Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice

Background

Current clinical guidelines recognize that the use of more than one agent is necessary to achieve target BP in the majority of patients. The ASCOT-BPLA trial demonstrated that the free combination of amlodipine and perindopril effectively controlled BP and was better than a β-adrenoceptor antagonist (β-blocker)/diuretic combination in reducing total mortality and cardiovascular outcomes.

Objective

To evaluate the efficacy and tolerability of a fixed combination of perindopril and amlodipine in the clinical setting.

Study design

The STRONG (SafeTy & efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension) study was a prospective, observational, multicenter trial.

Setting

This was a naturalistic, real-world, clinic-based, outpatient study involving 336 general practitioners/ primary care physicians in 65 cities in India.

Patients

Adults aged 40–70 years with newly diagnosed/untreated stage 2 hypertension (BP ≥ 160/100 mmHg), hypertension uncontrolled with monotherapy (BP > 140/90 mmHg), or hypertension inadequately managed with another combination therapy.

Intervention

Fixed combination perindopril 4 mg/amlodipine 5 mg once daily for 60 days.

Main outcomes measure

The primary outcomes were the mean change in BP from baseline and the proportion of patients achieving adequate BP control (≤ 140/90 mmHg, or ≤ 130/80 mmHg in patients with diabetes mellitus) in the intent-to-treat (ITT) population. Secondary analyses included incidence of adverse events (ITT) and treatment adherence rate (completers).

Results

In total, 1250 patients comprised the ITT population: 32.6% with newly diagnosed hypertension; 40.5% with hypertension uncontrolled with monotherapy; and 26.9% with hypertension inadequately managed with another combination therapy. Mean SBP/DBP decreased significantly from baseline (167.4±15.2/101.4±9.1 mmHg) over 60 days (?41.9 ± 34.8/?23.2 ± 21.8 mmHg; p<0.0001). Target BP was achieved in 66.1% of patients in the total population, 68.3% of untreated patients, 68.4% of patients uncontrolled with monotherapy, and 59.9% of patients inadequately managed with combination therapy. In 161 patients with SBP >180 mmHg at baseline (newly diagnosed: n = 50; uncontrolled on monotherapy: n = 53; inadequately managed on combination therapy: n = 58), BP was reduced by 63.2 ± 32.5/29.0 ± 21.9 mmHg (p<0.0001) at day 60. The fixed combination was safe and well tolerated. All 1175 patients completing the 60-day study (94%) adhered to their treatment regimen.

Conclusion

Fixed combination perindopril/amlodipine was found to be an effective and well tolerated antihypertensive treatment, with an excellent rate of treatment adherence in the clinical setting. Fixed combination perindopril/amlodipine is expected to be useful in the management of hypertension in primary healthcare, with a positive impact on treatment adherence.     

Comparison of the Efficacy and Safety of Fixed-Dose Amlodipine/Losartan and Losartan in Hypertensive Patients Inadequately Controlled with Losartan

Background

Fixed-dose combination drugs may enhance blood pressure (BP) goal attainment through complementary effects and reduced side effects, which leads to better compliance.

Objective

This study aimed to evaluate the efficacy and safety profiles of once-daily combination amlodipine/losartan versus losartan.

Methods

This was an 8-week, double-blind, multicenter, randomized phase III study conducted in outpatient hospital clinics. Korean patients with essential hypertension inadequately controlled on losartan 100 mg were administered amlodipine/losartan 5 mg/100 mg combination versus losartan 100 mg. The main outcome measures were changes in sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP) and BP response rate from baseline values, which were assessed after 4 and 8 weeks of treatment. Safety and tolerability were also assessed.

Results

At week 8, both groups achieved significant reductions from baseline in DBP (11.7 ± 7.0 and 3.2 ±7.9 mmHg), which was significantly greater in the amlodipine/losartan 5 mg/100 mg combination (n = 70) group (p < 0.0001). Additionally, the amlodipine/losartan 5 mg/100 mg combination group achieved significantly greater reductions in SBP at week 8 and in SBP and DBP at week 4 compared with the losartan 100 mg (n = 72) group (all p<0.0001). Response rates were significantly higher in the amlodipine/losartan 5 mg/100 mg group versus the losartan 100 mg group (81.4% vs 63.9% at week 4, p < 0.0192; 90.0% vs 66.7% at week 8, p<0.001). Both treatments were generally well tolerated.

Conclusion

Switching to a fixed-dose combination therapy of amlodipine/losartan 5 mg/100 mg was associated with significantly greater reductions in BP and superior achievement of BP goals compared with a maintenance dose of losartan 100 mg in Korean patients with essential hypertension inadequately controlled on losartan 100 mg.

Clinical Trial Registration

Registered at Clinicaltrials.gov as NCT00940680.     

