Efficacy and safety of valsartan 160/HCTZ 25 mg in fixed combination in hypertensive patients not controlled by candesartan 32 mg plus HCTZ 25 mg in free combination

ABSTRACT

Objective: Free combination hypertension medication is associated with a lower compliance and less persistence compared to fixed combination therapy and can, there­fore, be associated with insufficient blood pressure reductions. This non-randomized study investigated whether valsartan 160?mg/ hydrochlorothiazide 25?mg (Val 160/HCTZ 25) in fixed dose combination could provide additional blood pressure control in hypertensive patients not adequately controlled by the free combination of candesartan 32?mg plus HCTZ 25?mg.

Research design and methods: One hundred and ninety-seven patients with a mean sitting diastolic blood pressure (MSDBP) between 100 and 110?mmHg entered a 4-week treatment phase with 32?mg of candesartan in free combination with 25?mg of HCTZ once daily. One hundred and thirty-eight patients with uncontrolled BP at Week 4, entered a second 4-week treatment phase with Val160/ HCTZ 25 once daily.

Main outcome measures: The primary efficacy parameter was the reduction in MSDBP at trough between Week 4 and Week 8 in the intent-to-treat population.

Results: At baseline, MSDBP was 103.0 ± 2.8?mmHg. After Week 4, MSDBP had decreased to 93.8 ± 4.5?mmHg. Subsequent treatment with Val 160/HCTZ 25 for 4 weeks reduced MSDBP to 88.7 ± 8.6?mmHg. This represented an additional decrease in MSDBP of 5.1 ± 7.9?mmHg (?p < 0.0001). Val 160/ HCTZ 25 reduced mean sitting systolic BP by 3.4 ± 13.0?mmHg (?p = 0.0029).

Conclusions: The fixed dose combination of valsartan 160/HCTZ 25?mg provided a statistically and clinically significant additional BP reduction in patients not controlled by the free combination of candesartan 32?mg and HCTZ 25?mg.     

Combination antihypertensive therapy with valsartan and hydrochlorothiazide in Chinese patients with mild-to-moderate hypertension

ABSTRACT

Objectives: To compare the efficacy and safety of valsartan (VAL)/ HCTZ 80/12.5?mg with VAL 80?mg in Chinese patients with mild-to-moderate essential hypertension not adequately controlled with VAL 80?mg alone.

Research design and methods: This was a multicenter, double-blind, double-dummy, randomized, active-controlled, parallel-group trial. Patients (1175) with mild-to-moderate essential hypertension (mean sitting diastolic blood pressure [MSDBP] ≥?95 and <?110?mmHg) from 26 centers in China received VAL 80?mg o.d. for 4?weeks, 864 patients whose MSDBP remained ≥?90 and <?110?mmHg were randomized (1:1) to receive VAL80/HCTZ12.5?mg (n?= 429) or VAL80?mg (n?= 435) for 8?weeks.

Main outcome measures: The efficacy variable was changed from baseline to endpoint in trough MSDBP. The secondary efficacy variables were changed in mean sitting systolic blood pressure (MSSBP), response rate, and control rate.

Results: Significant reductions in MSDBP and MSSBP from baseline to endpoint were observed in both groups. There were significantly greater reductions in MSDBP (8.4?mmHg vs. 6.2?mmHg) and MSSBP (10.2?mmHg vs. 6.7?mmHg), higher response (64.2% vs. 52.5%) and control rates (53.9% vs. 40.9%) in the VAL80/HCTZ12.5 group as compared with the VAL80 group at endpoint (?p?<?0.001). VAL80/HCTZ12.5 was equally effective in both age subgroups (≥?65 and <?65?years) and was well tolerated. There were no deaths and the two serious adverse events reported were unrelated to study medication.

Conclusion: In Chinese patients with mild-to-moderate essential hypertension not adequately controlled by VAL 80?mg alone, VAL80/HCTZ12.5?mg combination was well tolerated and showed additional BP reduction. The limitations of this study were the inability to include an HCTZ arm as a control group and the short trial duration.

