title: A dose escalation trial comparing the combination of diltiazem SR and hydrochlorothiazide with the monotherapies in patients with essential hypertension. Changes in arterial structure and function under trandolapril-verapamil combination in hypertension. Treatment of hypertension by enalapril and hydrochlorothiazide separately and together: a multicenter study. The results of a large multicentre study comparing low-dose lisinopril-hydrochlorothiazide with the monocomponents. A comparison of the efficacy of cilazapril versus cilazapril plus hydrochlorothiazide in patients with mild to moderate essential hypertension Comparative study of once-daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension. Controlled Multicenter Study with Quinapril, Hydrochlorothiazide, and Combination in Patients with Moderate to Severe Hypertension Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial. Atenolol and bendrofluazide in hypertension. The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension. Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy Captopril and Nifedipine Interactions in the Treatment of Essential Hypertensives: A Crossover Study Short report: Ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension. Pilot study of combined blockade of the renin–angiotensin system in essential hypertensive patients Efficacy of eprosartan in combination with HCTZ in patients with essential hypertension A comparison of candesartan, felodipine, and their combination in the treatment of elderly patients with systolic hypertension. Is Low‐Dose Hydrochlorothiazide Effective? [Effectiveness and tolerance of combined verapamil retard and hydrochlorothiazide. Results of a double-blind, randomized study]. Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Lisinopril versus lisinopril plus hydrochlorothiazide in essential hypertension. Double-blind, parallel, comparative multicentre study of a new combination of diltiazem and hydrochlorothiazide with individual components in patients with mild or moderate hypertension. Antihypertensive Effects of Valsartan/Hydrochlorothiazide Combination in Essential Hypertension Improved antihypertensive efficacy of the felodipine-metoprolol extended-release tablet compared with each drug alone. Effect on intra-arterial blood pressure of slow release metoprolol combined with placebo or chlorthalidone. Quinapril, hydrochlorothiazide, and combination in patients with moderate to severe hypertension. Diltiazem and atenolol in essential hypertension: additivity of effects on blood pressure and cardiac conduction with combination therapy. Effects of once daily indapamide and pindolol on blood pressure, plasma aldosterone concentration and plasma renin activity in a general practice setting Comparison of effects of captopril used either alone or in combination with a thiazide diuretic on insulin action in hypertensive Type 2 diabetic patients: a double-blind crossover study. Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects Evaluation of the Efficacy and Tolerability of a Low-Dose Combination of Isradipine and Spirapril in the First-Line Treatment of Mild to Moderate Essential Hypertension Chlorthalidone does not increase the hypotensive effect of nifedipine in essential hypertensives: a crossover multicentre study. Effects of the Combination of Low-Dose Nifedipine GITS 20 mg and Losartan 50 mg in Patients with Mild to Moderate Hypertension Effectiveness of enalapril in combination with low-dose hydrochlorothiazide versus enalapril alone for mild to moderate systemic hypertension in black patients. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Ambulatory Blood Pressure Profiles in Patients Treated with Once-Daily Diltiazem Extended-Release or Indapamide Alone or in Combination Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Nifedipine and acebutolol in combination for the treatment of moderate to severe essential hypertension. Losartan with hydrochlorothiazide in the treatment of hypertension A randomized, controlled trial comparing diltiazem, hydrochlorothiazide, and their combination in the therapy of essential hypertension. Effects of verapamil and trandolapril in the treatment of hypertension. Trandolapril Study Group. Double‐Blind Comparison of Antihypertensive Treatment with Ramipril and Piretanide, Given Alone or in Combination Clinical evaluation of labetalol alone and combined with chlorthalidone in essential hypertension: A double-blind multicentre controlled study Study of the efficacy and safety of the combination ramipril 2.5 mg plus hydrochlorothiazide 12.5 mg in patients with mild-to-moderate hypertension. ATHES Study Group. Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination. Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension. Verapamil SR and trandolapril combination therapy in hypertension--a clinical trial of factorial design. German Hypertension Study Group. Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER. Indapamide and atenolol in the treatment of hypertension: double-blind comparative and combination study. Hemodynamic comparisons of enalapril and felodipine and their combination. Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension. Nicardipine and propranolol in the treatment of essential hypertension. Combined Versus Single Effect of Fosinopril and Hydrochlorothiazide in Hypertensive Patients Controlled Multicenter Study of the Antihypertensive Effects of Lisinopril, Hydrochlorothiazide, and Lisinopril plus Hydrochlorothiazide in the Treatment of 394 Patients with Mild to Moderate Essential Hypertension Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. Metoprolol with and without chlorthalidone in hypertension. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. [The treatment of hypertension in the elderly using a beta-blocker: acebutolol (author's transl)]. Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination. 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. Enalapril, hydrochlorothiazide, and combination therapy in patients with moderate hypertension. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide A double-blind, crossover study of acebutolol and hydrochlorothiazide/amiloride diuretic in Sudanese patients with essential hypertension. A comparison of the efficacy and safety of irbesartan/HCTZ combination therapy with irbesartan and HCTZ monotherapy in the treatment of moderate hypertension The treatment of hypertension with propranolol and bendrofluazide. Atenolol and chlorthalidone in combination 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. Lisinopril-hydrochlorothiazide combination compared with the monocomponents in elderly hypertensive patients. Evaluation of the effect of timolol alone and in combination with hydrochlorothiazide and amiloride in the treatment of mild to moderate arterial hypertension: a double-blind, controlled study. Additive effects of diltiazem and lisinopril in the treatment of elderly patients with mild-to-moderate hypertension. Low-dose atenolol-chlorthalidone combination for treatment of mild hypertension. Comparative studies: enalapril versus hydrochlorothiazide as first-step therapy for the treatment of primary hypertension. Beta blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial. Assessment of a fixed-dosage combination of atenolol and chlorthalidone (Tenoretic) in hypertensive Nigerians. Combination of verapamil and beta blockers in systemic 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. Felodipine, metoprolol and their combination compared with placebo in isolated systolic hypertension in the elderly. First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension. Amlodipine and lisinopril in combination for the treatment of essential hypertension: efficacy and predictors of response 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. Usefulness of piretanide plus ramipril for systemic hypertension: a multicenter trial. The Combination of Chlorthalidone with Nifedipine Does Not Exert an Additive Antihypertensive Effect in Essential Hypertensives: A Crossover Multicenter Study A comparison of initial treatment with losartan/HCTZ versus losartan monotherapy in chinese patients with mild to moderate essential hypertension. Comparison and interaction of low dose felodipine and enalapril in the treatment of essential hypertension in elderly subjects. [A combination of methyldopa, hydrochlorothiazide and amiloride in the treatment of essential hypertension]. A comparison of a combination of penbutolol and frusemide with the two compounds individually in the treatment of hypertension. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. THE ANTIHYPERTENSIVE PROPERTIES OF THE ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR MOEXIPRIL GIVEN ALONE OR IN COMBINATION WITH A LOW DOSE OF A DIURETIC Multiclinic evaluation of the antihypertensive effect of a methyldopa, hydrochlorothiazine, and amiloride combination. The fixed combination of propranolol and bendrofluazide in the treatment of hypertension. Moxonidine and hydrochlorothiazide in combination: a synergistic antihypertensive effect. Effects of enalapril alone, and in combination with hydrochlorothiazide, on renin-angiotensin-aldosterone, renal function, salt and water excretion, and body fluid composition.
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 BACKGROUND AND PURPOSE Converting enzyme inhibition and calcium blockade alter large arteries in hypertension . However , the heterogeneity of the response according to the site of cardiovascular measurements has never been investigated . METHODS In a double-blind study , we compared for 180 days 3 hypertensive patient groups treated with verapamil , tr and olapril , or their combination .  Using echo-Doppler technique and applanation tonometry , we independently measured mean pressure , local pulse pressure , arterial diameter , and distensibility at 3 arterial sites ( brachial and common carotid arteries and abdominal aorta ) , as well as cardiac and carotid wall structure . RESULTS Mean and pulse pressure decreased significantly to a greater extent with the drug combination . Regarding arterial and cardiac hemodynamics , significant and similar changes were noted in the 3 groups : decreases in abdominal aorta and carotid but not brachial diameter ; increases in carotid artery , abdominal aorta , and brachial distensibility even after adjustment to mean blood pressure reduction ; and more substantial regression of cardiac mass than carotid wall thickness . CONCLUSIONS This study shows that both compounds and more significantly combination therapy decreased mean and pulse pressures measured independently and that the changes in diameter , thickness , and stiffness were influenced primarily by the site of cardiovascular measurements , result ing in a predominant increase in distensibility of muscular arteries , little change in carotid wall thickness , but a significant regression of cardiac hypertrophy The efficacy and safety of enalapril and hydrochlorothiazide was investigated in a multicenter study of 81 patients with mild to moderate essential hypertension . The subjects were r and omly assigned to one of three groups and , following a placebo period , given enalapril maleate ( 20 mg ) , hydrochlorothiazide ( 12.5 mg ) , or a combination of the two drugs ( 32.5 mg ) . A significant decrease in blood pressure was observed after only 2 weeks in the enalapril and enalapril-hydrochlorothiazide groups . A double dose was required to achieve a satisfactory response in one-third of the patients in both the enalapril ( 9 of 27 ) and the enalapril-hydrochlorothiazide groups ( 8 of 27 ) . Adverse reactions included cough in one patient and mild hyperkalemia in another , both of whom received enalapril . Two patients on the drug combination developed side effects -- symptomatic orthostatic hypotension in one and impotence in the second . Enalapril alone and in combination with hydrochlorothiazide appears to be effective and well tolerated The efficacy , tolerability and metabolic effects of a fixed combination of lisinopril 10 mg and hydrochlorothiazide 12.5 mg ( L/HCTZ ) and those of the monocomponents were compared in 286 mild to moderate hypertensive patients in a 17-centre study using a double-blind , r and omized , parallel-group design . After 2 weeks of placebo run-in , patients were r and omized to one of the three treatments for 8 weeks . Supine and st and ing BPs were measured at peak blood levels ( 4 - 8 hours post dose ) after 4 weeks , and at trough blood levels ( 24 - 28 hours post dose ) after 8 weeks . The BP reduction from baseline was greater with L/HCTZ than with the monocomponents at weeks 4 and 8 ; at week 8 the reduction was statistically significant vs lisinopril for st and ing DBP ( P less than 0.027 ) but not for st and ing SBP ; the reduction was significant with L/HCTZ vs hydrochlorothiazide at week 4 [ P = 0.0002/0.0001 ( SBP/DBP ) supine ; P = 0.0002/0.0002 st and ing ] and at week 8 ( P = 0.0001/0.0001 supine and st and ing ) . Response at week 8 ( supine DBP less than or equal to 90 mm Hg ) with L/HCTZ ( 87.0 % ) was greater than with hydrochlorothiazide ( 29.0 % ; P less than 0.0001 ) and marginally greater than with lisinopril ( 74.2 % ; P = 0.069 ) . Heart rate fell statistically significantly more with L/HCTZ ( by 3.3 beats/minute ) than with HCTZ ( by 0.86 beats/minute ; P = 0.018 ) . L/HCTZ treatment significantly increased plasma uric acid levels compared with lisinopril . L/HCTZ decreased potassium , while lisinopril  increased potassium . L/HCTZ decreased cholesterol ; HCTZ increased it . Adverse effects were more common on L/HCTZ vs lisinopril ( P = 0.033 ) but not vs hydrochlorothiazide . ( ABSTRACT TRUNCATED AT 250 WORDS Summary The efficacy of cilazapril monotherapy and in combination with hydrochlorothiazide 12.5 mg was compared in a multicentre , double blind , r and omised parallel group study in 87 patients with mild to moderate essential