Comparison of a fixed-dose combination of 40 mg telmisartan plus 12.5 mg hydrochlorothiazide with 40 mg telmisartan in the control of mild to moderate hypertension

This study investigated whether a fixed-dose combination of 40 mg of the angiotensin II antagonist telmisartan plus 12.5 mg of the diuretic hydrochlorothiazide (HCTZ) was superior to 40 mg telmisartan in patients with mild to moderate hypertension who failed to respond adequately to 40 mg telmisartan monotherapy. One hundred forty-six patients were withdrawn before randomization. Nonresponders (n = 327) were double blind and randomized to 40 mg telmisartan + 12.5 mg HCTZ (n = 160) or 40 mg telmisartan (n = 167). After 8 weeks of treatment, 40 mg telmisartan + 12.5 mg HCTZ lowered diastolic blood pressure (DBP) by an additional 3.5 mm Hg (P <.01) and systolic blood pressure (SBP) by 7.4 mm Hg (P <.01) compared with 40 mg telmisartan. Most of the additional effect of the combination was seen after 4 weeks of treatment. At week 8, blood pressure was normalized (SBP <140 mm Hg and DBP <90 mm Hg) in 51.6% of patients on 40 mg telmisartan + 12.5 mg HCTZ compared with 23.5% on 40 mg telmisartan (P <.05). The combination of 40 mg telmisartan + 12.5 mg HCTZ normalized DBP in 64.8% of patients, whereas 40 mg telmisartan normalized DBP in 40.1% (P <.05). SBP decreased by > or =10 mm Hg from baseline in 63.5% of patients receiving the fixed-dose combination compared with 42.6% of those receiving 40 mg telmisartan (P <.05). Both treatments were well tolerated. Adverse events were predominantly mild, transient, and considered unrelated to therapy. These findings indicate that a fixed-dose combination of 40 mg telmisartan + 12.5 mg HCTZ is clinically and statistically superior to 40 mg telmisartan in patients with mild to moderate hypertension failing to respond to 40 mg telmisartan alone.     

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

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 randomized 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 randomized 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.     

Efficacy and safety of combination therapy using high- or low-dose hydrochlorothiazide with valsartan or other angiotensin-receptor blockers

Only a minority of patients treated for hypertension achieve controlled blood pressure (BP) levels. Therapy with fixed-dose combinations of an angiotensin-receptor blocker (ARB) and low-dose hydrochlorothiazide (HCTZ) is commonly prescribed but not always sufficient to achieve the target BP. The efficacy and safety of the fixed-dose combination of valsartan 160 mg and HCTZ 25 mg was evaluated in patients in whom BP had not been controlled with a fixed-dose combination of another ARB and low-dose HCTZ (12.5 mg) in a multicenter trial. After a wash-out period for antihypertensive drugs, patients with a mean sitting diastolic BP (DBP) at trough ≥100 mm Hg but < 110 mm Hg were treated with candesartan cilexetil 16 mg plus HCTZ 12.5 mg or telmisartan 80 mg plus HCTZ 12.5 mg for 4 weeks (phase 1). Patients whose BP was still uncontrolled (DBP ≥90 mm Hg) after 4 weeks of therapy were then given valsartan 160 mg plus HCTZ 25 mg for an additional 4 weeks (phase 2). The primary efficacy parameter was the reduction in DBP between week 4 and week 8 in the intention-to-treat (ITT) population. BP reduction during phase 1 was -14.3±11.3/-7.5±3.9 mm Hg. DBP was controlled in 26% of the patients after phase 1. In patients treated with valsartan 160 mg plus HCTZ 25 mg during phase 2, DBP decreased by an additional 10.3±6.5 mm Hg and the mean sitting systolic BP (SBP) by an additional 11.0±11.7 mm Hg. The additional decrease was significant (P< .0001) for both parameters and independent of the fixed-dose combination used during phase 1. Among patients whose BP remained uncontrolled during phase 1, 74% achieved a controlled DBP after phase 2. The incidence of adverse events during both phases was comparably low and the results of laboratory tests were unremarkable. Treatment with valsartan 160 mg/HCTZ 25 mg offered a substantial benefit for patients with hypertension not controlled with the combination of candesartan cilexetil 16 mg or telmisartan 80 mg and low-dose HCTZ, while maintaining a comparable safety and tolerability profile.     