Effect of an Olmesartan Medoxomil-Based Treatment Algorithm on Systolic Blood Pressure in Patients with Stage 1 or 2 Hypertension

Background and Objective

Elevated systolic BP (SBP) is a major contributor to cardiovascular disease. SBP control reduces the occurrence of stroke, heart failure, and cardiovascular and total mortality. The aim of this study was to analyze the magnitude of SBP reductions and the achievement of individual SBP targets in the original BENIFORCE study.

Methods

An olmesartan medoxomil-based treatment algorithm was evaluated in a double-blind, placebo-controlled titration study in 276 patients with stage 1 (47.1%) or 2 (52.9%) hypertension. After placebo run-in, patients were randomized to placebo (12 weeks) or olmesartan medoxomil 20 mg/day (weeks 1–3). Olmesartan medoxomil was uptitrated to 40 mg/day (weeks 4–6), then olmesartan medoxomil/hydrochlorothiazide (HCTZ) 40/12.5 mg per day (weeks 7–9), and olmesartan medoxomil/HCTZ 40/25 mg per day (weeks 10–12) if BP remained ≥120/80 mmHg at any time interval.

Setting

The BENIFORCE study was a multicenter (29 sites) study conducted between January and October 2007 in the US.

Results

In patients receiving olmesartan medoxomil-based therapy, 81.0%, 67.2%, and 46.6% of patients with stage 1 hypertension and 70.4%, 49.4%, and 23.5% of patients with stage 2 hypertension achieved SBP targets of <140, <130, and <120 mmHg, respectively (all p<0.01 vs placebo). The proportions of patients achieving SBP targets increased with escalating doses of olmesartan medoxomil and HCTZ, administered alone or in combination, and was highest for combination therapy. Similarly, escalating doses of olmesartan medoxomil or olmesartan medoxomil/HCTZ increased the proportion of patients achieving SBP reductions of >15 but ≤30, >30 but ≤45, and >45 mmHg compared with placebo.

Conclusion

An olmesartan medoxomil-based treatment algorithm effectively reduced SBP and achieved SBP targets in patients with stage 1 or 2 hypertension. This regimen resulted in >80% of patients achieving SBP reductions of ≥15 mmHg while 44% achieved SBP reductions of >30 mmHg.     

Evaluation of the Dose-Response Relationship of Amlodipine and Losartan Combination in Patients with Essential Hypertension

Background

Despite recommendations for more intensive treatment and the availability of several effective treatments, hypertension remains uncontrolled in many patients.

Objective

The aim of this study was to determine the dose-response relationship and assess the efficacy and safety of amlodipine or losartan monotherapy and amlodipine camsylate/losartan combination therapy in patients with essential hypertension.

Methods

This was an 8-week, randomized, double-blind, factorial design, phase II, multicenter study conducted in outpatient hospital clinics among adult patients aged 18?C75 years with essential hypertension. At screening, patients received placebo for 2?C4 weeks. Eligible patients (n = 320) were randomized to one of eight treatment groups: amlodipine 5 mg or 10 mg, losartan 50 mg or 100 mg, amlodipine camsylate/losartan 5mg/50mg, 5mg/100mg, 10mg/50mg, or 10mg/100mg.

Main Outcome Measures

The assumption of strict superiority was estimated using the mean change in sitting diastolic blood pressure (DBP) at 8 weeks. Safety was monitored through physical examinations, vital signs, laboratory test results, ECG, and adverse events.

Results

The reduction in DBP at 8 weeks was significantly greater in patients treated with the combination therapies compared with the respective monotherapies for all specified comparisons except amlodipine camsylate/losartan 10mg/100mg versus amlodipine 10mg. The incidence of adverse events in the group of patients treated with the amlodipine camsylate/losartan 10mg/50mg combination tended to be higher than for any other group (27.9%, 12/43); however, the effect was not statistically significant.

Conclusion

Combination amlodipine camsylate/losartan (5mg/50mg, 5mg/100mg and 10mg/50mg) resulted in significantly greater BP lowering compared with amlodipine or losartan monotherapy, and was determined to be generally safe and tolerable in patients with essential hypertension.

Clinical Trial Registration

Registered at clinicaltrials.gov: NCT00942344.     

An Olmesartan Medoxomil-Based Treatment Algorithm is Effective in Achieving 24-Hour BP Control in Patients with Type 2 Diabetes Mellitus, Regardless of Age, Race, Sex, or Severity of Hypertension

Background

Hypertension often occurs concomitantly with diabetes mellitus, such that >50% of adults with type 2 diabetes have hypertension. These individuals are at a greater risk of developing renal and cardiovascular disease. The currently recommended BP goal of <130/80 mmHg for patients with type 2 diabetes is achieved in only 37.5% of treated patients with diabetes and hypertension.