hypertension over 8 weeks . After a 2 week single blind placebo run-in period , patients received either 2.5 mg cilazapril or 2.5 mg cilazapril plus 12.5 mg hydrochlorothiazide once daily . At Week 4 the cilazapril dose was increased from 2.5 mg to 5.0 mg if the mean sitting diastolic blood pressure was greater than 90 mmHg or had not decreased by more than 10 mmHg . After 8 weeks treatment 72 % of patients responded to 2.5 mg cilazapril increasing to 88 % with cilazapril 5.0 mg . For cilazapril plus hydrochlorothiazide , 83 % responded to 2.5 mg cilazapril increasing to 96 % on 5.0 mg cilazapril . The high response rate to low dose cilazapril monotherapy and hydrochlorothiazide combination therapy has important implication s for minimising the cost of therapy with ACE inhibitors 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 Summary : In an 8-week , double-blind , r and omized , active-controlled , multicenter study with three parallel treatment groups , we compared the efficacy and safety of once-daily 20 mg quinapril plus 12.5 mg hydrochlorothi-azide ( HCTZ ) with each drug as monotherapy in patients with moderate to severe hypertension . Hypertensive out patients with supine diastolic blood pressure ( DBF ) ≤105 and ≥120 mm Hg at the end of a 2− to 4-week placebo-baseline period were r and omly assigned to one of the treatment groups . Of the 323 patients who were r and omized to double-blind medication , 297 completed the study , but 6 patients were excluded for violations of protocol ; therefore , statistical analysis was performed in 291 patients . Only 7 patients withdrew owing to lack of efficacy ( 2 receiving combination therapy ) . In all three treatment groups , clinical ly significant reductions in DBF were achieved . Combination therapy was statistically more effective than each component in both evaluable data and intent-to-treat analyses . The incidence of adverse events ( AE ) was 24 % in the quinapril monotherapy group , 14 % in the combination therapy group , and 11 % in the HCTZ monotherapy group . Orthostatic hypotension with related symptoms was observed in 4 patients ( 2 receiving quinapril monotherapy , 1 receiving HCTZ monotherapy , and 1 receiving combination therapy ) . Once-daily quinapril plus HCTZ provided increased reduction of DBF as compared with the monotherapies and was well tolerated in patients with moderate to severe hypertension 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 BACKGROUND Combination therapy with at least 2 antihypertensive agents is usually needed to achieve appropriate blood pressure ( BP ) control in patients with isolated or predominant systolic hypertension . A currently recommended combination is a diuretic added to an angiotensin-receptor blocker . OBJECTIVE This was a study of the effects on sitting systolic BP (SBP)of 2 combinations of valsartan and hydrochlorothiazide ( HCTZ ) compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension ( SBP > or = 160 mm Hg and < or = 200 mm Hg ) with or without other cardiovascular risk factors . METHODS After a placebo run-in period , patients were r and omized to receive double-blind treatment with either valsartan 80 mg OD(monotherapy group ) or valsartan 160 mg OD ( combination-therapy groups ) for 4 weeks , followed by forced titration to valsartan 160 mg OD ( V160 ) , valsartan 160 mg plus HCTZ 12.5 mg OD ( V160 + HCTZ12.5 ) , or valsartan 160 mg plus HCTZ 25 mg OD ( V160 + HCTZ25 ) for an additional 4 weeks . End points were the change in SBP between the groups receiving combination therapy and the monotherapy group , between-group changes in diastolic BP ( DBP ) , responder rates ( SBP < 140 mm Hg or a reduction in SBP of > or = 20 mm Hg ) , and tolerability . RESULTS A total of 774 patients were r and omized to treatment : 261 to V160 , 258 to V160+HCTZ12.5 , and 255 to V160 + HCTZ25 . The intent-to-treat population consisted of 767 patients ( 411 men , 356 women ; mean age , 60 years ; mean weight , 84 kg ; clinic mean [ SD ] baseline BP , 167.5 [8.1]/93.4 [ 9.1 ] mm Hg ) . All treatments produced significant reductions in SBP from baseline ( mean [ SD ] reduction , 20.7 [ 15.7 ] mm Hg with V160 , 27.9 [ 13.8 ] mm Hg with V160 + HCTZ12.5 , and 28.3 [ 13.1 ] mm Hg with V160+HCTZ25 ; all , P < 0.05 ) . DBP was reduced by 6.6 ( 8.9 ) mm Hg in the V160 group and by 10.2 ( 7.7 ) and 10.1 ( 7.8 ) mm Hg in the V160+HCTZ12.5 and V160 + HCTZ25 groups , respectively ( all , P < 0.05 ) . The additional reductions in BP with V160+HCTZ25 did not reach statistical significance compared with V160+HCTZ12.5 . Responder rates were 56.9 % in the V160 group , 74.4 % in the V160+HCTZ12.5 group , and 75.0 % in the V160 + HCTZ25 group P < 0.05 , combination therapy vs monotherapy ) . Adverse events were reported by 27.5 % of patients in the monotherapy group , compared with 28.6 % and 34.0 % in the groups that received V160+HCTZ12.5 and V160+HCTZ25 , respectively ; the differences were not significant between treatment groups . CONCLUSIONS Monotherapy with V160 was effective in these patients with stage 2 or 3 systolic hypertension . Significant additional reductions in SBP and DBP and an increase in responder rates were achieved with the addition to V160 of HCTZ12.5 and HCTZ25 , with no significant effect on tolerability The effect of atenolol , a new beta-1-adrenergic receptor blocking agent , was studied in a double-blind cross-over trial in 24 carefully selected hypertensive out patients . After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day , atenolol 400 mg/day , a combination of atenolol 200/mg day with bendrofluazide 5 mg/day , and bendrofluazide 5 mg/day alone , according to a r and om sequence . Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except st and ing systolic pressure than bendrofluazide alone . There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate . The addition of bendrofluazide to atenolol result ed in a further significant lowering of the blood pressure . A significant effect of thiazide on weight was noted . The study shows that atenolol , a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity , is an effective and well-tolerated hypotensive agent 1 . The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril ( 2.5 mg ) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine ( 5 mg ) were assessed in a double-blind , double dummy placebo controlled , r and omised , crossover study in 20 patients ( mean age 55.4 years ; range 46 - 69 ) with uncomplicated mild to moderate hypertension ( supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo ) . The four r and omised , double-blind , crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo , monotherapy with each drug and the combination .  Noninvasive ambulatory blood pressure monitoring ( Spacelabs 90207 ) was performed for 24 h at the end of each phase . 2 . The mean 24 h ambulatory blood pressure ( mmHg ) was 147.9/92.0 following placebo , 141.3/87.8 following monotherapy with ramipril 2.5 mg , 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg . All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo . The antihypertensive efficacy of the combination was additive . 3 . The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER 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 In order to evaluate the antihypertensive effect and the tolerability of combination therapy with an angiotensin converting enzyme inhibitor ( captopril ) and a dihydropyridine calcium antagonist ( nifedipine ) compared with monotherapy and placebo , we studied 32 uncomplicated essential hypertensives . At the end of a 1-month placebo washout period , their diastolic blood pressure was > 105 and < 120mmHg . The subjects then received , according to a double-blind r and omized crossover design , captopril ( 50 mg twice daily ) , nifedipine ( 20 mg twice daily ) , captopril plus nifedipine at the same doses and the corresponding placebo , each treatment being given for 1 month . Both captopril and nifedipine significantly reduced mean blood pressure , which was further and significantly reduced by the combination of the two drugs . The decreases in mean blood pressure induced by nifedipine were significantly greater than those induced by captopril , and those induced by the combined therapy were significantly greater than those induced by either drug on monotherapy . The heart rate was significantly increased only by nifedipine , and to a similar , but not significant , extent by the combination therapy . Plasma renin activity was similarly and significantly increased and urinary aldosterone tended to decrease to a similar extent under the three active treatments . Adverse effects were mild to moderate in intensity ; their incidence under captopril was lower than that under placebo , while the incidence under nifedipine and combined therapy was greater than under placebo .  Ankle oedema disappeared under the combined therapy in three out of four patients who developed this side effect under nifedipine , although one additional patient developed ankle oedema under combination therapy . These data indicate that : ( 1 ) captopril and nifedipine are effective antihypertensive drugs with a balanced cost-benefit ratio , since even if nifedipine alone was more effective in reducing blood pressure , it was less well tolerated than captopril ; ( 2 ) the combination of captopril and nifedipine exerted an additive antihypertensive effect without aggravating , and possibly even reducing , the incidence of adverse effects due to nifedipine . These findings confirm that the association of an angiotensin converting enzyme inhibitor with a dihydropyridine calcium antagonist can be useful in the treatment of essential hypertension 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 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 Background Additive hemodynamic effects of combined blockade of the renin – angiotensin system by an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist have been observed in sodium-depleted normotensive volunteers and in patients with congestive heart failure . Objective To investigate whether the same additive hemodynamic effects occur in patients with hypertension and to verify the safety of such an approach . Design Multicenter , r and omized , double-blind , parallel-group , pilot study . Patients 177 patients with mild-to-moderate hypertension [ diastolic blood pressure ( DBP ) : 95–115 mmHg after a 4-week placebo run-in period ] were included in the study . Intervention Combination therapy consisting of 50 mg losartan daily and 10 mg enalapril daily was administered for 6 weeks . The effects of this therapeutic regimen was compared with similar groups of patients who received either 50 mg losartan daily or 10 mg enalapril daily Main outcome measures 24-hour ambulatory mean DBP and clinic DBP measured at trough after 6 weeks of treatment . Results 24-hour ambulatory mean DBP did not significantly differ between treatment groups although the combination tended to lower BP more . The combination therapy was more effective on clinic DBP measured at trough than was losartan by 3.2 mmHg [ confidence interval ( 95 % , CI ) 0.7–5.7 mmHg , P = 0.012 ] , and more effective than enalapril by 4.0 mmHg ( 95 % CI , 1.5–6.4 mmHg , P = 0.002 ) . In a subgroup of 28 patients , higher plasma active renin and angiotensin I levels during blockade by the combination therapy were observed . This finding confirmed that the combination of the two agents inhibited the renin – angiotensin system to a greater extent than did either agent alone . Conclusion A combination of 10 mg enalapril daily and 50 mg losartan daily safely induces a supplementary , although modest , fall in clinic DBP in patients with mild-to-moderate essential hypertension This r and omised , double-blind study was design ed to investigate the efficacy of a once-daily ( OD ) combination of the AT1 receptor blocker , eprosartan 600 mg , and the thiazide diuretic , hydrochlorothiazide ( HCTZ ) 12.5 mg , in patients with mild to moderate hypertension ( sitting diastolic blood pressure ( sitDBP ) ⩾98 mm Hg and ⩽114 mm Hg ) not adequately controlled with eprosartan 600 mg OD . A total of 494 patients entered the open-label monotherapy run-in phase , which consisted of eprosartan 600 mg OD for 3 weeks . Patients who responded to monotherapy were not eligible to enter the r and omised phase of the study and were withdrawn . The remaining 309 patients were then r and omised to either eprosartan 600 mg plus HCTZ 12.5 mg OD or to continue on eprosartan 600 mg OD . In the eprosartan plus HCTZ combination group , both sitDBP and sitting systolic blood pressure ( sitSBP ) were significantly reduced compared with the eprosartan monotherapy group . In addition , the response rate was higher in the combination group compared with the monotherapy group . There were no significant effects on reduction of sitDBP due to gender , prior use of antihypertensives or baseline severity of hypertension . The tolerability profile for the combination group was similar to that for the monotherapy group . Headache was the most frequent adverse event in both treatment groups . The majority of adverse events were mild to moderate in intensity . In this study of patients who were unresponsive to eprosartan monotherapy for 3 weeks , a combination product of eprosartan 600 mg and HCTZ 12.5 mg was shown to be an effective and well tolerated treatment Monotherapy frequently does not cause adequate blood pressure ( BP ) reduction and goal BP is not achieved . This double-blind , r and omized , crossover , placebo-controlled study investigated , using a factorial design , the interaction between a dihydropyridine calcium channel blocking drug ( felodipine 5 mg ) and an angiotensin type I receptor blocking drug ( c and esartan 16 mg ) on the control of BP as assessed by 24-h ambulatory monitoring . A total of 31 elderly patients with systolic hypertension completed all four arms of the study . C and esartan and felodipine lowered mean 24-h BP to a similar extent ( c and esartan 12.2 + /- 2.6/7.5 + /- 1.8 ; felodipine 11.9 + /- 2.2/5.7 + /- 1.4 mm Hg ) . The combination lowered it by 21.0 + /- 2.1/11.2 + /- 1.2 mm Hg , and this fall was significantly greater than with either of the monotherapies ( P < .005 ) and was fully additive with no interactive term . The responder rate with the combination ( 90 % ) was greater than with c and esartan ( 61 % ) or felodipine ( 55 % ) . Microalbuminuria or proteinuria was present in 12 of 31 patients at r and omization despite previous BP control . C and esartan and the combination both reduced urinary albumin excretion . Albumin excretion was not reduced by felodipine despite BP control similar to that achieved with c and esartan .  