Trial registration: NCT00250562.     

Long-term safety,tolerability and efficacy of aliskiren in combination with valsartan in patients with hypertension: a 6-month interim analysis

ABSTRACT

Background: Renin–angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hyper­tension.

Methods: A total of 601 patients with hyper­tension (msDBP ≥?90 and <?110?mmHg) received a combination of aliskiren/valsartan 150/160?mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320?mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (≥?140/90?mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a pre-defined safety outcome. BP was measured at regular intervals during the study.

Results: At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations >?5.5?mmol/L. Only one patient (0.2%) exhibited potassium levels ≥?6.0?mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4?mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (<?140/90?mmHg; LOCF).

Conclusions: Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combin­ation provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hyper­tension.     

Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared to hydrochlorothiazide

Objective: To compare the antihypertensive efficacy of a new angiotensin II antagonist, valsartan, with a reference therapy, hydrochlorothiazide (HCTZ). Methods: In this double-blind study, 167 adult outpatients with mild-to-moderate essential hypertension were randomly allocated in equal number to receive valsartan 80 mg or HCTZ 25 mg for 12 weeks. In patients whose blood pressure (BP) remained uncontrolled after 8 weeks of monotherapy, atenolol 50 mg was added to the initial treatment. Patients were assessed at 4, 8 and 12 weeks. The primary efficacy variable was change from baseline in mean sitting diastolic BP (SDBP) at 8 weeks. Secondary variables included change in sitting systolic BP (SSBP) and responder rates (percentage of patients with SDBP <90 mmHg or drop ≥10 mmHg compared to baseline) at 8 weeks. Results: Valsartan and HCTZ were both effective at lowering diastolic and systolic blood pressure at all time points. Similar falls were seen in both groups with no significant differences between treatments. For the primary variable (decrease in SDBP) there was no significant difference between treatments. For SSBP there was also no significant difference observed. Responder rates at 8 weeks were 74% for valsartan and 62% for HCTZ (P = 0.10). Both treatments were well tolerated, both as monotherapy, and when combined with atenolol 50 mg per day. Conclusion: The data show valsartan 80 mg to be as effective as HCTZ in the treatment of mild-to-moderate hypertension. The results also show valsartan to be well tolerated when taken alone or in combination with atenolol. Received: 7 March 1996 / Accepted in revised form: 29 July 1996     

A double-blind,randomized study evaluating losartan potassium monotherapy or in combination with hydrochlorothiazide versus placebo in obese patients with hypertension

ABSTRACT

Objectives: The objective of this study was to evaluate the effects of losartan ± hydrochlorothiazide (HCTZ) versus placebo in obese patients with systolic and diastolic hypertension.

Research design and methods: Randomized patients (n = 261) were non-diabetic with systolic blood pressure (SBP) ≥ 140 and ≤ 180?mmHg and diastolic BP (DBP) ≥ 95 and ≤ 115?mmHg, body mass index > 30?kg/m², and waist circumference > 40 (males)/> 35 (females)?inches. Patients were randomized to placebo or a forced titration of losartan 50?mg titrated at 4-week intervals to losartan 100?mg, losartan 100?mg/HCTZ 12.5?mg, and losartan 100?mg/HCTZ 25?mg. Primary efficacy measurements were change from baseline in SBP and DBP at 12 weeks. Secondary measurements were change from baseline in BPs at 8 and 16 weeks, percent responders at 12 and 16 weeks, and safety/tolerability. Post-hoc analyses were BP at 4 weeks and achieve­ment of controlled BP (SBP < 140 and/or DBP < 90?mmHg) at 12 and 16 weeks.

Results: Losartan 50?mg reduced BP from 151.6/99.2?mmHg at baseline to 140.1/89.8?mmHg at week 4 (post hoc), 139.5/89.6?mmHg with losartan 100?mg at week 8 (secondary), 134.3/85.9?mmHg with losartan 100?mg/HCTZ 12.5?mg at week 12 (primary), and 132.1/84.9?mmHg with losartan 100?mg/HCTZ50?mg at week 16 (secondary) (all p < 0.05). Rates of clinical adverse experi­ences were similar between treatment groups. A limitation of these analyses is the relatively rapid rate of study drug titration, which may not have allowed for the evaluation of the full treatment effect at each titration step.