Methods

The antihypertensive efficacy of olmesartan medoxomil (OM) ± hydrochlorothiazide (HCTZ) was investigated in prespecified subgroups (age <65/≥65 years, Blacks/non-Blacks, males/females, or stage 1/ stage 2 hypertension) of patients with hypertension and type 2 diabetes enrolled in an open-label, single-arm study (n= 192). Patients started treatment with OM 20 mg/day and were uptitrated at 3-week intervals to OM 40, OM/HCTZ 40/12.5, and OM/HCTZ 40/25 mg/day if BP was ≥120/70 mmHg. The primary endpoint was the change in mean 24-hour ambulatory SBP from baseline to week 12, assessed by mean 24-hour ambulatory BP monitoring. Secondary endpoints included changes in mean 24-hour ambulatory DBP, mean daytime ambulatory BP, mean nighttime ambulatory BP, and mean office seated BP, and the proportions of patients achieving prespecified ambulatory BP targets.

Setting

This was a multicenter study (24 sites) that took place between November 2006 and November 2007 in the US.

Results

BP reductions were significant (p<0.0001) and similar among subgroups of patients with type 2 diabetes. Following dose titration to OM/HCTZ 40/25 mg/day, similar proportions of patients in the age, race, and sex subgroups (approximately 60–64% across these subgroups) achieved an ambulatory BP target of <130/80 mmHg. A larger proportion of patients with type 2 diabetes and stage 1 hypertension achieved this same goal compared with patients with stage 2 hypertension (75% vs 46.3%). The combination of OM/HCTZ was well tolerated in all patient subgroups irrespective of age, race, sex, or hypertension severity.

Conclusions

In this open-label study, OM/HCTZ combination therapy was efficacious and well tolerated in subgroups of 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.     

Dose-Dependent Antihypertensive Efficacy and Tolerability of Perindopril in a Large, Observational, 12-Week, General Practice-Based Study

Background

Current guidelines recommend the use of full therapeutic dosages of antihypertensive agents, or combination therapy, to improve BP control of hypertensive patients in primary healthcare.

Objective

The aim of this study was to assess the dose-dependent antihypertensive efficacy and safety of perindopril 4 and 8 mg/day in the clinical setting.

Study Design and Setting

The CONFIDENCE study was a prospective, observational, multicenter trial. This was a real-world, clinic-based, outpatient study involving 880 general practitioners/primary-care clinics and 113 specialists in Canada.

Patients

The study included untreated or inadequately managed patients with hypertension (i.e. seated BP≥140/90 mmHg, or ≥130/80 mmHg in the presence of diabetes mellitus, renal disease, or proteinuria) without coronary artery disease (CAD).

Intervention

Treatment consisted of perindopril 4 mg/day, uptitrated to 8 mg/day as required for BP control at visit 2, for 12 weeks. Among the patients already being treated at baseline, perindopril either directly replaced all previous ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), or was added to antihypertensive treatment with calcium channel blockers (CCBs), diuretics, or β-adrenoceptor antagonists (β-blockers).

Main Outcomes Measures

The primary outcomes were the mean changes in BP from baseline following treatment with perindopril 4 and 8 mg/day as well as the proportion of patients achieving BP control (BP <140/90 mmHg, or <130/80 mmHg in diabetic patients) in the intent-to-treat (ITT) population. Secondary analyses included the incidence of adverse events and compliance.

Results

A total of 8298 hypertensive patients entered the study: 56% with newly diagnosed hypertension and 44% with uncontrolled hypertension. Mean SBP/DBP decreased significantly from baseline (152.5 ±10.8/89.5 ±9 mmHg) over 12 weeks (?18.5/?9.7 mmHg; p < 0.001). At visit 2, 23% of patients were uptitrated to perindopril 8 mg/day, which resulted in an additional mean 10.1/5.3 mmHg BP reduction; this reduction was even greater (15.1/5.7 mmHg) among a separate group of severely hypertensive patients (i.e. SBP >170 mmHg or DBP > 109 mmHg at baseline). Target BP was achieved in 54% of the ITT population. Both perindopril 4 mg/day and perindopril 8 mg/day were well tolerated and compliance was high throughout the study.

Conclusion

In the clinical outpatient setting, perindopril was found to be an effective dose-dependent and well tolerated antihypertensive treatment, with good compliance. Uptitration to the full therapeutic dosage of perindopril is an efficient approach for the management of a broad range of hypertensive patients without CAD.     

Efficacy and tolerability of telmisartan plus amlodipine in added-risk hypertensive patients

Abstract

Objectives:

Added-risk hypertensive patients with co-morbidities such as diabetes and metabolic syndrome often require two or more antihypertensives to achieve blood pressure (BP) targets. The aim of this sub-analysis was to determine the efficacy and safety of telmisartan 40 or 80?mg plus amlodipine 5 or 10?mg in patients with hypertension, stratified according to certain criteria such as type 2 diabetes mellitus and metabolic syndrome.     

Antihypertensive Efficacy of Triple Combination Perindopril/Indapamide Plus Amlodipine in High-Risk Hypertensives: Results of the PIANIST Study (Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients)

Objective

Our objective was to evaluate a triple-drug antihypertensive strategy for blood pressure control in patients with difficult-to-treat hypertension.