Side effects were infrequent and were fewer on the combination than on placebo or on the monotherapies . The combination of felodipine 5 mg and c and esartan 16 mg has additive effects on BP in elderly patients with systolic hypertension . The combination was well tolerated and is suitable for use in patients who do not have an adequate response to monotherapy In a double-blind crossover study , 13 patients with pretreatment diastolic blood pressure between 95 and 109 mm Hg received nadolol , 80 mg/day , plus placebo of hydrochlorothiazide and nadolol , plus three different doses of active hydrochlorothiazide . Patients remained on each active regimen for 3 weeks , with an intervening placebo period of 2 to 4 weeks . With 12.5 mg of hydrochlorothiazide daily plus nadolol , there was no greater reduction of blood pressure than with nadolol alone . A dose of 25 mg of hydrochlorothiazide was associated with a significantly greater decrease in systolic but not diastolic pressure , as compared with nadolol alone . A significantly greater reduction in both systolic and diastolic blood pressure was obtained only with the 50 mg/day dose of hydrochlorothiazide . Extension to 6 weeks of treatment with 12.5 mg/day failed to lower the blood pressure more than the level seen at 3 weeks . These results suggest that in combination with nadolol , 12.5 mg of hydrochlorothiazide per day has no significant antihypertensive effect . There was no evidence of a flat doseresponse curve in the daily dose range of 12.5 to 50 mg . For most patients , a dose of 50 mg of hydrochlorothiazide was required to lower both systolic and diastolic blood pressure significantly below the level obtained with nadolol alone AIM To determine , in a multicenter study , whether the fixed combination of verapamil retard ( 240 mg ) and hydrochlorothiazide ( 12.5 mg ) is capable of lowering blood pressure more effectively than either of the substances alone or placebo , while retaining good tolerability . METHOD A total of 173 patients who , after a four-week run-in period had a diastolic blood pressure of at least 100 and not more than 115 mm Hg , were r and omized to six weeks of monotherapy with one of the two substances , placebo or the fixed combination .  RESULTS Combination treatment proved superior to monotherapy with either substance in lowering the diastolic blood pressure ( p < 0.05 ) . Also in terms of normalization ( diastolic pressure < 90 mm Hg ) the combination was clearly superior ( p < 0.05 ) . During the study no side effects beyond those associated with the single substances , occurred 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 The efficacy of a new angiotensin converting enzyme inhibitor , lisinopril , used alone ( group A ) was compared with lisinopril plus hydrochlorothiazide ( group B ) in 26 patients with essential hypertension . Therapy with both regimens was equally effective in lowering blood pressure compared to placebo .  Mean antihypertensive dose of lisinopril was lower when given in combination with hydrochlorothiazide than when given alone ( 48 + /- 6 vs 68 + /- 12 mg daily ) . Plasma renin activity increased in both groups of patients , but more in group B ( p less than 0.05 ) . Plasma aldosterone concentrations and serum uric acid levels were also higher in the group receiving lisinopril plus hydrochlorothiazide ( p less than 0.05 ) . Serum potassium concentrations were unaffected in either group . The incidence of side effects was similar in groups A and B ( 44 % and 38 % , respectively ) . This study suggests that lisinopril alone or in combination with hydrochlorothiazide effectively lowers blood pressure in patients with essential hypertension without any major side effects OBJECTIVE To compare the antihypertensive efficacy and tolerability of a new combination preparation of diltiazem ( 150 mg ) and hydrochlorothiazide ( 12.5 mg ) with the individual constituents in patients with mild/moderate hypertension . DESIGN Multi-centre , double-blind , r and omised parallel group study . PATIENTS Seventy-one patients with essential hypertension were recruited to the study . TREATMENT Following completion of the placebo run-in period 63 patients fulfilled the prer and omisation criteria and entered the 10 week treatment period . Patients were r and omised to receive either the combination preparation ( D 150 mg/H 12.5 mg ) , diltiazem ( 150 mg ) or hydrochlorthiazide ( 12.5 mg ) . The dosage was increased in three patients who had not attained target blood pressure ( BP ) control after 6 weeks . OUTCOME MEASURES Response to treatment assessed by change from baseline in clinic and 24 h ambulatory BP . RESULTS The proportion of patients achieving target BP ( a reduction in resting supine diastolic blood pressure ( DBP ) to below 90 mm Hg or a reduction of 10 mm Hg from baseline ) was 80 % in the combination group , 55 % in the diltiazem group , and 38 % in the hydrochlorothiazide group . The respective figures for reduction in supine DBP from baseline were 13.5 mm Hg , 11.2 mm Hg and 5.9 mm Hg . A similar treatment order appeared throughout each of the efficacy variables . BP control throughout the 24 h dosing interval was demonstrated by ambulatory BP monitoring . Each treatment was well tolerated . CONCLUSION This study provides clear evidence of the efficacy of combination therapy with diltiazem and hydrochlorothiazide in the management of patients with hypertension Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999 . We compared in a r and omized , double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide ( HCTZ ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy . Two hundred and seventeen patients whose blood pressure ( BP ) control remained poor ( 95 mmHg h sitting diastolic BP < 115 mmHg ) after a 4-week single-blind period with HCTZ 12.5 mg were r and omized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg ( V/HCTZ ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks . Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated . Reduction in trough diastolic BP was most pronounced in the V/HCTZ group ( –11.3 mmHg ) and significantly greater than in the HCTZ 12.5 mg group ( –2.9 mmHg , p < 0.001 ) and the HCTZ 25 mg group ( –5.7 mmHg , p < 0.001 ) . Tolerability of study medication was comparable between all three groups . In conclusion , switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy In this double-blind , r and omised , three-way crossover ( latin square design ) , multicentre study , the aim was to compare the efficacy and tolerability of the fixed combination of felodipine and metoprolol with the individual components as monotherapy . A total of 58 patients with supine diastolic blood pressure of 100 - 115 mmHg were treated with ( 1 ) a fixed combination of felodipine plus metoprolol 5/50 - 10/100 mg ( FM ) , ( 2 ) felodipine 5 - 10 mg ( F ) or ( 3 ) metoprolol 50 - 100 mg ( M ) , for 12 weeks each . All treatments were extended-release formulations administered once daily and blood pressure was measured 24 h after dosing . Dose titration was performed after 6 weeks if diastolic blood pressure was > 90 mmHg . After 12 weeks of active treatment , the mean supine blood pressures were 153/89 , 159/93 and 163/94 mmHg with FM , F and M , respectively . The mean differences in systolic/diastolic blood pressure were -5.6/-3.1 mmHg ( p = 0.007/p = 0.002 ) , -10.2/-4.4 mmHg ( p < 0.0001/p < 0.0001 ) and -4.6/-1.4 mmHg ( p = 0.03/p = 0.15 ) for FM vs F , FM vs M , and F vs M , respectively . Blood pressure control ( supine diastolic blood pressure < or = 90 mmHg ) after 12 weeks was achieved in a significantly greater proportion of patients during treatment with FM than with F or M ; 71 % , 45 % and 40 % were controlled with the respective treatments . With FM , 45 % of the patients were taking the higher dose after 12 weeks of treatment . The corresponding figures for F and M were 60 % and 67 % , respectively . Thirteen of the 58 patients ( 22 % ) were controlled only with FM . ( ABSTRACT TRUNCATED AT 250 WORDS Thirty patients with essential hypertension participated in a double blind crossover trial in which they were r and omly allocated to treatment with either once daily slow release metoprolol ( 200 mg ) with placebo or once daily slow release metoprolol ( 200 mg ) with chlorthalidone ( 25 mg ) . Ambulatory intra-arterial blood pressure was recorded continuously for 24 - 48 hours before treatment and two months after each change in regimen . The response of blood pressure and pulse rate to a st and ard exercise protocol that included supine rest and tilt , isometric , and dynamic bicycle exercise was measured during the same recording periods . Both treatments appreciably reduced blood pressure and pulse rate ; mean daytime intra-arterial blood pressure was reduced from 174/95 mm Hg to 158/85 mm Hg by metoprolol plus placebo and to 143/78 mm Hg by metoprolol plus chlorthalidone . This reduction with the combined treatment was significantly greater than with metoprolol and placebo ( p systolic = 0.001 , p diastolic = 0.004 ) . Mean night time pressures were reduced from 148/78 mm Hg to 139/75 mm Hg by metoprolol plus placebo and to 116/61 mm Hg by metoprolol plus chlorthalidone . Again the reduction in blood pressure was significantly greater with combined treatment ( p less than 0.001 ) than with metoprolol plus placebo . Once daily slow release metoprolol is effective in controlling blood pressure , but this effect is greatly enhanced by the addition of a diuretic This 8-week , double-blind , multicentre study compared the efficacy and safety of the combination of quinapril and hydrochlorothiazide ( HCTZ ) with each drug as monotherapy . Out patients with moderate to severe hypertension defined as supine diastolic blood pressure ( DBP ) > or = 105 mmHg and < or = 120 mmHg at the end of a 2 to 4-week placebo-baseline period were r and omly assigned to one of the three treatments : once-daily 10 mg quinapril plus 12.5 mg HCTZ or monotherapy with these doses . After 4 weeks , the doses were to be doubled for the remaining 4 weeks . Three hundred and sixty-eight patients were r and omized to double-blind medication ; 346 completed the study . Seven patients withdrew due to lack of efficacy . Four patients withdrew due to side effects .  In all three treatment groups , clinical ly significant reductions in DBP were achieved . Combination therapy was statistically more effective than each component taken as monotherapy . Adverse events were infrequent in all treatment groups . No patients experienced symptomatic hypotension or orthostatic hypotension In 15 patients with mild to moderate essential hypertension , the effects of diltiazem ( 120 mg twice daily ) were compared with those of atenolol ( 50 mg once daily ) , the two drugs in combination , and placebo in a r and omized double-blind cross-over study with treatment phases of 4 weeks duration . Blood pressure was reduced in the active treatment phases ( supine blood pressure : diltiazem , 172/92 mmHg ; atenolol , 172/92 mmHg ; diltiazem plus atenolol , 164/88 mmHg ; pooled estimate of s.e.m . by analysis of variance = 3/1 ) compared with placebo ( 180/101 mmHg ) . Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination . The time interval from the beginning of the P wave to the beginning of the QRS complex ( P-R interval ) was longer during combination therapy ( 0.184s ) compared with either diltiazem ( 0.175s ) or atenolol ( 0.174s ) alone , or placebo ( 0.164s ) ; s.e.m . by analysis of variance = 0.003 . No clinical ly significant conduction disturbances occurred . Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem . Thus , in subjects with uncomplicated essential hypertension , diltiazem and atenolol had equal antihypertensive efficacy when used alone , and fully additive effects in combination , on both blood pressure and cardiac conduction 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 AIMS It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction . It has also been suggested that angiotensin converting enzyme ( ACE ) inhibitors reduce insulin resistance and that , if used together with thiazide diuretics , the adverse effects of thiazides on insulin sensitivity may be eliminated . We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients . METHODS Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind , r and omized , crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril ( C ) ( 100 mg ) alone or in combination with bendrofluazide ( CB ) ( 2.5 mg ) . RESULTS Blood pressure was lower following CB compared to C ( 128/82 vs. 144/ 88 mmHg ; P<0.005 ) and both were lower than baseline ( 162/101 mmHg ; P < 0.001 ) . CB result ed in a significant increase in fasting plasma glucose compared to C ( 9.7+/-0.8 vs. 8.5+/-0.6 mmol/ ; P < 0.05 ) . Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C ( 22.3+/-2.4 vs. 27.4+/-4.2 mol x kg(-1 ) x min(-1 ) ; P < 0.05 ) . Suppression of endogenous glucose production was reduced after CB compared to baseline ( 4.0+/-0.6 vs. 2.4+/-0.5 mol x kg(-1 ) x min(-1 ) ; P < 0.05 ) . CONCLUSIONS Combination of bendrofluazide with captopril lowered blood pressure but result ed in deleterious effects on insulin action compared to captopril alone Context Hypertension is a recognized risk factor for the development of congestive heart failure ( CHF ) . By measuring blood pressure , however , we have not yet been able to underst and the significance of pulse pressure as a contributor to CHF in middle-aged men and women . Contribution Using data from the Framingham Heart Study , the authors found that although elevations of systolic , diastolic , and pulse pressure were all related to the risk for CHF , the relation was strongest for systolic and pulse pressure . Caution s Underst and ing the relationships between systolic , diastolic , and pulse pressure and risk for CHF is helpful ; however , they do not help determine the increased risk faced by a person with systolic hypertension who also has increased pulse pressure . The Editors Hypertension is the most common risk factor for congestive heart failure ( CHF ) . It confers a twofold risk for the occurrence of CHF and also carries the highest population attributable risk among all risk factors for CHF ( 1 , 2 ) . Placebo-controlled clinical trials in patients with hypertension have demonstrated a consistent reduction in risk for CHF attributable to the lowering of elevated blood pressure ( 3 - 6 ) . The causal role of hypertension in the pathogenesis of CHF underscores the need to identify high-risk patients because early treatment may prevent or delay the occurrence of CHF ( 2 , 7 ) . The prognostic significance of systolic and diastolic blood pressure in CHF has been reported . However , blood pressure may also be divided into two other components : steady ( mean arterial pressure ) and pulsatile ( pulse arterial pressure ) ( 8 - 10 ) . Pulse pressure , a simple correlate of conduit vessel stiffness , is associated with left ventricular hypertrophy ( 11 ) . Increased pulse pressure has also been implicated in the development and progression of large-vessel atherosclerosis and small-vessel disease ( 12 - 14 ) . Accumulating evidence indicates that pulse pressure ( defined as the difference between systolic and diastolic blood pressure ) may be an important predictor of cardiovascular events ( 15 - 18 ) . Pulse pressure predicts the risk for CHF in elderly persons ( 19 , 20 ) ; however , the association of pulse pressure with CHF in middle-aged men and women has not been examined . The Framingham Heart Study provides an opportunity to examine the long-term associations of systolic , diastolic , and pulse pressure with the new onset of  CHF in middle-aged and elderly men and women .  Blood pressure and traditional risk factors have been measured repeatedly at serial examinations in this community-based cohort with long-term follow-up . We examined systolic blood pressure , diastolic blood pressure , and pulse pressure as predictors of risk for CHF in the Framingham Heart Study . Methods The Framingham Heart Study , which began in 1948 , has followed 5209 participants ( 28 to 62 years of age at entry to the study ) as part of a prospect i ve epidemiologic study of cardiovascular disease . Enrollment criteria and study design have been published previously ( 21 ) . Biennial follow-up visits included a medical history , physical examination , blood pressure measurements , 12-lead electrocardiography , and laboratory tests . Eligibility requirements for inclusion in our study were as follows : Participants had to be free of coronary heart disease and CHF and not be receiving antihypertensive therapy at Framingham Heart Study clinic baseline examinations 10 , 11 , or 12 ( 1968 to 1973 ) . Participants were followed for onset of CHF through mid-1994 . We obtained data for selected risk factors from the baseline examination . Methods for assessing risk factors have been published previously ( 21 , 22 ) . Risk factors , including age , sex , cigarette smoking , heart rate , antihypertensive medication use , and total and high-density lipoprotein cholesterol levels , were assessed .  Sitting systolic and diastolic blood pressure were measured twice by the examining physician ( using a mercury column sphygmomanometer ) and averaged . We used body mass index ( kg/m2 ) as a measure of obesity . Participants were categorized as smokers if they smoked cigarettes regularly within the 1-year period before the baseline examination . Electrocardiography revealed left ventricular hypertrophy when increased voltage was associated with major ST-T repolarization changes ( strain pattern ) ( 22 ) . Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L ( > 140 mg/dL ) , two r and om nonfasting blood glucose levels greater than 11.10 mmol/L ( > 200 mg/dL ) , or the use of insulin or an oral hypoglycemic agent . Diagnostic criteria for CHF have been described previously ( 21 , 22 ) . At each clinic examination , a history of interim hospitalizations and symptoms of CHF were obtained . Outside medical records of participants who did not attend an examination were evaluated for incident CHF . All suspected interim events were review ed by a panel of three physicians who evaluated relevant Framingham Heart Study clinic notes , outside physician reports , and hospitalization records . Congestive heart failure was diagnosed when at least two major or one major and two minor criteria were present . Minor criteria were considered only if their presence could not be attributed to another disease process . Major criteria were paroxysmal nocturnal dyspnea , pulmonary rales , distended jugular veins , enlarging heart size on chest radiography , acute pulmonary edema , hepatojugular reflux , third heart sound , jugular venous pressure of 16 cm or greater , and weight loss of 4.5 kg or greater in response to diuresis . Major criteria also included pulmonary edema , visceral congestion , or cardiomegaly on autopsy . Minor criteria were bilateral ankle edema , nocturnal cough , shortness of breath on ordinary exertion , hepatomegaly , pleural effusion , decrease in vital capacity by one third from the previous maximum recorded value , and heart rate of 120 beats/min or more . Statistical Analysis We used multivariable Cox proportional-hazards regression models to examine the relations of systolic , diastolic , and pulse pressure with CHF . After accounting for age and sex and using a P value less than 0.15 as the selection criterion , we determined covariates by stepwise selection from the following list : body mass index , diabetes , smoking status , total cholesterol level , high-density lipoprotein ( HDL ) cholesterol level , totalHDL cholesterol ratio , left ventricular hypertrophy , and heart rate . Only total cholesterol level and totalHDL cholesterol ratio did not enter the model . After accounting for relevant covariates , we used Cox proportional-hazards models to obtain hazard ratio estimates with 95 % CIs for st and ardized values of systolic , diastolic , and pulse pressure . These estimates were obtained individually and pairwise by using SAS software ( SAS Institute , Inc. , Cary , North Carolina ) ( 23 ) . We repeated analyses for participants stratified according to hypertension status and sex . Because blood pressure and age are correlated , we conducted separate analyses for participants younger than 60 years of age and 60 years of age and older . To examine constancy of effects over time , follow-up was divided into early and late periods ( < 10 years , 10 years ) , and hazard ratios were calculated separately for early and late follow-up . In addition , we analyzed blood pressure as a time-varying covariate and assessed the effect of antihypertensive treatment after the baseline blood pressure measurements . We used the KaplanMeier method to plot age- and sex-st and ardized cumulative incidence rates for CHF as a function of pulse pressure tertile at baseline . Descriptive data are presented as percentages or means ( SD ) . A P value less than 0.05 was considered statistically significant . Role of the Funding Sources The funding sources had no role in the design , conduct , analyses , and reporting of the study or in the decision to su bmi t the manuscript for publication . Results A total of 894 men and 1146 women , age 50 to 79 years , fulfilled criteria for inclusion in our study . Table 1 presents baseline clinical characteristics for these persons . During 35 497 person-years of follow-up ( mean , 17.4 years [ range , 0.06 to 24 years ] ) , CHF developed in 234 ( 11.8 % ) persons . Myocardial infa rct ion preceded CHF in 59 ( 25 % ) persons . Table 1 . Baseline Clinical Characteristics of the Study Participants Increments of 1 SD in systolic pressure , pulse pressure , and diastolic pressure were associated with hazard ratios for congestive failure of 1.56 , 1.55 , and 1.24 , respectively , after adjustment for age , sex , smoking , left ventricular hypertrophy , body mass index , diabetes mellitus , HDL cholesterol level , and heart rate ( Table 2 ) . When blood pressure tertiles were used , similar associations were observed among various components of blood pressure and CHF . No threshold effect or J-shaped association was documented ( Table 2 ) . The cumulative incidence of CHF according to tertiles of baseline pulse pressure is plotted in the Figure . Table 2 . Risk FactorAdjusted Association of Blood Pressure with Congestive Heart Failure Figure . Cumulative incidence of congestive heart failure according to pulse pressure tertiles at the baseline examination . The joint influences of different blood pressure components were also examined , with adjustment for the covariates mentioned previously . Of note , correlations among the blood pressure variables ranged from modest to very high ( r = 0.20 for diastolic and pulse pressure , r = 0.65 for diastolic and systolic pressure , and r = 0.88 for systolic and pulse pressure ) . Diastolic pressure was not significant ( hazard ratio , 1.12 [ CI , 0.98 to 1.29 ] ) in conjunction with pulse pressure ( hazard ratio , 1.51 [ CI , 1.33 to 1.72 ] ) . Likewise , diastolic pressure was not significant ( hazard ratio , 0.86 [ CI , 0.72 to 1.03 ] ) in conjunction with systolic pressure ( hazard ratio , 1.71 [ CI , 1.45 to 2.01 ] ) , but joint estimates were less stable than those obtained for individual pressure variables . Finally 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 To investigate the concept of initiating therapy with low doses of a calcium antagonist and an ACE inhibitor , a fixed combination of isradipine 2.5 mg plus the ACE inhibitor spirapril 3 mg was compared with its components , with the full-dose monotherapies ( isradipine 5 mg or spirapril 6 mg ) , and with placebo . After a 2-week wash out phase in pretreated patients and a subsequent 2-week placebo period , 405 patients with a diastolic blood pressure ( DBP ) between 100 and 114 mmHg were r and omly allocated to 12-week once-daily double-blind treatment in one of the six treatment arms . In patients whose blood pressure was not normalized ( defined as DBP≤90 mmHg ) after 6 weeks of treatment , the dosage of either medication was doubled or , in the placebo group , was switched to the fixed combination . After week 6 , the mean reductions from baseline in sitting systolic/diastolic blood pressure 24 hours after dosing ( trough ) for the fixed combination or the monotherapies isradipine 5 mg , isradipine 2.5 mg , spirapril 6 mg , spirapril 3 mg , and placebo were10.4/8.7 , 10.0/9.4 , 6.5/6.7 , 10.0/8.3 , 7.0/5.8 , and 2.2/4.7 mmHg , respectively . The blood pressure changes obtained with the low-dose fixed combination were essentially identical to those observed with the full-dose monotherapies , thus showing an additive effect of low-dose isradipine and spirapril . In terms of tolerability , the lowest rate of any adverse events was found in the combination group . In this group , typical adverse events of calcium antagonists , such as headache , flushing , ankle edema , or palpitations , were observed only in 5 % , 2 % , 1 % , and 0 % , respectively , dry cough , considered typical for ACE inhibitors , was observed in only 1 % of the combination group . In conclusion , the low-dose components isradipine 2.5 mg and spirapril 3 mg were shown to have an additive effect when combined , exerting a blood pressure – lowering effect comparable with the full doses and a trend to a better tolerability profile in comparison with the st and ard doses . Thus , low-dose combination therapy with these drugs appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension 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 Most hypertensive patients require more than one medication to effectively control elevated blood pressure ( BP ) values . This multicenter , r and omized , double-blind study was aim ed at testing the efficacy and safety of the combination of low-dose nifedipine GITS 20 mg/ losartan 50 mg compared with either monotherapy in patients with grade 1 to 3 hypertension over an eight-week period . Of 352 patients enrolled in the study , 300 were r and omized . All the three treatments lowered elevated BP without clinical ly relevant changes in heart rate . All the three treatments lowered mean 24-hour diastolic BP :  nifedipine GITS/losartan −10.6 mm Hg , losartan −5.4 mm Hg , nifedipine GITS 20 mg −8.0 mm Hg . There was a statistically significant difference of diastolic BP change between patients receiving losartan compared with those receiving combination treatment ( P < 0.05 ) . Diastolic BP trough-to-peak ratio and smoothness index were highest in the patient group receiving combination therapy ( 70 % ) . Nifedipine GITS monotherapy had the highest systolic BP trough-to-peak ratio of all treatment arms ( 78 % ) and higher diastolic BP trough-to-peak ratio and smoothness index than losartan monotherapy . All treatments were safe . These data provide evidence that in hypertensive patients combination of nifedipine GITS 20 mg and losartan 50 mg improves control of systolic and diastolic BP compared with either monotherapy The importance of concomitant low-dose hydrochlorothiazide was assessed in black hypertensive patients treated with enalapril .  