Conclusions: We conclude that losartan alone or in combination with HCTZ was generally well tolerated and effective in the treatment of elevated systolic and diastolic BP in obese patients with hypertension.     

Antihypertensive efficacy and tolerability of aliskiren/hydrochlorothiazide (HCT) single-pill combinations in patients who are non-responsive to HCT 25 mg alone*

ABSTRACT

Objective: Thiazide diuretics such as hydrochlorothiazide (HCT) are a widely used first-line treatment for hypertension, but most patients will not achieve blood pressure (BP) control with HCT alone and so will require combination therapy. In this study the efficacy, safety and tolerability of a single-pill combination (SPC) of the direct renin inhibitor aliskiren with HCT were investigated in patients non-responsive to HCT 25?mg therapy.

Methods: In this study, 722 patients with hypertension and an inadequate response to 4?weeks of HCT 25?mg (mean sitting diastolic BP ≥90 and <110?mmHg) were randomized to once-daily, double-blind treatment for 8?weeks with an SPC of aliskiren/HCT 300/25?mg or 150/25?mg, or continued HCT 25?mg monotherapy. Least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from double-blind baseline were analyzed for the ITT population at week?8 endpoint.

Results: Aliskiren/HCT 300/25?mg and 150/25?mg SPCs lowered msSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5?mmHg, respectively, both significantly greater reductions than HCT 25?mg alone (7.1/4.8?mmHg; both p?<?0.001). Rates of BP control (<140/90?mmHg) were also significantly higher with aliskiren/HCT 300/25?mg (58%) and 150/25?mg (49%) than with HCT (26%; both p?<?0.001). Aliskiren/HCT 300/25?mg provided significantly greater msSBP/DBP reductions and rates of BP control than the 150/25?mg SPC dose (all p?<?0.05). Aliskiren/HCT SPC treatment showed similar tolerability to HCT alone and a numerically lower incidence of hypokalemia (serum potassium <3.5?mmol/L; aliskiren/HCT, 1.3–2.2%: HCT alone, 3.4%).

Conclusion: Aliskiren/HCT SPCs provide clinically significant BP reductions and improved BP control rates in patients who are non-responsive to HCT 25?mg monotherapy. Limitations of the study were the mainly Caucasian patient population and the non-responder design.     

Achieving BP goals with valsartan and HCTZ alone and in combination: pooled analysis of two randomized,double-blind,placebo-controlled studies

ABSTRACT

Background: Most patients with hypertension will require combination therapy to achieve blood pressure (BP) goals, especially the elderly, obese, or those with stage?2 hypertension.

Objective: To assess BP response and time to achieve BP goals in a diverse population of hypertensive patients treated with hydrochlorothiazide, valsartan, or a combination.

Methods: For this secondary post-hoc analysis, data were pooled from two similar randomized, double-blind, 8-week trials that evaluated hydrochlorothiazide (12.5–25?mg) and valsartan (160?mg) monotherapies, their combination (160/12.5?mg), and placebo. Subgroups were defined by age, hypertension severity, and obesity. Adults with diastolic BP ≥?95 and ≤?115?mmHg were included. Goal rates were estimated from a logistic model with treatment, study, age group, race, and baseline body mass index as factors and baseline diastolic BP as a covariate. Kaplan–Meier estimates were used to calculate the time to achieve BP goals.

Main outcome measures: Efficacy variables were reductions from baseline to study end in systolic BP and diastolic BP, rates of achieving BP goals (<?140/90?mmHg), and time to achieve BP goals. Adverse events were also reported for the pooled trials.

Results: BP reductions at study end and goal achievement rates were greater with combination therapy (–20/15?mmHg and 72%, respectively) than with either monotherapy (valsartan 160?mg: –14/11?mmHg, 61%; hydrochlorothiazide 25?mg: –14/10?mmHg, 50%) for the overall population (N?=?1313) and in patient subgroups. Patients treated with initial combination therapy reached goal in 27–56% of the time needed for those treated with monotherapy. Combination therapy was well tolerated and was associated with a decreased incidence of hypokalemia compared with hydrochlorothiazide monotherapy.

