 2.5 mg a day . Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects . Previous trials with bendrofluazide have used too high doses Summary 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 clinical ly 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 multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy . After a 4‐wk placebo control period 100 patients with mild hypertension were r and omly assigned doubleblind to 12.5‐ , 25‐ , 50‐ , or 75‐mg regimens of chlorthalidone or to placebo for 12 wk . The groups of patients taking 25 , 50 , and 75 mg had declines in blood pressure which were not significantly different from each other . Serum potassium decreased in the 50‐ and 75‐mg groups but not significantly in the 25‐mg group . We conclude that chlorthalidone , 25 mg daily , was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium . Use of smalter initial diuretic doses may provide equal efficacy with fewer side effects for many patients We examined the biochemical changes and the efficacy of indapamide in the prevention of  calcium stone recurrences . Seventy-five patients with calcium nephrolithiasis and hypercalciuria were r and omly assigned to three different therapies : diet and fluid ( group A ) , diet and fluid plus indapamide 2.5 mg/day ( group B ) . and diet and fluid plus indapamide 2.5 mg/day plus allopurinol 300 mg/day ( group C ) . Before treatment and after 6 , 12 , 24 , and 36 months of therapy , we evaluated blood pressure , serum and urine risk parameters ( including relative supersaturations of calcium oxalate . calcium phosphate and uric acid ) , stone rate , and the proportion of calculi-free patients .  During the 3 years of treatment , urinary calcium greatly decreased in groups B and C. dropping to 50 % of the pretreatment values : urinary oxalate also significantly declined in group B ( - 24 % ) and group C ( -27 % ) . Relative supersaturations of calcium oxalate and calcium phosphate decreased to the same extent in groups B and C ( about one-half of the pretreatment value ) , and relative supersaturation of uric acid was particularly reduced in group C ( -65 % of the pretreatment value ) . The stone rate improved in all three groups ( p > 0.005 ) . but using actuarial analysis in the evaluation of calculi-free patients , indapamide , and indapamide plus allopurinol groups were found to have a significantly more favorable effect than diet and fluid treatment ( p > 0.02 ) , without any difference between the two drug groups . Because indapamide has fewer side effects than thiazide diuretics , we conclude that indapamide could be an interesting alternative to thiazides in the prevention of calcium stones in hypercalciuric patients Two recent , multicenter , double-blind , placebo-controlled studies established the efficacy and safety of low-dose bisoprolol/hydrochlorothiazide ( HCTZ ) in patients with mild to moderate essential hypertension .  Bisoprolol , a cardioselective beta-blocker , was used in a dose of 2.5 mg , 5 mg , or 10 mg . HCTZ was used at a dose of 6.25 mg . This low-dose compound was developed to minimize dose-related adverse effects . The addition of HCTZ to each of the doses of bisoprolol was compared with monotherapy and placebo . Results of both studies demonstrated that this once-a-day , low-dose option effectively reduced sitting diastolic and systolic blood pressure measured at the end of the 24-hour dosing period . Drug-related adverse effects , including those generally associated with traditional beta-blocker therapy , were infrequent in individuals who received the low-dose bisoprolol/HCTZ regimen . Dose-related side effects were minimized because of the low doses of the two agents used together . There were no significant changes in mean total cholesterol , triglycerides , or serum glucose with bisoprolol/HCTZ 6.25 mg therapy versus placebo ( analysis of variance statistical methods ) . The incidence of treatment-induced hypokalemia with bisoprolol/HCTZ 6.25 mg was not significant ; uric acid elevations were minimized , and the incidence of hyperuricemia was significantly ( P < 0.01 ) less with bisoprolol/HCTZ 6.25 mg than with 25 mg of HCTZ . Once-a-day dosing with the low-dose agent controlled ( defined as a sitting diastolic blood pressure < or = 90 mmHg and /or a decrease from baseline > or = 10 mmHg ) blood pressure in up to 80 % of patients for a full 24 hours after dosing . ( ABSTRACT TRUNCATED AT 250 WORDS To determine whether the combination of nifedipine + chlorthalidone exerts an additive antihypertensive effect when compared with single-drug treatment , we studied 66 uncomplicated essential hypertensives , with diastolic blood pressure of greater than 100 and less than 115 mmHg . At the end of a 1-month washout placebo period , using a double-blind crossover design , the patients were r and omly allocated to nifedipine ( 20 mg twice a day ) , chlorthalidone ( 25 mg once a day ) , the two drugs combined at the same doses and the corresponding placebo . Compared with the r and omly allocated placebo , the three active treatments significantly reduced blood pressure without changing the heart rate or body weight . Both the absolute and percentage decreases in mean blood pressure induced by nifedipine and the combination compared with placebo were similar and significantly greater than those induced by chlorthalidone . Taken together , these data show that the combination of nifedipine + chlorthalidone does not exert any additive antihypertensive effect compared with nifedipine alone . This finding indicates that the combination of a dihydropyridine calcium antagonist + a thiazide diuretic is probably devoid of any particular clinical significance in the treatment of uncomplicated essential hypertensives Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ . To characterize the lower end of the dose-response curve a double-blind , parallel group trial was performed as multicentre study in Sc and inavia . One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension ( untreated diastolic blood pressure of 95 - 115 mmHg after 4 weeks placebo ) were r and omly allocated to various doses of hydrochlorothiazide ( 3 , 6 , 12.5 or 25 mg ) or placebo for 6 weeks . Blood pressure and biochemical variables ( plasma renin activity , serum potassium , magnesium , urate , fasting glucose , total cholesterol , HDL-cholesterol , triglycerides and apolipoproteins A1 and B were measured . 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect . Biochemical changes were seen in plasma renin activity , serum potassium and urate after the 12.5 and 25 mg dose . Three and 6 mg had no effect on blood pressure or metabolic parameters Summary The dose response curve for 25 , 50 , 75 and 100 mg doses of chlorthalidone was studied in double blind fashion over an 8 week period in patients who presented with untreated mild hypertension . One hundred and thirty four patients completed this multicentre , family practice study . After 2 week 's medication , a decline in blood pressure was noted in all dosage groups and this was maximal by 4 weeks . At 8 weeks all doses of chlorthalidone induced a significant reduction in both systolic and diastolic blood pressures ( mean −18 and −10 mmHg respectively ) . Amongst the 4 dosage groups , no differences in response were noted result ing in a flat dose response curve . During the study , mean blood urea and serum uric acid rose whilst serum potassium fell , the urea and potassium being least affected in the 25 mg dosage group . As the dosage of chlorthalidone increased , so the tendency for abnormal laboratory values increased . Unwanted effects sought during the study were relatively few in number . No clear dose response relationship was evident although the positive responses in the 25 mg dosage group were less than in the higher dosages . These results suggest that 25 mg chlorthalidone is the optimum dosage for initiation of therapy in patients with mild to moderate hypertension . This dosage is associated with less adverse biochemical changes and unwanted effects than the higher dosages studied Summary Men and women with isolated systolic hypertension who were at least 60 years of age were treated for 1 year with chlorthalidone ( 25–50 mg daily ) or matching placebo as the step I drug . Most patients reached goal blood pressure without requiring a step II drug . The blood pressure response was similar in all age , sex and race subgroups , with an overall difference between the r and omised groups of 17 mm Hg for systolic blood pressure ( p<0.001 ) and 6 mm Hg for diastolic blood pressure ( p<0.001 ) . The only common adverse effects were asymptomatic changes in the serum concentrations of potassium ( 0.5 mmol/L lower in the chlorthalidone group , p<0.001 ) , uric acid ( 0.9 mg/dl higher , p<0.001 ) , and creatinine ( 0.08 mg/dl higher , p=0.02 . Compliance was good , and more than 80 % of participants were still taking the study medications at the end of the year . RésuméLes hommes et les femmes porteurs d’une hypertension systolique isolée , âgés au moins de 60 ans , ont été traités , en première intention , pendant 1 an avec du chlorthalidone ( 25–50 mg par jour ) ou par le traitement placebo apparié . La plupart des malades ont atteint la pression sanguine recherchée sans qu’il soit nécessaire de passer au degré II du traitement médicamenteux . La réponse de la pression sanguine a été similaire dans tous les sous-groupes âge , sexe et race , avec une différence extrême entre les groupes tirés au sort de 17 mmHg pour la pression systolique ( p<0.001 ) et 6 mmHg pour la pression diastolique ( p<0.001 ) . Les effets indésirables les plus fréquents ont été des changements asymptomatiques dans les concentrations sériques de potassium ( moins 0,5 mmol/l dans le groupe chlorthalidone , ( p<0.001 ) , d’acide urique ( plus 0,9 mg/dl , p<0.001 ) , et de créatinine ( plus 0,08 mg/dl , p=0.02 ) . L’adhésion au traitement a été bonne , et plus de 80 % des participants continuaient de prendre leurs médicaments à la fin de l’année de traitement . ZusammenfassungMänner und Frauen mit einer isolierten systolischen Hypertonie , die mindestens 60 Jahre alt waren , wurden über ein Jahr mit  Chlorthalidon ( 25–50 mg täglich ) oder gleichartigem Placebo als Pharmaka der ersten Stufe beh and elt . Die meisten Patienten erreichten den erwünschten Blutdruck , ohne daβ ein Medikament der zweiten Stufe erforderlich war . Die Blutdruck-Reaktion war in allen Alters- , Geschlechts-und Rassen-Untergruppen ähnlich mit einem Gesamtunterschied zwischen den r and omisierten Gruppen von 17 mmHg für den systolischen Blutdruck ( p<0,001 ) und 6 mmHg für den diastolischen Blutdruck ( p<0,001 ) . Die einzige gemeinsame Nebenwirkung best and in einer asymptomatischen Veränderung des Kalium in den Serumkonzentrationen ( 0,5 mmol/L niedriger in der Chlorthalidon-Gruppe , p<0,001 ) , Harnsäure ( 0,9 mg/dl höher , p<0,001 ) und Kreatinin ( 0,08 mg/dl höher , p=0,02 . Bei einer guten Compliance nahmen 80 % der Teilnehmer die Medikationen der Untersuchung noch am Ende des Jahres . ResumenHombres y mujeres con hipertensión sistólica aislada , que tenían por lo menos 60 años de edad , se han tratado durante 1 año con clortalidona ( 25–50 mg diarios ) , o placebo de análogo aspecto , como fármaco de etapa I. La mayoría de los pacientes alcanzaron la presión deseada sin necesitar medicamento de etapa II . La respuesta tensional fue semejante en todos los grupos de edad , sexo y raza con una diferencia total entre los grupos aleatorizados de 17 mm Hg para la presion sistólica ( p<0,001 ) y de 6 mm Hg para la diastólica ( p<0,001 ) . Los únicos efectos adversos de manifestación frecuente fueron modificaciones asintomáticas de las concentraciones séricas de potasio ( 0,5 mmol/l menos en el grupo clortalidona , p<0,001 ) , de ácido úrico ( 0,9 mg/dl mas , p<0,001 ) y de cretinina ( 0,08 mg/dl más , p=0,02 ) . La aceptación fue buena y más del 80 % de participantes todavía estaban tom and o las medicaciones en estudio al final del año . ResumoHomens e mulheres com hipertensão sistólica isolada e com idade mínima de 60 anos foram tratados por um ano com  clortalidona ( 25 a 50 mg por dia ) ou placebo  equivalente como drogas de primeira escolha . A maioria dos pacientes atingiu o nível de pressão sanguínea objetivado sem recorrerem a outras drogas . A reação da pressão sanguínea foi semelhante em todos os subgrupos , fossem por idade , sexo ou raça , com uma diferença global entre os grupos selecionados de 17 mmHg para a pressão sistólica ( p<0,001 ) e 6 mmHg para a pressão diastólica ( p<0,001 ) . Os únicos efeitos adversos comuns a todos foram mudanças assintomáticas nas concentrações de potássio no soro ( 0,5 mmol/L abaixo , no grupo com clortalidona , cortalidona , p<0,001 ) , no ácido ùrico ( 0,9 mg/dl acima , p<0,001 ) e na creatinina ( 0,08 mg/dl acima , p=0,02 ) . O indice de observância ao tratamento foi bom , sendo que mais de 80 % dos participantes ainda estavam a tomar os medicamentos empregados durante a experiência ao final do ano . RiassuntoSoggetti di entrambi i sessi di almeno 60 anni con ipertensione sistolica isolata furono trattati per un anno con clortalidone ( 25–50 mg al giorno ) o placebo , come farmaco di primo livello . La maggior parte dei pazienti normalizzarono la loro pressione arteriosa senza richiedere un farmaco di secondo livello . La risposta pressoria fu simile in tutti i sottogruppi di età , sesso e razza , con una differenza totale tra i gruppi r and omizzati di 17 mm Hg per la pressione sistolica ( p<0.001 ) e 6 mm Hg per la diastolica ( p<0.001 ) . I soli comuni effetti indesiderati furono modificazioni asintomatiche nette concentrazioni sieriche di potassio ( di 0,5 mmol/1 inferiore nel gruppo trattato con clortalidone , p < 0.001 ) , acido urico ( di 0.9 mg/dl più alto , p<0.001 ) e creatinina ( di 0.08 mg/dl maggiore , p<0.02 ) . La compliance fu buona e più dell’80 % dei partecipanti allo studio era ancora in trattamento alla fine dell’anno In this study we compared the antihypertensive efficacy and tolerability of captopril at 25 mg twice daily , hydrochlorothiazide ( HCTZ ) , 12.5 mg twice daily and placebo in a multicentre , double-blind , r and omized study that included 152 essential hypertensive patients ( 77 males , 75 females , 87 WHO stage I , 65 WHO stage II , aged 69 + /- 4 years , mean + /- s.d . ) .  Supine and st and ing blood pressure were similarly reduced by captopril and HCTZ ( P less than 0.01 for both compared with placebo ) . The heart rate did not change . Captopril ( 25 - 30 mg twice daily ) and HCTZ ( 12.5 mg twice daily ) , alone or in combination , maintained their antihypertensive effect during a 24-week single-blind follow-up study . During the follow-up , diastolic blood pressure remained less than 100 mmHg in seven essential hypertensives on placebo , in 45 on captopril and in 25 on HCTZ .  Side effects were observed in seven essential hypertensives during placebo ( treatment withdrawn in two ) , in eight during HCTZ and in three during captopril .  