Antihypertensive efficacy and safety of fixed-dose combination therapy with losartan plus hydrochlorothiazide in Japanese patients with essential hypertension.

A randomized, double-blind, placebo-controlled, parallel-group multicenter study was conducted to evaluate the antihypertensive efficacy and safety of 8-week treatment with one of three fixed-dose combinations-losartan 50 mg plus hydrochlorothiazide 12.5 mg, losartan 50 mg plus hydrochlorothiazide 6.25 mg, or losartan 25 mg plus hydrochlorothiazide 6.25 mg-in comparison with those of hydrochlorothiazide 12.5 mg alone, losartan 50 mg alone, or placebo in Japanese patients with essential hypertension. Significant reductions in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were seen in all three combination groups compared with the placebo group (each p<0.001). The greatest reductions in DBP and SBP were observed in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group (12.7 and 18.0 mmHg, respectively). The reductions in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group were significantly greater (each p<0.001) than those in the placebo group and each of the monotherapy groups. There were no significant differences in the incidences of clinical and laboratory drug-related adverse events between any of the combination groups and the placebo group. All combination groups showed improved hypokalemia and hyperuricemia compared to the hydrochlorothiazide 12.5 mg group. These results demonstrated that once-daily, fixed-dose combination therapy with losartan 50 mg plus hydrochlorothiazide 12.5 mg is well tolerated and more efficacious in lowering DBP and SBP than monotherapy in Japanese hypertensive patients.     

Dose Response to Hydrochlorothiazide in Hypertensives Receiving A Calcium Channel Blocker

ABSTRACT

Seven hypertensive patients receiving the dihydropyridine calcium channel blocking agent nicardipine were given placebo, 6.25, 12.5, 25 and 50 mg hydrochlorothiazide (HCTZ) in a randomized crossover design. Blood pressure (BP) decreased by about 7/3 mmHg irregardless of dose. In contrast, potassium, glucose and uric acid increased in a dose-dependent fashion. The hypokalemic and hyperglycemic responses at 50 mg were larger than usually seen with HCTZ. Low doses of HCTZ provided a modest antihypertensive effect, but 25 and 50 mg of HCTZ were no more effective in lowering BP and gave unusually large metabolic side effects when combined with a calcium channel blocker.     

Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination

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, randomized, double-blind, placebo-controlled, unbalanced factorial study (N = 1571) was designed to determine whether hydrochlorothiazide (HCT) and extended release (ER) metoprolol both contribute to an antihypertensive effect. Hypertensive adults with sitting diastolic BP (SiDBP) 95 to 114 mm Hg and systolic BP (SiSBP) <180 mm Hg received one of three hydrochlorothiazide doses (6.25 mg, 12.5 mg, or 25 mg), one of four ER-metoprolol doses (25 mg, 50 mg, 100 mg, 200 mg), or one of nine of the combinations or placebo for 8 weeks. RESULTS: Blood pressure decreased with all combinations (P < .001 v placebo); reductions were dose related, ranging from 8.7 to 15.7 mm Hg (SiDBP) and 9.7 to 18.9 mm Hg (SiSBP) (model-derived values). Reductions with placebo were 5.3 (SiDBP) and 4.2 mm Hg (SiSBP). Both active agents contributed to the combination effect (P = .0015 for SiDBP; P = .0006 for SiSBP). Several low-dose combinations were approximately as effective as high doses of the individual agents (differences within 1 to 2.5 mm Hg). The adverse event discontinuation rate was 2.9%. Serum potassium decreased and uric acid increased with increasing doses of HCT. CONCLUSIONS: Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components.     