Left ventricular ( LV ) mass and function , metabolic parameters , 24-hour ambulatory blood pressure ( BP ) , exercise duration , and systolic BP response were evaluated before and after drug therapy . Enalapril 20 mg ( group 1 ) or enalapril 20 mg plus hydrochlorothiazide 12.5 mg ( single tablet ; group 2 ) was given to 38 patients for 9 weeks in a double-blind , placebo-controlled , r and omized study . LV mass measured 61 + /- 17 versus 102 + /- 23 g/m2 , and 24-hour ambulatory BP measured 120 + /- 8/75 + /- 6 versus 155 + /- 12/100 + /- 6 mm Hg in matched control subjects ( n = 40 ) versus hypertensive patients , respectively . No clinical ly important changes occurred in total cholesterol , serum uric acid or potassium in either group . Enalapril slightly reduced 24-hour ambulatory BP from 154 + /- 15/100 + /- 7 mm Hg to 148 + /- 19/96 + /- 11 mm Hg after treatment ( p < 0.05 for systolic BP ) ; systolic BP load ( 70 % to 59 % , p < 0.05 ) , and diastolic BP load ( 67 % to 60 % , p = NS ) decreased . Baseline BP decreased from 157 + /- 9/101 + /- 6 to 132 + /- 13/86 + /- 8 mm Hg ( p < 0.0001 ) ; systolic BP load ( 64 % to 29 % , p < 0.0001 ) , and diastolic BP load ( 64 % to 33 % , p < 0.0001 ) decreased in group 2 . Exercise systolic BP was attenuated ( p = 0.007 , group 2 ; p = NS , group 1 ) and duration increased ( p = NS ) only in group 2 . ( ABSTRACT TRUNCATED AT 250 WORDS 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 & NA ; This r and omized , double-blind , placebo-controlled , parallel-group study evaluated the efficacy and safety of single daily dose diltiazem extended-release ( XR ) and indapamide , given alone and combined , in 255 male and 170 female patients with mild to moderate hypertension .  Blood pressure was assessed both manually in the office and by 24-hour ambulatory blood pressure monitoring ( ABPM ) techniques . Between-treatment efficacy comparisons were based on ABPM plots and changes from baseline in supine systolic ( SuSBP ) and diastolic ( SuDBP ) blood pressure after 6 weeks of doubleblind treatment . Periodic 12-lead electrocardiograms ( ECG ) , clinical laboratory tests , and physical examinations were used to assess safety . Both diltiazem XR 180 , 240 , and 360 mg and indapamide 2.5 mg monotherapy reduced ambulatory blood pressure to a greater extent than placebo . The ABPM data demonstrate that 2.5 mg indapamide produces an additional reduction in diastolic blood pressure when combined with fixed doses of diltiazem XR ( 120 , 180 , and 240 mg ) . The reduction was consistent over the entire 24-hour recording period for all combinations . Compared with monotherapy groups , higher therapeutic response rates ( SuDBP ≤ 90 mm Hg or & Dgr ; SuDBP ≥ 10 mm Hg decrease from baseline ) were also observed with combination therapy . Office blood pressure data qualitatively and quantitatively supported the observations made from the ABPM data . There were no unexpected adverse events or side-effect trends and no dose-response or clinical ly significant laboratory , ECG , or physical examination adverse effects . The combination therapy regimens were well tolerated with safety profiles comparable with those of the individual therapies 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 In a r and omised , crossover study of patients with moderate to severe essential hypertension , the effects of the calcium entry antagonist nifedipine and the beta-receptor blocking drug acebutolol were studied on their own , and in combination . After 4 weeks of nifedipine tablets 20 mg twice daily ( Adalat , Bayer ) , mean supine blood pressure ( BP ) fell by 20 mmHg and after 4 weeks of acebutolol 200 mg twice a day ( Sectral , May & Baker ) by 11 mmHg . When nifedipine and acebutolol were given in combination in the above doses for 4 weeks , there was a significantly greater fall in BP than with either agent alone , supine mean arterial pressure falling by 27 mmHg . The above BPs were measured 2 h after the last dose of tablets . Measurements 12 h after the last dose showed smaller falls in BP , with a significantly greater fall with combination treatment than with acebutolol alone . The fall in BP 12 h after the last dose of the combination was greater than with nifedipine alone but this difference was not statistically significant . This r and omised , controlled study showed that nifedipine and acebutolol have a marked additive effect on BP which is sustained for at least 12 h after treatment 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 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 The combination of an angiotensin converting enzyme inhibitor with a calcium antagonist has become a common way of treating patients with essential hypertension who respond insufficiently to monotherapy . This double-blind , r and omized , parallel , placebo-controlled , multicenter , outpatient study evaluated the antihypertensive efficacy and safety of a calcium antagonist ( verapamil SR ) and an angiotensin converting enzyme inhibitor ( tr and olapril ) in patients with mild-to-moderate ( stages I and II ) essential hypertension . Six hundred thirty-one patients were enrolled in this 10-week study . After a 4-week single-blind placebo phase , patients received one of the following daily dosage regimens in a double-blind fashion for 6 weeks : placebo , 4 mg of tr and olapril , 240 mg of verapamil SR , or a combination of 4 mg of tr and olapril and 240 mg of verapamil SR .  Trough sitting diastolic blood pressure was lowered by 4.5 mm Hg , 4.3 mm Hg , and 8.1 mm Hg more than placebo in the tr and olapril , verapamil SR , and combination groups , respectively . In the combination group , sitting diastolic blood pressure was significantly lowered ( P < .01 ) by 3.6 mm Hg more than in the tr and olapril group and by 3.8 mm Hg more than in the verapamil SR group . An analysis of the trough-to-peak ratio for sitting diastolic blood pressure revealed values of 0.75 and 0.67 , for the 4-mg tr and olapril and the combination groups , respectively , at end point . The overall incidence of adverse reactions was similar for all treatment groups . In this study the combination of an angiotensin converting enzyme inhibitor and calcium antagonist was well tolerated and more effective than either agent administered alone for the treatment of mild-to-moderate essential hypertension Summary : In a double-blind , r and omized , multicenter trial , we compared the efficacy and safety of the fixed combination of 5 mg ramipril and 6 mg piretanide and the respective component monotherapies in hypertensive patients [ supine diastolic blood pressure ( DBP ) 100–114 mm Hg ] . After a single-blind run-in period on placebo , 611 patients were r and omized to ramipril ( n = 209 ) , piretanide ( n = 201 ) , or the combination therapy  ( n = 201 ) . At r and omization , the three groups had the same characteristics ( 51 % men , age 55 ± 10 years , BP 165 ± 18/104 ± 6 mm Hg ) . At 4 weeks , BP decreased more with combined therapy than with monotherapy . As compared with piretanide monotherapy , the gain in the antihypertensive effect in the supine position averaged 2.1 mm Hg [ 90 % confidence interval ( CI ) - 0.8–5.0 mm Hg ; p = 0.07 ] systolic BP ( SBP ) and 1.9 mm Hg ( CI 0.3–3.5 mm Hg , p = 0.02 ) DBP and , as compared with ramipril monotherapy , these differences were 4.2 mm Hg ( CI 1.3–7.0 mm Hg , p = 0.008 ) and 2.0 mm Hg ( CI 0.5–3.6 mm Hg , p = 0.009 ) . The incidence of adverse events ( AE ) and the changes in biochemical measurements were similar in the three treatment groups with the exception of spontaneously reported polyuria and serum uric acid concentration . Polyuria was reported more frequently ( p < 0.001 ) with piretanide therapy ( n = 23 ) and combined therapy ( n = 19 ) than with ramipril therapy ( n = 1 ) . Similarly , serum uric acid increased more ( p < 0.001 ) in the piretanide group ( + 24 μM ) and in the group receiving combined therapy ( + 18 μM ) as compared with the ramipril group ( + 0 μM ) . However , serum uric acid levels and the incidence of polyuria were similar with piretanide and combined therapy . As compared with the respective monotherapies , combined treatment with ramipril and piretanide produced an additional BP-lowering effect and did not lead to more frequent side effects 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 In a double-blind , parallel-group multicentre study , the efficacy and safety of a fixed low-dose combination of ramipril 2.5 mg and hydrochlorothiazide ( HCT ) 12.5 mg was compared with each of the component drugs when given as monotherapy . After a four-week placebo run-in , patients were r and omized to receive either ramipril 2.5 mg ( n = 218 ) or HCT 12.5 mg ( n = 220 ) , or the fixed-dose combination of ramipril 2.5 mg and HCT 12.5 mg ( n = 222 ) , for a period of eight weeks . At the end of the study , in which 624 patients had completed treatment , it was found that the decrease in supine diastolic blood pressure ( the main efficacy parameter ) was greater in the ramipril-HCT combination group than in either the ramipril or the HCT monotherapy groups , the difference being statistically significant when compared with the HCT group ( -14.3 , -13.1 and -12.4 mm Hg , respectively ) . Reductions in st and ing DBP and supine and st and ing systolic blood pressure ( SBP ) were also greatest in the combination group . The incidence of adverse events was lower in the combination group than in either of the monotherapy groups , and there were no serious clinical ly significant laboratory abnormalities in the combination group In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily , with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by r and omised Latin squares . For each patient there were four treatment phases , each of four weeks duration , which together 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 blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and st and ing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30 - 50 % . The mechanism of the attenuated hypotensive effect of the combined agents has not been determined . Plasma atrial natriuretic peptide ( ANP ) concentration was doubled in the presence of atenolol ( P less than 0.01 ) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker 1 A placebo-controlled , r and omised double-blind comparison of captopril 25 mg three times a day , hydrochlorothiazide 15 mg three times a day , and the combination was conducted in 207 patients with essential hypertension with supine diastolic blood pressures of 92 - 110 mm Hg . Significant decreases in blood pressure were seen in all three groups ; the magnitude of decrease seen with captopril and hydrochlorothiazide was similar , while the combination produced an additive response greater ( p less than 0.001 ) than captopril or hydrochlorothiazide alone . 2 The major side effect reported was a rash in fewer than 6 % of patients taking  captopril  alone or in combination . Loss of taste or proteinuria was not observed . 3 The addition of captopril of hydrochlorothiazide blunted the hypokalaemia and hyperuricaemia observed with hydrochlorothiazide alone in addition to its antihypertensive synergy . These observations indicate that this relatively low dose of captopril is safe and efficacious in the treatment of mild to moderate hypertension alone and particularly when combined with a thiazide diuretic AIMS To investigate the dose-response relationship and contribution of verapamil SR and tr and olapril given in combination once a day for the treatment of essential hypertension . METHODS A r and omized , double-blind , placebo controlled , factorial , 12 arm parallel group comparison with placebo , verapamil SR ( 120 , 180 mg ) , tr and olapril ( 0.5 , 1.0 , 2.0 mg ) covering all combinations of both drugs . A 4 week placebo run-in period followed by 6 weeks of treatment . Four hundred and fifty-six patients from office practice ( 22 centres ) with mild to moderate hypertension enrolled and 426 with diastolic pressure > or = 100 mm Hg at the end of run-in period were r and omized . Main outcome measures were reduction in sitting systolic ( SBP ) and sitting diastolic ( DBP ) blood pressure . RESULTS The combination of verapamil SR and tr and olapril , particularly verapamil SR 180 mg and tr and olapril 0.5 or 1.0 mg was significantly superior to both monocomponents at the same dose ( P<0.05 ) . For these combinations , the adjusted mean reductions in DBP from baseline to last visit were 14.1 and 16.0 mm Hg , respectively . Response surface analysis provided further evidence that these combinations were optimal for antihypertensive efficacy . All treatments were well tolerated . The incidence of adverse events did not differ significantly between treatment groups ; the profile of adverse events on combination therapy was mild and consistent with that of each monocomponent . CONCLUSIONS All dosage combinations of verapamil SR and tr and olapril produced significantly greater reduction of blood pressure than the monotherapy at the same dosage . However , verapamil SR 180 mg in combination with tr and olapril 1.0 mg was the dosage with the greatest blood pressure reduction and had the greatest effects compared with the monocomponents The aim of the study was to identify the most appropriate dosage combination of ramipril and felodipine ER ( an extended release tablet ) for mild-to-moderate hypertension . Hypertensive patients ( N = 507 ) with supinediastolic blood pressure ( DBP ) values between 100 - 115 mm Hg were included in a r and omized , multicenter , double-blind study of 3x4 factorial design with a 2 - 4 week single-blind , placebo run-in and 6 week active treatment phase . The patients were r and omized to 12 groups : placebo , ramipril ( 2.5 , 5 , 10 mg ) , felodipine ER ( 5 , 10 mg ) , or ramipril-felodipine ER combinations ( 2.5/5 mg , 2.5/10 mg , 5/5 mg , 5/10 mg , 10/5 mg , 10/10 mg ) . Although the greatest reductions in blood pressure were observed with ramipril-felodipine ER ( 10/10 mg ) , consideration of the antihypertensive efficacy and safety factors suggest that the ramipril-felodipine ER ( 5/5 mg ) combination has the best efficacy/tolerability ratio of the combinations tested . The incidence of adverse events with ramipril-felodipine ER  combination therapy was similar to that with felodipine ER monotherapy , but peripheral edema , tachycardia and vasodilatation occurred less frequently with ramipril-felodipine ER ( 5/5 mg ) combination than with felodipine ER monotherapy . The combination of ramipril-felodipine ER ( 5/5 mg ) can be considered to be the most suitable option for hypertensive patients with an inadequate response to either of the monocomponents Fifteen out- patients with moderate hypertension were r and omly and sequentially treated with atenolol , indapamide and a combination of the two drugs after a wash-out period of at least 1 week and a 2-week placebo run-in period . The duration of treatment was 4 weeks in each case . The dosage was 2.5 mg indapamide and 100 mg atenolol , in single tablets which were taken at 11.00 hours . All the treatment regimens produced a highly significant ( p less than 0.001 ) reduction in systolic and diastolic , supine and st and ing blood pressure ; these reductions were not significantly different for the single drugs but were significantly greater for the combined therapy . The number of patients reaching the end-point of a diastolic blood pressure of 95 mmHg or less was the same with either atenolol or indapamide , i.e. 7 ( 46.6 % ) , but was greater with the combined therapy , i.e. 10 ( 66.6 % ) . A significant ( p less than 0.001 ) reduction in pulse rate was observed with the treatments involving atenolol .  