Olmesartan medoxomil/amlodipine/hydrochlorothiazide: fixed-dose combination in hypertension

The antihypertensive agents olmesartan medoxomil, amlodipine and hydrochlorothiazide (HCTZ) are now available as a fixed-dose combination tablet (olmesartan medoxomil/amlodipine/HCTZ). In a 12-week, randomized, double-blind, multicentre trial (TRINITY) in adults with moderate to severe hypertension, olmesartan medoxomil?+?amlodipine?+?HCTZ triple combination therapy produced significantly greater least squares mean reductions from baseline in seated diastolic blood pressure (BP) [primary endpoint] and seated systolic BP than olmesartan medoxomil/amlodipine, olmesartan medoxomil/HCTZ or amlodipine?+?HCTZ. Furthermore, significantly more patients achieved BP goals and targets with the triple combination regimen than with any of the dual combination regimens at week 12, with olmesartan medoxomil?+?amlodipine?+?HCTZ also demonstrating benefit over the dual regimens in terms of ambulatory BP control. According to subgroup analyses of the TRINITY trial, olmesartan medoxomil?+?amlodipine?+?HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies, irrespective of hypertension severity, age, sex, race or diabetes mellitus status. Data from a number of smaller clinical studies indicated that olmesartan medoxomil?+?amlodipine?+?HCTZ triple combination therapy provides antihypertensive efficacy in patients whose BP is not adequately controlled with olmesartan medoxomil?+?amlodipine. Olmesartan medoxomil?+?amlodipine?+?HCTZ was generally well tolerated in the TRINITY study, with adverse events usually being mild or moderate in severity.     

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.     

Efficacy and Safety Study of Olmesartan Medoxomil,Amlodipine, and Hydrochlorothiazide Combination Therapy in Patients with Hypertension Not Controlled with Olmesartan Medoxomil and Hydrochlorothiazide Combination Therapy: Results of a Randomized,Double-Blind,Multicenter Trial

Background

This study was to evaluate the efficacy and safety of triple fixed-dose combination (FDC) therapy with olmesartan medoxomil (OM) 20  mg, amlodipine (AML) 5 mg, and hydrochlorothiazide (HCTZ) 12.5 mg (OM/AML/HCTZ 20/5/12.5) in Korean patients with moderate hypertension not controlled with dual FDC therapy (OM/HCTZ 20/12.5).

Methods

In this multicenter, randomized, double-blind, parallel-group study, Korean patients aged 20 to 75 years with stage 2 hypertension who had a mean seated diastolic blood pressure (msDBP) ≥100 mmHg were enrolled when their BP was uncontrolled [mean seated systolic BP (msSBP)/msDBP >140/90 mmHg or msSBP/msDBP >130/80 mmHg with diabetes or chronic kidney disease] with 4-week dual FDC therapy (OM/HCTZ 20/12.5). The patients were randomized to receive either OM/AML/HCTZ 20/5/12.5 or OM/HCTZ 20/12.5 once daily for 8 weeks. At the end of 8 weeks, patients with uncontrolled BP were assigned to receive either OM/AML/HCTZ 40/5/12.5 or OM/AML/HCTZ 20/5/12.5 in an additional 8-week open-label extension period.

Results

A total of 623 patients received a 4-week run-in treatment with OM/HCTZ, 341 patients were randomized, and finally, 167 patients in the OM/AML/HCTZ group and 171 patients in the OM/HCTZ group were analyzed for the full analysis set. Non-responders after the 8 weeks of double-blind treatment continued the 8-week open-label treatment with OM/AML/HCTZ 40/5/12.5 mg (n = 32) or OM/AML/HCTZ 20/5/12.5 mg (n = 71). After 8 weeks of double-blind treatment, the changes in msDBP were ?9.50 (8.46) mmHg in the OM/AML/HCTZ group and ?4.23 (7.41) mmHg in the OM/HCTZ group (both p < 0.0001 vs. baseline; p < 0.0001 between groups). The response rates for both msSBP and msDBP at week 8 were 65.27 % in the OM/AML/HCTZ group and 37.43 % in the OM/HCTZ group (p < 0.0001 between groups). The response rates for both msSBP and msDBP at week 16 after open-label treatment were 18.75 % in the OM/AML/HCTZ 40/5/12.5 group and 46.48 % in the OM/AML/HCTZ 20/5/12.5 group (p = 0.0073 between groups). All medications were well tolerated.