The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized study. METHODS: The Angiotensin II Receptor Antagonist Micardis in Isolated Systolic hypertension (ARAMIS) study compared the antihypertensive efficacy after 6 weeks of once-daily fixed doses of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo in patients (n = 1039, aged 35-84 years) with ISH (seated blood pressure 150-179/< 90 mmHg). The prospective substudy analysed UAE using spot morning samples. RESULTS: Urinary albumin (> 2.2-901.6 mg/l) was detected at baseline in 614 out of 918 patients who were included in the substudy analysis. In the telmisartan group (n = 354, all doses combined), a median reduction in UAE from a baseline of 14.1% [95% confidence interval (CI) 7.3, 21.8] was observed versus 1.1% (95% CI -13.5 to 16.0) and 2.7% (95% CI -0.9 to 19.9) in the hydrochlorothiazide (n = 140) and placebo (n = 120) groups, respectively. The difference between telmisartan and hydrochlorothiazide was significant (P = 0.017). Reductions in UAE with telmisartan were observed in patients with baseline normoalbuminuria, microalbuminuria or macroalbuminuria. Telmisartan and hydrochlorothiazide produced comparable reductions in systolic blood pressure in these patients. CONCLUSION: In patients with ISH unselected for baseline albuminuria, telmisartan 20-80 mg after 6 weeks' treatment afforded significantly greater lowering of UAE than hydrochlorothiazide 12.5 mg, irrespective of the baseline UAE, and despite comparable reductions in systolic blood pressure with both drugs.     

Relation Between Low Dose of Hydrochlorothiazide, Antihypertensive Effect and Adverse Effects

Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ. To characterize the lower end of the dose-response curve a double-blind, parallel group trial was performed as multicentre study in Scandinavia. One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension (untreated diastolic blood pressure of 95-115 mmHg after 4 weeks placebo) were randomly allocated to various doses of hydrochlorothiazide (3, 6, 12.5 or 25 mg) or placebo for 6 weeks. Blood pressure and biochemical variables (plasma renin activity, serum potassium, magnesium, urate, fasting glucose, total cholesterol, HDL-cholesterol, triglycerides and apolipoproteins A1 and B were measured. 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect. Biochemical changes were seen in plasma renin activity, serum potassium and urate after the 12.5 and 25 mg dose. Three and 6 mg had no effect on blood pressure or metabolic parameters.     

Hydrochlorothiazide with or without amiloride for hypertension in the elderly. A dose-titration study

The blood pressure response to increasing doses of hydrochlorothiazide with or without amiloride was examined in 130 elderly hypertensive patients. After four weeks of placebo, patients were randomly allocated to increasing doses of hydrochlorothiazide or hydrochlorothiazide with amiloride for 12 weeks using a parallel, double-blind study design. Both hydrochlorothiazide and hydrochlorothiazide with amiloride significantly reduced mean (+/- SEM) baseline supine and standing blood pressure (171 +/- 2/102 +/- 1 and 167 +/- 2/102 +/- 1 mm Hg) to 148 +/- 2/84 +/- 1 and 146 +/- 3/85 +/- 1 mm Hg, respectively, at week 16. Amiloride did not exert any additional antihypertensive effect. Only eight patients required hydrochlorothiazide at 100 mg/d, with the remainder responding to 25 to 50 mg/d. Hydrochlorothiazide decreased mean serum potassium level from 4.3 +/- 0.1 mEq/L (4.3 +/- 0.1 mmol/L) during placebo to 4.0 +/- 0.1 mEq/L (4.0 +/- 0.1 mmol/L) at week 16. Ten patients receiving hydrochlorothiazide developed hypokalemia compared with only two receiving hydrochlorothiazide with amiloride. Relatively low doses of hydrochlorothiazide (25 to 50 mg/d) effectively reduce blood pressure in elderly hypertensive patients. Hypokalemia may occur with hydrochlorothiazide alone but is much less common when hydrochlorothiazide is combined with amiloride.     

24-hour ambulatory blood-pressure effects of valsartan and hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk: a VAST sub-study