Acceptability of the treatments was very good ; the number of volunteered and elicited complaints during the different treatments being less compared to the placebo period , particularly for the combined treatment . No significant difference was observed in the blood biochemistry tests . The results are discussed in light of the mechanisms of action of the two drugs , which seem well integrated with each other , and the duration of the antihypertensive effect , which allows a single administration with consequent good treatment compliance Thirty-six patients ( 33 male , 3 female ) with a mean age of 67 years and a diastolic blood pressure between 95 and 115 mm Hg , after a four-week placebo run-in period entered a double-blind crossover study comparing felodipine 5 and 10 mg with enalapril 5 and 10 mg and their combination ( enalapril 5 mg + felodipine 5 mg ) . Combined therapy caused a fall in blood pressure of 24/16 mm Hg at trough level that was greater than the falls with the higher doses of monotherapy . The fall with felodipine was greater than with enalapril . Similar patients responded to felodipine and enalapril but more patients achieved blood pressure control with felodipine . When patients not controlled with enalapril 5 mg had felodipine 5 mg or enalapril 5 mg added , felodipine was more effective at lowering blood pressure than the increase in enalapril dosage . A similar effect occurred in those not controlled with felodipine 5 mg . Adverse effects occurred in 22 patients on felodipine , 14 patients on enalapril and 8 on combined therapy . The lipoprotein profile was not altered significantly . Glomerular filtration rates as assessed by 24-hour creatinine clearance were 90 ml/min at r and omization , 125 ml/min on felodipine , 108 ml/min on enalapril and 120 ml/min on the combination . Felodipine and enalapril in low doses are effective antihypertensive agents in elderly people .  Felodipine monotherapy is more effective than enalapril monotherapy but a greater blood pressure lowering effect can be obtained with the combination of low doses of enalapril and felodipine . This has the advantage that the number of side effects is less A factorial design was applied in this multicenter , double-blind , placebo-controlled trial of the calcium-channel blocker verapamil and the ACE inhibitor enalapril to assess the hypotensive effects of the combination compared with monotherapy , to evaluate safety , and to determine the effects on quality of life ( QOL ) of both drugs , alone and in combination . The study consisted of a 3 x 2 factorial design wherein 186 men and women with a sitting diastolic blood pressure ( BP ) of between 95 mm Hg and 114 mm Hg , after a 4-week placebo washout , were r and omized to one of six treatment groups for 4 weeks of active treatment . Monotherapy with both 240 mg verapamil and 10 mg enalapril reduced systolic and diastolic BP to a similar extent and significantly more than placebo . The 240 mg verapamil + 10 mg enalapril combination was additive for both systolic and diastolic blood pressure ; 120 mg verapamil + 10 mg enalapril was additive for systolic BP only . The total number of adverse events reported was similar for all six treatment groups . QOL scores were unchanged from baseline and not different between treatment groups . The combination of 240 mg verapamil and 10 mg enalapril was significantly more effective at reducing BP than either drug alone ; this additivity of effect was not linked to a higher rate of adverse experiences or to a deterioration in QOL . Thus , combination therapy at lower doses may offer an alternative treatment option to higher dose monotherapy Two hundred thirty-four patients with supine diastolic blood pressure of between 95 and 114 mm Hg were enrolled into a double-blind , r and omized , parallel , multicenter trial . The patients were r and omized to either nicardipine 30 mg tid , propranolol 40 mg tid , or nicardipine 30 mg tid and propranolol 40 mg tid for six weeks . Two hundred six patients yielded data for analyses . Of the 28 not included , seven had missing data , whereas the remaining 21 were excluded because they either failed to meet inclusion criteria or were noncompliant at endpoint . Both nicardipine and propranolol as monotherapies and in combination achieved statistically significant , ( P less than .01 ) , supine diastolic blood pressure reduction relative to baseline . The combination of nicardipine and propranolol showed a greater reduction in supine diastolic and systolic measurements than either of the monotherapies . Nicardipine produced greater blood pressure reductions one hour after dosing , whereas the propranolol treatment tended to produce slightly greater blood pressure decreases eight hours after dose . The combination always result ed in the greatest blood pressure reduction , independent of time after dose . Adverse experiences were reported by 26 % of patients in the nicardipine-treated group , most often transient vasodilatory effects , by 17 % of the propranolol-treated patients , and by 18 % of the combination-treated group . This study demonstrated at the doses studied that nicardipine alone produced equivalent blood pressure reductions to those obtained by propranolol alone , but that the combination of these two drugs produced greater reductions in blood pressures than either of the monotherapies 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 Lisinopril ( LIS ) is a lysine analog of enalaprilat , the active metabolite of enalapril , an angiotensin-converting enzyme inhibitor ( ACEI ) . Unlike enalapril , the precursor of enalaprilat , LIS is not a prodrug but has equal ACEI efficacy and potency and a slightly longer duration of action after oral administration . Short-term ( 12 weeks ) and long-term ( 24 weeks ) blood pressure control has been studied with LIS , hydrochlorothiazide ( HCTZ ) , and LIS + HCTZ when given once a day . Drug treatment had three phases : ( i ) 2–4 weeks of single-blind placebo washout ; ( ii ) 12 weeks of double-blind comparison therapy with LIS 20 , 40 . and 80 mg vs. HCTZ 12.5 , 25 , and 50 mg , vs. LIS + HCTZ 20 + 12.5 , 40 + 25 . and 80 + 50 mg ; ( iii ) 13–24 weeks single-blind LIS vs. LIS + HCTZ . Starting double-blind therapy at the lowest dose , all three groups doubled the dose at weeks 4 and 8 if BP was not controlled with sitting diastolic BP ( SDBP ) < 90 mm Hg . At the end of 12 weeks of double-blind therapy , uncontrolled HCTZ-only and LIS-only treatment groups were advanced to combination LIS + HCTZ therapy but uncontrolled LIS + HCTZ patients were dropped . Mean BP reductions ( systolic/diastolic , mm Hg ) for all three groups after 12 weeks of double-blind comparison therapy were : ( i ) LIS ( n = 162 ) , – 16.6/-12.5 ; ( ii ) HCTZ ( n = 155 ) , – 10.4/-6.8 : ( iii ) LIS + HCTZ ( n = 74 ) . −23.9/- 18.2 with p < 0.01 for all groups compared to baseline . Significant ( p < 0.01 ) decreases in SDBP with all therapies were seen regardless of race , but nonblack patients responded better than black patients to LIS alone . During the second treatment period ( weeks 13–24 ) , 89 % of patients ( 177/199 ) at week 24 had SDBP ≤ 85 mm Hg or ≥ 10 mm Hg SDBP reduction . By 24 weeks , 82 % ( 72/88 ) of LIS-treated patients maintained this BP control , whereas 84 % ( 48/57 ) of LIS + HCTZ-treated patients and 67 % ( 36/54 ) of HCTZ-treated patients sustained identical BP control . By 22 weeks , 68 % ( 81/119 ) of patients maintained BP control on LIS monotherapy . With ≤ 20 mg LIS therapy , 41 % ( 33/81 ) achieved long-term BP control , whereas 65 % and 72 % of these patients responded to ≤ 40 mg and ≥ 80 mg LIS doses , respectively . Serious adverse clinical effects in all groups were rare ( < s3 % ) during short-term and long-term therapy . In conclusion , LIS therapy alone ( 20–80 mg q.d . ) is more efficacious than HCTZ therapy alone ( 12.5–50 mg q.d . ) . LIS + HCTZ [ ( 20 + 12.5)-(80 + 50 ) mg q.d . ] is more efficacious than either LIS therapy alone ( 20–80 mg q.d . ) or HCTZ therapy alone ( 12.5–50 mg q.d . ) . Lisinopril and LIS + HCTZ  are effective and well tolerated antihypertensive agents in both short- and long-term therapy 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 After a control period on a placebo , 45 patients with mild to moderate hypertension were treated with metoprolol , 100 mg twice daily alone and in free combination with chlorthalidone 50 mg daily using a double-blind crossover technique . The beta-blocker alone induced a significant fall in blood pressure ; the diastolic pressure was reduced to 100 mg Hg or less in 37 of the 45 patients and to 95 mm Hg or less in 19 patients . The addition of chlorthalidone enhanced the antihypertensive effect so that in 33 patients diastolic pressure fell to 95 mm Hg or less . The drugs were well tolerated even by a small number of patients with chronic bronchitis and diabetes mellitus . None of the patients developed cardiac failure . Adding a diuretic caused a small reduction in serum potassium concentrations , and the relevance of this observation is discussed BACKGROUND By blocking the renin-angiotensin-aldosterone system ( RAAS ) at its rate-limiting step , renin inhibition may provide improved RAAS suppression . We investigated the blood pressure (BP)-lowering effects of the oral direct renin inhibitor aliskiren , alone or in combination with the angiotensin receptor blocker valsartan . METHODS In this multicenter , r and omized , placebo-controlled , 8-week trial , 1123 patients with mild-to-moderate hypertension underwent a 3 to 4 week single-blind placebo run-in and were then r and omized in a modified factorial study design to receive once-daily , double-blind oral treatment with placebo , aliskiren monotherapy ( 75 , 150 , or 300 mg ) , valsartan monotherapy ( 80 , 160 , or 320 mg ) , aliskiren and valsartan in combination , or valsartan/hydrochlorothiazide ( 160/12.5 mg ) . The primary efficacy variable was the change from baseline in mean sitting diastolic BP ( DBP ) at endpoint . RESULTS Once-daily oral treatment with aliskiren 300 mg significantly ( P < .0001 ) lowered mean sitting DBP and systolic BP ( SBP ) compared with placebo ; aliskiren monotherapy demonstrated a safety and tolerability profile comparable to placebo . Changes in DBP and SBP were fitted to a first-order dose-response surface ( lack-of-fit test , P = .65 ) , which showed that aliskiren and valsartan alone and in combination produced dose-related reductions in DBP and SBP . Coadministration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone , comparable in magnitude to the effect of valsartan/hydrochlorothiazide , with similar tolerability to the component monotherapies and to placebo . CONCLUSIONS Aliskiren monotherapy provides antihypertensive efficacy and placebo-like tolerability in patients with hypertension .  