Design

The Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients (PIANIST) trial was an observational, 4-month, open-label study.

Patients and interventions

A total of 4,731 patients at high or very high cardiovascular risk with hypertension that was not properly controlled despite antihypertensive therapy, and for whom study treatment (fixed-dose perindopril 10 mg/indapamide 2.5 mg + amlodipine 5 or 10 mg) was consistent with their existing therapeutic plan, were included.

Outcomes

One-sample t tests and Chi-squared tests were performed to evaluate changes in blood pressure.

Results

Mean baseline office blood pressure (OBP) was 160.5 ± 13.3/93.8 ± 8.7 mmHg. After 4 months of therapy, OBP decreased by 28.3 ± 13.5/13.8 ± 9.4 to 132.2 ± 8.6/80.0 ± 6.6 mmHg (p < 0.0001). Blood pressure targets were reached by 72.0 % of patients and by 81 and 91 % of patients previously treated with an angiotensin-converting enzyme inhibitor/hydrochlorothiazide or an angiotensin receptor blocker/hydrochlorothiazide, respectively. Changes in OBP were 18.7 ± 8.3/9.7 ± 7.2 mmHg for grade 1 (n = 1,679), 30.4 ± 10.1/14.7 ± 8.6 mmHg for grade 2 (n = 2,397), and 45.4 ± 15.1/20.7 ± 12.1 mmHg for grade 3 patients (n = 655; all p < 0.0001). In patients who underwent ambulatory blood pressure monitoring (n = 104), 24-h mean blood pressure decreased from 147.4 ± 13.8/82.1 ± 11.9 to 122.6 ± 9.1/72.8 ± 7.4 mmHg (p < 0.0001). Ankle edema was infrequent (0.2 % of patients).

Conclusion

Triple combination perindopril/indapamide/amlodipine was effectively and safely administered to a large population of high- and very high-risk hypertensive patients who had not reached target OBP values with previous treatment.     

Comparing Antihypertensive Effect and Plasma Ciclosporin Concentration between Amlodipine and Valsartan Regimens in Hypertensive Renal Transplant Patients Receiving Ciclosporin Therapy

Background

Hypertension, a major complication in kidney transplant recipients, is associated with premature death and graft loss. However, an optimal antihypertensive therapy for these patients has not been established [Chinese Clinical Trial Registry No. ChiCTR-TRC-10001071].

Objective

The aim of the present study was to evaluate the effect of amlodipine and valsartan on BP control in renal transplant patients and to analyze the correlation between cytochrome P450 (CYP) 3A5 or multidrug resistance-1 gene (MDR1) genotype and the antihypertensive effect of these two regimens.

Methods

150 renal transplant patients with stage 1 or 2 hypertension were enrolled in the trial. Patients were randomly assigned to amlodipine or valsartan. Metoprolol was added if BP was not under control after 4 weeks. BP and plasma levels of ciclosporin were monitored during the 24-week trial. CYP3A5 and MDR1 genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

The demographic features and baseline BP were similar between these two groups. During the 24-week trial, the reduction of systolic BP (SBP) was similar between the amlodipine and valsartan groups. However, the reduction of diastolic BP (DBP) was significantly greater in the amlodipine group compared with the valsartan group at 12, 16, and 24 weeks of treatment. The plasma level of ciclosporin at 2 hours of medication was significantly higher in the amlodipine group than in the valsartan group after 4 weeks of the trial. The reduction of DBP at 24 weeks was greater in the subjects with CYP3A5 *3/*3 variant than in those with CYP3A5*1/*1 variant (?13.5± 1.9mmHg vs ?8.7± 1.6mmHg, p<0.05).

Conclusion

The present study demonstrated that amlodipine produced a greater reduction of DBP than valsartan, although both amlodipine and valsartan resulted in satisfactory control of BP in patients with renal transplantation. Administration of amlodipine significantly increased the plasma concentration of ciclosporin, and its effects on BP control and ciclosporin concentration may be associated with the CYP3A5 genotype in these subjects [Chinese Clinical Trial Registry No. ChiCTR-TRC-10001071].     

Blood Pressure Effects of High-Dose Amlodipine-Benazepril Combination in Black and White Hypertensive Patients Not Controlled on Monotherapy

Background

Black hypertensive patients are more resistant to angiotensin-converting enzyme (ACE) inhibitor monotherapy than White patients. This resistance can be overcome with the combination of ACE inhibitors with diuretics or calcium-channel blockers (CCBs).

Objectives

The objective of this clinical investigation was to evaluate the antihypertensive effectiveness of monotherapy with the ACE inhibitor benazepril or the CCB amlodipine and their combination in Black and White hypertensive patients in two separate studies.