Increased efficacy and tolerability with losartan plus hydrochlorothiazide in patients with uncontrolled hypertension and therapy-related symptoms receiving two monotherapies

The efficacy and tolerability of losartan 100 mg/hydrochlorothiazide (HCTZ) 25 mg and enalapril 10 mg/HCTZ 25 mg were compared in a double-blind, randomized trial in hypertensive patients inadequately controlled and experiencing side effects on prior therapy. Patients with moderate or severe hypertension, currently treated with at least two single-agent drugs (excluding angiotensin-converting enzyme inhibitors), with a sitting diastolic blood pressure (DBP) above 90 mm Hg, and at least one undesirable drug-related symptom were randomized to once-daily treatment with one of the combinations for 12 weeks. Losartan/HCTZ lowered sitting DBP from the prior therapy baseline by 13.7 mm Hg and sitting systolic blood pressure 19.3 mm Hg; similar reductions occurred with enalapril/HCTZ. Trough sitting DBP was reduced to normal levels (< 90 mm Hg) in 63% of patients switched to the losartan combination and in 58% of those treated with the enalapril combination. Each combination was associated with improved tolerability compared with prior therapy, although fewer patients reported each of 24 undesirable symptoms after 12 weeks of losartan/HCTZ. The improvement from prior therapy in the occurrence of cough was significantly greater with losartan/HCTZ (P = .005). Enalapril/HCTZ, but not losartan/HCTZ, increased serum uric acid levels at week 12. In conclusion, the combination of losartan 100 mg/HCTZ 25 mg offers a beneficial therapeutic option for patients with a history of moderate to severe hypertension whose blood pressure is not adequately controlled or who exhibit side effects while on two or more single-agent antihypertensive drugs. In this population, the switch from prior antihypertensive therapies to once daily losartan 100 mg/HCTZ 25 mg improves blood pressure control and reduces side effects.     

Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators

OBJECTIVE: The goal of this multicenter, double-blind, randomized, parallel-group study was to compare the effects of losartan potassium (hereafter referred to as losartan), candesartan cilexitil (hereafter referred to as candesartan), and losartan/hydrochlorothiazide (HCTZ) in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] 95-115 mm Hg). METHODS: A total of 1161 patients were randomized in a 2:2:1 ratio to 12 weeks of treatment with losartan 50 mg QD, possibly titrated to 100 mg QD (n = 461); candesartan 8 mg QD, possibly titrated to 16 mg QD (n = 468); or losartan 50 mg QD, possibly titrated to losartan 50 mg plus HCTZ 12.5 mg QD (n = 232). At 6 weeks, the regimens of patients not reaching a goal SiDBP <90 mm Hg were titrated as described, whereas patients achieving this goal continued with low-dose monotherapy. The single primary end point at 12 weeks tested the equivalence of the 2 monotherapy regimens, predefined as a maximum between-treatment difference in the mean change from baseline trough SiDBP of 2.5 mm Hg. RESULTS: At 12 weeks, changes in SiDBP/sitting systolic blood pressure (SiSBP) of -12.4/-14.4 mm Hg with losartan 50 mg/100 mg and -13.1/-15.8 mm Hg with candesartan 8 mg/16 mg demonstrated equivalence between the 2 monotherapy regimens (95% CI for difference in SiDBP, -1.6 to 0.2). At 12 weeks, the losartan 50 mg/50 mg plus HCTZ 12.5 mg regimen had reduced SiDBP/SiSBP significantly more (-14.3/-18.0 mm Hg) than either the candesartan 8 mg/16 mg (SiDBP, P = 0.045; SiSBP, P = 0.017) or losartan 50 mg/100 mg regimen (SiDBP and SiSBP, P = 0.001). During the last 6 weeks, patients whose regimen had been titrated to losartan 50 mg plus HCTZ 12.5 mg (n = 114) showed a greater reduction in SiDBP/SiSBP (-14.5/ -18.7 mm Hg) than did those whose regimen had been titrated to either losartan 100 mg (-10.5/-12.3 mm Hg; n = 211) or candesartan 16 mg (-11.5/-13.2 mm Hg; n = 206), representing a clinically meaningful > or = 2.5-mm Hg) difference. All 3 treatments were well tolerated, with few patients experiencing drug-related adverse events (6.9% losartan 50 mg/100 mg, 7.5% candesartan 8 mg/16 mg, 3.0% losartan 50 mg/ 50 mg plus HCTZ 12.5 mg). Candesartan 8 mg/16 mg increased serum uric acid levels (0.13 mg/dL; 95% CI, 0.04 to 0.23), whereas losartan 50 mg/100 mg decreased them (-0.14 mg/dL; 95% CI, -0.24 to -0.04), and losartan 50 mg/50 mg plus HCTZ 12.5 mg left them unchanged (0.06 mg/dL; 95% CI, -0.07 to 0.20). CONCLUSIONS: Losartan 50 mg/100 mg and candesartan 8 mg/16 mg were comparable treatments in terms of blood pressure reduction. After titration, losartan 50 mg plus HCTZ 12.5 mg was superior to either candesartan 16 mg or losartan 100 mg in reducing hypertension. Losartan, but not candesartan, lowered serum uric acid levels and attenuated the expected increase in uric acid levels with HCTZ 12.5 mg.     