Serum potassium was reduced ( P less than 0.05 ) and uric acid was increased ( P less than 0.01 ) only during HCTZ . We conclude that captopril and HCTZ have similar antihypertensive efficacy in the elderly ; however , captopril appears to be better tolerated Objective : To compare the antihypertensive efficacy of moexipril , a new angiotensin-converting enzyme ( ACE ) inhibitor , to treatment with hydrochlorothiazide ( HCTZ ) . Patients : Two hundred and one non-hospitalized male and female patients between 65 and 80 years of age with essential hypertension . Methods : This was a multicentre , placebo-controlled , double-blind study with a parallel group design . Subjects with a sitting diastolic blood pressure ( DBP ) ≥ 95 mmHg were r and omized to monotherapy with placebo , moexipril 7.5 mg o.d . , moexipril 15 mg o.d . or HCTZ 25 mg o.d . for 8 weeks . Results : Throughout the study period treatment with moexipril and HCTZ result ed in significant reductions of DBP compared with placebo , but there were no significant differences between the active treatment groups . At end point the adjusted mean reductions were 10.5 , 8.7 and 10.1 mmHg in the HCTZ , moexipril 7.5 mg and moexipril 15 mg groups , respectively , compared to 3.9 mmHg in the placebo group . Treatment with moexipril was associated with two cases of first dose hypotension and two cases of moderate and reversible increases in serum creatinine levels . Otherwise , both dosages of moexipril were well tolerated and the overall percentages of patients who had adverse experiences were smaller than in the placebo group . Conclusion : Moexipril is well tolerated and is at least as effective as HCTZ in elderly patients with essential hypertension BACKGROUND 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 r and omized , double-blind , placebo-controlled , 3 x 4 factorial trial of bisoprolol , a beta 1-selective adrenergic blocking agent , and hydrochlorothiazide . METHODS A total of 512 patients with mild to moderate essential hypertension were r and omized 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 . RESULTS 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 . CONCLUSIONS 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 The Trial of Antihypertensives Interventions and Management ( T AIM ) was a multicenter double-blind placebo-controlled clinical trial of drug and diet combinations for the treatment of mild hypertension among 878 participants , ages 21 to 65 , 110 % to 160 % ideal weight , and with baseline diastolic blood pressure 90 to 100 mm Hg . The drugs used were placebo , chlorthalidone ( 25 mg/daily ) or atenolol ( 50 mg/daily ) . The diets studied were usual , weight loss , sodium reduction/potassium increase . Trial end points were 6-month diastolic blood pressure change , cardiovascular risk change , and quality of life change . Either drug combined with weight loss produced the greatest blood pressure reduction of 15 mm Hg , compared to 8 mm Hg on placebo/usual diet . Adding sodium restriction to either drug did not enhance blood pressure lowering effect . Drugs outperformed diet in terms of antihypertensive effect . However , those on placebo and assigned to weight reduction who lost more than 4.5 kg and those on sodium restriction who reduced sodium to less than 70 mEq daily lowered blood pressure to a similar extent as those on either of the two drugs alone . Cardiovascular risk at 6 months relative to baseline ranged from 0.85 in weight loss/atenolol subgroup to 1.04 in the usual diet/chlorthalidone subgroup . Blacks were more responsive to chlorthalidone plus weight loss and whites to atenolol plus weight loss . Quality of life , as measured by scales of distress and well-being , was favorably affected by weight reduction . Although there were few side effects of the drugs and most patients improved on most parameters , sexual complaints were worsened among those on chlorthalidone and usual diet compared to placebo . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND 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 . METHODS This double-blind study evaluated losartan concomitantly administered with hydrochlorothiazide as initial therapy in 703 patients with essential hypertension . RESULTS 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 . CONCLUSION 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 The antihypertensive effect of once and twice daily hydrochlorothiazide administration was compared in 24 ambulatory patients with essential hypertension .  Hydrochlorothiazide 100 mg daily taken as a single morning dose or as a twice daily divided dose was administered to 24 previously diagnosed hypertensive patients in a double-blind cross-over fashion for 12 weeks . No patient received other antihypertensive agents or medications known to influence blood pressure . Sitting and st and ing blood pressure , weight , pulse , tablet count , and subjective complaints of side effects were obtained at study weeks 3 and 6 on each treatment schedule . There was no significant difference between the mean sitting systolic ( 133 and 131 mm Hg ) or diastolic ( 85 and 84 mm Hg ) blood pressure measurements at study weeks 3 and 6 for each treatment schedule . Comparison of st and ing mean systolic and diastolic blood pressure and mean arterial pressure produced similar results . Subjective complaints of medication side effects , including orthostasis or urinary frequency , did not differ between treatment schedules . This study suggests that hydrochlorothiazide may be effectively administered once daily for the treatment of hypertension BACKGROUND Increased left ventricular mass ( LVM ) by echocardiography is associated with increased risk of cardiovascular disease . Thus , it is of interest to compare the effects of both pharmacological and nonpharmacological approaches to the treatment of hypertension on reduction of LVM . METHODS AND RESULTS Changes in LV structure were assessed by M-mode echocardiograms in a double-blind , placebo-controlled clinical trial of 844 mild hypertensive participants r and omized to nutritional-hygienic ( NH ) intervention plus placebo or NH plus one of five classes of antihypertensive agents : ( 1 ) diuretic ( chlorthalidone ) , ( 2 ) beta-blocker ( acebutolol ) , ( 3 ) alpha-antagonist ( doxazosin mesylate ) , ( 4 ) calcium antagonist ( amlodipine maleate ) , or ( 5 ) angiotensin-converting enzyme inhibitor ( enalapril maleate ) . Echocardiograms were performed at baseline , at 3 months , and annually for 4 years . Changes in blood pressure averaged 16/12 mm Hg in the active treatment groups and 9/9 mm Hg in the NH only group . All groups showed significant decreases ( 10 % to 15 % ) in LVM from baseline that appeared at 3 months and continued for 48 months . The chlorthalidone group experienced the greatest decrease at each follow-up visit ( average decrease , 34 g ) , although the differences from other groups were modest ( average decrease among 5 other groups , 24 to 27 g ) . Participants r and omized to NH intervention only had mean changes in LVM similar to those in the participants r and omized to NH intervention plus pharmacological treatment . The greatest difference between groups was seen at 12 months , with mean decreases ranging from 35 g ( chlorthalidone group ) to 17 g ( acebutolol group ) ( P = .001 comparing all groups ) . Within-group analysis showed that changes in weight , urinary sodium excretion , and systolic BP were moderately correlated with changes in LVM , being statistically significant in most analyses . CONCLUSIONS NH intervention with emphasis on weight loss and reduction of dietary sodium is as effective as NH intervention plus pharmacological treatment in reducing echocardiographically determined LVM , despite a smaller decrease in blood pressure in the NH intervention only group . A possible exception is that the addition of diuretic ( chlorthalidone ) may have a modest additional effect on reducing LVM The 4 year prospect i ve trial on the effectiveness of the antihypertensive treatment was performed in 100 mild hypertensive patients of the aged , the average age being 76.1 years . Dropouts during the drug-off control period were 9 cases . The matched pair group was selected by the age , sex , and blood pressure . Forty-four drug treated cases and 47 placebo treated cases were comparable in blood pressure as well as in laboratory data . Cerebrovascular and cardiac complications were observed in 4 cases or 10.5 % in the drug group , and in 9 cases or 22.0 % in the placebo group . When 8 cases of blood pressure elevation over 200/110 mmHg in the placebo group were added to the cardiovascular complications , dropouts in placebo group reached 41.5 % , and this showed the significant difference . Other complications were observed in 12 cases or 31.6 % in the drug group and in 17 cases or 41.5 % in the placebo group . Major complications were cancers , infections , and bone or joint diseases . Blood pressure was decreased from 171/87 to 151/80 in the drug group , and the average decrease was 20/7 mmHg in 4 year period . No significant changes in hematocrit , serum protein , urea nitrogen , uric acid , sodium , and potassium were observed during the trial period . The present study suggested that antihypertensive treatment was effective in the aged with mild hypertension , and that careful follow up was needed not only for cardiovascular complications but also for general health condition Aim : 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 Patients and methods : A r and omly 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 r and omly 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 Results : 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 Conclusions : 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 A blood lipid-lipoprotein elevating effect of the diuretics hydrochlorothiazide and chlorthalidone in mildly hypertensive men has been established by a cross-over , r and omized controlled trial , confirming previous clinical observations . Compared to baseline , plasma total cholesterol increased 6 % and 8 % and triglycerides 17 % and 15 % under treatment with hydrochlorothiazide and chlorthalidone , respectively . A cholesterol-lowering diet largely prevents this increase . Because these effects may be long-lasting and may cancel part of the potential benefit of blood pressure control in mildly hypertensive patients , with thiazide diuretics attention should be given to prescription of a cholesterol-lowering diet and to periodic monitoring of blood lipid levels . Different antihypertensive agents might be considered in patients with elevated blood lipid levels . Other antihypertensive agents currently in use need to be studied for potential effects on lipid metabolism STUDY OBJECTIVES 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 . DESIGN Multicenter , r and omized , double-blind , placebo-controlled , parallel-group trial with a 6-week treatment phase . SETTING Private and university-based clinics . PATIENTS AND PARTICIPANTS 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 . INTERVENTIONS 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 . MEASUREMENTS AND MAIN RESULTS 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 . CONCLUSIONS The addition of a diuretic to sustained-release diltiazem produced an enhanced antihypertensive effect compared with monotherapy with either individual agent During a 12-week , multicenter study to evaluate the efficacy and safety of lisinopril and hydrochlorothiazide ( HCTZ ) for the treatment of obesity-related hypertension , ambulatory blood pressure ( ABP ) monitoring was performed both at baseline and at study completion in 124 patients . Patients were r and omized to three groups : placebo , lisinopril ( 10 , 20 , or 40 mg/day ) , or HCTZ ( 12.5 , 25 , or 50 mg/day ) . All groups were matched with regard to sex , race , age , body mass index , and waist/hip ratio . The primary analysis of ABP data revealed that both lisinopril and HCTZ effectively lowered mean 24-h systolic ( SBP ) and diastolic ( DBP ) blood pressure compared with placebo , ( mean change from baseline SBP/DBP : -12.0/-8.2 , -10.6/-5.5 , and -0.3/-0.5 mm Hg , respectively ) ; however , lisinopril lowered DBP better than HCTZ ( P < .05 ) . Secondary analyses of groups revealed that men responded better to lisinopril than HCTZ ( -11.9/-7.3 v -6.6/-3.5 mm Hg , respectively ) , whereas women responded well to both drugs . White patients responded better to lisinopril than HCTZ , whereas black patients showed a significant response to HCTZ only . Response to treatment was also influenced by patient classification of 24-h blood pressure profiles , ie , " dipper " or " nondipper . " Overall , the majority of obese  hypertensives  were nondippers . Nondippers ( n = 82 ) responded well to both drugs ( -10.4/-6.9 v -12.5/-5.7 mm Hg , P < .05 v placebo ) , whereas dippers ( n = 42 ) responded to lisinopril ( -11.7/ -9.4 mm Hg , P < .05 v placebo and HCTZ ) , but not HCTZ ( -5.6/-4.1 mm Hg , P = NS v placebo ) . Results of 24-h ABP data show that both lisinopril and HCTZ are effective therapies for obesity-related hypertension and that response to treatment is influenced by sex , race , and dipper/nondipper status A factorial design method was applied in this multicentre trial of the angiotensin-converting enzyme inhibitor quinapril hydrochloride ( Accupril ) in combination with the diuretic hydrochlorothiazide ( HCTZ ) to assess the additive effects of the combination versus monotherapy , to characterise the dose-response relationship of each drug in the presence of the other and to determine if quinapril would attenuate the hypokalemic effect of HCTZ . Following a two to four week placebo-baseline period , 460 qualifying patients with a DBP > or = 100 mmHg and < or = 115 mmHg were r and omised to an eight week double-blind phase with one of 16 parallel treatments : placebo , one of three doses of quinapril monotherapy , one of three doses of HCTZ monotherapy or one of nine possible corresponding combinations of quinapril and HCTZ .  