BACKGROUND: There is a lack of data on the effects of angiotensin-receptor blocker and diuretic combinations on ambulatory blood pressure (ABP) in hypertensive patients with additional cardiovascular risk factors. METHODS: In a randomized, double-blind trial, the effects on 24-h ABP of the combination valsartan 160 mg od and hydrochlorothiazide 25 or 12.5 mg during 24 weeks of therapy were compared with the effects of amlodipine 10 mg monotherapy (group A10) in 474 stage-II hypertensive patients with additional cardiovascular risk factors. After a two-week single-blind placebo run-in period, patients were randomized to receive valsartan 160 mg od or amlodipine 5 mg od. At week 4, HCTZ 12.5 mg (group V160/HCTZ12.5) and 25 mg (group V160/HCTZ25) were added to the valsartan groups and in the A10 patients the amlodipine dose was force-titrated to 10 mg od. RESULTS: All three treatments reduced 24-h BP as well as night-time and daytime BP levels from baseline. Twenty-four hour systolic blood pressure (SBP) was reduced by 15.9+/-1.0 mmHg (least-squares mean change+/-SE), 19.3+/-1.0 mmHg and 16.1+/-1.1 mmHg in the V160/HCTZ12.5, V160/HCTZ25 and A10 groups, respectively and 24-h diastolic blood pressure (DBP) was reduced by 9.3+/-0.6 mmHg, 11.4+/-0.6 mmHg and 9.6+/-0.7 mmHg in the three groups. The differences between the V160/HCTZ25 group and the A10 group were significant (p<0.05) for the changes in 24-h systolic BP as well as for changes in daytime systolic BP and night-time diastolic BP. Control rates defined as ABPM < or =130/80 mmHg were: 48.4%, 60.8% and 50.9% in the V160/HCTZ12.5, V160/25 and A10 groups, respectively. The differences in control rates between the V160/HCTZ25 group and the other two treatment groups were significant at p<0.05. CONCLUSIONS: The fixed-dose combination of valsartan 160 mg+HCTZ 25 mg od is an attractive therapeutic option measured on the effects on 24-h ABPM, night-time and daytime BP reduction and control rates in hypertensive patients at additional cardiovascular risk.     

氯沙坦及氯沙坦与双氢克尿噻合剂对原发性高血压患者肾素活性影响的比较

目的比较血管紧张素Ⅱ受体拮抗剂氯沙坦及氯沙坦与双氢克尿噻合剂对原发性高血压患者的降压疗效和肾素活性水平的影响。 方法坐位舒张压95～115mmHg(1mmHg=0.133kPa)的76例原发性高血压患者,经1周药物洗脱期,2周安慰剂期后,随机服用氯沙坦50mg(氯沙坦组,n=37),每日1次或氯沙坦50mg与双氢克尿噻12.5mg合剂(氯沙坦+双氢克尿噻合剂组,n=39),每日1次。4周末坐位舒张压≥90mmHg者,剂量分别加倍,继续服用4周。于安慰剂期末及服药8周末测量诊室坐位血压和测定立位血浆肾素活性水平。 结果服药8周末平均坐位舒张压氯沙坦组(n=35)下降10.1±9.1mmHg;氯沙坦+双氢克尿噻合剂组(n=33)下降14.6±7.5mmHg(组间比较P＜0.05);同时服用末次药24小时后氯沙坦组的平均血浆肾素活性从1.6ng/(ml*h)增加至5.4ng/(ml     

Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure

Low-dose thiazide-type diuretics are recommended as initial therapy for most hypertensive patients. Chlorthalidone has significantly reduced stroke and cardiovascular end points in several landmark trials; however, hydrochlorothiazide remains favored in practice. Most clinicians assume that the drugs are interchangeable, but their antihypertensive effects at lower doses have not been directly compared. We conducted a randomized, single-blinded, 8-week active treatment, crossover study comparing chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. The main outcome, 24-hour ambulatory blood pressure (BP) monitoring, was assessed at baseline and week 8, along with standard office BP readings every 2 weeks. Thirty patients completed the first active treatment period, whereas 24 patients completed both. An order-drug-time interaction was observed with chlorthalidone; therefore, data from only the first active treatment period was considered. Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day (24-hour mean = -12.4+/-1.8 mm Hg versus -7.4+/-1.7 mm Hg; P=0.054; nighttime mean = -13.5+/-1.9 mm Hg versus -6.4+/-1.8 mm Hg; P=0.009). Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day (-15.7+/-2.2 mm Hg versus -4.5+/-2.1 mm Hg; P=0.001); however, by week 8, reductions were statistically similar (-17.1+/-3.7 versus -10.8+/-3.5; P=0.84). Within recommended doses, chlorthalidone is more effective in lowering systolic BPs than hydrochlorothiazide, as evidenced by 24-hour ambulatory BPs. These differences were not apparent with office BP measurements.     