Conclusion

In Korean patients with moderate hypertension not controlled with dual FDC therapy (OM/HCTZ 20/12.5) as first-line therapy, switching to triple FDC therapy (OM/AML/HCTZ 20/5/12.5) was associated with significant BP reductions and greater achievement of BP goals, and was well tolerated (ClinicalTrials.gov Identifier: NCT01838850).

     

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.     

Irbesartan/Hydrochlorothiazide : in moderate to severe hypertension

* The fixed-dose combination of irbesartan/hydrochlorothiazide (HCTZ) is approved in the US for use as initial therapy in patients who are likely to need multiple agents to achieve their blood pressure (BP) goals. * In a 12-week, randomized, double-blind, multicentre trial in 538 patients with moderate hypertension that was untreated or uncontrolled by monotherapy, the mean reduction from baseline in seated systolic BP (SeSBP) at week 8 (primary endpoint) was significantly greater with irbesartan/HCTZ than with either irbesartan or HCTZ as monotherapy. * In addition, the proportion of patients with moderate hypertension achieving controlled BP (SeSBP < 140 mmHg/seated diastolic BP [SeDBP] < 90 mmHg) at 12 weeks was significantly greater with irbesartan/HCTZ combination therapy than with irbesartan or HCTZ monotherapy. * In a 7-week, randomized, double-blind, multicentre trial in 697 patients with severe hypertension that was untreated or uncontrolled by monotherapy, a significantly greater proportion achieved a trough SeDBP of < 90 mmHg following 5 weeks of combination therapy with irbesartan/HCTZ compared with irbesartan monotherapy (primary endpoint). * Furthermore, the proportion of patients with severe hypertension achieving controlled BP of < 140/90 mmHg was significantly greater at all timepoints of the trial compared with irbesartan monotherapy. * Irbesartan/HCTZ combination therapy had a similar tolerability profile to irbesartan and HCTZ monotherapy. Most adverse events were of mild to moderate intensity.     

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.     

Valsartan: in children and adolescents with hypertension

Valsartan is an oral angiotensin II subtype 1 receptor antagonist with well established antihypertensive efficacy in adults. It is now approved in the EU and the US for the treatment of hypertension in children and adolescents. In two, randomized, double-blind trials, a once-daily regimen of valsartan reduced the blood pressure (BP) of children and adolescents with hypertension. In one trial in hypertensive children and adolescents aged 6-16 years, significant dose-dependent reductions from baseline in mean sitting systolic BP (msSBP) were observed for recipients of valsartan following 2 weeks' treatment (primary endpoint). There were corresponding dose-dependent and significant reductions in mean sitting diastolic BP. Following 2 further weeks of treatment, the reduction in msSBP was maintained in patients who were re-randomized to continue receiving the same dosage of valsartan but not in those re-randomized to placebo. In the other trial in hypertensive children and adolescents aged 6-17 years, valsartan was no less effective than enalapril in reducing BP. Following 12 weeks' treatment, the least square mean reduction from baseline in msSBP (primary endpoint) in recipients of valsartan was noninferior to that in recipients of enalapril. In addition, the proportion of patients achieving an msSBP <95th percentile for age, sex, and height at week 12 was not significantly different between recipients of valsartan and enalapril (67% vs 70%). Treatment with valsartan for up to 52 weeks was well tolerated in children and adolescents with hypertension.     