Mean reductions in sitting SBP/DBP at trough with combination therapy ranged from 7.8 mmHg/7.2 mmHg to 19.6 mmHg/15.1 mmHg ( n = 458 ) . Results of the response surface analyses indicate that the effects of the two drugs were additive and that the maximum antihypertensive effect of quinapril in combination with HCTZ within the doses studied is achieved approximately at a dose of 26 mg quinapril and 25 mg HCTZ . The degree of attenuation of the hypokalemic effect of HCTZ was directly related to the dose of quinapril . At 40 mg quinapril , the HCTZ dose-related decreases of serum potassium were not apparent and overall hypokalemic effects were attenuated by quinapril . Thus , the combination of quinapril and HCTZ given once daily provided additive antihypertensive effects of predictable degrees and the addition of quinapril attenuated the hypokalemic effect of HCTZ BACKGROUND African Americans with hypertension , particularly those with more severe blood pressure elevations , are generally less responsive to monotherapy from any antihypertensive class . These patients usually require treatment with drugs from > or = 2 antihypertensive classes to achieve adequate blood pressure control . OBJECTIVE The purpose of this study was to assess the antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide ( HCTZ ) in African American adults with mild to moderate hypertension . METHODS In this 12-week , multicenter , double-blind , r and omized , parallel-group , placebo-controlled study , African American patients were r and omized in a 3:3:1 ratio to I of 3 treatment groups : placebo , losartan monotherapy ( 50 to 150 mg ) , or losartan plus HCTZ ( 50/0 to 50/12.5 to 100/25 mg ) . Doses were titrated at weeks 4 and 8 if  sitting diastolic blood pressure ( SiDBP ) was > or = 90 mm Hg . Safety was assessed by determining the incidence of clinical and laboratory Adverse events and evaluating mean changes in pulse , body weight , electrocardiographic parameters , and laboratory test results . RESULTS A total of 440 patients were r and omized-188 to placebo , 193 to losartan monotherapy , and 59 to losartan/HCTZ ; 391 completed the study . At week 12 , the response rate with losartan monotherapy was 45.8 % , with a significant ( P < or = 0.01 ) lowering in mean SiDBP by 6.6 mm Hg compared with placebo ; the response rate with placebo was 27.2 % , with a mean SiDBP reduction of 3.9 mm Hg . Sitting systolic blood pressure ( SiSBP ) was significantly lowered with losartan monotherapy , by 6.4 mm Hg , compared with placebo ( reduction of 2.3 mm Hg ) . The response rate with losartan/ HCTZ was 62.7 % , with reductions in SiSBP and SiDBP of 16.8 mm Hg and 10.8 mm Hg , respectively ( P < or = 0.01 vs placebo and losartan monotherapy ) . The incidence of clinical adverse events was comparable in the 3 treatment groups . CONCLUSIONS The results of this study suggest that in African American patients , losartan monotherapy was significantly more effective than placebo in lowering SiSBP and SiDBP . Moreover , the losartan/ HCTZ combination regimen result ed in significant and clinical ly meaningful additional reductions in SiSBP and SiDBP compared with losartan monotherapy or placebo . Losartan monotherapy and the losartan/HCTZ regimens were generally as well tolerated as placebo Introduction : 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 . Methods : Thirty-seven hypertensive neuroradiologically proven ischaemic stroke patients were r and omized 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 infa rct ion and again 7 days later . Dynamic cerebral autoregulatory indices , pulse interval , BP variability and cardiac baroreceptor sensitivity were also calculated . Results : 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 . Conclusion : Following acute ischaemic stroke , the st and ard 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 st and ard dosage in the initial post-stroke period Twenty-two white men and two white women with uncomplicated essential hypertension participated in a r and omized double-blind trial comparing placebo with alpha-methyldopa ( 750 mg/d orally ) and chlorothiazide ( 450 mg/d orally ) , alone or in combination . There were no significant differences in blood pressures as measured with the patients lying down ; however , with the patients st and ing the systolic , diastolic and mean arterial blood pressures were significantly lower ( P < 0.05 ) after treatment with alpha-methyldopa or the combination product . The higher the blood pressure before treatment , the greater the fall with treatment . Adverse effects were infrequent Summary In a multicentre , double-blind , crossover , placebo-controlled study , the antihypertensive effect of labetalol 100 mg and chlorthalidone 10 mg , given alone or in combination , has been assessed in 32 hypertensive patients . The combination had a greater effect in reducing blood pressure than did its separate components . This was particularly evident after exercise . Heart rate increased during chlorthalidone therapy , decreased during labetalol therapy , and a summation effect was observed during treatment with the combination . In most cases additivity was observed , as no interaction between the single components was observed , except for heart rate after exercise , and for diastolic blood pressure in the upright position . No interaction was observed either in the biochemical indices or in the clinical side-effects To determine dose‐effect and concentration‐effect relationships in hypertension for pinacidil and hydrochlorothiazide when given alone and together , we conducted a r and omized , double‐blind , 4 × 3 factorial , modified fixed‐dose multicenter trial . Three hundred and eighty‐four patients with essential hypertension ( supine diastolic blood pressure , 95 to 110 mm Hg ) were assigned to one of 12 groups that received all combinations of four doses of pinacidil ( 0 , 12.5 , 25 , and 37.5 mg , b.i.d . ) with three doses of hydrochlorothiazide ( 0 , 12.5 , and 25 mg , b.i.d . ) . Significant dose‐ and concentration‐effect relationships were seen for pinacidil  and  hydrochlorothiazide  on diastolic blood pressure . For pinacidil  , dose‐ and concentration‐effect relationships were steeper after the dose than before the dose . A significant interaction with hydrochlorothiazide was noted such that , when combined with 12.5 mg hydrochlorothiazide , 12.5 mg pinacidil had near‐maximal effects on blood pressure at both peak and trough . Edema occurred in 47 % of those who received 37.5 mg pinacidil monotherapy ( 19 % discontinued ) . The administration of 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appears to be optimal for efficacy and safety In a joint Veterans Administration-National Heart , Lung , and Blood Institute study of mild hypertension , 1,012 men and women , 21 to 50 years of age and with diastolic pressure from 85 to 105 mm Hg , were r and omized into two double-blind treatment groups . Subjects in the active group received chlorthalidone or chlorthalidone plus reserpine , while the other subjects received matching placebo tablets . After one year of treatment , the chlorthalidone group had increases of 10.0 + /- 1.8 ( SE ) mg/dL in total cholesterol level , 9.8 + /- 5.2 mg/dL in triglyceride level , and 12.6 + /- 3.4 mg/dL in low-density lipoprotein-cholesterol level above the changes in the placebo group . There was no difference in high-density lipoprotein changes between the two groups ( 0.1 + /- 0.8 mg/dL ) . The possible net effect on risk of increasing lipid values while lowering pressure in the long-term treatment of mild hypertension with thiazides or related diuretics must be further evaluated Indapamide ( Lozol ) , an indoline antihypertensive drug with diuretic and vasodilating activities , was evaluated in 195 patients with mild to moderate essential hypertension ( sitting DBP between 95 and 110 mmHg ) in a multicentre , r and omised , double-blind , parallel-group design trial . A four week single-blind placebo wash-out period was followed by an eight week double-blind period . Patients were r and omised to indapamide 1.25 mg/day or to placebo . The primary efficacy endpoint was the mean change in sitting DBP from baseline to week 8 . Ninety patients in the placebo group ( 93 % ) and 82 patients ( 84 % ) in the indapamide group completed the eight weeks of double-blind therapy . Indapamide produced a mean ( SE ) decrease in sitting DBP of 7.4 ( 0.63 ) mmHg ( from 100.1 to 92.8 mmHg ) compared with a decrease of 3.6 ( 0.75 ) mmHg ( from 99.6 to 95.8 mmHg ) produced by placebo ( p < 0.0001 ) . Indapamide and placebo also produced mean decreases in st and ing DBP of 6.8 ( 0.75 ) and 2.8 ( 0.77 ) mmHg , respectively ( p = 0.0002 ) , in sitting SBP of 11.1 ( 1.18 ) and 3.2 ( 1.35 ) mmHg , respectively ( p = 0.0001 ) and in st and ing SBP of 11.4 ( 1.29 ) and 4.0 ( 1.43 ) mmHg , respectively ( P = 0.0002 ) . Reduction in BP of > or = 10 mmHg or to a DBP of < or = 90 mmHg was more frequent ( P = 0.0005 ) among indapamide ( 46.6 % ) compared with placebo ( 23.7 % ) treated patients . During the eight week double-blind treatment period , incidence rates for all adverse experiences and for drug-related adverse experiences were similar between the two treatment groups . ( ABSTRACT TRUNCATED AT 250 WORDS The object of this study was to determine the clinical ly relevant dose of bendrofluazide for the treatment of arterial hypertension . A material of 257 male and female subjects , age 25 - 70 years , with sitting diastolic blood pressures between 100 - 120 mmHg after six weeks of placebo treatment participated in this r and omized , double-blind placebo-controlled parallel group study . The patients were treated with either 0 , 1.25 , 2.5 , 5.0 or 10 mg bendrofluazide daily for 12 weeks . Blood pressure was measured with a r and om zero sphygmomanometer and a Tricuff . Compliance was checked by tablet counts . The mean decreases in diastolic blood pressure were 3.5 , 9.8 , 10.8 , 10.1 and 10.8 mmHg in the five treatment groups respectively . The heart rates were unchanged in all groups . Dose-effect relations were demonstrated for potassium , urate , glucose , cholesterol and apolipoprotein B. The lowest dose of bendrofluazide , 1.25 mg , affected only urate , whereas all of the mentioned biochemical variables were affected by the highest dose of 10 mg . It can be concluded that the optimal dose of bendrofluazide for aterial hypertension is 1.25 mg daily . Increase in the dose beyond this level only results in more pronounced adverse biochemical effects including the lipid-metabolism and subjective adverse events Unlike some thiazide diuretics , indapamide -- a non-thiazide chlorosulphonamide derivative -- has been shown to have a magnesium-sparing effect in normotensive subjects . This effect has not been studied in hypertensive subjects . In a r and omised double-blind trial indapamide 2,5 mg and placebo were given daily to a group of elderly patients with mild hypertension , with and without supplemental magnesium chloride .  Blood pressure and serum and red blood cell cations were measured . The significant antihypertensive effect of indapamide was confirmed . There was no effect of indapamide on serum and red cell magnesium concentrations compared with placebo , both with and without magnesium supplementation . Indapamide induced hypokalaemia with a shift of sodium into the red cells . In this group of elderly hypertensive subjects  indapamide induced potassium but not magnesium loss 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 £ 95 and £ 110 mm Hg ) were r and omized 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 −2.11−6.9 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 Thiazide diuretics are known to raise total and LDL cholesterol . To assess whether chlorthalidone affected levels of putatively atherogenic small , dense LDL ( LDL 3 ) , we conducted a 12 week double blind r and omized , placebo controlled clinical trial in 34 nonsmoking men aged 35 to 57 years with mild hypertension ( DBP 90 to 104 mm Hg ) . Our a priori hypothesis that chlorthalidone raised LDL 3 levels was not confirmed . However , the fall in LDL 3 ( P = .03 ) and total cholesterol ( P = .08 ) associated with weight loss was attenuated by chlorthalidone . Since weight loss is commonly prescribed during the clinical management of hypertensives with concomitant hypercholesterolemia , consideration should be given to the attenuating effect of chlorthalidone on cholesterol reduction in the management of these patients BACKGROUND To attain goal blood pressure ( BP ) , many hypertensive patients require combination antihypertensive therapy . Thiazide diuretic/beta-blocker regimens lower BP , and clinical studies indicate that they reduce the risk for cardiovascular consequences of hypertension . Fixed-dose combination tablets can simplify multidrug treatment regimens . METHODS This multicenter , r and omized , double-blind , placebo-controlled , unbalanced factorial study ( N = 1571 ) was design ed to determine whether hydrochlorothiazide ( HCT ) and extended release ( ER ) metoprolol both contribute to an antihypertensive effect .  Hypertensive adults with sitting diastolic BP ( SiDBP ) 95 to 114 mm Hg and systolic BP ( SiSBP ) < 180 mm Hg received one of three hydrochlorothiazide doses ( 6.25 mg , 12.5 mg , or 25 mg ) , one of four ER-metoprolol doses ( 25 mg , 50 mg , 100 mg , 200 mg ) , or one of nine of the combinations or placebo for 8 weeks . RESULTS Blood pressure decreased with all combinations ( P < .001 v placebo ) ; reductions were dose related , ranging from 8.7 to 15.7 mm Hg ( SiDBP ) and 9.7 to 18.9 mm Hg ( SiSBP ) ( model-derived values ) . Reductions with placebo were 5.3 ( SiDBP ) and 4.2 mm Hg ( SiSBP ) . Both active agents contributed to the combination effect ( P = .0015 for SiDBP ; P = .0006 for SiSBP ) . Several low-dose combinations were approximately as effective as high doses of the individual agents ( differences within 1 to 2.5 mm Hg ) . The adverse event discontinuation rate was 2.9 % . Serum potassium decreased and uric acid increased with increasing doses of HCT . CONCLUSIONS Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components The objective of this study was to evaluate the safety and efficacy of indapamide 1.25 mg once daily as monotherapy in elderly patients ( 65 years and older ) with mild to moderate essential hypertension . Two hundred and seventy-nine ( 279 ) elderly patients were enrolled in a washout period , during which patients received single-blind placebo for 4 weeks . Patients demonstrating supine diastolic pressures between 95 mm Hg and 114 mm Hg at the end of the 4-week placebo washout period were entered into the 8-week double-blind treatment period . Two hundred and four ( 204 ) patients qualified for the study and were r and omized to the double-blind treatment ; 103 patients received indapamide 1.25 mg and 101 patients received placebo for 8 weeks . Overall , 177 patients ( 92 indapamide  and 85 placebo ) completed the study . The primary efficacy criterion was the mean change in supine diastolic blood pressure ( DBP ) from double-blind baseline to the end of 8 weeks of therapy . By week 8 of the double-blind treatment period , indapamide 1.25 mg produced a statistically significant ( P = 0.0037 ) decrease in supine DBP of 8.2 mm Hg compared to a decrease of 5.3 mm Hg produced in the placebo group . Additionally , indapamide 1.25 mg was statistically ( P = 0.0028 ) more effective than placebo in reducing supine systolic BP ( SBP ) ( −10.1 vs −4.2 mm Hg ) . The incidence of drug-related adverse events during the double-blind treatment period was similar between the two treatment groups . A low dose of indapamide , 1.25 mg , given once daily for 8 weeks was effective as monotherapy with respect to BP reduction in an elderly population with mild to moderate hypertension .  