Low-dose captopril titration in patients with moderate-to-severe hypertension treated with diuretics

To study the value of low-dose captopril (6.25 and 12.5 mg) and a diuretic combination, the blood pressure and heart rate of 17 patients with moderate-to-severe hypertension were monitored for 6 hours (hospital) or 3 hours (office) after the single low-dose or larger (25, 50, 100 and 150 mg) captopril dosage. All patients had preserved renal function and were taking an oral diuretic (hydrochlorothiazide or furosemide) for at least 4 weeks. The supine and upright acute blood pressure lowering with 6.25 mg was not different from the larger captopril doses; none produced persistent or profound hypotension. There was no deterioration of renal function, new or persistent increase in proteinuria, neutropenia or agranulocytosis acutely or during 17 +/- 2 weeks of follow-up. Low-dose captopril (6.25 or 12.5 mg three times daily) normalized the supine blood pressure of 35% of these patients acutely. We suggest that in hypertensive patients already taking a diuretic, a lower starting dose of captopril than the recommended 25 mg three times daily may be desirable.     

A comparison of indapamide SR 1.5 mg with both amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients: a randomized double-blind controlled study

OBJECTIVE: To analyse the efficacy of indapamide sustained-release (SR) 1.5 mg in reducing blood pressure versus amlodipine 5 mg and hydrochlorothiazide 25 mg, in elderly hypertensive patients. DESIGN: Double-blind, randomized, 12 week study using three parallel groups. SETTING: European teaching hospitals and general practices. PATIENTS: Randomized patients, (n = 524) including 128 patients with isolated systolic hypertension (ISH); mean age: 72.4 years; mean systolic/diastolic blood pressures (SBP/DBP): 174.5/97.9 mmHg. MAIN OUTCOME MEASURES: Clinic systolic and diastolic blood pressure variations. RESULTS: Indapamide SR 1.5 mg demonstrates a similar efficacy to that of amlodipine 5 mg, as well as to that of hydrochlorothiazide 25 mg (equivalence P < 0.001); the mean decreases in SBP/DBP were -22.7/-11.8 mmHg, -22.2/-10.7 mmHg and -19.4/-10.8 mmHg, respectively. In the ISH subgroup, indapamide SR 1.5 mg tends to have greater efficacy than hydrochlorothiazide 25 mg in reducing the SBP (-24.7 versus -18.5 mmHg, respectively; equivalence P = 0.117), while similar results are obtained with amlodipine 5 mg (-23 mmHg, equivalence P < 0.001). The normalization rate was relatively high for indapamide SR 1.5 mg (75.3%), when compared with amlodipine (66.9%) and hydrochlorothiazide (67.3%), especially in the subgroup of isolated systolic hypertensive patients: 84.2 versus 80.0% for amlodipine, and versus 71.4% for hydrochlorothiazide. CONCLUSIONS: Indapamide SR 1.5 mg shows similar antihypertensive efficacy to amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients, while in patients with isolated systolic hypertension, indapamide SR 1.5 mg shows a similar efficacy to amlodipine 5 mg but a greater efficacy than hydrochlorothiazide 25 mg.     

Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide

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 >or=18 years with mean sitting diastolic blood pressure (MSDBP) 95-109 mmHg were randomized 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 resulted in more responders (patients with MSDBP < 90 mmHg and/or >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.     

Angiotensin II receptor antagonist telmisartan in isolated systolic hypertension (ARAMIS) study: efficacy and safety of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo

OBJECTIVE: To identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide (HCTZ) 12.5 mg, and are well tolerated, in lowering systolic blood pressure (SBP) in patients with isolated systolic hypertension (ISH). PATIENTS AND METHODS: A 2-4-week single-blind placebo run-in was followed by randomization of 1039 patients (age 36-84 years) with ISH [seated SBP 150-179 mmHg and seated diastolic blood pressure (DBP) < 90 mmHg] to once-daily double-blind treatment with telmisartan 20, 40 or 80 mg, HCTZ 12.5 mg, or placebo. The change in seated trough SBP after 6 weeks compared with baseline was the primary end point. Secondary end points were the percentage achieving the target fall in SBP and the change from baseline in seated trough DBP. Incidence and severity of adverse events and physical examination and laboratory parameters were monitored for the safety evaluation. RESULTS: Baseline demographics in telmisartan 20 mg (n = 206), 40 mg (n = 210), 80 mg (n = 207), HCTZ 12.5 mg (n = 205) and placebo (n = 211) treatment groups were comparable: (mean +/- SD) age, 63.0 +/- 10.9 years; SBP, 162.9 +/- 8.1 mmHg; and DBP 83.4 +/- 5.0 mmHg. No previous antihypertensive therapy had been received by 66% of the patients. Mean reductions in seated trough SBP (adjusted for baseline and country) were: telmisartan 20 mg, 15.6 mmHg (n = 204); 40 mg, 17.9 mmHg (n = 209); and 80 mg, 16.9 mmHg (n = 205), compared with placebo, 11.4 mmHg (n = 208), and HCTZ 12.5 mg, 15.7 mmHg (n = 204). The target fall in seated trough SBP (< or =140 mmHg or reduction by > or =20 mmHg) was achieved in 46.6% (telmisartan 20 mg), 51.7% (telmisartan 40 mg), 53.9% (telmisartan 80 mg), 27.4% (placebo) and 42.7% (HCTZ 12.5 mg); the response rate was significantly higher for telmisartan 80 mg than for HCTZ 12.5 mg (P = 0.03). All-causality adverse events occurred in 19.9, 17.6 and 20.3% receiving telmisartan 20, 40 and 80 mg, respectively; 20.9% receiving placebo and 22.0% receiving HCTZ 12.5 mg. No drug-related serious adverse events occurred. CONCLUSIONS: All doses of telmisartan (20-80 mg) were significantly superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ 12.5 mg. Tolerability of telmisartan was similar to that of placebo.     