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension.

OBJECTIVE: To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension. METHODS: In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed. RESULTS: At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean+/-SEM) by 11.3+/-0.5, 10.7+/-0.5 and 12.8+/-0.5 mmHg, and msSBP by 14.7+/-0.9, 12.0+/-0.9 and 16.6+/-0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0.043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021). All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril. CONCLUSIONS: Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.     

Aliskiren as Add-On Therapy in the Treatment of Hypertensive Diabetic Patients Inadequately Controlled with Valsartan/HCT Combination

Background

Hypertension frequently coexists with diabetes mellitus, resulting in increased cardiovascular risk. Thus, BP control is crucial in decreasing morbidity and mortality in this difficult-to-treat patient population.

Objective

The objective of this study was to evaluate the efficacy and safety of aliskiren in hypertensive patients with diabetes not adequately responsive to the combination of valsartan and hydrochlorothiazide (HCT).

Methods

After a 1-to 4-week washout period, patients with a mean sitting diastolic BP (msDBP) ≥95mmHg were treated with valsartan 160mg for 2 weeks followed by valsartan/HCT 160mg/25mg for an additional 4 weeks (single-blind active run-in period). Patients whose msDBP remained ≥85mmHg after the active run-in period were randomized (1 : 1) to receive aliskiren 150mg (n = 184) or placebo (n = 179) as add-on therapy for 6 weeks. Aliskiren was then force-titrated to 300mg once daily for another 6 weeks. Efficacy variables were: the change in msDBP and mean sitting systolic BP (msSBP) from baseline to week 12 endpoint, diastolic response (msDBP < 80mmHg or reduction of at least 10mmHg), and BP control rate (<130/80mmHg).

Results

Of the 363 patients randomized, 328 (90.4%) completed the study (aliskiren and placebo groups: 89.7% and 91.1%, respectively). At week 12 endpoint, the least squares mean (LSM) changes in msDBP (aliskiren vs placebo: ?5.8 vs ?4.8mmHg; p = 0.2767) and msSBP (aliskiren vs placebo: ?7.3 vs ?4.8 mmHg; p = 0.0725) were numerically greater in patients treated with aliskiren compared with those treated with placebo; however, this difference was not statistically significant. The proportion of diastolic responders (aliskiren and placebo: 68.5% and 72.9%, respectively; p = 0.8482) and patients achieving BP control (aliskiren and placebo: 16.0% and 16.4%, respectively; p = 0.7511) were similar for both groups. Overall, 63 (34%) and 59 (33%) patients in the aliskiren and placebo groups, respectively, experienced adverse events (AEs). The most commonly reported AEs were headache (placebo group: 6.1%) and dizziness (aliskiren group: 4.4%). Aliskiren was well tolerated.

Conclusion

The reductions in BP with aliskiren added to valsartan/HCT in this study were numerically greater compared with placebo added to valsartan/HCT, although not statistically significant. Trial Registration: ClinicalTrials.gov identifier NCT00219102.     

Efficacy and safety of triple antihypertensive therapy with the olmesartan/amlodipine/hydrochlorothiazide combination