Conclusions: Compared with monotherapy, combination therapy resulted in greater reductions in BP and achievement of goal BP in a shorter period of time. Although interpretation of this study is subject to the limitations associated with any post-hoc analysis, the results suggest that initiating treatment with combination therapy may be considered for expedient and effective BP control.     

Effect on blood pressure control of switching from valsartan monotherapy to losartan/hydrochlorothiazide in Asian patients with hypertension: results of a multicentre open-label trial

ABSTRACT

Study design: An open-label, multicentre study was conducted to evaluate the antihypertensive efficacy of a 4-week course of losartan 50?mg plus hydrochlorothiazide 12.5?mg in Asian patients with essential hypertension whose blood pressure had previously been treated with but not controlled by valsartan 80?mg.

Methods: A total of 237 eligible patients with mean trough sitting diastolic blood pressure (SiDBP) 95–115?mmHg and a mean trough sitting systolic blood pressure (SiSBP) < 190?mmHg entered the baseline period of treatment with valsartan 80?mg/day for 4 weeks. Those (n = 165) whose SiDBP remained > 90?mmHg and who were not excluded for other reasons were then switched to a single-tablet formulation of losartan 50?mg/hydrochlorothiazide 12.5?mg combination once daily for a further 4 weeks.

Results: Mean SiDBP (study primary endpoint) at the end of combination therapy was reduced to 86.9 mmHg from 95.2 mmHg. SiSBP (study secondary endpoint) was reduced to 132.6 mmHg from 140.7 mmHg. Mean reductions after switching from valsartan 80?mg to losartan 50?mg/hydrochlorothiazide 12.5?mg were thus 8.3 and 8.1 mmHg for SiDBP and SiSBP, respectively (?p ≤ 0.001 for both outcomes). The goal of SiDBP ≤ 90 mmHg was attained in 72% of the patients previously not controlled to the same level by valsartan 80?mg/day. Combination therapy with losartan 50?mg/hydrochlorothiazide 12.5?mg was generally well tolerated. Mean compliance with the losartan 50?mg/hydrochlorothiazide 12.5?mg combination was > 99%.

Conclusion: These results demonstrate that in Asian patients who do not reach the goal of mean trough SiDBP ≤ 90?mmHg with valsartan monotherapy at 80?mg once-daily, switching to a single-tablet combination of losartan 50?mg/hydrochlorothiazide 12.5?mg once-daily is well tolerated, provides effective control of blood pressure and is an excellent choice to achieve blood pressure reduction goals.     

Blood pressure reduction with olmesartan in mild-to-moderate essential hypertension:a planned interim analysis of an open label sub-study in German patients

ABSTRACT

Objective: To present the baseline characteristics and open-label treatment phase results for German patients in OLMEBEST, a European, multinational, partially randomized, partially double-blind study in patients with mild-to-moderate essential hypertension.

Research design and methods: After a 2‐week placebo run-in, patients received olmesartan 20?mg for 8 weeks. Controlled patients (mean sitting diastolic blood pressure [sDBP] < 90?mmHg) continued on olmesartan 20?mg/day for a further 4 weeks. Non-controlled patients (sDBP > 90?mmHg) were randomized to olmesartan 40?mg/day or olmesartan 20?mg/day plus 12.5?mg hydrochlorothiazide for 4 weeks. Of 823 patients included, 558 continued olmesartan 20?mg treatment and 228 patients were randomized to olmesartan 40?mg/day or combination therapy. Efficacy variables included the change from baseline in mean sitting DBP and systolic blood pressure [sSBP] at Week 8 (and Week 12 for controlled patients), and the proportion of controlled patients and responders (mean sDBP < 90?mmHg or improvement of > 10?mmHg from baseline at Week 8).