Candesartan and hydrochlorothiazide in isolated systolic hypertension

AIM: We investigated the efficacy and safety of daily candesartan 8/16mg and hydrochlorothiazide 12.5 mg as monotherapy and in combination in older patients with systolic hypertension. METHODS: The study used a double-blind randomized placebo-controlled crossover design. Treatment phases were of 6 weeks duration. For inclusion, patients were aged 55-84 years with sitting systolic blood pressure (SBP) 160-210 mmHg and diastolic blood pressure (DBP) < 95 mmHg. Nineteen patients (11 male, eight female, median age 68 years) completed the study. MAJOR FINDINGS: Compared with the placebo phase, clinic and ambulatory SBP was significantly reduced with both dose-adjusted candesartan and fixed-dose hydrochlorothiazide as monotherapy, the effect of candesartan being greater than that of hydrochlorothiazide. In combination, the effects of the two drugs were additive. Both drugs were well tolerated either as monotherapy or in combination. CONCLUSION: Both candesartan and a low dose of hydrochlorothiazide are effective and well-tolerated antihypertensive agents in isolated systolic hypertension with additive effects in combination. Candesartan was more effective than hydrochlorothiazide, although it is possible that dose adjustment only of candesartan could have enhanced its relative effectiveness.     

Comparison of antihypertensive and metabolic effects of losartan and losartan in combination with hydrochlorothiazide--a randomized controlled trial

INTRODUCTION: Losartan is an angiotensin II receptor blocker indicated for treatment of hypertension. It also inhibits platelet agreggation through blockade of thromboxane A2/ prostaglandin H2 receptors, and has a uricosuric effect We determined the effect on ambulatory blood pressure (ABP) of 100 mg losartan monotherapy (L100) versus 50 mg losartan/12.5 mg hydrochlorothiazide (HCTZ) combination therapy (L50H12.5C), in patients uncontrolled on 50 mg losartan. We also assessed the effects of losartan on platelet aggregation and serum urate at these clinically relevant doses. METHODS: This was a randomized, double-blind trial of L100 versus L50H12.5C, in moderate hypertensives (sitting diastolic blood pressure (DBP) >or = 95 mmHg and < 120 mmHg). After 4 weeks of placebo run-in, patients received 50 mg losartan for 6 weeks; patients uncontrolled (sitting DBP > or = 95 mmHg) were randomized to L100 or L50H12.5C for a further 6 weeks. Platelet function was assessed by measuring percentage inhibition of platelet aggregation, and serum uric acid was also measured. RESULTS: Monotherapy with 50 mg losartan reduced ABP by 16.0/9.9 mmHg during the day and 9.8/5.5 mmHg at night However, 16 out of 24 (66%) patients had uncontrolled blood pressure on this treatment L50H12.5C further reduced daytime ABP by 10.7(10.7)/8.4(6.5) mmHg mean (SEM) compared with L100 (-5.3(9.7)/-2.3(4.8), P = 0.013). 50 mg losartan and L100 did not affect platelet function or uric acid levels beyond placebo values; treatment with L50H12.5C was associated with a significant rise in serum urate above levels obtained on 50 mg losartan (366.9(67.6) versus 331.6(65.0), P=0.006), to levels similar to placebo (358.8(80.9)). CONCLUSION: L50H12.5C is an effective antihypertensive regimen in patients with moderate hypertension that is uncontrolled on 50 mg losartan monotherapy, and is the preferred treatment option in these patients compared with increasing the dose of losartan. The additional benefit of losartan on platelet inhibition was not evident in our population at these doses; however, there was evidence to suggest that the uricosuric effects of losartan might ameliorate the uric acid retention effects of therapy with hydrochlorothiazide.     