Background: European hypertension guidelines estimate that up to 15-20% of hypertensive patients are not controlled on a dual antihypertensive combination and require three or more different antihypertensive drug classes to achieve blood pressure (BP) control. Objective: This study in patients with moderate-to-severe hypertension assessed the efficacy and safety of adding hydrochlorothiazide (HCTZ) 12.5?mg and 25?mg to a range of olmesartan medoxomil (OLM)/amlodipine (AML) doses. Study Design: This phase III, multicentre study had a randomized, double-blind, parallel-group design that included a double-blind safety run-in and a double-blind treatment period. Intervention: Enrolled patients were screened and previous therapy was discontinued if required. During a 2-week, double-blind, safety run-in period (Weeks 0-2), patients were randomized to receive placebo, OLM/AML 20?mg/5?mg, OLM/AML 40?mg/5?mg or OLM/AML 40?mg/10?mg. During an 8-week, double-blind treatment period (Weeks 3-10), patients were allocated to eight groups depending on their initial treatment. They were either randomized to continue with the same dose of OLM/AML, or have HCTZ 12.5?mg or 25?mg added to treatment. Main Outcome Measure: The primary endpoint was formulated before data collection began. It was the change in mean diastolic BP (DBP) from baseline to Week 10 in groups with HCTZ added to OLM/AML, compared with the corresponding dual OLM/AML therapy. Results: Of 3195 patients who were screened, 2690 were randomized. Patients in every triple OLM/AML/HCTZ group had significantly greater mean reductions in DBP (p?≤?0.032 for each comparison) and systolic BP (SBP) by Week 10 (p?≤?0.0034 for each comparison), compared with patients on the corresponding OLM/AML therapy dose. The significant improvements in DBP and SBP reduction with triple OLM/AML/HCTZ therapy, compared with dual OLM/AML therapy, were observed after 4 and 6 weeks of therapy. Patients in each triple therapy group also had a significantly higher rate of BP <140/90?mmHg threshold achievement (p?≤?0.05 for each treatment comparison), compared with the dual OLM/AML groups. In three of the OLM/AML/HCTZ groups (40?mg/5?mg/25?mg, 40?mg/10?mg/12.5?mg and 40?mg/10?mg/25?mg), BP <140/90?mmHg threshold achievement by Week 10 was over 70%. Across the triple and dual combination therapy groups, treatment was well tolerated and no safety concerns for either treatment were identified. Conclusion: Adding HCTZ to a range of OLM/AML dose combinations is well tolerated and improved BP control by significantly lowering DBP and SBP and significantly increasing BP threshold achievement in patients with moderate-to-severe hypertension. Clinical Trial Registration: Registered at ClinicalTrials.gov identifier as NCT00923091.     

Single-pill combination of amlodipine and valsartan in the management of hypertension

Combination therapy is increasingly recommended for selected patients with hypertension to facilitate prompt attainment and maintenance of goal blood pressure (BP). Single-pill combination therapy simplifies treatment and optimizes long-term compliance. Amlodipine, a dihydropyridine calcium antagonist, and valsartan, an angiotensin receptor blocker, are well-established antihypertensive agents with complementary mechanisms of action. This combination lowers BP significantly more than either of its components, and valsartan reduces the incidence of dose-related amlodipine-induced edema. Rigorous clinical trial data have proven the BP-lowering efficacy and high tolerability of the amlodipine/valsartan combination in patients with moderate to severe hypertension as well as other difficult-to-treat populations. Amlodipine/valsartan is indicated as initial therapy in patients who are unlikely to be controlled with a single drug and as second-line therapy in patients not responding adequately to monotherapy.     

Aliskiren: a review of its use in the management of hypertension

Aliskiren (Tekturna) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents.Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was generally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowering effects when combined with HCTZ 12.5-25 mg/day, ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-based therapies in lowering BP after 6 months, and was similarly well tolerated.The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension.     