Results: After 8 weeks of olmesartan medoxomil 20?mg, mean reduction from baseline in sDBP was 11.8?mmHg and in sSBP was 17.1?mmHg. In controlled patients continuing open-label olmesartan medoxomil 20?mg, mean reduction from baseline at 12 weeks in sDBP was 14.9?mmHg and in sSBP was 20.1?mmHg. At Week 8, the response rate was 76% and the control rate was 70%. Olmesartan medoxomil 20?mg/day was well tolerated; 30.9% of patients experienced an adverse event, and the majority of these events were judged by the investigators to be mild.

Conclusion: Olmesartan medoxomil monotherapy at the recommended dosage of 20?mg once daily is effective and well tolerated in patients with mild-to-moderate hypertension.     

Bisoprolol/amlodipine combination therapy improves blood pressure control in patients with essential hypertension following monotherapy failure

Objective: The efficacy of a bisoprolol/amlodipine fixed-dose combination (FDC) in patients with essential hypertension who had not responded to bisoprolol or amlodipine monotherapy was investigated.

Research design and methods: In an 18 week, multicenter, randomized, comparative phase III study (ClinicalTrials.gov identifier: NCT01977794), patients with blood pressure uncontrolled by bisoprolol or amlodipine monotherapy (5?mg OD) began treatment with bisoprolol/amlodipine FDC 5/5?mg OD. Patients with controlled blood pressure (BP) at week 6/12 continued at current FDC strength, and patients with uncontrolled BP received FDC dose uptitration (maximum dose: 10/10?mg). The primary efficacy endpoint was change in systolic blood pressure (SBP) at week 18 versus baseline (corresponding to SBP under monotherapy), and secondary endpoints included change from baseline in SBP after week 6/12 and percentage of BP-controlled patients at week 6, 12 and 18. Safety was assessed by number/types of adverse events (AEs).

Results: Two hundred patients were randomized to treatment (100 with uncontrolled BP under bisoprolol and 100 under amlodipine monotherapy). Overall, 196 patients were eligible for analysis. The patient groups displayed similar mean SBP reductions from baseline by study end (bisoprolol monotherapy failure: 25.9?±?12.82?mmHg reduction; amlodipine monotherapy failure: 24.7?±?11.67?mmHg reduction; p?<?0.001 for both). Overall mean SBP decreased by 25.3?±?12.25?mmHg (p?<?0.001). Mean heart rate reductions were also observed (bisoprolol monotherapy failure: 6.6?±?9.67 bpm reduction; amlodipine monotherapy failure: 11.5?±?8.65 bpm reduction; p?<?0.001 for both). Most patients (83.2%) displayed BP control with bisoprolol/amlodipine 5/5?mg at 6 weeks. Treatment was well tolerated at all dose levels; treatment-related AEs (mostly of mild/moderate intensity) were reported by 52.5% of patients, with no severe or serious treatment-related AEs reported. As the study focused on hypertension, total cardiovascular risk was not assessed.

Conclusions: Bisoprolol/amlodipine FDC therapy is associated with significant BP improvements in patients with essential hypertension following monotherapy failure.     

Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination

ABSTRACT

Background and objective: For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160–179?mmHg and/or diastolic blood pressure [DBP] 100–109?mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10?mg plus valsartan 160?mg (A?10?+?Val 160) in patients not controlled by the free combination of amlodipine 10?mg plus olmesartan 20?mg (A?10?+?O 20).

Methods: In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100–109?mmHg at trough entered a 4 week treatment phase with A?10?+?O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A?10?+?Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population.

Results: In the total cohort, baseline SBP/DBP of 164.2?±?9.8/103.6?±?2.1?mmHg decreased by 19.2?±?12.4/14.1?±?7.4?mmHg at week 4. In patients who did not achieve BP control (n?=?175), subsequent treatment with A?10?+?Val 160 for 4 weeks reduced SBP from 149.6?±?11.1 at week 4 by 7.9?mmHg at week 8 (95% CI: 6.1–9.6, p?<?0.0001) and DBP from 93.4?±?3.9?mmHg by 9.1?mmHg (95% confidence interval: 8.1–10.2, p?<?0.0001). The combination of A?10?+?Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles.