Combination treatment with telmisartan and hydrochlorothiazide in black patients with mild to moderate hypertension

BACKGROUND: Hydrochlorothiazide (HCTZ) is commonly used to treat black patients with hypertension. To avoid the metabolic disturbances associated with high-dose HCTZ, blood pressure control may be achieved by combining low doses with another antihypertensive. HYPOTHESIS: The study was undertaken to assess the tolerability and antihypertensive dose-response efficacy of telmisartan and HCTZ and their combination in black patients with mild to moderate hypertension (mean supine blood pressure 140/95-200/114 mmHg). METHODS: Following a 4-week, single-blind, placebo run-in period, 222 black patients were randomized to once-daily treatment with one of 20 different double-blind combinations of telmisartan (0, 20, 40, 80, 160 mg) and HCTZ (0, 6.25, 12.5, 25 mg) for 8 weeks. Blood pressure was measured at baseline and after 2, 4, and 8 weeks. RESULTS: Telmisartan 80 mg/HCTZ 12.5 mg reduced supine trough diastolic blood pressure (DBP)--primary efficacy parameter--by 13.3 mmHg, and supine trough systolic blood pressure (SBP) by 21.5 mmHg. These reductions represented benefits of 13.7/8.7 mmHg over telmisartan 80 mg and 12.3/8.1 mmHg over HCTZ 12.5 mg (p < 0.01). Telmisartan 40 mg/HCTZ 12.5 mg reduced supine trough SBP/DBP by 14.3/10.0 mmHg, amounting to 12.3/3.3 mmHg more than telmisartan 40 mg and 5.1/4.8 mmHg more than HCTZ 12.5 mg. This reached significance for the comparisons with telmisartan 40 mg for SBP and HCTZ 12.5 mg for DBP (p<0.05). A response surface analysis and therapeutic response rates confirmed the additive antihypertensive effects of telmisartan and HCTZ. All treatments were well tolerated, with side-effect profiles comparable with placebo. Adverse events were mainly transient and of mild to moderate severity. CONCLUSIONS: Telmisartan 80 mg combined with HCTZ 12.5 mg is effective and well tolerated in black patients with mild to moderate hypertension, providing greater antihypertensive activity than the corresponding monotherapies.     

The FEVER (Felodipine EVEnt Reduction) trial; a randomised, double-blind, placebo-controlled trial in Chinese hypertensive patients

The FEVER trial observed the difference between intense and less intense treatment of hypertension by comparing combination therapy consisting of a low diuretic dose (12.5 mg of hydrochlorothiazide) and a low calcium antagonist dose (5 mg of felodipine) with monotherapy based on a low diuretic dose (12.5 mg of hydrochlorothiazide) in Chinese hypertensive patients. The trial enrolled 9711 hypertonics (of which 4841 on hydrochlorothiazide + felodipine combination and 4870 on hydrochlorothiazide + placebo combination). Blood pressure decreased from 158.7/92.4 to 138.1/82.3 mmHg and from 158.0/92.7 to 141.6/83.9 mmHg in the combination therapy group and monotherapy group, respectively. The average difference throughout the trial was 4.2/2.1 mmHg. The primary endpoint--fatal and non-fatal stroke (CVA)--was reduced by 27% in the combination therapy group. Among secondary endpoints, the success ratio of combination therapy was expressed by 27% reduction of all cardiovascular events, 35% reduction of all cardiac events, 32% reduction of coronary events and 31% reduction of deaths. The minor difference between systolic and diastolic blood pressure of approximately 4/2 mmHg was related to a decrease in the incidence of CVA and cardiovascular events in Chinese hypertonics.     