Low-dose combination treatment for hypertension versus single-drug treatment-bisoprolol/hydrochlorothiazide versus amlodipine, enalapril, and placebo: combined analysis of comparative studies

To assess the efficacy and safety of 2.5, 5, and 10 mg bisoprolol/6. 25 mg hydrochlorothiazide (HCTZ), 2.5, 5, and 10 mg amlodipine; and 5, 10, 20, and 40 mg enalapril in subjects (n = 541) with a sitting diastolic blood pressure of 95 to 114 mm Hg, data from two comparative studies were pooled. All drugs were titrated to a diastolic blood pressure 90 mm Hg or less. Both studies were double-blind, randomized, parallel dose escalation trials with similar designs and included three active treatments. The second study also had a placebo group. The mean change from baseline of systolic and diastolic blood pressure for placebo (n = 79) was -0. 1/-2.2 mm Hg; amlodipine (n = 154), -12.4/-10.3 mm Hg; enalapril (n = 155), -9.4/-8.2 mm Hg; and bisoprolol/HCTZ (n = 155), -14.0/-12.0. Overall efficacy analyses documented a statistically significant decrease in sitting diastolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo, amlodipine, and enalapril. There was a significant reduction in sitting systolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo and enalapril but not amlodipine. Also, there was a significant decrease in sitting heart rate for bisoprolol/6.25 mg HCTZ (-6.2 beats/min) compared with placebo (+0.1 beats/min), amlodipine (+1.2 beats/min), and enalapril (+0.5 beats/min). The control rate (diastolic blood pressure < or = 90 mm Hg) for bisoprolol/6.25 mg HCTZ (66.5%) was significantly better than for placebo (21.8%) and enalapril (47.1%) but not amlodipine (58.4%). Of those patients achieving and maintaining control, 49% of the bisoprolol/6.25 mg HCTZ subjects were on the lowest two doses compared with 30% of the amlodipine and 26% of the enalapril subjects. Percentages of patients reporting at least one drug-related adverse event through week 12 were 27%, 24%, 28%, and 25% for placebo, bisoprolol/6.25 mg HCTZ, amlodipine, and enalapril (not significant). Lower doses of two drugs in fixed combination can provide as good or better blood pressure control compared with higher doses of a single drug with similar tolerability and safety.     

Blood pressure control in patients with mild to moderate essential hypertension switched from nifedipine gastrointestinal therapeutic system (GITS) 30 mg to nifedipine GITS 20 mg