Conclusions: In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A?10?+?O 20, the single pill combination of A?10?+?Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.     

Effects of valsartan versus olmesartan addition to amlodipine/hydrochlorothiazide combination in treating stage 2 hypertensive patients

Objective: The objective of this study was to assess the effects of valsartan or olmesartan addition to dual therapy with amlodipine + hydrochlorothiazide (HCTZ) in the treatment of stage 2 hypertension.

Research design and methods: 180 patients with diastolic blood pressure (DBP) ≥ 99 and < 110 mm Hg were treated with amlodipine 5 mg + HCTZ 12.5 mg combination. After 4 weeks, 149 patients whose blood pressure (BP) was not controlled, were randomized to the combination of valsartan 160 mg + amlodipine 5 mg + HCTZ 12.5 mg or olmesartan 20 mg + amlodipine 5 mg + HCTZ 12.5 mg for 4 weeks.

Main outcome measures: At the end of each period, clinical and ambulatory BP measurements were recorded.

Results: Both triple combinations produced greater ambulatory and clinical SBP/DBP reduction than dual therapy. However, mean reduction from baseline in the valsartan + amlodipine + HCTZ-treated patients was significantly greater than in the olmesartan + amlodipine + HCTZ-treated patients. Compared with dual therapy, the add-on effect of valsartan was significantly greater than that of olmesartan, the difference being more evident for nighttime SBP/DBP values (-3.3 (95% CI 0.44 – 3.51)/3.0 (95% CI 0.59 – 3.34) mm Hg, p < 0.01).

Conclusions: The addition of valsartan to amlodipine + HCTZ produced greater BP reduction than the addition of olmesartan.     

Effects of valsartan or ramipril addition to amlodipine/hydrochlorothiazide combination on left ventricular mass in diabetic hypertensive patients with left ventricular hypertrophy

Objective: The objective of this study was to compare valsartan or ramipril addition to amlodipine + hydrochlorothiazide (HCTZ) on blood pressure (BP) and left ventricular hypertrophy (LVH) in hypertensive diabetic patients with LVH.

Research design and methods: 293 patients were treated with amlodipine 10 mg + HCTZ 12.5 combination and then randomized to receive valsartan 160 mg or ramipril 5 mg, in addition to the previous therapy, for 1 year.

Main outcome measures: Clinic BP was measured every month; echocardiographic assessments were performed at the end of the placebo period, both before the randomization and after 1-year of triple combination therapy.

Results: Both triple regimens similarly reduced SBP/DBP values (-13.5/10.9 mm Hg in the valsartan group and -13.4/10.4 mm Hg in the ramipril group). Triple combination including valsartan better reduced LVMI (-20.1%, p < 0.001), interventricular septal thickness (IVST) (-20.3%, p < 0.001) and left ventricular posterior wall thickness (PWT) (-16.3%, p < 0.001), compared with triple combination including ramipril (-14%, p < 0.01; -16.2%, p < 0.001 and -9%, p < 0.01, respectively); the difference between treatments being statistically significant (p < 0.05). Triple combination with valsartan gave a greater increase of E/A ratio (p < 0.05 between groups).

Conclusions: Valsartan addition to dual therapy with amlodipine + HCTZ was more effective than ramipril addition in reducing LVH.     

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACT

Objective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome.

Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3?±?10.7 years, mean BP: 158.8?±?14.2/93.4?±?10.0?mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5?mg OD. BP control was defined as <140/90?mmHg for all patients and <130/80?mmHg for those with diabetes mellitus or chronic nephropathy.

Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8?±?9.7/80.5?±?6.9?mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n?=?477), 74.8% of those with diabetes (n?=?214), 75.6% of those with chronic nephropathy (n?=?82), and 85.1% of patients with metabolic syndrome (n?=?745). No case of hypokalemia was reported.

Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.     

Effect of three months’ treatment with irbesartan on blood and pulse pressure of hypertensive type 2 diabetic patients: open,observational study in 31 793 patients

ABSTRACT

Objectives: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-II-receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability.