Efficacy of manidipine/delapril versus losartan/hydrochlorothiazide fixed combinations in patients with hypertension and diabetes

BACKGROUND: Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes. METHODS: This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment. RESULTS: Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups. CONCLUSION: The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.     

The efficacy and tolerance of one or two daily doses of eprosartan in essential hypertension. The Eprosartan Multinational Study Group

OBJECTIVE: The primary objective of this double-blind, parallel-group, placebo-controlled, multicentre study was to compare the antihypertensive efficacy of one versus two daily doses of eprosartan, a novel nonbiphenyl, nontetrazole angiotensin II receptor antagonist, in 243 patients with mild to moderate hypertension (sitting diastolic blood pressure > or = 95 to < or = 114 mmHg). PATIENTS AND METHODS: The patients were randomized to titrated doses of eprosartan at 400-800 mg once a day, eprosartan at 200-400 mg twice a day, or placebo, with the incremental dose titrated over a 9-week period. Patients reaching target blood pressure (sitting diastolic blood pressure of < or = 90 mmHg) continued the fixed-dose treatment for 4 weeks. The primary efficacy measure was the mean change in trough sitting diastolic blood pressure from baseline to the study endpoint, determined on an intent-to-treat basis. RESULTS: By the end of the study, eprosartan had significantly reduced mean trough sitting systolic and diastolic blood pressure relative to baseline and to placebo. The mean +/- SD change from baseline in diastolic pressure was -9 +/- 8.4 mmHg for the single daily dose, -9 +/- 8.5 mmHg for two doses a day and -4 +/- 8.1 mmHg for placebo (P < 0.0001 versus placebo for both eprosartan regimens). Similarly, both eprosartan regimens significantly reduced mean trough standing systolic and diastolic blood pressure. At the end of the study, the response rate in the single daily dose group (46.8%) was significantly higher than in the placebo group (25.6%). There were no significant differences between the treatment groups in the number of patients whose blood pressure responded to treatment; 41.7% of those taking eprosartan once a day and 44.4% of those taking eprosartan twice a day, and who responded to treatment, were maintained on their original starting doses. The total daily dose required to achieve target blood pressure was comparable, whether eprosartan was administered once or twice a day. Both eprosartan regimens were well tolerated and the incidence of adverse events with eprosartan was similar to that of placebo. CONCLUSIONS: These results demonstrate that there was no significant difference in antihypertensive efficacy or tolerance between eprosartan taken in one or in two daily doses. Both dosing regimens provided significant and clinically meaningful reductions in blood pressure that were superior to placebo. Eprosartan in a single daily dose was shown to be an effective antihypertensive agent. Because of the good adverse-effect profile and the simplicity of a single daily dose, eprosartan has the potential to improve patient compliance.     

The role of captopril as single therapy in hypertension and angina pectoris.

Eighteen hypertensive patients with a resting diastolic blood pressure between 100 and 120 mmHg who also had angina and proven coronary arterial disease entered a dose titration study to evaluate the efficacy of captopril as a single therapy in hypertension and coexisting stable angina. Captopril was administered for 2 weeks at 25 or 50 mg three times daily and the patients evaluated subjectively and by maximal symptom limited treadmill exercise testing. In comparison to placebo captopril 25 mg and 50 mg dosage increased time to 1 mm ST depression from 188.2 +/- 24.4 sec on placebo to 337.6 +/- 29.5 and 364.2 +/- 36.2 sec respectively (P less than 0.01). The maximum ST segment depression was reduced from 2.5 +/- 0.25 mm on placebo to 1.4 +/- 0.22 mm on captopril 25 mg and 1.2 +/- 0.30 mm on captopril 50 mg (P less than 0.01). Exercise duration increased from 310.3 +/- 21.4 sec on placebo to 438.3 +/- 27.3 sec on captopril 25 mg and to 460.9 +/- 26.5 sec on captopril 50 mg (P less than 0.01). The resting systolic blood pressure decreased from 184.1 +/- 4.7 mmHg on placebo to 159 +/- 4.2 mmHg on captopril 25 mg and to 150.9 +/- 4.6 mmHg on captopril 50 mg (less than 0.01). Similarly, diastolic blood pressure decreased from 111.6 +/- 2.1 mmHg on placebo to 93.8 +/- 1.3 mmHg on captopril 25 mg and to 90.0 +/- 1.7 mmHg on captopril 50 mg (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)