Indapamide 1.25 mg was safe and generally well tolerated in this elderly patient population BACKGROUND Losartan , an angiotensin II receptor antagonist , has been shown to decrease serum uric acid and to increase urinary excretion of uric acid . METHODS To determine if this effect can increase the risk of acute urate nephropathy , 63 hypertensive patients with thiazide-induced asymptomatic hyperuricemia ( serum uric acid 7.0 to 12.0 mg/dl ) were r and omized double-blind to losartan 50 mg every day ( q.d . ) , losartan 50 mg plus hydrochlorothiazide ( HCTZ ) 50 mg q.d . , HCTZ 50 mg q.d . , or placebo for three weeks . To potentiate the risk of crystal formation , patients received a 2 g/kg protein diet one day prior to each clinic visit on days 0 ( baseline ) , 1 , 7 , and 21 . RESULTS Adverse events typically associated with acute urate nephropathy , for example , flank pain , hematuria , or increased blood urea nitrogen/creatinine , were not reported . Uric acid excretion and urine pH increased four and six hours after losartan on day 1 compared with day 0 . Dihydrogen urate , the primary risk factor for crystal formation , decreased at four and six hours on day 1 compared with day 0 associated with the concurrent rise in urine pH. Day 7 and 21 changes , compared with day 0 , in uric acid excretion rate , urine pH , and dihydrogen urate with losartan were comparable to day 1 results but were not statistically significant . Serum uric acid was significantly reduced after 21 days of therapy with losartan . CONCLUSION Losartan decreased serum uric acid and increased uric acid excretion without increasing urinary dihydrogen urate , the primary risk factor for acute urate nephropathy , during 21 days of dosing in hypertensive patients with thiazide-induced hyperuricemia The possible beneficial or adverse effects of long-term diuretic use in the elderly were evaluated in 60 males ( mean age 80.0 years ) and 17 females ( mean age 84.3 years ) . All subjects were found to have no obvious need for diuretics when initially assessed and were not receiving concurrent digoxin therapy . Residents were r and omly allocated to placebo or active groups with stratification for prior hypertension or congestive heart failure ( CHF ) and they were followed for one year in a double-blind design . Mean BP , heart rate and weight at one year were similar to baseline values in both groups . Six active and two placebo subjects developed CHF and two other placebo subjects had a return of BP to hypertensive levels . Serum creatinine , cholesterol , potassium and BUN were significantly improved at one year in the placebo group . Chronic diuretic use did not alter appreciably the occurrence of CHF or hypertension in this elderly population and may not be necessary A double-blind study carried out on volunteer patienls with medium to severe grade II hypertension , did not show any slatistically significant difference between treatment with Baycaron 25 mg daily and hydrochlorothiazide 50 mg daily In a double-blind , crossover study , five white men with mild-to-moderate hypertension received placebo and fixed doses of atenolol , metoprolol , chlorthalidone , verapamil , and the combination of atenolol and chlorthalidone in a quasi-r and om order . Daily dosages were : atenolol , 100 mg ; metoprolol , 200 mg ; chlorthalidone , 50 mg ; verapamil , 240 mg ; and the same doses of atenolol and chlorthalidone in combination .  St and ard office and daytime ambulatory blood pressures were assessed at the end of each month-long trial . Atenolol , metoprolol , chlorthalidone , and verapamil  controlled office blood pressure with similar reductions . Verapamil did not lower ambulatory blood pressure at this dose ( which is lower than is now commonly used ) , but reductions in ambulatory blood pressure were similar for atenolol , metoprolol , and chlorthalidone . The combination of atenolol and chlorthalidone maintained blood pressure control more effectively than the single drug treatments in both office and ambulatory setting s , and the combined hypotensive effects were additive . However , reductions in the office due to the combination appeared to overestimate hypotensive effectiveness in the ambulatory setting . This study suggests that the effectiveness of commonly prescribed antihypertensive regimens varies according to setting as well as drug , and that assessment of treatment effectiveness can be improved by automated ambulatory blood pressure monitoring A double-blind , placebo controlled , crossover trial of 20 and 40 mg of xipamid once daily in the treatment of mild to moderate hypertension is reported and some of the difficulties and pitfalls of multicentre trials of this type are described . 2 Both doses were significantly more effective in reducing the blood pressure than the placebo and neither was superior to the other . Both produced some potassium loss .  Xipamid acted for at least 22 h and was effective in up to 83 % of the patients . 3 Further trials are suggested to investigate the activity of a lower dose than 20 mg BACKGROUND Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents , but this clinical ly important issue has not been examined in sufficiently large trials , involving all st and ard treatments , to determine the effect of such factors . METHODS In a r and omized , double-blind study at 15 clinics , we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg , after a placebo washout period , to receive  placebo or one of six drugs : hydrochlorothiazide ( 12.5 to 50 mg per day ) , atenolol ( 25 to 100 mg per day ) , captopril ( 25 to 100 mg per day ) , clonidine ( 0.2 to 0.6 mg per day ) , a sustained-release preparation of diltiazem ( 120 to 360 mg per day ) , or prazosin ( 4 to 20 mg per day ) . The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure , and the patients continued to receive therapy for at least one year . RESULTS The mean ( + /- SD ) age of the r and omized patients was 59 + /- 10 years , and 48 percent were black . The average blood pressure at base line was 152 + /- 14/99 + /- 3 mm Hg . Diltiazem therapy  had the highest rate of success : 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year .  Atenolol  was successful by this definition in 51 percent of the patients , clonidine in 50 percent , hydrochlorothiazide in 46 percent , captopril in 42 percent , and prazosin in 42 percent ; all these agents were superior to placebo ( success rate , 25 percent ) . Diltiazem ranked first for younger blacks ( < 60 years ) and older blacks ( > or = 60 years ) , among whom the success rate was 64 percent , captopril for younger whites ( success rate , 55 percent ) , and atenolol for older whites ( 68 percent ) . Drug intolerance was more frequent with clonidine ( 14 percent ) and prazosin ( 12 percent ) than with the other drugs . CONCLUSIONS Among men , race and age have an important effect on the response to single-drug therapy for hypertension . In addition to cost and quality of life , these factors should be considered in the initial choice of a drug Atenolol was compared with five other beta-blockers and a thiazide diuretic in a r and omised cross-over trial of once-daily treatment of essential hypertension .  Atenolol was significantly better at reducing resting and exercise blood pressures at 24 hours than any of the other drugs and had a low incidence of side effects . Both timolol and acebutolol had a significant hypotensive effect at 24 hours and a low incidence of side effects , suggesting that further increases in dosage might be effective and well tolerated . Labetalol proved ineffective when given once daily , and the high incidence of side effects , equalled only by pindolol , would probably prohibit further increases in dosage .  Bendrofluazide  was equal or superior to all the beta-blockers except atenolol at reducing resting blood pressure , and its cheapness still makes it an agent of first choice in mild or moderate essential hypertension Abstract . A 2‐year double‐blind trial design ed for study ing the separate and combined effects of bendroflumethiazide ( BFTZ ) and cyclical administration of 17β‐estradiol + estriol/norethisterone ( E/N ) on coronary risk factors and bone mineral loss ( reported elsewhere ) was undertaken . Serum lipids , fasting blood glucose , body weight and blood pressure were measured every 3 months in 97 normal women in their early menopause . All participants received a supplement of 500 mg calcium and were r and omized to one of the following treatment groups : 1 ) placebo ( P ) + P ( n = 33 ) ; 2 ) P + E/N ( n = 21 ) ; 3 ) BFTZ + E/N ( n = 22 ) ; and 4 ) BFTZ + P ( n = 21 ) A r and omized double-blind crossover trial of labetalol , bendrofluazide and placebo was carried out in 18 patients with mild to moderate hypertension . The reduction in blood pressure observed with labetalol and bendrofluazide was similar . The plasma levels of labetalol  showed a significant correlation with changes in blood pressure ( r = 0.07 ; P less than 0.021 ) ; and plasma level determinations of this drug may be of value in the management of patients who receive antihypertensive agents Objectives Aliskiren is a novel , orally active renin inhibitor . Its antihypertensive efficacy and safety , alone and in combination with hydrochlorothiazide ( HCTZ ) , were investigated in an 8-week , double-blind , placebo-controlled trial in hypertensive patients . The effects of these treatments on plasma renin activity ( PRA ) were also assessed . Methods A total of 2776 patients aged ≥ 18 years with mean sitting diastolic blood pressure ( MSDBP ) 95–109 mmHg were r and omized to receive once-daily treatment with aliskiren ( 75 , 150 or 300 mg ) , HCTZ ( 6.25 , 12.5 or 25 mg ) , the combination of aliskiren and HCTZ , or placebo , in a factorial design . The primary endpoint was the change in MSDBP from baseline to week 8 . PRA was assessed at these timepoints at selected study centers . Results Aliskiren monotherapy was superior to placebo ( P < 0.001 ; overall Dunnett 's test ) in reducing MSDBP and mean sitting systolic blood pressure ( MSSBP ) . Combination treatment was superior to both component monotherapies in reducing BP ( maximum MSSBP/MSDBP reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg ) , and result ed in more responders ( patients with MSDBP < 90 mmHg and /or ≥ 10 mmHg reduction ) and better control rates ( patients achieving MSSBP/MSDBP < 140/90 mmHg ) than either monotherapy . Aliskiren monotherapy reduced PRA by up to 65 % from baseline . Although HCTZ monotherapy increased PRA by up to 72 % , PRA decreased in all of the combination therapy groups . All active treatments were well tolerated . Conclusions Aliskiren monotherapy demonstrated significant BP lowering , and its effect was considerably greater when combined with HCTZ . Renin inhibition with aliskiren neutralized the compensatory rise in PRA induced by HCTZ Fifty-five patients with mild to moderate , renal or essential hypertension were admitted to a double blind cross-over trial of 18 weeks , involving treatment periods with placebo , the thiazide bendrofluazide ( 15 mg daily ) and the beta blocker atenolol ( 600 mg daily ) . Compared to the placebo period ( 190/117 mm Hg ) the hypotensive effect of atenolol ( -24/16 mm Hg ) was more pronounced than the hypotensive effect of bendrofluazide ( -17/6 mm Hg ) . Arguments in favor of initiating antihypertensive drug therapy with beta blocker were its more powerful hypotensive effect , the quicker onset of its action , less metabolic disturbance , decreased frequency of complaints and patient 's preference . On thiazides body weight and the frequency of swollen ankles decreased . Plasma renin concentration was not found to have a strong predicting power for the hypotensive effect of atenolol or bendrofluazide but low renin patients showed a more pronounced blood pressure decrease on bendrofluazide and high renin patients , especially essential hypertensives , on atenolol . While these points can be a guide to therapy today , the preference of one drug over the other must eventually be based on their relative efficacy in decreasing morbidity and mortality from the hypertensive disease In a double-blind trail in 22 patients with mild to moderate essential hypertension , indapamide was compared with chlorathiazide and placebo . Dosage levels were set at 5 mg . indapamide and 500 mg . chlorothiazide daily , for 5 days out of 7 , and patients were treated alternately , in r and om sequence , with each drug for a month over a 3-month period . Blood pressure readings and blood chemistry investigations were carried out before and after each treatment period and a careful history was kept of subjective symptoms and patients ' tolerance of therapy . The results show that both active treatments produced drops in systolic and diastolic pressures , but were only statisically significant and different from placebo in the case of indapamide . Indapamide also produce much greater subjective improvement ( 74 % ) in patients with functional symptoms compared with chlorothiazide ( 15 % ) . In an overall assessment , indapamide produced an excellent to good response to treatment in 57 % of patients . Comparable responses for chlorotiazide and placebo were 25 % and 20 % respectivlely . Using patients as their own controls to compare the relative effectiveness of the three periods of treatment , indapamide was shown to be more effective than placebo in 65 % of cases and more effective han chlorothiazide in 60 % . Although patient tolerance of indapamide was slightly better , both drugs were well accepted and no significant changes from baseline levels were noted in any of the laboratory parameters investigated Arterial compliance , assessed by the ratio of stroke volume to pulse pressure , and baroreceptor sensitivity ( Oxford method ) , were determined in ten patients with essential hypertension , treated with placebo or indapamide ( 2.5 mg/day ) , in a cross-over , single blind study . After three months of therapy , mean arterial pressure was significantly reduced from 127 + /- 10 to 118 + /- 9 mmHg , ( P less than 0.001 ) , as was total peripheral vascular resistance ( from 3017 + /- 561 to 2457 + /- 614 dyne/sec/cm-5/m2 , P less than 0.001 ) . Significant increases occurred in cardiac index ( 3.47 + /- 0.55 to 4.03 + /- 0.86 l/min/m2 , P less than 0.01 ) , baroreceptor sensitivity assessed with phenylephrine  ( from 11.69 + /- 7.9 to 15.0 + /- 9.1 msec/mmHg , P less than 0.01 ) or with nitroglycerine ( from 4.77 + /- 1.6 to 7.11 + /- 2.7 msec/mmHg , P less than 0.01 ) and arterial compliance ( from 1.27 + /- 0.42 to 1.55 + /- 0.57 , P less than 0.01 ) . A significant direct correlation was found between arterial compliance and baroreceptor sensitivity assessed during induced increase and reduction of BP , both during placebo ( r = 0.88 , P less than 0.001 and r = 0.77 , P less than 0.01 , respectively ) and during active therapy ( r = 0.94 , P less than 0.001 and r = 0.92 , P less than 0.001 , respectively ) . These results support the conclusion that chronic treatment with indapamide enhances arterial compliances and reduces the heart load and blood vessel stress . The same effect could explain the enhancement of baroreceptor sensitivity promoted by the drug Benazepril hydrochloride is a new angiotensin‐converting enzyme inhibitor . In a multicenter study , 206 patients with mild to moderate hypertension were r and omized 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 : −12.217.7 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 < 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 hématologie 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 AIM To compare the efficacy of indapamide ( 1.25 mg daily ) and low-salt diet ( < 100 mmol/day ) separately and in combination in essential hypertensive patients with inadequate BP response to perindopril .  