Methods

This was a post hoc analysis of data from two separate studies, pooled because of their similarities, to increase the sample size. Outpatient Black and White hypertensive patients were selected for these studies. In study H2303, 201 patients of both sexes and races, whose mean seated diastolic blood pressure (MSDBP) was ≥95 mmHg after 4 weeks of single-blind treatment with benazepril 40mg/day, were randomized into two groups. Group 1 received benazepril 40mg/day and group 2 received amlodipine/benazepril 5/40mg/day, which was uptitrated to amlodipine/benazepril 10/40 mg/day at week 4 of the study. In study H2304, 812 similar patients, whose MSDBP was ≥95 mmHg after 4 weeks of single-blind treatment with amlodipine 10 mg/day, were randomized into three groups. Group 1 received amlodipine/benazepril 10/20 mg/day, uptitrated to amlodipine/benazepril 10/40 mg/day after 2 weeks. Group 2 received amlodipine/benazepril 10/20 mg/day. Group 3 received amlodipine 10 mg/day. All three groups were followed up for 6 additional weeks.

Results

This report presents the results of post hoc analysis of pooled data from two separate but similar studies. Combination therapy resulted in greater lowering of MSDBP and mean seated systolic blood pressure (MSSBP) than monotherapy with either benazepril or amlodipine (p< 0.001). With respect to combination therapy, the combination of amlodipine/benazepril 10/20 mg/day resulted in greater blood pressure (BP) reductions in White patients than in Black patients (p<0.004). In contrast, the combination of amlodipine/benazepril 10/40 mg/day resulted in similar BP reductions in both Black and White hypertensive patients. There were no serious clinical or metabolic side effects noted, with the exception of pedal edema, which was more common with amlodipine monotherapy.

Conclusion

This study showed that combination therapy with amlodipine/benazepril is more effective in BP lowering than monotherapy with the component drugs. Black hypertensive patients are responsive to the combination of amlodipine/benazepril; however, they require higher dose combinations for BP reductions similar to those achieved in White hypertensive patients.     

Combination Therapy with Olmesartan Medoxomil and Hydrochlorothiazide

Background

The combination of olmesartan medoxomil and hydrochlorothiazide (HCTZ) [olmesartan medoxomil/HCTZ] has previously been shown to produce significantly greater SBP/DBP reductions than monotherapy with either agent alone in a randomized, double-blind, factorial study in patients with stage 2 hypertension. Compared with the evaluation of a single mean BP reduction in a patient population, determining the efficacy of an antihypertensive agent in achieving multiple BP targets provides additional information about the range of BP reductions attainable within this study population.

Objective

To conduct a secondary analysis of this study to evaluate the proportion of patients achieving combined SBP/DBP targets recommended in current hypertension treatment guidelines as well as individual SBP and DBP targets.

Methods

A total of 502 patients with DBP ≥100 and ≤115 mmHg were randomized to 8 weeks of treatment with placebo, HCTZ 12.5 or 25 mg/day, olmesartan medoxomil 10, 20, or 40 mg/day, or olmesartan medoxomil/HCTZ 10/12.5, 10/25, 20/12.5, 20/25, 40/12.5, or 40/25 mg/day. Mean baseline SBP ranged from 151.9 to 156.6 mmHg and mean baseline DBP ranged from 102.6 to 104.4 mmHg across the twelve treatment arms. The chi-squared test was used to compare the proportion of patients achieving each BP goal in each of the 11 active treatment regimens with that in the placebo group.

Results

The proportion of patients achieving an SBP <140 or <130 mmHg, DBP <90, <85, or <80 mmHg and combined SBP/DBP <140/90, <130/85, <130/80, or <120/80 mmHg typically increased with escalating dosages of olmesartan medoxomil and HCTZ when administered alone or in combination, but was always highest in those treated with the combination. As the BP goal became progressively more stringent, the proportion of patients achieving the BP goal decreased in each treatment group, although the trend toward greater reductions in patients treated with combination therapy remained intact. All combined SBP/DBP goals were achieved by a statistically significant proportion of patients (p<0.05) in the olmesartan medoxomil/HCTZ 20/25, 40/12.5, and 40/25 treatment groups.

Conclusions

A majority of patients with uncomplicated stage 2 hypertension can achieve recommended BP goals when treated with the combination of olmesartan medoxomil and HCTZ.     

Placebo Effect and Efficacy of Nebivolol in Patients with Hypertension not Controlled with Lisinopril or Losartan: A Phase IV, Randomized, Placebo-Controlled Trial

Background

Most patients with hypertension require more than one antihypertensive to achieve blood pressure (BP) control.

Objective

The purpose of this trial was to assess the efficacy and tolerability of add-on nebivolol, a vasodilatory β-blocker, in patients with untreated or poorly controlled hypertension, receiving stable therapy with lisinopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin II receptor blocker).