Aliskiren and valsartan in combination may provide additive BP-lowering effects with maintained tolerability The tolerance and antihypertensive action of acebutolol , as a sole drug and in combination with a diuretic , were studied in a population of 34 female subjects aged over 65 years , with a mean of 81 years , suffering from well tolerated essential hypertension . The study was carried out in the form of double blind permutations , each subject receiving successively in an order determined by r and om selection each of three therapeutic phases : acebutolol , acebutolol in combination with a diuretic and a placebo . The results showed that in the elderly acebutolol had a moderate diuretic action which was remarkably potentialised by diuretics . The tolerance of this beta-blocker was excellent : no cases of cardiac failure , and no disturbances in atrioventricular conduction developed during the phases with active treatment 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 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 Using a placebo baseline , positive controlled , double-blind , r and omized titration to effect our study protocol , we assessed the antihypertensive actions of enalapril , hydrochlorothiazide , and their combination in 37 patients with moderate essential hypertension . Patients were maintained on their regular diets and received a placebo for 4 weeks . Patients with moderate systemic hypertension were r and omized to receive enalapril monotherapy at a dose of 10 mg twice daily ( n = 16 ) , hydrochlorothiazide monotherapy at a dose of 25 mg twice daily ( n = 15 ) , or combination therapy consisting of 10 mg enalapril and 25 mg hydrochlorothiazide twice daily ( n = 6 ) . Therapy could be titrated to twice the starting dose . All treatment regimens reduced blood pressure , but only one patient had blood pressure normalized ( diastolic blood pressure less than or equal to 90 mmHg ) with enalapril ( 7 % ) , two patients with hydrochlorothiazide ( 15 % ) , and 80 % of patients with combination therapy . The patients who had not achieved normal blood pressure received combination treatment , and after 8 additional weeks , more than 70 % showed normal blood pressure . After one year of combination therapy , 92 % of the patients continue to have normal blood pressure . Both the monotherapy and combination regimens were very well tolerated in this study . In conclusion , enalapril , hydrochlorothiazide , and their combination are effective in reducing blood pressure in patients with moderate hypertension . However , monotherapy is successful in normalizing blood pressure only in a small percentage of patients . Combination therapy achieved normalization of blood pressure in almost all patients , suggesting that most patients on regular diets with moderate hypertension may require a diuretic-ACE inhibitor combination rather than monotherapy to achieve effective blood pressure control 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 A double-blind , crossover study was carried out in 32 Sudanese patients with essential hypertension to assess the effectiveness of single daily doses of 400 mg acebutolol when given alone and in combination with single daily doses of hydroclorothiazide/amiloride diuretic . The results show that in both groups there was a statistically significant reduction in systolic and diastolic levels throughout the treatment period . After crossover at 6 weeks , those patients initiated on acebutolol alone showed a further reduction in both systolic and diastolic pressures when the hydrochlorothiazide/amiloride combination was added . Both treatment regimens were well-tolerated and only a few side-effects were reported This prospect i ve , double-blind , parallel-group study r and omized patients with moderate hypertension ( seated systolic blood pressure ( SeSBP ) 160–179 mm Hg when seated diastolic blood pressure ( SeDBP ) < 110 mm Hg ; or SeDBP 100–109 mm Hg when SeSBP < 180 mm Hg ) 3:1:1 to treatment with irbesartan 300 mg/hydrochlorothiazide ( HCTZ ) 25 mg combination therapy  ( n=328 ) , irbesartan 300 mg monotherapy ( n=106 ) or HCTZ monotherapy 25 mg ( n=104 ) . Treatment was initiated at half dose , with forced titration to full dose after two weeks followed by ten further weeks ' treatment . The primary efficacy variable was the mean reduction in SeSBP from baseline to week 8 . Baseline characteristics were similar between groups , with mean baseline blood pressure approximately 162/98 mm Hg ; the mean age was 55 years . At week 8 there was a reduction in SeSBP of 27.1 mm Hg with irbesartan/HCTZ , compared with 22.1 mm Hg with irbesartan monotherapy ( P=0.0016 ) and 15.7 mm Hg with HCTZ ( P<0.0001 ) . Both the rate of decline and the total degree of decline achieved were greatest with irbesartan/HCTZ and least with HCTZ . A significantly greater percentage of patients reached a treatment goal of SeSBP < 140 mm Hg and SeDBP < 90 mm Hg by week 8 with irbesartan/HCTZ ( 53.4 % ) , compared with irbesartan ( 40.6 % ; P=0.0254 ) and HCTZ ( 20.2 % ; P<0.0001 ) alone . Treatment was well tolerated in all three-treatment groups with a slight increase in adverse events in the combination therapy group . In conclusion , irbesartan/HCTZ ( 300/25 mg ) is well tolerated and achieves rapid and sustained reductions in both systolic blood pressure and diastolic blood pressure in patients with moderate hypertension In 101 hypertensive patients , the effects of a combination of propranolol and bendrofluazide were compared with those of each drug alone . After an introductory period with a placebo , the patients received , in a double-blind r and omized trial , propranolol 80 mg twice a day , bendrofluazide 2.5 mg twice a day , or both drugs together twice daily . The combination produced significantly greater reductions in lying , st and ing , and post-exercise systolic and diastolic blood pressure than either drug separately . Side-effects were minimal and the combination was well accepted by patients 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 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 The fixed combination of lisinopril 20 mg and hydrochlorothiazide 12.5 mg ( L/HCTZ ) was compared with each of the monocomponents in a multicentre , double-blind , r and omized , parallel-group study involving elderly patients with mild to severe hypertension . At the end of the trial , a total of 278 patients had completed 8 weeks of treatment . SBP reduction from baseline in the L/HCTZ group was significantly greater , sitting and st and ing , compared with both the monotherapy groups . Sitting DBP reduction from baseline in the L/HCTZ group was significantly greater than in the hydrochlorothiazide group . Uric acid levels were raised significantly more in the L/HCTZ group compared with the lisinopril group , and the fall in potassium levels were significantly smaller in the L/HCTZ group compared with the hydrochlorothiazide group . Safety and tolerability were equivalent for the three groups 1 . The effects of timolol alone and in combination with a fixed dose of hydrochlorothiazide and amiloride have been studied in a double-blind , controlled study in fifty-four patients with mild to moderate essential hypertension . 2 . After a 4 weeks placebo period patients were r and omly assigned to enter groups receiving timolol alone ( group A ) , hydrochlorothiazide + amiloride ( group B ) or timolol + hydrochlorothiazide + amiloride ( group C ) . Each treatment was carried out for 6 weeks . 3 . The use of timolol ( 10 mg ) , hydrochlorothiazide ( 25 mg ) and amiloride ( 2 - 5 mg ) in a combination tablet given twice daily gave better control of blood pressure in patients with mild to moderate essential hypertension than did equivalent dosages of timolol alone or of hydrochlorothiazide and amiloride . 4 . Clinical and laboratory side effects were minimal A multicenter , double-blind , placebo-controlled trial with multifactorial design was conducted to evaluate the safety and efficacy of the calcium-channel blocker diltiazem , in a sustained release preparation , and the angiotensin converting enzyme inhibitor , lisinopril , in the treatment of elderly Chinese patients with mild-to-moderate hypertension . In addition to the hypotensive effects of combinations of both drugs compared with monotherapy , all given once daily , the effect on quality of life was also evaluated . This study consisted of a 3 x 2 multifactorial design in which 156 women and men with a sitting diastolic pressure of between 95 mm Hg and 114 mm Hg , after a 4-week placebo washout phase , were r and omized to one of six treatment groups for 12 weeks of active treatment . Monotherapy with diltiazem 120 or 240 mg produced increasing reductions of systolic and diastolic blood pressure . Compared with placebo , lisinopril 10 mg had an effect intermediate between the diltiazem doses . The combinations of diltiazem 240 mg + lisinopril 10 mg and diltiazem 120 mg + lisinopril 10 mg showed increased efficacy in reducing systolic and diastolic blood pressure compared to these drug doses used in monotherapy , but the effect of the combinations was less than predicted by an additive model . Although the total number of other adverse events reported was similar for all active treatment groups compared to placebo , lisinopril-induced cough was common with an incidence of 31 % after rechallenge . Premature drug withdrawal was necessary in four of 78 patients receiving lisinopril , due to intractable cough . The combination of diltiazem 240 mg and lisinopril 10 mg was significantly more effective at reducing blood pressure than either drug alone ; this additive effect did not result in a higher rate of adverse effects or impairment of quality of life . Thus , combination therapy with these agents was well tolerated and result ed in increased efficacy in these elderly patients In a r and omized , double-blind , within-patient study , 28 out- patients with mild to moderate hypertension were given , at the end of a 3-week placebo wash-out period , four different antihypertensive treatments for 3 weeks each . the treatments were 50 mg atenolol , 100 mg atenolol , 12.5 mg chlorthalidone and a fixed combination of 50 mg atenolol and 12.5 mg chlorthalidone . All treatments were given once daily . Visits were scheduled for the last day of each treatment period , 24 - 26 hours after the last dose , and there was an intermediary wash-out period between each pair of active treatments . Supine systolic/diastolic blood pressure was 165/102 on placebo , 153/93 mmHg on 50 mg atenolol , 155/91 mmHg on 100 mg atenolol , 148/93 mmHg on 12.5 mg chlorthalidone and 144/89 mmHg on the combination . All the changes in pressure were significant ( p less than 0.01 ) versus placebo .  Supine systolic blood pressure was lower on the combination than on 100 mg atenolol alone ( p less than 0.05 ) and upright systolic pressure was lower on the combination than on 100 mg atenolol ( p less than 0.05 ) or 50 mg atenolol ( p less than 0.05 ) alone . The heart rate was lowered by atenolol alone or combined with chlorthalidone but did not fall below 56 bpm in any patient . Serum potassium levels were lower on 12.5 mg chlorthalidone than on placebo ( 3.88 mEq/l vs 4.09 mEq/l -- p less than 0.05 ) but the difference was trivial ; on the combination of atenolol-chlorthalidone there was no significant difference versus placebo ( 3.97 mEq/l vs 4.09 mEq/l -- NS ) . ( ABSTRACT TRUNCATED AT 250 WORDS Thirty-nine patients were entered into a 12-week , r and omized , double-blind , parallel protocol to assess the safety and efficacy of enalapril ( MK-421 , 10 to 20 mg bid ) , hydrochlorothiazide ( HCTZ , 25 to 50 mg bid ) , or combined drug therapy ( MK-421 + HCTZ ) for the treatment of primary hypertension . Specifically monitored were the effects of each drug program on BP and pulse , serum chemistries , body fluid composition and weight , renal function , and the renin-angiotensin-aldosterone axis . Results indicate that MK-421 , HCTZ , and combined therapy were equally effective in lowering BP ; none of the therapies significantly altered glomerular filtration rate or effective renal plasma flow . Patients on MK-421 experienced no change in volume , an increase in plasma potassium , no change in fractional sodium or potassium excretion , and a decreased urine osmolality associated with an enhanced free-water clearance . Plasma renin activity was increased , plasma angiotensin II was decreased , and plasma aldosterone was unchanged . In contrast , patients on HCTZ developed volume contraction , hypokalemia associated with an increase in fractional sodium and potassium excretion , and an increased urine osmolality associated with a decreased free-water clearance . Plasma renin activity was increased , however , plasma angiotensin II and plasma aldosterone were unchanged . Patients on combined therapy  with MK-421 + HCTZ demonstrated qualitatively similar changes in serum chemistries , body fluid volumes , and renal function compared with patients receiving HCTZ alone , whereas changes in the renin-angiotensin-aldosterone system in these patients were qualitatively similar , but more marked , compared with those occurring in patients receiving MK-421 alone . We conclude that MK-421 is an effective first-step antihypertensive agent that does not produce adverse metabolic , volume , or renal effects 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 The antihypertensive effect of a fixed dosage combination of the cardioselective beta-adrenoceptor blocker , atenolol , and the oral thiazide-like diuretic , chlorthalidone ( Tenoretic ) was studied in 24 hypertensive Nigerians in a double-blind , cross-over comparison with three other treatments . These were atenolol alone , 100 mg daily , chlorthalidone alone , 25 mg daily , and atenolol ( 100 mg ) plus chlorthalidone ( 25 mg ) daily taken as separate formulations . Tenoretic was taken as a once-daily tablet containing 100 mg atenolol plus 25 mg chlorthalidone . The order of administration of the drugs was r and omized . Each drug was taken for 4 weeks . The results showed that atenolol and chlorthalidone lowered blood pressure to the same extent . Combination of the two drugs whether taken separately or in fixed-dosage combination was better than either product singly . The drugs were well tolerated The efficacy and safety of verapamil and propranolol were examined in 14 hypertensive patients ( mean age 51.2 , range 30 to 65 ) in a double-blind , r and omized , crossover study of verapamil , 360 mg , propranolol , 240 mg , these 2 formulations in combination and placebo , each given for 4 weeks . Supine blood pressure , heart rate , atrioventricular conduction ( PR interval ) and left ventricular function were measured . All treatments reduced diastolic blood pressure ( mean + /- st and ard deviation ) ( p less than 0.001 ) : placebo to 106.6 + /- 8.1 mm Hg ; propranolol to 93.8 + /- 7.7 ; verapamil to 89.8 + /- 7.8 ; the combination to 84.1 + /- 6.1 , but the effect of the combination was