Amlodipine/Valsartan: fixed-dose combination in hypertension

Amlodipine, a dihydropyridine calcium channel blocker, and valsartan, an angiotensin II receptor blocker, are established antihypertensive agents. Fixed-dose combinations of amlodipine/valsartan are available in several European countries and in the US. Individual dose titration with amlodipine and valsartan is generally recommended before changing to the fixed-dose combination. Amlodipine/valsartan, at approved dosage regimens, achieved significantly greater reductions in mean sitting diastolic and systolic blood pressure (BP) than amlodipine or valsartan monotherapy, or placebo in two randomized, double-blind, factorial trials in patients with mild to moderate hypertension. Approximately 80-90% of patients receiving approved dosages of amlodipine/valsartan achieved a response, defined as a mean sitting diastolic BP <90 mmHg or a >or= 10 mmHg reduction from baseline. Subgroup analyses of data from the two trials showed that the antihypertensive efficacy of amlodipine/valsartan in the elderly, Black patients and those with stage 2 hypertension was consistent with that observed in the overall study population. Marked reductions in BP were also observed in patients whose BP was previously uncontrolled on monotherapy (with various antihypertensives) who were switched (without washout) to amlodipine/valsartan in a phase IIIb-IV study. Amlodipine/valsartan was generally well tolerated in clinical trials. In particular, the incidence of peripheral oedema was significantly lower in patients receiving amlodipine/valsartan than in those treated with amlodipine monotherapy.     

Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension

Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300?mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2 (mild to moderate) hypertension, alone or in combination with other antihypertensives, including HCTZ, valsartan or amlodipine.     

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.     

A Review of the Efficacy of Fixed-Dose Combinations Olmesartan Medoxomil/ Hydrochlorothiazide and Amlodipine Besylate/ Benazepril in Factorial Design Studies

In order to adequately control hypertension, the majority of patients will require treatment with more than one antihypertensive agent. Fixed-dose combination therapy offers several advantages, including improved efficacy, tolerability, and treatment compliance. Certain combinations have benefits in specific patient populations, such as the elderly or those with comorbidities. In this review, we evaluate the BP-lowering efficacy of olmesartan medoxomil/hydrochlorothiazide (HCTZ) and amlodipine besylate/benazepril in similarly designed, randomized, placebo-controlled studies in similar patient populations. This indirect comparison showed that both combinations significantly improve both systolic and diastolic BP compared with monotherapy with the individual agents or placebo; it also demonstrated that the combinations were well tolerated. Both combination therapies significantly improved response rates, but olmesartan medoxomil/HCTZ achieved the highest control rates compared with the individual agents. On the basis of an indirect comparison of published factorial design studies, olmesartan medoxomil/HCTZ appears to be at least as effective as amlodipine besylate/benazepril and may provide quantitatively greater reductions in diastolic BP at commonly used dosages. A randomized clinical trial comparing the two combinations is needed to confirm these findings.     

Telmisartan/Amlodipine

Telmisartan/amlodipine is a single-pill combination of telmisartan, an angiotensin II receptor antagonist, and amlodipine, a dihydropyridine calcium channel antagonist, which is taken orally once daily for the treatment of hypertension. In the US and the EU, single-pill telmisartan/amlodipine can be used as a replacement for separate telmisartan and amlodipine tablets, and by patients not achieving BP goals with amlodipine monotherapy. In addition, the US indication includes patients not achieving BP goals with telmisartan (or another angiotensin II receptor antagonist or calcium channel antagonist other than amlodipine) alone, and as initial therapy in patients considered likely to require multiple drugs to achieve their BP goals. In an 8-week, randomized, double-blind, factorial-design, placebo-controlled, multicenter study in adult patients with hypertension (n =1461), mean DBP was reduced from baseline to a significantly greater extent in recipients of telmisartan 40 or 80mg/day plus amlodipine 5 or 10mg/day than in those receiving equivalent dosages of telmisartan or amlodipine monotherapy. Single-pill telmisartan/amlodipine recipients had significantly greater reductions in BP than telmisartan or amlodipine monotherapy recipients in an 8-week, randomized, double-blind, multicenter study in adult patients with severe hypertension (n = 858), and in four 8-week, randomized, double-blind, multicenter trials in patients who had not responded to amlodipine (n = 1097, 947, and 531) or telmisartan (n = 314) monotherapy. Telmisartan/amlodipine was generally well tolerated in clinical trials, including two 36-week follow-up studies.     

Olmesartan medoxomil: a review of its use in the management of hypertension

Olmesartan medoxomil (Olmetec, Benicar) is an angiotensin II type 1 (AT(1)) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus, Benicar-HCT] combination therapy may be initiated. Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.     