DESIGN AND METHODS R and omized double-blind , double-dummy , crossover design . The r and omized treatments were indapamide 1.25 mg daily , sodium chloride 80 mmol daily , the combination of indapamide and sodium chloride and placebo . All patients received perindopril 4 mg daily and maintained a low-sodium diet . RESULTS 19 patients entered and 17 completed the study . Prior to r and omization , average clinic sitting blood pressure was 162/101 mm Hg and average 24-h urine sodium excretion was 157 mmol/day . Compared to the phase in which patients received perindopril with sodium repletion , clinic and ambulatory BPs were significantly reduced ( p<0.01 ) in all the other phases . Indapamide had a greater effect on BP than dietary sodium restriction , and in combination their effects were additive . The effect of indapamide on ambulatory BP persisted throughout 24 h , but the effect of the low-salt diet was predominantly observed during waking hours . CONCLUSIONS In hypertensives with BP resistant to the angiotensin converting enzyme ( ACE ) inhibitor perindopril , the diuretic indapamide had greater additional efficacy and longer duration of action than dietary sodium restriction . In combination they had additive effects on BP In accordance with international recommendations on the need to decrease doses of antihypertensive drugs , a low-dose ( 1.5 mg ) sustained-release form of indapamide was developed so as to optimize the safety/efficacy ratio , while maintaining a once-daily administration . The new formulation ensures that the active ingredient release occurs in a sustained manner over 24 hours , with mean concentrations close to the maximal concentration over a prolonged period , while avoiding peak plasma concentrations . Clinical data were obtained mainly through two European multicenter , r and omized , double-blind trials , totalling 690 patients . Firstly , the antihypertensive efficacy ' of the new indapamide 1.5 mg form was demonstrated by measuring blood pressure 24 hours after the last drug intake , using a mercury sphygmomanometer ; the equivalence of its antihypertensive efficacy with the immediate-release form of indapamide 2.5 mg was then verified . Biochemical safety data showed better acceptability with indapamide 1.5 mg with in particular a reduction of more than 50 % of the number of patients with kalemia < 3.4 mmol/l ; clinical safety data confirmed the good acceptability observed with the 2.5 mg immediate-release form of indapamide since many years , especially regarding glucose and lipid neutrality . In conclusion , the 1.5 mg sustained-release form of indapamide has an improved antihypertensive efficacy/safety ratio which is in accordance with international recommendations for the usage of low doses of antihypertensive drugs and diuretics in the first-line treatment of hypertension 1 The hypotensive effect of single daily dosing with atenolol 100 mg and chlorthalidone 25 mg given alone or in combination has been assessed in a double-blind , crossover , placebo controlled trial in fifteen hypertensive patients . 2 Average lying blood pressures were : Placebo 155.4/103.9 mm Hg , atenolol 134.6/85.8 mm Hg , chlorthalidone 139.5/90.1 mm Hg , combination 127.7/82.5 mm Hg . 3 The effect of the combination therapy in reducing lying diastolic pressure compared with placebo ( a fall of 21.4 mm Hg ) was significantly less than the 31.9 mm Hg fall predicted from the sum of the individual effects ( P = 0.01 ) . 4 Observations on blood pressure at rest and under mental , isometric and bicycle ergometer stress were made pre-dose and post-dose for a 12 h period at the end of the last treatment period . 5 Lying blood pressure declined from the zero hour ( pre-dose ) reading on all treatments to a low at 15.00 - -18.00 h and then rose again . 6 The rise in systolic blood pressure after isometric exercise and mental stress was of a similar magnitude with all four treatment regimes . 7 Atenolol , alone and in combination with chlorthalidone , reduced the blood pressure and the pulse rate increase on exercise 2 h post-dose when compared with readings 24 h post-dose . 8 Once daily dosing with a combination of atenolol and chlorthalidone produced a fall in supine blood pressure over a 24 h period but the effect on exercise induced changes was not uniform over this period We r and omised ambulatory men with diastolic blood pressure ( BP ) 95 - 109 mmHg without anti-hypertensive medication to single drug treatment with either  hydrochlorothiazide 12.5 - 50 mg/day , atenolol 25 - 100 mg/day , captopril 25 - 100 mg/day , clonidine 0.2 - 0.6 mg/day , diltiazem-SR 120 - 360 mg/day , prazosin 4 - 20 mg/day or placebo in a double-blind prospect i ve trial . The assigned drug was titrated to a goal BP of < 90 mm Hg . Patients not achieving goal BP were rer and omised to an alternative single active drug . Non-responders to the second drug received the first drug in combination with the second . Of the 102 non-responders to both drugs who qualified for the combination , 59 ( 57.8 % ) responded . The combination pairs that included a diuretic achieved diastolic goal BP in 69 % and < 140 mm Hg systolic in 77 % compared with 51 % and 46 % , respectively , for those combinations without a diuretic ( P = 0.067 ; P = 0.002 ) . Six of the eight terminations due to adverse drug reactions were in combinations containing prazosin ; three of these six were hypotensive reactions . We conclude that two single drugs of insufficient efficacy to control BP individually have a high probability of achieving goal BP when combined , especially if the combination contains a diuretic BACKGROUND Reducing systolic blood pressure ( BP ) is of major benefit to patients with isolated systolic hypertension , but lowering normal diastolic BP may be harmful in terms of cardiovascular risk . Effects of different drugs on systolic BP , diastolic BP , and pulse pressure are therefore of interest . METHODS The NatriliX SR versus C and Esartan and amLodipine in the reduction of systoLic blood prEssure in hyperteNsive patienTs study ( X-CELLENT ) was a r and omized , double-blind , placebo-controlled study comparing the effects of three drugs on these BP components . Patients with systolic-diastolic or isolated systolic hypertension ( n = 1758 ) received indapamide ( 1.5 mg ) sustained release ( SR ) , c and esartan ( 8 mg ) , amlodipine ( 5 mg ) , or placebo once daily for 12 weeks . RESULTS Compared to placebo all active treatments reduced all BP components significantly ( P < .001 ) . For the patients with isolated systolic hypertension ( n = 388 ) , the three treatments significantly reduced systolic BP , but only indapamide SR did not change diastolic BP and thus reduced pulse pressure significantly relative to placebo ( P = .005 ) . In an ancillary study using ambulatory BP monitoring ( n = 576 ) , all three treatments significantly reduced BP components during 24 h relative to placebo . Changes in systolic BP and pulse pressure were similar with the three treatments , but the reduction in diastolic BP was significantly smaller , and therefore more favorable , with indapamide SR compared with c and esartan ( P = .039 ) . In patients with isolated systolic hypertension ( n = 106 ) , indapamide SR reduced 24-h systolic BP significantly more than amlodipine ( P = .037 ) , and only indapamide SR reduced 24-h pulse pressure significantly relative to placebo ( P = .03 ) . All three drugs were well tolerated . CONCLUSIONS This distinctive BP-lowering profile of indapamide SR seems highly beneficial when compared to the either of c and esartan or amlodipine BACKGROUND Increasing concern over long-term drug treatment of mild hypertension has stimulated several studies of weight reduction . Phase I of the Trial of Antihypertensive Interventions and Management demonstrated a short-term effect of weight loss on blood pressure control in overweight persons with mild hypertension , who were either taking placebo or taking low-dose monotherapy .  Phase II investigates the long-term benefit of weight loss on the ability to maintain blood pressure control . METHODS From 10148 community-based screenees , 587 persons ( 5.8 % ) , aged 21 to 65 years , entered a multicenter , r and omized drug ( double-blind , placebo-controlled ) and diet trial . Participants had a diastolic blood pressure between 90 and 100 mm Hg and were at 110 % to 160 % of their ideal weight . They were r and omized to a usual diet ( n = 296 ) or to a weight loss diet ( n = 291 ) and within each diet group to placebo , chlorthalidone , 25 mg/d , or atenolol , 50 mg/d . Treatment failure was defined as using additional antihypertensive medications if diastolic blood pressure rose above 90 mm Hg according to protocol -specified criteria . RESULTS At baseline ,  mean diastolic blood pressure was 93 mm Hg ; systolic blood pressure  , 143 mm Hg ; weight , 88 kg ; percent ideal weight , 137 % ; age , 48 years ; 56 % were men ; and 33 % were black . Mean follow-up was 4.5 years . There was a net loss of 2 to 3 kg with weight loss diet compared with usual diet over most of the follow-up period . The 5-year incidence of treatment failure was 56.7 per 100 participants with usual diet and 49.8 per 100 with weight loss . Long-term weight loss decreased failure of blood pressure control for those receiving placebo or low-dose diuretic or beta-blocker by 23 % . The results were similar in direction in each drug group . CONCLUSIONS The Trial of Antihypertensive Interventions and Management demonstrated that weight reduction is an effective long-term therapy for maintaining blood pressure in the normal range when used as monotherapy or in combination with either thiazide diuretics or beta-blockers . Consequently , weight loss should be recommended for the management of obese individuals with mild hypertension The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied . Thirteen patients with mild to moderate essential hypertension completed this r and omized , double-blinded , placebo-controlled , crossover study . After a three-week run-in period the patients entered three periods lasting four weeks each , wherein they were treated with placebo , spirapril , or hydrochlorothiazide .  Blood pressure , hemodynamic variables ( stroke volume , heart rate , cardiac output , index of contractility , and systemic vascular resistance ) , echocardiography ( left ventricular mass ) , and Doppler-derived atrial to early (A/E)-ratio velocity time integrals ( VTI ) were measured at the end of each of the four periods . Spirapril lowered the A/E-ratio VTIs ( 0.57 , 0.12 - 1.00 ) ( P < 0.02 ) as compared with both placebo ( 0.80 , 0.50 - 2.67 ) and hydrochlorothiazide ( 0.83 , 0.44 - 1.25 ) , and the drug normalized the A/E-ratio VTI in those patients with elevated values . The hemodynamic variables , left ventricular mass , and end-systolic wall stress were unchanged during all three treatments . There were no significant changes in mean blood pressure during the treatment periods . These results indicate that spirapril lowers A/E ratio within four weeks in patients with mild to moderate essential hypertension . It thereby seems able to improve left ventricular diastolic function . The effect is not dependent upon changes in hemodynamic variables , blood pressure , left ventricular mass , or end-systolic wall stress The efficacy of low dosages of diuretics was evaluated in two studies . In one , 62 ( 48 % ) of 130 patients became normotensive with 2.5 mg/day of metolazone . In the other , 28 ( 49 % ) of 57 patients became normotensive with 25 mg of chlorthalidone , compared with 12 ( 22 % ) of 55 patients given placebo . There was a marked variation in blood pressure response and the occurrence of hypokalemia ( less than 3.5 mEq/L of potassium ) from center to center and within patient groups in both studies . The mean decrease in serum potassium was between 0.5 and 0.6 mEq/L in the metolazone group and 0.44 mEq/L in the chlorthalidone-treated patients . This degree of hypokalemia is only slightly less than that noted when larger dosages of thiazide diuretics are used ( 0.6 to 0.7 mEq/L ) . It is concluded that 2.5 mg/day of metolazone or 25 mg/day of chlorthalidone are effective antihypertensive agents but that blood pressure lowering may be inconsistent at these dosage levels . It is reasonable , therefore , to begin diuretic therapy with low dosages , but larger dosages ( 5 mg of metolazone or 50 mg of chlorthalidone ) should be tried before adding another drug or concluding that diuretic therapy is ineffective if an acceptable blood pressure response is not obtained . The degree of hypokalemia that occurs at lower-dose therapy is variable but may be of less clinical significance than that noted with higher dosages of diuretics in some patients . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE 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 . DESIGN A 6-week , r and omized , double-blind , parallel study conducted at 24 centers . A placebo run-in period of 1 to 4 weeks preceded the double-blind phase . PARTICIPANTS AND SETTING Male and female out patients , 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 . INTERVENTIONS 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 . MAIN OUTCOME MEASURES The mean change from baseline in sitting diastolic blood pressure at end point ( last postr and omization 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 . RESULTS 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 . CONCLUSION 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 BACKGROUND One third of patients treated for hypertension attain adequate blood pressure ( BP ) control , and multidrug regimens are often required . Given the lifelong nature of hypertension , there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies . OBJECTIVE This study investigated the efficacy and tolerability of valsartan ( VAL ) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with essential hypertension . METHODS The first part of this study was an 8-week , multicenter , r and omized , double-blind , placebo controlled , parallel-group trial . Patients with essential hypertension ( mean sitting diastolic BP [ MSDBP ] , > or = 95 mm Hg and < 110 mm Hg ) were r and omized to 1 of 8 treatment groups : VAL 160 or 320 mg ; HCTZ 12.5 or 25 mg ; VAL/HCTZ 160/12.5 , 320/12.5 , or 320/25 mg ; or placebo .  Mean changes in MSDBP and mean sitting systolic BP ( MSSBP ) were analyzed at the 8-week core study end point . VAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week , open-label extension . Response was defined as MSDBP < 90 mm Hg or a > or = 10 mm Hg decrease compared to baseline . Control was defined as MSDBP < 90 mm Hg compared with baseline . Tolerability was assessed by monitoring adverse events at r and omization and all subsequent study visits and regular evaluation of hematology and blood chemistry . RESULTS A total of 1346 patients were r and omized into the 8-week core study ( 734 men , 612 women ; 924 white , 291 black , 23 Asian , 108 other ; mean age , 52.7 years ; mean weight , 92.6 kg ) . All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study , with each monotherapy significantly contributing to the overall effect of combination therapy ( VAL and HCTZ , P < 0.001 ) . Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo ( all , P < 0.001 ) . The mean reduction in MSSBP/MSDBP with VAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg , compared with 5.9/7.0 mm Hg with placebo . The reduction in MSSBP was significantly greater with VAL/HCTZ 320/25 mg compared with VAL/HCTZ 160/12.5 mg ( P < 0.002 ) . Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy . The incidence of hypokalemia was lower with VAL/HCTZ combinations ( 1.8%-6.1 % ) than with HCTZ monotherapies ( 7.1%-13.3 % ) . The majority of adverse events in the core study were of mild to moderate severity . The efficacy and tolerability of VAL/HCTZ combinations were maintained during the extension ( 797 patients ) . CONCLUSIONS In this study population , combination therapies with VAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy , were well tolerated , and were associated with less hypokalemia than HCTZ alone A low dose ( 1.25 mg ) of indapamide ( Lozol , Rhône-Poulenc Rorer Pharmaceuticals , Collegeville , PA ) was evaluated in 222 elderly patients ( > or = 50 years ) with mild to moderate essential hypertension in a multicenter , r and omized , double-blind , parallel-group clinical trial . A 4-week single-blind placebo washout period was followed by an 8-week double-blind treatment period . Patients were r and omized to receive indapamide 1.25 mg/day or to receive placebo . The primary efficacy variable was the mean change in sitting diastolic blood pressure from baseline to week 8 . Eighty-one patients in the indapamide group ( 73 % ) and 87 patients in the placebo group ( 78 % ) completed the 8 weeks of double-blind therapy . Therapy with 1.25 mg of indapamide produced greater reductions compared with placebo in sitting diastolic blood pressure after 8 weeks of therapy , with statistical significance ( P < or = 0.0015 ) seen after only 2 weeks of therapy and continuing throughout the 8 weeks . All secondary efficacy measures ( sitting systolic blood pressure , st and ing systolic and diastolic blood pressures , and > or = 10 mm Hg decrease or final value of < or = 90 mm Hg in sitting diastolic blood pressure ) also showed superior ( P < or = 0.0014 ) improvement in the indapamide group compared with placebo after 8 weeks of double-blind treatment . During the 8-week double-blind treatment period , incidence rates for all adverse events and for drug-related adverse events were similar between the two treatment groups . ( ABSTRACT TRUNCATED AT 250 WORDS Previous studies indicate that low dose bendrofluazide ( 1.25 mg/day ) has no deleterious effect on insulin sensitivity in contrast to conventional doses . To evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h , we studied 12 subjects in a r and omized , double blind , cross-over trial , comprising 8 weeks of either 1.25 mg/day bendrofluazide or placebo .  