Study Design

This was a phase IV double-blind, placebo-controlled trial conducted from August 2008 to March 2010 (ClinicalTrials.gov identifier: NCT00734630). Patients entered a 2-week, single-blind, placebo-only washout phase, followed by a 3- to 4-week open-label lead-in phase (lisinopril, 10–20 mg/day, or losartan, 50–100 mg/day), and a 12-week randomized, double-blind add-on treatment phase with placebo or nebivolol (5–40 mg/day).

Setting

This study was conducted at 76 outpatient centers in the United States.

Patients

Participants were men and women aged 18–85 years with a diagnosis of primary hypertension and seated trough systolic BP (SBP) at screening in the range of 170–200 mmHg if untreated, 155–180 mmHg if taking 1 antihypertensive medication, or 140–170 mmHg if taking 2 antihypertensive medications.

Intervention

The intervention was 12 weeks’ treatment with nebivolol 5–40 mg/day added to a background therapy of lisinopril 10–20 mg/day or losartan 50–100 mg/day.

Main Outcome Measures

Primary and secondary efficacy parameters were changes from baseline in seated trough cuff SBP and diastolic BP (DBP) at Week 12, respectively. Tolerability was assessed by monitoring treatment-emergent adverse events (TEAEs).

Results

A total of 491 patients were randomized to receive nebivolol (n = 258) or placebo (n = 233). Efficacy analyses were conducted for 256 nebivolol and 232 placebo patients (intent-to-treat population); completion rates were 88.8 % and 85.8 %, respectively. Mean baseline SBP/DBP values were 163.1/98.2 mmHg (nebivolol) and 162.4/96.8 mmHg (placebo). Nebivolol was associated with a non-significant mean ± SD reduction in SBP (?10.1 ± 16.9 mmHg) versus placebo (?7.3 ± 15.9 mmHg, P = 0.093) and significant mean DBP reduction (?7.8 ± 10.1 mmHg vs ?3.5 ± 10.6 mmHg, P < 0.001). Subgroup analysis suggested a significant effect on DBP for patients receiving background losartan treatment (?8.1 ± 9.2 mmHg vs ?3.1 ± 9.4 mmHg, P < 0.001), but not for those receiving lisinopril (?7.6 ± 10.8 mmHg vs ?3.8 ± 11.6 mmHg, P = 0.076). A total of 28 % nebivolol-treated and 22 % placebo-treated patients reported a TEAE, the most frequent being upper respiratory tract infection (4.3 % and 2.1 %, respectively), bradycardia (2.7 % and 0 %), headache (2.3 % and 2.1 %), and nasopharyngitis (2.3 % and 0.9 %).

Conclusion

These data suggest that nebivolol, when added to lisinopril or losartan, results in an additional BP reduction; however, only the effect on DBP reached statistical significance. A subanalysis suggests that the effect on DBP may be stronger in losartan-treated than lisinopril-treated patients. A relatively strong placebo effect may limit data interpretation. Nebivolol was well tolerated, as there was no difference in TEAEs between nebivolol and placebo.

Funding

This trial (NCT00734630) was funded by Forest Laboratories, Inc.     

Triple-Combination Therapy with Olmesartan, Amlodipine, and Hydrochlorothiazide in Black and Non-Black Study Participants with Hypertension

Background Although awareness of hypertension in Black patients has increased, blood pressure (BP) is frequently inadequately controlled. Objective This prespecified subgroup analysis of the TRINITY study evaluated the efficacy and safety of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the component dual-combination treatments in Black and non-Black study participants. Study Design TRINITY was a 12-week, randomized, double-blind, parallel-group evaluation. The first patient was enrolled in May 2008 and the last patient completed the study in February 2009. The study consisted of a 3-week washout period for participants receiving antihypertensive therapy and a 12-week double-blind treatment period. For the treatment phase, all study participants were stratified by age, race, and diabetes mellitus status and randomized to a treatment sequence that led to their final treatment assignment, which they received from weeks 4 to 12 (OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg). In the first 2 weeks of the double-blind treatment period, all participants received either dual-combination treatment or placebo. Participants assigned to dual-combination treatment continued treatment until week 4, and participants receiving placebo were switched at week 2 to receive one of the dual-combination treatments until week 4. At week 4, participants either continued dual-combination treatment or randomly received triple-combination treatment until week 12. Setting 317 clinical sites in the USA and Puerto Rico were included in the study. Patients Study participants eligible for randomization (N = 2492) were ≥18 years of age with mean seated blood pressure (SeBP) ≥140/100 mmHg or ≥160/90 mmHg (off antihypertensive medication). Intervention The intervention was with dual- or triple-combination antihypertensive treatment: OM 40 mg/AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg. Main Outcome Measure The primary efficacy variable was the change in least squares (LS) mean seated diastolic BP (SeDBP) from baseline to week 12. Secondary efficacy variables included the LS mean change in seated systolic BP (SeSBP), percentage of study participants reaching BP goal, and safety parameters. >Results In both Black and non-Black participants, triple-combination treatment resulted in significant and similar mean reductions in SeDBP and SeSBP (p≤0.0001 vs each dual-combination treatment) with a greater proportion of participants reaching BP goal compared with dual-combination treatments, regardless of race. Most treatment-emergent adverse events were mild or moderate in severity and no new safety concerns were identified. Conclusion Triple-combination treatment provided greater BP reductions than dual-combination treatments regardless of race. Clinical Trial Registration Registered at ClinicalTrials.gov as NCT00649389.     