Efficacy and tolerability of combination therapy with valsartan/hydrochlorothiazide in the initial treatment of severe hypertension

ABSTRACT

Objective: Most patients with severe hypertension are at high risk for cardiovascular events and require prompt blood pressure (BP)-lowering and combination therapy to achieve BP goals. This study evaluated the therapeutic efficacy and tolerability of initial treatment with the combination of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with severe hypertension.

Research design and methods: This was a 6-week, randomized, double-blind, multicenter, forced titration study that compared initial therapy with the combination of valsartan/HCTZ 160/12.5?mg (force titrated to 160/25?mg after 2 weeks and to 320/25?mg after 4 weeks) to monotherapy with valsartan 160?mg (force titrated to 320?mg after 2 weeks and sham-titrated to 320?mg after 4 weeks). Eligible patients were 18–80 years old with severe essential hypertension (mean sitting diastolic BP?≥?110?mmHg and <120?mmHg and mean sitting systolic BP?≥?140?mmHg and <200?mmHg). The Clinical Trial Registry number was NCT00273299.

Main outcome measures: The primary efficacy variable was the rate of BP control (mean sitting BP?<?140/90?mmHg) at Week 4. Tolerability was evaluated by monitoring all adverse events, vital signs, and laboratory tests including hematology and biochemistry.

Results: A total of 608 patients were randomized to either valsartan/HCTZ (n?=?307) or valsartan monotherapy (n?=?301). Significantly more patients achieved overall BP control (<140/90?mmHg) with valsartan/HCTZ compared to monotherapy at Week 4 (primary efficacy variable and timepoint) (39.6% vs. 21.8%; p?<?0.0001) and Week 6 (48.2% vs. 27.2%; p?<?0.0001). Mean reductions in BP at Week 4 were significantly greater for valsartan/HCTZ (30.8/22.7?mmHg vs. 21.7/17.5?mmHg; p?<?0.0001), with further reductions at Week 6. BP control rates were greater with combination therapy as early as Week 2. The overall incidence of adverse events was comparable between the combination therapy (34.9%) and monotherapy (36.7%) treatment groups. A potential limitation of the forced-titration design is that some patients were titrated to higher doses despite having achieved goal BP. This may impact the interpretation of the incidence of dose-dependent adverse events.

Conclusions: Initial therapy with valsartan/HCTZ is effective and well tolerated in patients with severe hypertension.     

Telmisartan/hydrochlorothiazide: in the treatment of essential hypertension

Oral telmisartan/hydrochlorothiazide (HCTZ) combines two antihypertensive agents, a selective angiotensin II receptor antagonist with a long half-life and once-daily administration, and a thiazide diuretic. In two large, 8-week, double-blind trials, patients with hypertension unresponsive to monotherapy who received combined telmisartan/HCTZ 80/12.5 or 40/12.5 mg/day, achieved significantly larger reductions in diastolic and systolic blood pressure (BP), than recipients of continued telmisartan monotherapy (p < 0.05 for all). Compliance with telmisartan/HCTZ 80/12.5 mg/day was 98.9%. In patients with hypertension, telmisartan/HCTZ resulted in similar BP reductions to oral enalapril/HCTZ and atenolol/HCTZ in 26-week double-blind trials and greater reductions than oral losartan/HCTZ 50/12.5 mg/day in a 6-week randomised open-label trial (p < 0.001). Up to one-third of patients with hypertension initially responsive to telmisartan 40 or 80 mg/day in a 4-year study required the eventual addition of HCTZ 12.5 or 25 mg/day and/or another agent to maintain BP control. BP was controlled in about 75% of these by adding only HCTZ. In clinical trials of up to 4 years, including elderly patients, telmisartan/HCTZ had similar tolerability to placebo, with few reports of hypokalaemia. Most adverse events were mild to moderate.