Twenty-four-hour blood pressure averages were significantly lower after bendrofluazide compared with placebo ( systolic 125 + /- 4 v 136 + /- 3 mm Hg , P < .005 ; diastolic : 78 + /- 2 v 85 + /- 2 mm Hg , P < .01 ) . Trough : peak ratios were 0.67 + /- 0.07 for systolic and 0.72 + /- 0.15 for diastolic blood pressure reduction . In conclusion , 1.25 mg bendrofluazide daily produced a useful antihypertensive effect across the full 24-h period Ninety four patients with mild hypertension ( average supine diastolic blood pressure ( phase V ) 95 - 110 mm Hg ) were allocated at r and om to receive restriction of dietary sodium ( maximum allowed 70 mmol(mEq)/24 h ) or a normal diet . In addition , they received in r and om order 25 mg chlorthalidone , 200 mg metoprolol ( slow release ) , and a fixed combination of these two drugs . Each drug treatment was given for four weeks and alternated with four weeks of placebo . Forty four patients were allocated to sodium restriction ( group 1 ) and 50 to normal diet ( group 2 ) . The mean 24 hour urinary sodium excretion in group 1 was 74 ( SD 31 ) mmol(mEq)/24 h , and in group 2 132 ( 51 ) mmol/24 h. Compared with the screening blood pressure the average decrement of the supine blood pressure in group 1 was 16.0/8.6 mm Hg with placebo , 21.7/11.5 mm Hg with the diuretic , 28.5/17.8 mm Hg with the beta blocker , and 28.9/18.4 mm Hg with the combined agent ; in group 2 these values were 13.3/6.1 , 20.3/9.7 , 21.3/12.9 , and 29.4/16.8 mm Hg , respectively . There was a sharp decrease of the average potassium concentration during chlorthalidone and combination treatment periods ( average value 3.3 mmol(mEq)/1 ) . These results suggest that moderate salt restriction used as sole treatment has a limited though demonstrable blood pressure lowering effect but that when it is used as an adjuvant to beta blocker treatment its value is greatly enhanced Guanfacine , 1 to 3 mg/day , and clonidine , 0.1 to 0.3 mg twice a day , were compared in a 24‐week double‐blind , r and omized , parallel study of 42 patients with hypertension that was inadequately treated by chlorthalidone , 25 mg/day .  Mean reduction of blood pressure was 18/9 mm Hg after guanfacine and 14/8 mm Hg after clonidine . To determine the incidence of rebound hypertension , subjects were hospitalized for 7 days during chlorthalidone therapy for collection of baseline data and once again immediately after abrupt withdrawal of the α‐agonist after 24 weeks of dosing . Although blood pressure and heart rate rose significantly in both groups , the changes after clonidine withdrawal were greater and occurred earlier ( day 2 ) than those after guanfacine withdrawal ( day 4 ) . Forty percent of the subjects receiving guanfacine and 64 % of subjects receiving clonidine  had diastolic blood pressure elevations ≥10 mm Hg from baseline . There were increases in urinary norepinephrine levels in both groups after drug withdrawal , but these correlated poorly with blood pressure rise . Side effects after guanfacine were much the same as those after clonidine . Guanfacine taken once a day provides an effective and safe alternative  to clonidine in the management of essential hypertension A r and omized , 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 BACKGROUND Recent surveys reveal continuing deficiencies in the awareness , treatment , and control of hypertension . In many cases , failure to achieve blood pressure targets may be attributable to the use of antihypertensive monotherapy . OBJECTIVES This study was undertaken to identify combinations of telmisartan , a new oral angiotensin II type 1-receptor antagonist , and hydrochlorothiazide ( HCTZ ) that might provide greater antihypertensive efficacy than monotherapy with either agent in the treatment of mild to moderate hypertension . It also examined the dose-response surface for the 2 drugs alone and in combination . METHODS This was a multicenter , r and omized , double-blind , placebo-controlled , parallel-group study that employed all cells of a 4 x 5 factorial design . After a 4-week , single-blind , placebo run-in period , men and women between 18 and 80 years of age with mild to moderate hypertension ( defined as mean supine diastolic blood pressure [ DBP ] between 95 and 114 mm Hg during the last 2 weeks of the placebo run-in period and systolic blood pressure [ SBP ] between 114 and 200 mm Hg immediately before r and omization ) were eligible to enter the 8-week , double-blind , double-dummy treatment period . Study comparisons were between once-daily telmisartan monotherapy ( 20 , 40 , 80 , or 160 mg ) , HCTZ monotherapy ( 6.25 , 12.5 , or 25 mg ) , 12 combinations of these telmisartan/HCTZ doses , and placebo . The focus was on 2 combinations : telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg . The primary efficacy variable was change in supine trough DBP from baseline to the last evaluable measurement during double-blind treatment . Plasma renin activity and safety parameters , including treatment-emergent adverse events , physical findings , electrocardiograms , and serum electrolyte levels ( which are known to increase with HCTZ treatment ) , were also assessed . RESULTS Of 1293 patients screened , 818 ( 63.3 % ) were enrolled at 47 centers . Of these 818 , 749 ( 91.6 % ) completed the study . The intent-to-treat population ( r and omized with > or = 1 postr and omization blood pressure measurement ) consisted of 807 patients ( 98.7 % ) . Telmisartan 80 mg/HCTZ 12.5 mg significantly decreased mean supine trough SBP/DBP by 23.9/14.9 mm Hg , a benefit of 8.5/3.4 mm Hg compared with telmisartan 80 mg and of 17.0/7.6 mm Hg compared with HCTZ 12.5 mg ( both comparisons , P < 0.01 ) . Telmisartan 40 mg/HCTZ 12.5 mg significantly reduced mean supine SBP by 18.8 mm Hg , a benefit of 6.6 mm Hg compared with telmisartan 40 mg and 11.9 mm Hg compared with HCTZ 12.5 mg ( both , P < 0.01 ) . This same combination significantly reduced mean supine DBP by 12.6 mm Hg , a benefit of 5.3 mm Hg compared with HCTZ 12.5 mg ( P < 0.01 ) , but was not significantly different from telmisartan 40 mg . Telmisartan 80 mg/HCTZ 12.5 mg was significantly more effective than telmisartan 40 mg/HCTZ 12.5 mg in reducing mean supine DBP and SBP ( both , P < 0.05 ) . The response surface and responder analyses confirmed the additive antihypertensive efficacy of the combination of telmisartan and HCTZ . All regimens were well tolerated . CONCLUSIONS Once-daily telmisartan 80 mg/HCTZ 12.5 mg was effective and well tolerated when used to reduce SBP and DBP in patients with mild to moderate hypertension . In addition to enhancing efficacy , this combination protected against potassium depletion , a common side effect of thiazide monotherapy 1 . A within-patient r and omized double-blind crossover study was performed on mechanisms of action of bendrofluazide in mild essential hypertension . Significant reductions in lying , st and ing and post-exercise blood pressure were seen after both 3 days and 10 weeks treatment with bendrofluazide ( 10 mg daily ) . 2 . Plasma levels of 6-oxo-prostagl and in F1 alpha , the chemical hydrolysis product of prostacyclin , were significantly increased by both 3 days and 10 weeks therapy with bendrofluazide . This raises the possibility that thiazides may reduce peripheral resistance by increasing prostacyclin bio synthesis A within‐patient r and omized , double‐blind , crossover study was performed to investigate mechanisms of action of bendroflumethiazide in mild essential hypertension . Significant reductions in lying , st and ing , and postexercise blood pressure were seen after both 3 days and 10 wk treatment with bendroflumethiazide 10 mg daily . Plasma levels of 6‐oxo‐PGF1α , the chemical hydrolysis product of prostacyclin , were increased by both 3 days and 10 wk therapy with bendroflumethiazide . This raises the possibility that thiazides may reduce peripheral resistance by increasing prostacyclin bio synthesis The antihypertensive efficacy of a 1.5-mg sustained-release formulation ( SR 1.5 ) of indapamide , a diuretic related to thiazide , has been pointed out by using conventional sphygmomanometric measurement 24 h after dosing in clinic , in two large European r and omized , double-blind , controlled studies ( 2 and 3 months ) . One of these studies was then extended to 12 months , as a complementary open study .  Quality -controlled ambulatory blood pressure monitoring ( ABPM ) data for a total of 216 patients from these studies are presented , including subgroups of hypertensives and responders .  Indapamide SR 1.5 achieves an adequate 24-h blood pressure control by significantly reducing the 24-h , diurnal , and nocturnal blood pressures versus baseline , confirming the sphygmomanometric data . The benefit at 2 and 3 months is maintained at 1 year , which confirms the long-term efficacy of SR 1.5 mg . The trough-to-peak ratio -- not previously calculated for a diuretic according to international guidelines --meets Food and Drug Administration requirements and confirms the 24-h efficacy of indapamide SR 1.5 This 30-center , r and omized , double-blind , placebo-controlled , parallel-group study was design ed to ( 1 ) establish that 6.25 mg of hydrochlorothiazide ( HCTZ ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II ( mild to moderate ) systemic hypertension ; and ( 2 ) assess whether this formulation was more effective or possessed a safety advantage over st and ard monotherapy with bisoprolol or 25 mg of HCTZ . Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg . Bisoprolol 5 mg/HCTZ 6.25 mg ( B5/H6.25 ) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure ( -15.8 mm Hg/-12.6 mm Hg ) than bisoprolol 5 mg alone ( -10.0 mm Hg/-10.5 mm Hg ) and HCTZ 25 mg alone ( -10.2 mm Hg/-8.5 mm Hg ) . A 73 % response rate was achieved with the low-dose formulation compared with 61 % for the bisoprolol 5 mg ( B5 ) group and 47 % for the HCTZ 25 mg ( H25 ) group . B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients , regardless of gender , race , age , or smoking history . Antihypertensive effects were maintained during the 24-hour dosing interval . The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences ; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group . B5/H6.25 was shown to provide safety advantages over H25 , as shown by less hypokalemia ( < 1 % with B5/H6.25 versus 6.5 % with H25 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The hypotensive and hormonal effects of the angiotensin converting enzyme ( ACE ) inhibitor enalapril ( 10 mg twice daily ) were compared with those of hydrochlorothiazide ( 25 mg twice daily ) , with the two drugs in combination and with placebo in 21 patients with essential hypertension . For each patient there were four r and omised double-blind treatment phases , each of four weeks ' duration , which comprised a 2 X 2 factorial experiment . All blood pressure parameters were reduced in the three active treatment phases compared to placebo ( p less than 0.001 ) . Supine mean blood pressures were 119 mmHg ( placebo ) , 113 mmHg ( hydrochlorothiazide ) , 108 mmHg ( enalapril ) , and 98 mmHg ( hydrochlorothiazide plus enalapril ) ( SEM 3 mmHg , ANOVA ) . Enalapril and hydrochlorothiazide were equally effective and well tolerated and their hypotensive effects were additive . Enalapril increased plasma renin activity ( PRA ) , reduced plasma angiotensin II ( AII ) and aldosterone concentrations , and reduced ACE activity , whereas hydrochlorothiazide increased PRA , plasma AII , and aldosterone concentrations without altering ACE activity . With combination treatment the effects of enalapril on PRA and plasma AII concentrations were potentiated whereas those on plasma aldosterone concentration and ACE activity were additive . Atrial natriuretic factor plasma concentration in the placebo phase was 92 pg/ml and increased to 145 pg/ml in the hydrochlorothiazide phase ( p less than 0.001 , SEM 13 pg/ml ) , but there was no significant change in either the enalapril or combination phases The effects of nebivolol , a new beta-blocker with vasodilating properties , and hydrochlorothiazide ( HCTZ ) as monotherapies and in combination on BP and plasma lipids , lipoproteins and apolipoproteins were compared with placebo in a parallel 3 x 4 factorial design study . After an eight week wash-out period , 240 patients with primary hypertension were r and omised to receive either placebo , nebivolol 1 , 5 or 10 mg , HCTZ 12.5 or 25 mg or one of the six possible combinations of nebivolol and HCTZ .  Twenty patients were assigned to each of the 12 parallel groups . After 12 weeks of treatment , there was a significant dose-related reduction in BP among all active treatment groups . Apart from a slight and isolated increase in triglycerides with HCTZ 12.5 mg , lipid , lipoprotein and apolipoprotein levels as well as lipoprotein and apolipoprotein ratios were not significantly modified by 12 week active treatments when compared with placebo treatment . The results of this multifactorial study with 12 small sample size groups , suggest that nebivolol as monotherapy and in combination with HCTZ does not cause deleterious effects on the lipid profile The antihypertensive effect of indapamide ( 2.5 mg/day ) was compared to that obtained with a placebo in a controlled trial carried out by 11 physicians in their private practice . Thirty-one patients with uncomplicated essential hypertension were included . After a run-in period of 3 weeks without any treatment , either indapamide ( n = 16 ) or a placebo ( n = 15 ) were administered for 8 weeks in double-blind fashion . Blood pressure decreased in both groups . In patients treated with indapamide , systolic pressure was significantly lower than in those given the placebo at 3 out of the 4 follow-up visits ; diastolic pressure , however , was significantly lower only at the end of the trial . Both the active drug and the placebo were well tolerated . No significant change in body weight , plasma potassium and uric acid occurred during the study in either group of patients . It appears therefore that indapamide , at a dose which apparently has no major diuretic effect , may be useful for practitioners in managing patients with mild to moderate hypertension The effects of timolol ( 10 mg thrice daily ) and hydrochlorothiazide ( 50 mg/day ) have been compared in a double-blind factorial trial in 20 patients with essential hypertension . There were four r and omised test phases of 8 weeks each during which patients received timolol alone , hydrochlorothiazide alone , timolol plus hydrochlorothiazide , and no treatment ( placebo ) .  