Blood Pressure-Lowering Response to Amlodipine as a Determinant of the Antioxidative Activity of Small, Dense HDL3

Background and Objective

High-density lipoproteins (HDLs) exert multiple antiatherogenic activities including protection of low-density lipoproteins (LDLs) from oxidative stress. Beneficial effects of calcium channel blockers on cardiovascular disease may in part be related to the reduction of oxidative stress, potentially enhancing the antioxidative activity (AOX) of HDLs. This study aimed to assess the effect of 1 month’s treatment with amlodipine on HDL AOX in hypertensive subjects.

Methods

This was a prospective trial of amlodipine 10 mg/day administered for 1 month in primary-care patients with hypertension (n = 28), 46% of whom were obese and 57% of whom displayed the metabolic syndrome. The main outcome measure was HDL AOX, assessed as the capacity of small, dense HDL3c particles to attenuate LDL oxidation induced in vitro by an azo initiator (AAPH).

Results

Mean (±SD) systolic (SBP) and diastolic (DBP) BP were reduced by amlodipine by 22.1mmHg (±13.2) and 10.4mmHg (±7.5), respectively (p<0.001). Body mass index, waist circumference, and plasma levels of triglycerides, cholesterol, and fasting blood glucose did not change significantly. Amlodipine treatment did not modify HDL3c AOX in the whole study population; changes in AOX were, however, positively correlated with SBP (r = 0.37, p = 0.05 for maximal diene concentration; r = 0.34, p = 0.08 for LDL oxidation rate). When the population was divided into two subgroups according to the BP response to amlodipine (change in SBP below or above the median), HDL3c AOX was significantly improved in hyperresponders (BP-lowering response >22/10 mmHg) as compared with hypo-responders (BP-lowering response <22/10mmHg: mean [± SD] change in the LDL oxidation rate in the presence of HDL3c, ?6.8% [± 11.2] vs +1.9% [±5.2], respectively, p = 0.04; maximal diene concentration, ?8.6% [±13.0] vs +1.9% [±8.2], respectively, p<0.05). By contrast, neither plasma concentrations of oxidized LDL, a marker of systemic oxidative stress, nor the chemical composition of HDL3c were modified between the subgroups.

Conclusions

In hypertensive patients, amlodipine treatment enhanced HDL AOX in subjects who had a BP reduction that exceeded the median response. This effect appears to be secondary to the hypotensive effect, rather than to the direct antioxidant properties, of the drug.     

Efficacy of Olmesartan Medoxomil and Hydrochlorothiazide Fixed-Dose Combination Therapy in Patients Aged 65 Years and Older with Stage 1 and 2 Hypertension or Isolated Systolic Hypertension

Background: The incidence of hypertension, particularly isolated systolic hypertension, increases with in-creasing age, as does the risk of fatal cardiovascular disease. A combination antihypertensive therapy regimen may be required to reach recommended BP goals in older patients. Objectives: This study set out to report blood pressure (BP) data in elderly patients across the subgroups of stage 1 and stage 2 hypertension (prespecified subgroup) and isolated systolic hypertension (ISH) [post hoc]. Design and Setting: This was a subgroup analysis of a prospective, open-label study carried out in a multicenter, outpatient setting (e.g. the BeniSILVER [Benicar Efficacy: New Investigation Shows OM Treatment Increasingly Leads to Various Elderly Populations to Safe BP Reductions; ClinicalTrials.gov identifier: NCT00412932] study). The study included 176 patients with a mean age of approximately 72 years; stage 1 hypertension, 60, stage 2 hypertension, 116, and ISH, 98. Intervention: After a 2- to 3-week placebo run-in period, patients were uptitrated every 3 weeks from olmesartan medoxomil (OM) 20 mg daily to OM 40 mg, OM/hydrochlorothiazide (HCTZ) 40 mg/12.5 mg, and OM/HCTZ 40 mg/25 mg, if seated cuff BP (SeBP) was ≥120/70 mmHg. Measurements: Measurements included change from baseline in mean 24-hour ambulatory BP and SeBP after 12 weeks of treatment, percentage of patients achieving a cumulative SeBP goal of <140/90mmHg (stage 1 and stage 2 cohorts) or seated cuff systolic BP (SeSBP) goal of <140 mmHg (ISH cohort), and the incidence of adverse events (AEs). Results: Combination therapy was required by 159 patients. Changes from baseline in mean 24-hour ambulatory BP (±standard deviation [SD]) were ?24.2 (± 11.8)/?11.8 (± 6.9) mmHg, ?26.5 (± 11.8)/?12.6 (± 6.7) mmHg, and ?24.7 (? 12.5)/?11.2 (± 6.4) mmHg in the stage 1, stage 2, and ISH cohorts, respectively (all p< 0.001 vs baseline). Mean SeBP changes (± SD) from baseline in patients titrated to OM/HCTZ 40 mg/25 mg were ?24.6 (± 11.4)/?10.5 (± 7.3) mmHg in the stage 1 cohort, ?26.4 (± 17.2)/?11.3 (±9.7) mmHg in the stage 2 cohort, and ?21.5 (± 15.6)/?6.8 (± 7.8) mmHg in the ISH cohort (all p <0.001). The cumulative proportions of patients achieving an SeBP goal of <140/90mmHg by week 12 were 88.3%, 56.0%, and 72.4% in the stage 1, stage 2, and ISH cohorts, respectively, while 72.4% of patients achieved an SeSBP of <140 mmHg in the ISH cohort. Treatment-emergent AEs ranged from 32.3% to 32.8%, with <3% of patients reporting drug-related hypotension. Conclusion: An OM/HCTZ-based titration regimen enabled elderly patients with hypertension to safely reduce BP throughout the 24-hour dosing interval and allowed the majority of these patients to achieve a BP target of <140/90 mmHg or <140 mmHg.     