BACKGROUND: Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides sustained plasma nifedipine concentrations throughout the 24-hour dosing interval. OBJECTIVE: This study was undertaken to determine if adult patients with mild to moderate essential hypertension whose blood pressure had been controlled for > or = 3 months with nifedipine GITS 30 mg could be successfully switched to a 20-mg daily dose with continued antihypertensive efficacy. METHODS: This was a randomized, double-blind, parallel-group study. Patients entered a 1-week run-in period during which they continued to receive their usual antihypertensive medication, including nifedipine GITS 30 mg. After baseline assessment, patients entered a 6-week treatment period during which they were randomly assigned to receive nifedipine GITS 30 or 20 mg. Men and women were eligible to participate if they were > or = 55 years of age, had received a diagnosis of mild to moderate essential hypertension (sitting diastolic blood pressure [DBP] 95-114 mm Hg), and had exhibited good blood pressure control (sitting DBP < or = 90 mm Hg) while taking nifedipine GITS 30 mg once daily for > or = 3 months. Systolic blood pressure (SBP), DBP, and heart rate were recorded at baseline and after 1, 3, and 6 weeks of treatment. Adverse events were reported by patients. The responder rate was defined as the percentage of patients whose sitting DBP was < 95 mm Hg at the final study assessment. Results were based on the intent-to-treat analyses, which included data for all patients who received > or = 1 dose and had 1 postbaseline blood pressure assessment. Statistical significance was set at P < 0.05. RESULTS: Seventy-five patients entered the 1-week run-in period; 71 patients (94.7%) were randomized to treatment. Twenty-four patients received nifedipine GITS 30 mg for 43.0 +/- 3.3 days, and 47 patients received nifedipine GITS 20 mg for 42.5 +/- 6.7 days. Both groups exhibited a sustained decrease in blood pressure throughout the study; minor variations were not statistically significant. End-point SBP and DBP for the 30- and 20-mg groups were 135.5 +/- 9.8/81.7 +/- 5.4 mm Hg and 138.6 +/- 11.8/82.9 +/- 7.6 mm Hg, respectively. Changes from baseline in end-point SBP and DBP did not differ significantly between groups. At the end of treatment, goal DBP (< 95 mm Hg) was achieved by 24 of 24 patients (100%) receiving the 30-mg dose and 45 of 47 patients (95.7%) receiving the 20-mg dose. Blood pressure control (sitting DBP < 90 mm Hg) was achieved by 21 of 24 (87.5%) patients in the 30-mg group and 35 of 47 (74.5%) patients in the 20-mg group. The most commonly reported adverse event was headache; 2 patients discontinued the study because of adverse events. Overall, 9 of 24 patients (37.5%) in the 30-mg group and 14 of 47 patients (29.8%) in the 20-mg group experienced > or = 1 treatment-related adverse event. CONCLUSIONS: Patients whose mild to moderate essential hypertension is controlled with nifedipine GITS 30 mg once daily may be able to switch to 20 mg once daily with continued antihypertensive efficacy. In addition to safety and economic advantages, such a switch may be a reasonable alternative in patients with lower body weight or as an adjunct to existing antihypertensive therapy.     

Effect of losartan plus hydrochlorothiazide on nitric oxide status in 'nondipper' hypertensive patients

The objective of this study was to investigate the effects of losartan (100 mg) plus hydrochlorothiazide (HCTZ; 25 mg) on nitric oxide (NO) production and blood pressure (BP) in "nondipper" severe hypertensive patients. Twelve hypertensive "nondipper patients" (6 of each gender) with sitting systolic/diastolic BP of 188.0 +/- 5.2/116.2 +/- 1.2 mm Hg were studied by 24-hour ambulatory blood pressure monitoring (ABPM) after daily administration of 100 mg losartan plus 25 mg HCTZ for a period of 12 weeks. Office and mean 24-hour, as well as mean awake- and sleep-time systolic/diastolic BP, serum NO levels, and urinary excretion of NO were measured after the placebo period (3 weeks) and after 12 weeks of therapy. At the end of the 12-week treatment period, the mean 24-hour systolic/diastolic BP decreased significantly from 158.6 +/- 4.7/102.2 +/- 2.6 mm Hg (placebo period) to 140.3 +/- 4.8/90.9 +/- 3.3 mm Hg (P = 0.001/< or = 0.002). The mean BP (systolic/diastolic) during the waking period was reduced from 159.3 +/- 4.4/103.0 +/- 2.5 mm Hg to 135.0 +/- 4.4/88.2 +/- 3.1 (P < or = 0.007/P < or = 0.002), whereas the mean BP (systolic/diastolic) during the sleeping hours changed from 154.9 +/- 5.3/98.9 +/- 3.1 to 140.9 +/- 4.6 (P = 0.035)/91.7 +/- 3.2 mm Hg (P = 0.035/P = 0.051). Serum NO levels increased from 40.89 +/- 5.69 microM/L (placebo period) to 67.35 +/- 6.96 microM/L (posttreatment; P < or = 0.007), whereas the 24-hour urinary NO excretion did not change significantly (69.71 +/- 3.68 microM/L [placebo period] vs 79.64 +/- 4.25 microM/L [posttreatment]; P < or = 0.16). Urinary clearance of NO also did not change. Serum NO levels increased significantly without a significant change in urinary NO excretion. BP was significantly reduced but without modifying the nondipper pattern in these patients.     