Blood-pressure was measured weekly , alternately at the outpatient clinic and at the patient 's home . Supine mean arterial pressure fell from 119 mm Hg in the placebo phase to 110 mm Hg in the hydrochlorothiazide phase , 106 mm Hg in the timolol phase , and 101 mm Hg in the combined timolol plus hydrochlorothiazide phase . Factorial analysis revealed that these effects of the two drugs were additive without any potentiation or antagonism . Mean plasma-renin activity ( P.R.A. ) was 5 - 02 ng/ml/3 h in the placebo phase falling to 1 - 79 in the timolol phase and rising to 9 - 54 in the diuretic phase , but remaining unchanged in the combined treatment phase ( 5 - 40 ng/ml/3 h ) . The data suggest that the hypotensive action of timolol is not dependent on the concomitant fall in P.R.A. The methods described provide a valuable tool for quantitating the effects of a given drug , and hence a valid basis for objective comparison To assess the duration of antihypertensive effect of a single daily dose of the short‐acting diuretic hydrochlorothiazide , a double‐blind crossover study was performed in 11 patients previously well controlled with diuretics . Each patient received hydrochlorothiazide 100 mg in the morning for 12 wk and blood pressures were recorded 4 times daily ( 8 A.M. , 12 noon , 4 A.M. , and 8 P.M. ) on 3 separate visits . The crossover design also included a 12‐wk placebo period either preceding or following active therapy . Blood pressure control was excellent and sustained throughout the day in all patients studied , indicating that a single daily dose of hydrochlorothiazide is a suitable regimen for hypertension therapy . The use of a placebo period before initiating the trial and during the active part of the trial confirmed the observation that patients who have been adequately treated for long periods will maintain lowered blood pressure for a variable period after stopping therapy To evaluate whether the combination of nifedipine with chlorthalidone exerts an additive antihypertensive effect when compared to single-drug treatment , 66 uncomplicated essential hypertensives , whose diastolic blood pressure was > 100 and < 115 mm Hg at the end of a 1-month washout placebo period , received , according to a r and omized , double-blind , crossover design , nifedipine ( 20 mg b.i.d . ) , chlorthalidone ( 25 mg o.d . ) , the two drugs combined at the same doses , and the corresponding placebo . When compared to the r and omized placebo the three active treatments significantly ( p < 0.001 ) reduced blood pressure without changing heart rate and body weight . However , blood prssure values were similarly reduced under nifedipine and the combination and were significantly lower ( p < 0.05 ) than those under chlorthalidone . Moreover , the percentage of responders and normalized patients under nifedipine and the two drugs combined were similar and significantly ( normalized , p < 0.001 ; responders , p < 0.02 ) greater than those under chlorthalidone . Under chlorthalidone and its combination with nifedipine , plasma potassium tended to decrease and blood glucose and serum uric acid were significantly ( p < 0.05 ) increased . These data show that the combination of nifedipine with chlorthalidone does not exert any additive antihypertensive effect when compared to nifedipine alone and that this combination increases both blood glucose and serum uric acid . Taken together these findings indicate that the combination of a dihydropyridine calcium antagonist with a thiazide diuretic is devoid of any clinical significance in the treatment of uncomplicated essential hypertensives Two multicenter , double-blind , r and omized studies were performed to determine the antihypertensive efficacy and effects on laboratory values of a new , shorter-acting formulation of metolazone in patients with mild to moderate hypertension . After baseline placebo-control periods , 105 patients were r and omly assigned to receive single daily doses of either placebo or 0.5 , 1.0 , or 2.0 mg of the new formulation of metolazone for six weeks in one study , and 164 patients were r and omized to receive 0.5 , 1.0 , or 2.0 mg of the new formulation of metolazone or 2.5 mg of the older , long-acting metolazone in the other . Mean blood pressure reductions in all three metolazone groups were statistically and clinical ly significant . Blood pressures of 51 % to 58 % of patients in the 0.5-mg metolazone group were controlled ( diastolic blood pressure less than 90 or a fall of greater than or equal to 10 mmHg from baseline ) . Reductions in mean serum potassium levels were dose-related . We conclude that 0.5 mg of metolazone is safe and effective therapy for hypertension ; it will significantly reduce systolic and diastolic blood pressure and minimizes changes in laboratory test values The echocardiographic predictors of ventricular arrhythmias are reported for the Hypertension Arrhythmia Reduction Trial . Men with mild hypertension were withdrawn from their diuretic therapy and repleted with 40 mEq/day of oral potassium and 20 mEq/day of oral magnesium for 1 month . M-mode echocardiography and 24-hour continuous ambulatory electrocardiography were performed on 123 men , mean age 62 years . Forty-eight men ( 39 % ) had echocardiographic evidence of left ventricular ( LV ) hypertrophy defined as an LV mass index greater than 134 g/m2 and this finding was not related to the presence of LV hypertrophy on electrocardiogram or to age . Men who had echocardiographic LV hypertrophy were more likely than men without echocardiographic LV hypertrophy to have greater than or equal to 30 ventricular premature complexes (VPCs)/hr ( odds ratio = 2.7 ; 95 % confidence interval = 0.9 , 8.0 ) , multiform extrasystoles ( odds ratio = 1.7 ; confidence interval = 0.8 , 3.7 ) , episodes of ventricular tachycardia ( odds ratio = 2.3 ; confidence interval = 0.7 , 7.1 ) and the combination of frequent ( greater than or equal to 30 VPCs/hr ) or complex ( ventricular couplets , multiform extrasystoles or episodes of ventricular tachycardia ) ventricular arrhythmia ( odds ratio = 1.7 ; confidence interval = 0.8 , 3.5 ) . Similar associations between echocardiographic LV hypertrophy and ventricular arrhythmias were observed on 24-hour tracings obtained on entry to the study ( before electrolyte repletion ) in the 96 men who were taking diuretics at this time . The combination of a frequent or complex arrhythmia was also more common in men aged 60 to 70 compared to men aged 35 to 59 ( odds ratio = 3.4 ; confidence interval = 1.4 , 8.2 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Objective To compare with placebo the efficacies of once-daily administrations of lacidipine and hydrochlorothiazide separately and in combination to elderly patients with systolic hypertension . Design and methods Nineteen elderly subjects ( five men and 14 women , median age 71 years , range 62–79 years ) participated in the study , which had a r and omized double-blind crossover design . For each subject there were four treatment phases , each of duration 4 weeks . The initial treatments in each phase were 2 mg lacidipine once a day and 25 mg hydrochlorothiazide once a day , separately and in combination , and placebo . Doses of each agent could be doubled after 2 weeks in each phase if the patient 's goal systolic blood pressure had not been achieved . The numbers of subjects administered the higher dose of each treatment were 13 for placebo , 14 for lacidipine , 11 for hydrochlorothiazide and eight for lacidipine plus hydrochlorothiazide .  Results End-of-phase mean clinic blood pressures were 164/85 mmHg with placebo , 159/82 mmHg with lacidipine , 157/84 mmHg with hydrochlorothiazide and 152/82 mmHg with lacidipine plus hydrochlorothiazide . Systolic blood pressure was significantly reduced during all active treatment phases compared with placebo and that for the lacidipine plus hydrochlorothiazide phase was also significantly less than those for both of the other active treatment phases . There was no difference between sitting and st and ing blood pressure for any phase . Factorial analysis of the main effects of treatment indicated that the effects of lacidipine and hydrochlorothiazide on clinic blood pressure were additive and also that heart rate was higher when hydrochlorothiazide had been administered . Ambulatory blood pressure monitoring confirmed the pattern of the responses of blood pressure and showed that administration of hydrochlorothiazide had a significantly greater effect on systolic blood pressure and a longer duration of action than did administration of lacidipine . There was no difference in the frequency of adverse effects among any of the phases . Conclusions In treating elderly systolic hypertensives the diuretic hydrochlorothiazide is a more effective antihypertensive agent with a longer duration of action than is the calcium channel antagonist lacidipine . In combination the effects of these two drugs on blood pressure are additive OBJECTIVE To investigate the patterns of electrolyte abnormalities result ing from thiazide administration and whether they cause ventricular arrhythmias , and to help resolve the controversy over whether clinicians should routinely prescribe potassium-conserving therapy to all patients treated with thiazides .  DESIGN Double-blind , r and omized controlled trial . PARTICIPANTS A total of 233 hypertensive men aged 35 to 70 years . INTERVENTIONS Participants were withdrawn from prior diuretic treatment and were replenished with oral potassium chloride and magnesium oxide . They were then r and omized to 2 months of treatment with ( 1 ) hydrochlorothiazide ; ( 2 ) hydrochlorothiazide with oral potassium ; ( 3 ) hydrochlorothiazide with oral potassium and magnesium ; ( 4 ) hydrochlorothiazide and triamterene ; ( 5 ) chlorthalidone ; or ( 6 ) placebo . MAIN OUTCOME MEASURES Ventricular arrhythmias on 24-hour Holter monitoring and serum and intracellular potassium and magnesium levels . RESULTS Of the 233 participants , 212 ( 91 % ) completed the study .  Serum potassium levels were 0.4 mmol/L lower in the hydrochlorothiazide group than in the placebo group ( P less than 0.01 ) , and this mean difference was not affected by supplementation with potassium , with potassium and magnesium , or with triamterene . However , the supplements did prevent the occasional occurrence of marked hypokalemia ; all 12 of the men who developed serum potassium levels of 3.0 mmol/L or less were among the 90 who received diuretics without supplementation ( P less than 0.01 ) . Similarly , the overall proportion of men with ventricular arrhythmias was not affected by r and omized treatment , but there was a twofold increase in the proportion with arrhythmias among the 12 men with serum potassium levels of 3.0 mmol/L or less ( P = .02 ) . Serum magnesium and intracellular potassium and magnesium levels were not reduced by hydrochlorothiazide , nor were they related to ventricular arrhythmias . CONCLUSIONS In the majority of hypertensive patients , treatment with 50 mg/d of hydrochlorothiazide does not cause marked hypokalemia or ventricular arrhythmias . However , because some individuals will develop hypokalemia after starting diuretic therapy , serum potassium levels should be monitored and potassium-sparing strategies should be used when indicated OBJECTIVE 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 . DESIGN Multicenter , double-blind , placebo-controlled outpatient study of 12 weeks ' duration . PATIENTS After 4 weeks of single-blind placebo treatment , 505 patients whose sitting diastolic blood pressure was 100 to 114 mm Hg were r and omized 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 . RESULTS 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 ) . CONCLUSIONS 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 In a double-blind study , thirty patients having mild to moderate essential hypertension were r and omly assigned to a six week regimen of either tienilic acid , hydrochlorothiazide , or placebo .  Blood pressure was significantly reduced with tienilic acid and hydrochlorothiazide although more so with tienilic acid .  Serum uric acid declined strikingly with tienilic acid and increased significantly with hydrochlorothiazide .  Serum potassium declined slightly with tienilic acid but more so with hydrochlorothiazide .  Serum creatinine and blood urea nitrogen increased slightly more with tienilic acid than with hydrochlorothiazide . There were no clinical adverse effects to any of the medications during this study . Twenty-four months of continuous administration of tienilic acid revealed maintenance of blood pressure effect , but with slight increases in blood urea nitrogen , serum creatinine and uric acid and slight decreases in serum potassium as compared to six weeks administration . Tienilic acid appears to be a useful new antihypertensive agent . The hypouricaemic effect is profound and strongly suggests the need for continuing evaluation of this compound because of its unique combination of diuretic , antihypertensive and hypouricaemic properties In a double-blind , placebo-controlled , crossover study in 16 hypertensives , 4 weeks of 50 mg  hydrochlorothiazide twice daily , caused significant elevations in total plasma cholesterol , high density lipoprotein (HDL)-cholesterol , low density lipoprotein (LDL)-cholesterol , very low density lipoprotein (VLDL)-cholesterol and triglycerides . Significant elevations in fasting plasma glucose and in plasma insulin were observed , but no correlation between individual lipid elevations and either glucose or insulin elevations was apparent . The metabolic effects developed within 2 weeks , and dissipated within 4 weeks . Changes induced within 4 weeks of treatment with hydrochlorothiazide were unaltered at 6 months . Hydrochlorothiazide induces elevation of all lipoprotein cholesterol fractions and VLDL-triglyceride . However , as the important ratio between LDL- and HDL-cholesterol is unchanged , coronary risk may be unchanged & NA ; This study compared the effects of beta‐blockers differing in degree of central nervous system penetration on Type A behavior and cardiovascular reactivity to mental stress . Forty‐six male hypertensives were assigned r and omly to receive either highly lipophilic and nonselective propranolol , hydrophilic and cardioselective atenolol , the diuretic hydrochlorothiazide , or placebo . Subjects were administered parallel forms of the Structured Interview ( SI ) and performed mental arithmetic and a cognitive task prior to and after 6 weeks of therapy . Results indicated that diuretic and placebo subjects ( subsequently combined into a single control group ) did not differ and that both beta‐blockers reduced heart rate but not blood pressure reactivity to mental stress ( p less than 0.02 ) , an effect that was strongest during the mental arithmetic test . Analysis of SI components indicated a reduction only in explosive speech for beta‐blockers versus controls ( p less than 0.05 ) . For global SI classifications , seven out of 12 subjects ( 58 % ) receiving propranolol , three of 12 ( 25 % ) receiving atenolol , and four of 22 control subjects ( 18 % ) became less Type A ( p less than 0.05 ) . These data do not replicate results of a prior study obtained with atenolol and suggest that only a subset of hypertensive individuals show reduced Type A behavior  with propranolol . Central nervous system mechanisms may be important in producing these effects The objective of this study was to determine which of the common groups of antihypertensive drugs is most effective at lowering systolic blood pressure ( SBP ) in elderly patients with previously untreated hypertension and the percentage of patients controlled with single or sequential monotherapy . Subjects were recruited from patients attending other outpatient clinics and entered into the study if their SBP was more than 150 mm Hg after three visits . Patients were given a low and high dose of each of the main classes of drugs or placebo for 1 month each . The study was a balanced , r and omized crossover design with five periods : placebo ; angiotensin converting enzyme inhibitors ; beta-blocking drugs ; calcium-blocking drugs ; and thiazide diuretics .  