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).

     

Physiologically Based Pharmacokinetic Modeling of Fimasartan,Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials

Purpose

To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug–drug interaction (DDI) potentials.

Methods

The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model.

Results

The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide.

Conclusions

The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.

     

氨氯地平为基础的不同用药方案治疗原发性高血压的疗效观察

目的:探讨氨氯地平联合复方阿米洛利或替米沙坦治疗原发性高血压的临床疗效和安全性.方法:采用随机开放对照盲终点评估的方法,入选原发性高血压患者180例,随机分为氨氯地平+复方阿米洛利(阿米洛利组)和氨氯地平+替米沙坦组(替米沙坦组),均服药12周,观察血压、降压达标率、有效率、不良反应,检测脉搏波速度(Pulse wave velocitv PWV)、生化指标结果:治疗12周后,阿米洛利组和替米沙坦组之间收缩压和舒张压下降幅度差异无统计学意义(P＞0.05).两组降压达标率、有效率和不良反应率之间差异无统计学意义(P＞0.05).治疗前后两组患者双侧PWV均明显下降(P＜0.05).治疗后替米沙坦组尿酸水平明显下降(P＜0.05).结论:氨氯地平联合复方阿米洛利或替米沙坦均能显著降低原发性高血压患者血压,耐受性好,不良反应少.两组均能有效改善患者动脉僵硬程度,替米沙坦组能更好的降低患者尿酸水平.     

Amlodipine Fatality in an Infant with Postmortem Blood Levels

Introduction

Amlodipine is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris. Toxic effects reported from amlodipine include hypotension, reflex tachycardia, metabolic acidosis, and pulmonary edema. We report a rare fatality in an infant after ingestion of amlodipine with benazepril, with postmortem blood concentrations.

Case report

An 11-month-old, 10.88-kg boy ingested 10 to 45?mg amlodipine with 40 to 180?mg benazepril. No action was taken initially because the parents believed only one or two capsules had been ingested. A later count revealed a maximum of nine capsules missing. The child was observed at home and vomited once with possible capsule fragments. Forty-five minutes post-ingestion, the child was noted to be suddenly unresponsive and was brought the local emergency department by a private vehicle. Upon arrival (90?min post-ingestion), the child was unresponsive with the following vital signs HR 133?bpm, BP 67/42?mmHg, respiratory rate 40/min, and temperature 97.5°F. Pertinent abnormal laboratory values were HCO₃ 13?mmol/l and glucose 302?mg/dl. The child was placed on oxygen via a non-rebreather mask and was intubated 45?min post-arrival. The patient became progressively bradycardic, and 55?min after arrival, the patient was in asystole with no palpable blood pressure. Resuscitation measures included chest compressions, epinephrine atropine, sodium bicarbonate, and calcium gluconate. Rescue insulin therapy was begun with 4?units IVP followed by 10?units per hour. Resuscitation efforts persisted for 1?h without success. An autopsy revealed pulmonary edema and no gross or microscopic evidence of natural disease. Stomach contents revealed food matter with small white fragments. Analysis of postmortem heart blood showed amlodipine 1,300?ng/ml (therapeutic <20?ng/ml). Benazepril levels were not available.

Discussion

We believe this is the first reported fatality in an infant from amlodipine. While benazepril may have contributed, ACE inhibitors have not been previously associated with rapid cardiovascular collapse.

Conclusion

Small doses of amlodipine (0.9 to 4.1?mg/kg) may produce rapid and fatal cardiovascular collapse in an infant.