Comparison of the effects of telmisartan and nifedipine gastrointestinal therapeutic system on blood pressure control, glucose metabolism, and the lipid profile in patients with type 2 diabetes mellitus and mild hypertension: a 12-month, randomized, double-blind study

BACKGROUND: Angiotensin receptor blockers (ARBs) provide effective blood pressure control. Whereas none of the ARBs appear to affect glucose homeostasis, some ARBs have been associated with a decrease in cholesterolemia. OBJECTIVE: This study was conducted to evaluate blood pressure control glucose homeostasis, and the plasma lipid profile in patients with type 2 diabetes mellitus and mild hypertension during 12 months of treatment with the ARB telmisartan or nifedipine gastrointestinal therapeutic system (GITS). METHODS: In this double-blind trial, patients taking oral hypoglycemic agents were randomized to receive telmisartan 40 mg or nifedipine GITS 20 mg once daily for 12 months. At the time of enrollment, patients were given advice on diet (1400-1600 kcal/d) and exercise (stationary bicycle for > or =30 min, 4 d/wk). Assessments of systolic blood pressure (SBP), diastolic blood pressure, body mass index (BMI), fasting plasma glucose concentrations, glycosylated hemoglobin, fasting plasma insulin concentrations, the homeostasis model assessment of insulin resistance, and the lipid profile were performed at baseline and after 6 and 12 months of treatment. RESULTS: One hundred sixteen patients were divided into 2 age- and sex-matched treatment groups (58 men, 58 women; mean [SD] age, 52.5 [5] years). All patients were in good general health at baseline; had achieved adequate glycemic control with diet and oral hypoglycemic agents; were taking antihypercholesterolemic drugs; and had no evidence of macroangiopathy, microalbuminuria, or neuropathy. There were significant reductions from baseline in seated trough SBP after 12 months of treatment with both telmisartan and nifedipine GITS (from 139 [4] to 132 [4] mm Hg and from 140 [4] to 130 [4] mm Hg, respectively; both, P < 0.01). No change in BMI or glucose metabolism was observed with either treatment. After 12 months, there were significant improvements in concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) with telmisartan (-9% and -11.5%, respectively; both, P < 0.01) compared with nifedipine GITS (-2% and -1.5%). CONCLUSIONS: In this selected sample of patients with type 2 diabetes and mild hypertension, both telmisartan and nifedipine GITS produced significant reductions in blood pressure. Telmisartan was associated with a slight but statistically significant improvement in plasma TC and LDL-C concentrations compared with nifedipine GITS.     

Nifedipine tablet vs. hydralazine in patients with persisting hypertension who receive combined diuretic and beta-blocker therapy

The antihypertensive effects of a 20 mg tablet of nifedipine were compared with those of hydralazine in a randomized, double-blind, placebo-controlled study. Nineteen patients with a diastolic blood pressure (BP) between 95 and 120 mm Hg despite combined diuretic and beta-blocker therapy completed the protocol. After 2 weeks of placebo each subject received increasing doses of nifedipine (20, 40, and 60 mg b.i.d.) and hydralazine (25, 50, and 100 mg b.i.d.) if tolerated or until goal BP (supine and standing diastolic BP less than 85 mm Hg) was achieved. Both nifedipine and hydralazine significantly lowered supine BP from placebo baseline (146 +/- 3/96 +/- 2 mm Hg) to 119 +/- 3/80 +/- 2 and 129 +/- 2/81 +/- 2 mm Hg, respectively. The decrease in systolic BP with nifedipine was significantly lower than that with hydralazine at 9 weeks. Neither drug significantly altered heart rate. Mean left ventricular ejection fractions were similar for nifedipine (67% +/- 2%), hydralazine (69% +/- 3%), and placebo (66% +/- 2%). The nifedipine tablet appears to be an effective antihypertensive agent in patients whose BP remains high despite combined diuretic and beta-blocker therapy.     

Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension

BACKGROUND: African Americans with hypertension, particularly those with more severe blood pressure elevations, are generally less responsive to monotherapy from any antihypertensive class. These patients usually require treatment with drugs from > or = 2 antihypertensive classes to achieve adequate blood pressure control. OBJECTIVE: The purpose of this study was to assess the antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide (HCTZ) in African American adults with mild to moderate hypertension. METHODS: In this 12-week, multicenter, double-blind, randomized, parallel-group, placebo-controlled study, African American patients were randomized in a 3:3:1 ratio to I of 3 treatment groups: placebo, losartan monotherapy (50 to 150 mg), or losartan plus HCTZ (50/0 to 50/12.5 to 100/25 mg). Doses were titrated at weeks 4 and 8 if sitting diastolic blood pressure (SiDBP) was > or = 90 mm Hg. Safety was assessed by determining the incidence of clinical and laboratory Adverse events and evaluating mean changes in pulse, body weight, electrocardiographic parameters, and laboratory test results. RESULTS: A total of 440 patients were randomized-188 to placebo, 193 to losartan monotherapy, and 59 to losartan/HCTZ; 391 completed the study. At week 12, the response rate with losartan monotherapy was 45.8%, with a significant (P < or = 0.01) lowering in mean SiDBP by 6.6 mm Hg compared with placebo; the response rate with placebo was 27.2%, with a mean SiDBP reduction of 3.9 mm Hg. Sitting systolic blood pressure (SiSBP) was significantly lowered with losartan monotherapy, by 6.4 mm Hg, compared with placebo (reduction of 2.3 mm Hg). The response rate with losartan/ HCTZ was 62.7%, with reductions in SiSBP and SiDBP of 16.8 mm Hg and 10.8 mm Hg, respectively (P < or = 0.01 vs placebo and losartan monotherapy). The incidence of clinical adverse events was comparable in the 3 treatment groups. CONCLUSIONS: The results of this study suggest that in African American patients, losartan monotherapy was significantly more effective than placebo in lowering SiSBP and SiDBP. Moreover, the losartan/ HCTZ combination regimen resulted in significant and clinically meaningful additional reductions in SiSBP and SiDBP compared with losartan monotherapy or placebo. Losartan monotherapy and the losartan/HCTZ regimens were generally as well tolerated as placebo.     

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.

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, randomized, 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 randomization) 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 (randomized with > or = 1 postrandomization 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.     

Efficacy of quadropril (spirapril) vs capropril in treatment of essential hypertension

AIM: To compare the efficacy of monotherapy with quadropril (spirapril) vs captopril in essential hypertension. MATERIAL AND METHODS: 20 female patients aged 55 +/- 2 years with moderate hypertension (WHO classification) were included in the study. 16 patients had congestive heart failure stage II NYHA and 4 patients stage III NYHA. ECG and echocardiography were performed in all the patients. Two patient groups of 10 patients were treated for 6 weeks. Group 1 received 6 mg quadropril once daily. Group 2 received 25 mg captopril 3 times daily. The therapy was considered to be efficient if diastolic pressure (BP) was reduced to 90 +/- 5 mm Hg and systolic BP to 140 +/- 10 mm Hg from baseline values in the range of 210/120-170/100 mm Hg. RESULTS: The hypotensive effect of quadropril resulted in stabilisation of BP during the second week of therapy. A significant BP decrease was achieved at the end of 6 week therapy. Systolic BP fell from 178.8 +/- 3.2 to 145 +/- 5.6 mm Hd and diastolic BP from 109.7 +/- 1.2 to 92.4 +/- 1.7 mm Hg. Central and cardiac hemodynamic parameters improved. In one patient the condition improved from CHF stage III to stage II NYHA. No adverse effects were observed. A hypotensive effect of captopril reduced significantly systolic blood pressure from 182.1 +/- 2.7 to 150 +/- 4.6 mm Hg and diastolic BP from 110.4 +/- 1.1 to 100.1 +/- 1.9 mm Hg. Two patients developed adverse effects: cough and chest dyscomfort. CONCLUSION: Quadropril monotherapy showed to be more effective in diastolic BP decrease compared with captopril monotherapy and had advantages in one daily dose regimen, absence of the first dose effect and side effects.     