significantly greater than that of either drug alone ( p less than 0.05 ) . Heart rate at rest ( placebo , 80.2 + /- 12.2 beats/min ) was reduced by propranolol ( 63.3 + /- 9.4 , p less than 0.001 ) , but not by verapamil ( 79.0 + /- 8.9 ) . However , the addition of verapamil to propranolol led to a further reduction in heart rate ( 56.9 + /- 8.4 , p less than 0.005 ) . PR interval was prolonged significantly by the combination ( 185.5 + /- 35.3 ms ) when compared with placebo ( 154.0 + /- 22.7 ) ; propranolol ( 159.1 + /- 21.2 ) and verapamil ( 165.5 + /- 32.4 ) ( p less than 0.005 for each ) . The active drugs increased end-diastolic dimension and end-systolic dimension . For each variable , the effect of the combination was statistically significant ( p less than 0.01 ) . Fractional shortening was not altered significantly by any of the treatments . Thus verapamil plus propranolol is a very effective antihypertensive combination but heart rate , atrioventricular conduction and left ventricular function may be affected adversely , necessitating careful monitoring of therapy 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 This study compared with placebo the efficacy and tolerability of optimised doses of felodipine 5 - 20 mg daily , metoprolol 50 - 200 mg daily and their combination in subjects 60 years or over with isolated systolic hypertension . The study employed a r and omised double-blind crossover design with allocation of treatment order within subjects by Latin squares . For each subject , after a single-blind run-in placebo phase , there were four r and omised treatment phases each of six weeks duration , with a dose titration step at three weeks if necessary . Twenty-eight subjects entered the r and omised phases of the study and twenty-one completed all four phases--13 male , 8 female ( ages : median 71 , range 59 - 85 years ) . At the end of both the felodipine and metoprolol phases systolic and diastolic pressure were reduced at 2 hours postdose compared with the placebo phase ( p < 0.001 ) , the blood pressure reduction with felodipine ( -40/-20 mmHg ) being greater than that with metoprolol ( -15/-9 mmHg ) ( p < 0.01 ) . Immediately predose ( 12 hours postdose ) there was a persisting reduction of supine systolic blood pressure ( -17 mmHg ) with felodipine ( p < 0.001 ) , but there was no significant effect of metoprolol . At both measurement times the two drugs when in combination had an additive effect on blood pressure . There was a 20 % increase in reported symptoms during each of the active treatment phases . Four subjects withdrew during the r and omised phases because of probable drug-related adverse events and six subjects required dosage reductions during the felodipine or combination phases . ( ABSTRACT TRUNCATED AT 250 WORDS 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 Objective : We have shown previously that the combination of captopril and nifedipine was effective at peak response but was very short acting . We therefore decided to study the longer-acting angiotensin converting enzyme inhibitor lisinopril and the long-acting calcium antagonist amlodipine , each alone and in combination , in a double-blind , r and omized crossover study in which blood pressures were measured at peak and trough . This study provided the opportunity to investigate what parameters in these patients might possibly predict the fall in blood pressure with the individual drugs and with the combination Methods : Fifteen patients with essential hypertension ( eight male , 10 Caucasian ; mean age 53 years ) were studied . After 1 month observation on no treatment they were entered into a single-blind run-in of placebo given once a day for 1 month . Patients were then allocated r and omly to amlodipine ( 5 mg once a day ) , lisinopril ( 10 mg once a day ) or their combination ( once a day ) for 1 month in a double-blind crossover study . All patients were studied on their usual diet and no dietary advice was given . Blood pressure was measured by semi-automatic ultrasound sphygmomanometer both 24 h and 6 h ( trough and peak ) after the last dose Results : During the crossover part of the study there was a significant additional blood pressure-lowering effect ( at trough ) of the combination compared with either amlodipine or lisinopril alone . Similar results were observed for the blood pressures at peak . The fall in blood pressure with lisinopril was related to baseline plasma renin activity , whereas when amlodipine was given , either alone or in combination , the fall in blood pressure was independent of baseline renin activity . The Blacks ( n=5 ) appeared not to respond as well to lisinopril as the Caucasians ( n=10 ) . Finally , the blood pressure response to amlodipine tended to be associated with the severity of hypertension Conclusions : The results of the present study indicate that : amlodipine and lisinopril in combination have a marked additional effect on blood pressure compared with either given as a monotherapy ; their potentiation of action is long-acting ; Black patients tend not to respond to the monotherapy with lisinopril as well as Caucasian patients , although they respond similarly to the combination ; the response to amlodipine tends to be greater the higher the initial blood pressure ; and , finally , the response to lisinopril is greater the higher the plasma renin 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 To test the dose responses of piretanide , ramipril , and their combination in patients with essential hypertension , a prospect i ve , r and omized , double-blind , placebo-controlled trial was conducted in 480 patients . Twelve separate groups were studied : placebo , piretanide 3 mg , piretanide 6 mg , ramipril 2.5 mg , ramipril 5 mg , ramipril 10 mg , and their combinations , as single daily morning doses . Patients were r and omized after a 2-week run-in period without drugs ; treatment was given for 6 weeks . A dose response compared with placebo was found for both drugs ; the combination was more effective than either drug alone . Piretanide 6 mg , combined with ramipril 5 mg , provided optimal blood pressure reduction . Self-reported adverse effects of both drugs and their combinations did not exceed those reported for placebo . A surface analysis suggested that piretanide primarily reduced systolic blood pressure , whereas ramipril was more effective in reducing diastolic blood pressure . The data attest to a combined efficacy of piretanide and ramipril in decreasing arterial blood pressure 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 The antihypertensive efficacy and tolerability of losartan/hydrochlorothiazide ( HCTZ ) and losartan monotherapy as initial treatment were compared in a double-blind trial in Chinese patients with mild to moderate essential hypertension . Patients were r and omised to initial treatment with either losartan/HCTZ ( 50 mg/12.5 mg ) or losartan alone ( 50 mg ) . The doses were doubled after four weeks if diastolic blood pressure (SiDBP)was > 90 mmHg . Both losartan/HCTZ and losartan alone significantly reduced SiDBP and SiSBP from baseline at the first measurement at 4 weeks ( -10.1/-15.3 and -6.1/-6.9 mmHg , respectively ; p<0.001 ) and at 8 weeks ( -13.1/-18.5 and -8.7/-10.9 mmHg ; p<0.001 ) . The reductions with losartan/HCTZ were significantly greater than with losartan alone at weeks 4 and 8 ( p<0.001 ) . Both regimens were similarly well tolerated . In conclusion , initial therapy with losartan/HCTZ is effective and well tolerated in the treatment of Chinese patients with mild to moderate essential hypertension and produces a greater reduction in blood pressure than losartan alone The antihypertensive effect and tolerance of the combined low doses of felodipine and enalapril ( 5 + 5 mg daily ) were compared with those of either drug at a higher dose level ( 10 mg daily ) . Our double-blind , three-way crossover study ( balanced Latin square design ) involved 36 elderly subjects ( mean age 67 + /- 6 years ) with essential hypertension . After a 4-week placebo run-in phase the subjects were r and omized to the active treatment periods , starting with 5 mg felodipine plus 5 mg enalapril , 5 mg felodipine , or 5 mg enalapril daily for the first 4 weeks . The doses in the felodipine and enalapril periods were then doubled for another 2 weeks . All medication was given once daily in the morning , and blood pressure was measured 24 h after a previous dose . The supine blood pressure for subjects given placebo was 178/101 mm Hg . After 6 weeks ' treatment systolic and diastolic supine blood pressures were significantly lower with 5 mg felodipine plus 5 mg enalapril ( 154/85 mg Hg ) than with 10 mg felodipine ( 159/88 mm Hg ) or with 10 mg enalapril ( 162/91 mm Hg ) , and the diastolic blood pressure was significantly lower with felodipine than with enalapril . At the end of the felodipine plus enalapril , felodipine , and enalapril treatment periods , 75 , 69 , and 56 % of the subjects , respectively , had a supine diastolic blood pressure 90 mm Hg or less . The combination was tolerated better than either monotherapy . The most commonly reported adverse event was swollen ankles , which occurred in one , nine , and five subjects during felodipine plus enalapril , felodipine , and enalapril treatment , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS 41 patients ( 35 males and 6 females ) with moderate hypertension were treated with a combination of methyldopa/hydrochlorothiazide/amiloride ( M/HCT/A ) . In a double blind study the blood-pressure-lowering effect of this combination was compared with the effect of M or HCT/A alone . After 8 weeks of treatment , the combination of M/HCT/A lowered the elevated blood pressure more efficiently than the two monotherapies . M counteracted the potassium-loosing effect of HCT/A , but did not prevent the elevation of serum urea , creatinine and uric acid which is observed under treatment with Forty-one patients completed a r and omized , double-blind , between-group comparison of a combination of penbutolol and frusemide , with penbutolol alone , and frusemide alone in the management of mild to moderate essential hypertension . The results suggest that the combination caused a superior reduction in systolic and diastolic pressure compared with penbutolol and a superior reduction in systolic blood pressure compared with frusemide 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 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 A multiclinic , double-blind , r and omized study in 361 patients with essential hypertension compared Aldoretic , ( Merck & Co. , Inc. , New Jersey ) , a combination of methyldopa , hydrochlorothiazide , and amiloride with the combination of hydrochlorothiazide and amiloride and with methyldopa alone . At the end of week 12 , the proportion of patients who were classified as normotensive ( diastolic less than or equal to 90 mm Hg ) was 61 % in the group treated with Aldoretic , which was statistically significantly greater than the 48 % in the hydrochlorothiazide/amiloride group and the 35 % in the methyldopa group The antihypertensive effect of Inderectic , a new combination capsule of propranolol 80 mg and bendrofluazide 2.5 mg , given twice daily was investigated in 21 hypertensive patients using a double-blind r and omized crossover method . Inderectic was compared with either agent used alone and with the same combination given as separate tablets . It gave a greater fall in mean lying and st and ing systolic and diastolic blood pressure than either agent alone . There was no statistically significant difference for the effect on these variables between the free combination and combined formulation . Only minor side-effects were recorded , no patient having to be withdrawn from the study and no biochemical changes were observed 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 Enalapril is a new , oral , long-acting nonsulfhydral angiotensin converting enzyme inhibitor . Thirty-nine patients with primary hypertension were entered into a r and omized , double-blind protocol to assess the efficacy of enalapril ( 10 to 20 mg bid ) , hydrochlorothiazide ( 25 to 50 mg bid ) , or combined drug therapy . Enalapril , either alone or in combination with hydrochlorothiazide , effectively controlled blood pressure .  Enalapril monotherapy was associated with an increase in plasma renin activity and a decrease in angiotensin II concentration ; in patients with an initial inulin clearance less than or equal to 80 mL/min/1.73 m2 , inulin and para-aminohippurate clearances were markedly improved , without producing adverse effects on salt and water excretion or body fluid composition . Combination therapy was associated with a marked increase in plasma renin activity ; however , only those patients with an initial inulin clearance less than or equal to 80 mL/min/1.73 m2 demonstrated suppression of angiotensin II concentration and marked improvement in inulin and para-aminohippurate clearances . These observations suggest that enalapril , either alone or in combination with a diuretic , has the potential to reverse renal function abnormalities encountered in the hypertensive state
target: The effect was similar to that obtained when thiazides are used as a single agent .
  Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug .
  This means that the BP lowering effect of thiazides is additive .
  Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose .
  Because of the short duration of the trials and lack of reporting of adverse events , this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug
background: BACKGROUND Diuretics are widely prescribed for hypertension not only as a first-line drug but also as a second-line drug .
  Therefore , it is essential to determine the effects of diuretics on blood pressure ( BP ) , heart rate and withdrawals due to adverse effects ( WDAEs ) when given as a second-line drug .