Methods: 8714 general practitioners included 31?793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300?mg as monotherapy or in combination with hydrochlorothiazide 12.5?mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP ≥ 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability.

Results: Thirty-eight per cent of patients received irbesartan 300?mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5?mmHg, diastolic blood pressure by 10.7?mmHg (baseline values: 160.2 and 93.2?mmHg). Pulse pressure fell on average by 11.6?mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140?mmHg and DBP < 90?mmHg), respectively 73.8% (DBP < 90?mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7?mg/L. Only 0.3% of patients experienced adverse events.

Conclusions: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.     

Comparative effect of canrenone or hydrochlorothiazide addition to valsartan/amlodipine combination on urinary albumin excretion in well-controlled type 2 diabetic hypertensive patients with microalbuminuria

Objective: To compare the effect of adding canrenone or hydrochlorothiazide (HCTZ) to valsartan/amlodipine combination on urinary albumin excretion (UAE) in microalbuminuric type 2 diabetic hypertensives.

Research design and methods: After a 2-week placebo period and after 4 weeks of valsartan 160 mg plus amlodipine 5 mg combination, 120 patients whose blood pressure (BP) was not controlled (> 130/80 mmHg) were randomized to canrenone 25 mg or HCTZ 12.5 mg in addition to the previous therapy for 24 weeks. After the first 6 weeks of triple therapy, canrenone or HCTZ doses were doubled in the patients whose BP was yet uncontrolled. At the end of each period (placebo, dual combination and triple combination therapy), clinic and ambulatory BP measurements were recorded and 24 h UAE was evaluated.

Results: Both triple combinations produced greater clinical and ambulatory BP reduction than dual therapy, with no difference between the two groups. UAE was reduced by both regimens, but the decrease associated with canrenone add-on therapy was more pronounced. At week 24, UAE decreased by 45.3% in the canrenone group and by 20.3% in the HCTZ group (p < 0.01).

Conclusions: These findings indicate that, despite similar BP-lowering effect, the addition of canrenone to valsartan/amlodipine combination was more effective in reducing UAE than HCTZ addition.     

Long-term tolerability and efficacy of the combination of amlodipine/valsartan in hypertensive patients: a 54-week,open-label extension study*

ABSTRACT

Objective: To evaluate the long-term tolerability and efficacy of the amlodipine/valsartan 5/320?mg once daily (o.d.) combination in hypertensive patients.

Methods: This was a 54-week, multicenter, open-label extension study in patients with mild-to-moderate essential hypertension selected after successfully completing a core study during which they received either placebo, amlodipine, valsartan or combination therapy. Eligible patients (mean sitting diastolic blood pressure [MSDBP] ≤?95?mmHg and mean sitting systolic blood pressure [MSSBP] ≤?150?mmHg; n?=?403) were started with amlodipine/valsartan 2.5/160?mg o.d. Following the initial 2-week treatment period, patients were force titrated to amlodipine/valsartan 5/320?mg o.d. for the remainder of the trial. Only the first 150 patients who successfully completed 28 weeks of the extension study were eligible to continue further treatment for 12 months. Efficacy variables were change from core study baseline in MSDBP and MSSBP at study (extension) endpoint. Safety assessments consisted of monitoring and recording all adverse events and serious adverse events.

Results: Reductions in MSDBP and MSSBP were achieved at each extension visit. At endpoint, the reductions in MSDBP and MSSBP were 17.0 and 24.2?mmHg. Summary statistics by subgroup indicate that the combination of amlodipine/valsartan 5/320?mg was effective regardless of age, gender, or stage of hypertension. Peripheral edema occurred in 1.2% of the patients. No case of edema was classified as serious or severe, and no patient was discontinued due to edema. No deaths or clinically significant laboratory findings were observed during this extension study.

Conclusions: Long-term treatment with the amlodipine/valsartan 5/320?mg combination was well-tolerated. Clinically significant and persistent reductions in blood pressure were achieved. Limitations included an open-label design and inclusion of only those patients at or near goal blood pressure after the preceding core trial.     