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

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, randomized, 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 randomized 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 randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry. RESULTS: A total of 1346 patients were randomized 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 effects of irbesartan added to hydrochlorothiazide for the treatment of hypertension in patients non-responsive to hydrochlorothiazide alone

AIM: To evaluate the antihypertensive efficacy and safety of adding irbesartan to hydrochloride (HCTZ) in patients not adequately controlled by HCTZ alone. PATIENTS AND METHODS: In this multicenter study, after a single-blind, placebo lead-in period, hypertensive patients received single-blind HCTZ 25 mg once daily. After 4 weeks, 238 patients with seated diastolic blood pressure of 93-110 mmHg continued on HCTZ 25 mg once daily and were randomized to double-blind irbesartan 75 mg once daily or matching placebo for 12 weeks. At week 6, the dosage of irbesartan or placebo was doubled for seated diastolic blood pressure > or = 90 mmHg. RESULTS: At weeks 2, 6, and 12, irbesartan/HCTZ resulted in significantly greater (P<0.01) reductions from baseline in trough seated diastolic and systolic blood pressure compared with placebo/HCTZ. At week 12, the mean reductions in trough seated diastolic and systolic blood pressure were 7.2 mmHg (95%, C.I., 5.1-9.3 mmHg) and 11.1 mmHg (95% C.I., 7.9-14.3 mmHg) greater, respectively, with irbesartan/HCTZ compared with placebo/HCTZ. At week 12, significantly (P < 0.01) more patients were normalized (trough seated diastolic blood pressure < 90 mmHg) with irbesartan/HCTZ (67%) compared with placebo/HCTZ (29%). The frequency of adverse events, serious adverse events, and discontinuations attributed to adverse events was similar in both groups, and there were no clinically relevant changes in serum creatinine, potassium, or any other laboratory parameter. CONCLUSION: Irbesartan was effective and well tolerated when added to a background of HCTZ 25 mg in patients whose blood pressure was not adequately controlled by HCTZ alone.     

Comparison of the effectiveness of a beta blocker (atenolol) and a diuretic (chlorthalidone) in black hypertensive patients

A double-blind crossover trial of atenolol and chlorthalidone was done in black Jamaican hypertensive patients. After an initial four weeks of single drug therapy, the beta blocker and thiazide diuretic were used in combination. Chlorthalidone at a daily dose of 25 mg produced a significant (P less than .05) fall in the mean systolic and diastolic pressures (19.4 mm Hg and 12.2 mm Hg, respectively); atenolol produced a significant fall in the diastolic blood pressure (6.5 mm Hg); and combination therapy produced a reduction in systolic and diastolic blood pressures (27.8 mm Hg and 17.8 mm Hg, respectively). The study showed that combination therapy using a low dose of thiazide diuretic and a beta blocker was synergetic, but that a thiazide was more effective than a beta blocker in lowering the blood pressure in black hypertensive patients.     

Efficacy of low-dose captopril given twice daily to patients with essential hypertension uncontrolled by a beta blocker plus thiazide diuretic

Thirty-two patients with moderate to severe essential hypertension whose supine diastolic blood pressure (SDBP) was greater than or equal to 95 mm Hg following 2 weeks' treatment with the optimal dosage of beta blocker-diuretic combination were randomly assigned to the addition of either captopril 25 mg or 50 mg b.i.d. After 6 weeks' treatment, if patients were not normalized (SDBP less than 95 mm Hg), the dose of captopril was doubled for a further 6 weeks. The addition of captopril led to a significant fall in standing and supine diastolic and systolic blood pressure at the end of the sixth and twelfth week of treatment. There was no difference in the change in blood pressure between the two groups. At the end of the study SDBP was normalized in 66% of patients and a further 12.5% had their SDBP reduced by greater than 10%. Captopril 25 or 50 mg administered twice daily proved to be a very effective antihypertensive agent when added to a beta blocker-diuretic combination in patients resistant to optimal doses of these drugs.     

Combination Treatment with Sustained-Release Verapamil and Indapamide in the Treatment of Mild-to-Moderate Hypertension