Blood pressure ( BP ) was measured 24 to 26 h after the previous dose . A question naire for side effects was administered at each visit . Seventy-four patients entered the study . beta-Blockers could not be used in 15 patients because of asthma or bronchospasm and these had two placebo periods . There were 9 of 66 patients on P , 9 of 46 on beta-blockers , 4 of 65 on calcium-blocking drugs , 4 of 65 on diuretic , and 1 of 62 patients on ACE inhibitors who did not progress to the higher dose because of side effects . Decreases in SBP compared to r and omized placebo were calcium-blocking drugs 15 mm Hg = diuretic 13 mm Hg > ACE inhibitors 8 mm Hg = beta-blockers 5 mm Hg . Blood pressure decrease correlated with placebo BP ( P < .0005 , r = 0.53 to 0.70 ) . When corrected for placebo , target SBP ( < 140 mm Hg ) was reached in between 6 % to 15 % of patients on monotherapy . Sequential monotherapy achieved target in 29 % . Angiotensin converting enzyme inhibitors , calcium-blocking drugs , and diuretics had no more side effects than placebo . Patients on beta-blockers had more side effects and the well-being score was reduced . Diuretics and calcium-blocking drugs are more effective in elderly patients at lowering SBP pressure . beta-Blockers were relatively ineffective , were frequently contraindicated , and had more side effects . Monotherapy achieved control in only a small number of patients . In elderly people with essential hypertension , therapy should be instituted with diuretics or calcium-blocking drugs , but combination therapy will usually be required to achieve goal The antihypertensive effects of low doses of hydrochlorothiazide have not been examined in black African hypertensive patients although hydrochlorothiazide is commonly used as first-line therapy . The antihypertensive effects of hydrochlorothiazide in a daily dose of 6.25 , 12.5 , 25 and 50 mg were examined in 19 black Zimbabwean hypertensive patients in a double-blind , r and om order , placebo-controlled , cross-over trial . The mean systolic blood pressure on placebo was 170.2 mmHg ( 95 % CI + /- 9.0 mmHg ) and on daily doses of hydrochlorothiazide decreased to : 161.1 mmHg ( 95 % CI + 10.0 mmHg ) on 6.25 mg ; 156.6 mmHg ( 95 % CI + /- 8.6 mmHg ) on 12.5 mg ; 154.9 mmHg ( 95 % CI + /- 8.5 mmHg ) on 25 mg and 149.1 mmHg ( 95 % CI + /- 9.2 mmHg ) on 50 mg . The mean diastolic blood pressure on placebo was 101.4 mmHg ( 95 % CI + /- 5.0 mmHg ) and decreased to : 98.0 mmHg ( 95 % CI + /- 5.7 mmHg ) on 6.25 mg ; 96.1 mmHg ( 95 % CI + /- 4.5 mmHg ) on 12.5 mg ; 93.6 mmHg ( 95 % CI + /- 5.3 mmHg ) on 25 mg and 90.5 mmHg ( 95 % CI + /- 3.9 mmHg ) on 50 mg . Hydrochlorothiazide in doses of 25 mg and 50 mg decreased systolic and diastolic blood pressure and the 12.5 mg dose decreased systolic blood pressure significantly more than placebo . We conclude that in this population maximum antihypertensive effect is not seen with the lower doses of hydrochlorothiazide and 25 mg is an appropriate starting dose for most patients The antihypertensive characteristics of the angiotensin-converting enzyme inhibitor moexipril were evaluated in 413 patients with baseline sitting diastolic blood pressures between 95 and 114 mm Hg . The study was double blind , with patients r and omized to placebo or to differing doses of  moexipril alone or in combination with a low dose of hydrochlorothiazide . Compared with placebo , moexipril 3.75 mg daily was not different , but single daily doses of 7.5 , 15 , and 30 mg were significantly more effective ( as measured at trough , approximately 24 h after dosing ) in decreasing the diastolic blood pressuring during an 8-week treatment period . The dose – response relationship indicated that no additional blood-pressure-lowering effect occurred above 15 mg daily . Hydrochlorothiazide 12.5 mg was not significantly more effective than placebo , but the combinations of the diuretic with moexipril doses of 3.75 , 7.5 , and 15 mg all produced significant antihypertensive actions . Interestingly , the 3.75-mg moexipril-hydrochlorothiazide combination was equally as efficacious as the higher doses . The combinations were all more effective than their respective moexipril and hydrochlorothiazide monotherapies . There were no meaningful laboratory changes except for decreased potassium concentrations in the patients on diuretic alone ; this effect was attenuated in the low-dose moexipril combination . Only 14 of the 413 patients who entered the double-blind study period ( 3 % ) discontinued treatment because of adverse experiences . Thus , moexipril is a well-tolerated drug that has clear antihypertensive efficacy as a single agent in once-daily doses of 7.5–30 mg . When combined with hydrochlorothiazide 12.5 mg , it is effective in daily doses as low as 3.75 mg The antihypertensive effect of captopril , metoprolol , and hydrochlorothiazide was compared in 23 non-insulin-dependent ( NIDDM ) diabetic patients less than or equal to 75 years of age , with borderline to moderate primary hypertension . In a double blind , placebo-controlled cross-over trial the patients were treated with 25 to 50 mg captopril , 50 to 100 mg metoprolol , 12.5 to 25 mg hydrochlorothiazide , and placebo , each given twice daily for 8 weeks . Antidiabetic treatment remained unchanged during the study . After receiving placebo for a 4 week run-in period , arterial blood pressure was 168/101 + /- 93/10 ( mean + /- SEM ) mm Hg . Diastolic blood pressure was lowered significantly during all active treatment periods compared to the placebo value of 97 + /- 2 mm Hg : captopril , 92 + /- 1 mm Hg ; metoprolol , 90 + /- 1 mm Hg ; hydrochlorothiazide , 91 + /- 1 mm Hg . Metabolic variables were not significantly altered by captopril and metoprolol , while hydrochlorothiazide treatment increased hemoglobin A1c from 7.5 + /- 0.3 to 8.2 + /- 0.4 % ( P less than .001 ) , decreased high-density lipoprotein-cholesterol from 1.19 + /- 0.08 to 1.10 + /- 0.06 mmol/L ( P less than .05 ) . Glomerular filtration rate , urinary albumin excretion , orthostatic blood pressure response , and digital systolic blood pressure in the lower limb remained unchanged during the active treatment periods . The frequency of subjective adverse effects was acceptable during active treatment and not significantly different compared to placebo . We conclude that antihypertensive treatment for 8 weeks with captopril or metoprolol in NIDDM patients is well-tolerated and causes no deterioration in metabolic control and kidney function , while hydrochlorothiazide causes a slight deterioration in glycemic control and lipid profile 本態性高血圧に対する利尿降圧剤 tripamide 1日15～60mg単独投与の有用性を60歳以上の老年者33例 ( 平均年齢65.9歳 ) と59歳以下の壮年者59例 ( 平均年齢50.0歳 ) に於て二重盲検法により検討した.降圧効果 ( 20/10mmHgまたは平均血圧13mmHg以上下降 ) は老年者で84.8 % , 壮年者で59.3%で , 老年者の降圧効果が有意に高いことを認めた ( p<0.05 ) . しかし降圧幅は老年者で32.0/13.2mmHg , 壮年者で26.9/11.2mmHgであり , 有意差を認めず , 老年者で過度の降圧を来さないことを示唆した.臨床検査のうち , 血液学検査では両年齢群とも有意の変動を認めず , 血液濃縮は見られなかった. 生化学検査では老年者では血清Cl , アルカリフォスファターゼの低下と尿素窒素 , 尿酸の上昇を , 壮年者では血清Clの低下と総コレステロール , Ca , 尿酸 , 尿素窒素の上昇を認めた. 血清Na , K , 空腹時血糖値には両年齢群とも変化を認めなかった. 心胸比は老年者で減少した. これらの変化は有意差を認めたものの正常範囲内の変化であり臨床的意義は少ないと思われる.副作用は壮年者で5例8%に認められたが , 老年者では認められなかった. 副作用に臨床検査値の異常変化例を含めると壮年者で9例15 % , 老年者で4例12%でいずれも有意差は見られなかった.従って有用性 ( 有用以上 ) は , 老年者で78.8 % , 壮年者で52.5%と有意差を認め ( p<0.05 ) , 利尿降圧剤 tripamide In a double blind placebo controlled r and omised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug . After a four week placebo washout period 53 patients with diastolic blood pressures between 90 - 110 mm Hg were r and omly assigned to 50 , 125 , or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment . Blood pressure was measured in the patients ' homes by the same observer every two weeks . Serum urea , electrolytes , urate , and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods . After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo . The decrement in serum potassium concentration ( 0.6 mmol/l ) and increase in serum urate concentration 0.06 mmol/l ) were greatest with the 500 micrograms dose , the increase in serum urate concentration alone being significant . No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide . Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity ( 1.8 ( 95 % confidence interval 0.2 to 3.4)-5.4 ( 3.9 to 6.8 ) nmol angiotensin I/l/h ) ; the other doses like the placebo had no effect . Cyclopenthiazide 125 micrograms , a dose lower than is currently marketed , produced a similar hypotensive response to 500 micrograms of the drug without up setting the biochemical profile This study was design ed as a multicenter , double-blind , placebo-controlled , parallel-group , prospect ively r and omized study comparing , after a 4-week placebo run-in phase , moxonidine 0.4 mg once daily ( o.d . ) , hydrochlorothiazide 25 mg o.d . , and the combination of the two with placebo . A total of 160 patients were analyzed in an intent-to-treat analysis . Moxonidine 0.4 mg o.d . was effective in significantly lowering blood pressure in this group of mild-to-moderate hypertensive patients in comparison with placebo . The efficacy and the side-effect profile of moxonidine were comparable to those of the first-line antihypertensive agent hydrochlorothiazide . The combination of moxonidine and hydrochlorothiazide in the same dosage as a monotherapy improves efficacy significantly without additive effects on the safety profile . Response rate after monotherapies was calculated with 70.3 and 70.0 % , respectively , after combination treatment in 87.8 % of all patients in the treatment group . The trial gives support to a recommended dosage regimen of moxonidine 0.4 mg o.d . This profile of moxonidine is highly comparable to a st and ard first-line antihypertensive drug such as hydrochlorothiazide , without sacrificing tolerance and safety for increased efficacy , in combination with hydrochlorothiazide The Systolic Hypertension in the Elderly Program ( SHEP ) is a r and omized , blinded test of the efficacy of antihypertensive drug treatment . In a large feasibility trial , 551 men and women who had isolated systolic hypertension and were at least 60 years old received chlorthalidone ( 25 to 50 mg/day ) or matching placebo as the step I drug . After 1 year , 83 % of the chlorthalidone group and 80 % of the placebo group were still taking SHEP medications . Of those still taking chlorthalidone , 88 % had reached goal blood pressure ( BP ) without requiring a step II drug , and most had responded to the lower dose ( 25 mg/day ) . The BP response was similar in all age , sex and race subgroups , with an overall mean difference between r and omized groups of 17 mm Hg for systolic BP ( p less than 0.001 ) and 6 mm Hg for diastolic BP ( p less than 0.001 ) . The only common adverse effects were asymptomatic changes in the serum levels of potassium ( 0.5 mEq/liter lower in the chlorthalidone group , p less than 0.001 ) , uric acid ( 0.9 mg/dl higher , p less than 0.001 ) and creatinine ( 0.08 mg/dl higher , p = 0.02 ) . This study indicates that chlorthalidone is effective for lowering BP in elderly patients with systolic hypertension and sets the stage for a larger trial of the effects of such treatment on the incidence of cardiovascular disease In this multicenter , placebo-controlled , double-blind , 4 x 3 factorial design study , 1,162 patients r and omized into 12 parallel groups received either placebo  ( n = 97 ) , cilazapril ( CLZ 0.5 , 5 , or 10 mg ; n = 288 total ) , hydrochlorothiazide ( HCTZ 12.5 or 25 mg ; n = 198 total ) , or one of the six possible combinations of the two drugs ( n = 579 total ) given orally once daily for 4 weeks . The mean decrease from baseline in predose ( i.e. , 24 h postdose ) sitting diastolic blood pressure ( SDBP ) was statistically significantly ( p < 0.01 ) greater for all combinations studied compared to placebo , as well as to their respective monotherapy components . Synergistic antihypertensive effects were noted for the 5/12.5 mg CLZ/HCTZ combination therapy . The normalization ( SDBP < or = 90 mm Hg ) rate of the 5/12.5 mg CLZ/HCTZ combination was essentially additive with respect to the component monotherapies . The tolerability profile of the CLZ/HCTZ combination was similar to its respective components and comparable to placebo . The CLZ/HCTZ group reported low serum potassium ( K+ ) and high serum uric acid less frequently than the HCTZ group . Therefore , the CLZ/HCTZ combination ( 5 mg/12.5 mg ) is an option for hypertensive patients not responding to single drug CLZ therapy 119 elderly , hypertensive patients were followed-up for 1 year and 48 for 2 years in a double-blind , r and omised , controlled trial in which they received either placebo or 25 - 50 mg hydrochlorothiazide and 50 - 100 mg of triamterene daily . Half of the active treatment group also received 250 mg to 2 g methyldopa daily . After 2 years the active treatment group had an average increase in fasting blood-sugar of 9.6 mg/dl compared with an average fall of 3.1 mg in the placebo group ( p less than 0.001 ) . Blood-glucose rose by an average of 26.6 mg/dl in the active group when determined 1 hour after 50 g oral glucose and decreased by an average of 5.3 mg/dl in patients who had been on placebo for two years ( p less than 0.05 ) . The hyperglycaemic effect of diuretics appeared to be related to potassium loss since , in both groups , impairment of glucose tolerance was most marked in those in whom the serum-potassium decreased over the 2 years
target: Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available : bendrofluazide , chlorthalidone , cyclopenthiazide , metolazone or indapamide .
  This is based on an informal indirect comparison of results observed in other Cochrane review s on ACE inhibitors , ARBs and renin inhibitors compared with placebo , which used similar inclusion /exclusion criteria to the present review .Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides .
  These effects were dose-related and were least for hydrochlorothiazide .
  Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides .
  This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect .
  Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides
background: BACKGROUND Hypertension is a modifiable cardiovascular risk factor .
  Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity , the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review .
  It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects .
  OBJECTIVES To determine the dose-related decrease in systolic and /or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension .
  Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium , uric acid , creatinine , glucose and lipids .