Attaining United States and European Guideline LDL-C Levels with Simvastatin in Patients with Coronary Heart Disease (the GOALLS Study)

SUMMARY

Objectives: The primary objective was to assess the effects of rilmenidine monotherapy and in combination with perindopril on blood pressure (BP) in patients assessed with grade 1 or 2 essential hypertension. The study also examined the effects of 2-year rilmenidine monotherapy on left ventricular hypertrophy (LVH) and on diastolic function of the left ventricle, along with the effects of rilmenidine on left ventricular mass index in hypertensive patients with no LVH, and the relationship between BP reduction and any change in LVH.

Research design and methods: Mild-to-moderate hypertensive patients (n?=?500) were enrolled in a multicentre 2-year open study and treated with rilmenidine (1-2?mg per day) monotherapy or rilmenidine plus perindopril (2, 4 or 8?mg per day) if control of hypertension was not achieved with rilmenidine monotherapy within 12 weeks. Blood pressure was recorded at regular intervals by the investigators and LVH measured by centralised single-blind echocardiographic reading.

Results: Rilmenidine monotherapy (average dose 1.42?mg) produced a significant decrease in BPfrom the baseline of 163?±?10/100?±?5?mmHg to 134?±?10/86?±?7?mmHg at 1 year and to 136?±?10/84?±?7?mmHg at 2 years (p?2 at 2 years (p?Conclusions: Long-term rilmenidine monotherapy was shown to be efficient in controlling BP and in reducing LVH. The addition of perindopril to rilmenidine monotherapy proved to be effective and well tolerated in those patients who did not respond to rilmenidine alone.     

Efficacy and tolerability of candesartan cilexetil/hydrochlorothiazide and amlodipine in patients with poorly controlled mild-to-moderate essential hypertension.

The antihypertensive efficacy and tolerability of combination therapy with candesartan cilexetil, 16 mg plus hydrochlorothiazide (CC/HCTZ), 12.5 mg was compared with that of amlodipine, in a multicentre, double-blind, randomised, parallel-group study in patients with mild-to-moderate essential hypertension inadequately controlled by monotherapy. After a two week run-in period on existing therapy, patients with a sitting diastolic blood pressure (DBP) of 90-110 mmHg and a sitting systolic blood pressure (SBP) 相似文献   

Effectiveness of a trandolapril-based treatment regimen in subjects with isolated systolic hypertension in Canada

ABSTRACT

Objective: This report evaluates the effectiveness of a titration-based, escalating dose regimen based on trandolapril in subjects with isolated systolic hypertension (ISH) treated in Canadian clinical practice.

Methods: Substudy of the TRAIL (Trandolapril Regimen Applied In real Life) study; a prospective, open-label, single cohort, multicentre study in 192 Canadian primary care practices. Subjects with ISH received trandolapril therapy, initiated at 1?mg/day (0.5?mg/day in subjects on diuretics) and increased to 2 or 4?mg at 4 and 9 weeks, respectively, in those not achieving blood-pressure (BP) targets, subject to tolerability. If BP was not controlled after 14 weeks of treatment subjects could be put on trandolapril 4?mg/verapamil 240?mg while continuing the diuretic, or verapamil could be added to the existing regimen. The observation period was 26 weeks. The primary outcome measure was the achievement of target BP levels after 14 weeks.

Results: Systolic BP (SBP) was significantly (p?<?0.01) reduced from 167.3?±?8.7?mmHg at baseline to 136.8?±?14.0?mmHg (means?±?SD) at Week 14. The reductions were maintained at Week 26: mean SBP at this time point was 137.4?±?12.5?mmHg. The target BP levels of ≤140/90?mmHg at Week 14 was reached by 67% of subjects with ISH. Among study limitations were the observational design; the lack of randomisation and control group, and the fact that subjects with ISH represented a comparatively small number of subjects.

Conclusions: A titration-based, escalating-dose regimen based on trandolapril is effective in subjects with ISH under treatment conditions seen in general clinical practice in Canada.