A multicenter study of the treatment of mild and moderate hypertension compared three once-daily regimens for efficacy and safety: Group I, verapamil sustained release (SR) 240 mg; Group II, verapamil SR 480 mg; and Group III, combination therapy of verapamil SR 240 mg plus indapamide 2.5 mg. After a 3-week placebo washout period and a 2-week preliminary treatment period with verapamil SR 240 mg daily, those patients with diastolic blood pressures of <95 mm Hg were excluded from further study; 137 remaining patients with sitting diastolic blood pressure of 95--115 mm Hg, representing "incomplete" responders to verapamil SR 240 mg, were randomized in a double-blind fashion to one of the three treatment groups for a duration of 16 weeks. Efficacy was assessed after 16 weeks of double-blind therapy or at end point. All three treatments significantly reduced sitting diastolic and systolic blood pressure from baseline levels. Compared with Group I (verapamil SR 240 mg daily), there was a significant reduction (p < 0.05) in Group II combination therapy of 8.6 mm Hg systolic and 3.0 mm Hg diastolic and a significant reduction (p < 0.05) in Group II (verapamil SR 480 mg daily) of 7.6 mm Hg systolic and 3.9 mm Hg diastolic BP. Patients who had the least change in blood pressure (diastolic blood pressure decreases of <5 mm Hg) to lead-in verapamil SR 240 mg daily, prior to randomization, tended to have a greater response to combination therapy than to verapamil SR 480 mg. Adverse experiences leading to withdrawal from the study occurred in 21% of patients receiving verapamil SR 480 mg daily (Group II). There was a significantly greater withdrawal from Group II than the other two treatment groups (8.5% from Group III and 4% from Group I). This trial demonstrated that adding indapamide 2.5 mg to the incomplete responders of verapamil SR 240 mg enhances efficacy and was well tolerated.     

Hydrochlorothiazide added to valsartan is more effective than when added to olmesartan in reducing blood pressure in moderately hypertensive patients inadequately controlled by monotherapy

This study was undertaken to evaluate the effects on blood pressure of hydrochlorothiazide (HCTZ) 12.5 mg added to valsartan 160 mg or to olmesartan 20 mg in hypertensive patients. After a 2-wk placebo period, 130 patients, aged 35 to 75 y, with diastolic blood pressure (DBP) ≥99 and <110 mm Hg were randomly assigned to olmesartan 20 mg once daily or to valsartan 160 mg once daily according to a prospective, parallel-arm study design. After 4 wk of monotherapy, patients whose BP was not controlled (DBP ≥90 mm Hg) were given combination treatment with HCTZ 12.5 mg for an additional 4 wk. At the end of the placebo period and at the end of each treatment period, clinical and ambulatory BP measurements were recorded. At the end of the combination therapy period, venous blood samples were drawn 2, 4, and 24 h after drug intake for evaluation of HCTZ plasma concentrations. Both combinations induced a greater ambulatory BP reduction than monotherapy. However, mean reduction from baseline in the valsartan/HCTZ-treated patients (-21.5/-14.6 mm Hg for 24 h, -21.8/-14.9 mm Hg for daytime, and -20.4/-13.7 mm Hg for nighttime systolic blood pressure [SBP]/DBP) was greater than in the olmesartan/HCTZ-treated patients (-18.8/-12.3 mm Hg for 24 h, -19.3/-12.8 mm Hg for daytime, and -17.4/-10.6 mm Hg for nighttime SBP/DBP). The difference between the effects of the 2 treatments was significant (P<.01). In particular, compared with monotherapy, the add-on effect of HCTZ 12.5 mg was significantly greater in the valsartan group than in those treated with olmesartan; the difference was more evident for nighttime BP values. Plasma concentrations of HCTZ were significantly greater with valsartan than with olmesartan at each determination time (P<.05). These findings suggest that the addition of HCTZ 12.5 mg to valsartan 160 mg monotherapy produces a greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 mg monotherapy.     

Effects of combination therapy with captopril and nifedipine in severe or resistant hypertension

To assess the effect of potent vasodilator therapy in patients with severe or resistant hypertension, 10 patients underwent therapy with captopril and nifedipine alone and in combination. Blood pressure (BP), heart rate, and blood chemistry values were monitored for 4 weeks during captopril monotherapy and after 8 weeks during combination therapy with captopril and nifedipine. Compared with baseline, the BP decreased during captopril monotherapy (180 +/- 11/98 +/- 7 vs. 209 +/- 16/118 +/- 12 mm Hg; P less than 0.005). After the addition of nifedipine, the BP was further reduced (148 +/- 23/85 +/- 16 mm Hg), but there was no change in heart rate. In three patients not achieving the diastolic BP goal during combination therapy with dosing every 8 hours, automatic 24-hour ambulatory BP monitoring demonstrated lack of antihypertensive control for only the last 2 to 3 hours of the dosing interval. These data demonstrate that combination therapy with captopril and nifedipine is effective in patients with severe hypertension, but frequent dosing intervals are necessary for adequate antihypertensive control.