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.     

Economic impact of switching from valsartan to other angiotensin receptor blockers in patients with hypertension

Abstract

Background:

The approaching availability of lower-cost generic angiotensin receptor blockers (ARBs) may affect formulary policies for patients maintained on the ARB valsartan.     

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.     

Antihypertensive efficacy of olmesartan medoxomil or valsartan in combination with amlodipine: A review of factorial-design studies

ABSTRACT

Background: Most patients with hypertension require more than one drug to attain recommended blood pressure (BP) targets. Initiating therapy with two agents is recommended for patients at high risk of a cardiovascular event or with a BP?>?20/10?mmHg above goal. Combination therapy is effective when comprised of agents with complementary mechanisms of action, such as calcium channel blockers (CCBs) and angiotensin II-receptor blockers (ARBs). Two fixed-dose CCB/ARB combinations are approved in the US: amlodipine/valsartan (AML/VAL) and amlodipine/olmesartan medoxomil (AML/OM).

Objectives: To review and describe the efficacy of AML/VAL and AML/OM combinations by discussing similarly designed clinical trials.

Methods: Three 8-week, randomized, double-blind, placebo-controlled, parallel-group factorial-design studies were examined (two AML/VAL; one AML/OM). The study endpoints presented in this review were: change from baseline in least-squares mean seated diastolic BP (SeDBP) and least-squares mean seated systolic BP (SeSBP). In addition to the efficacies of AML/VAL and AML/OM combinations, the efficacies of AML, VAL and OM administered as monotherapy are presented. Placebo-subtracted BP reductions were calculated for this review.

Results: Patient demographics were similar but mean baseline SeBP was higher in the OM study (163.8/101.6?mmHg) than in the VAL studies (152.8/99.3 and 156.7/99.1?mmHg), possibly suggesting that the OM study included a more difficult-to-treat patient population. AML/ARB combinations consistently produced greater mean SeBP reductions than monotherapy. Least squares (LS) mean SeDBP reductions were 19.4?mmHg (AML/OM 10/40?mg; placebo-corrected: 15.9?mmHg) and 18.6?mmHg (AML/VAL 10/320?mg; placebo-corrected: 9.8?mmHg). LS mean SeSBP reductions were 28.5?mmHg (AML/OM 10/40?mg; placebo-corrected: 25.7?mmHg) and 28.4?mmHg (AML/VAL 10/320?mg; placebo-corrected: 15.5?mmHg).

Conclusions: This review of published factorial-design studies showed that the maximal marketed doses of an amlodipine/olmesartan medoxomil combination (10/40?mg) and an amlodipine/valsartan combination (10/320?mg) produced large reductions in BP from baseline. Limitations of this review include the small number of studies analyzed and the inherent heterogeneity between patient populations. Further research is warranted to directly compare the efficacy of these combinations in a randomized, controlled trial, or additional published clinical trials are required to provide larger data sets for robust meta-analyses and to overcome heterogeneity observed within these studies.     

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.     

苯磺酸氨氯地平联合缬沙坦治疗高血压疗效分析

目的：探讨苯磺酸氨氯地平联合缬沙坦治疗高血压的临床疗效。方法：回顾性分析2009年8月～2011年4月本院收治的213例高血压患者,随机分为3组,苯磺酸氨氯地平组（氨氯地平5mg,每天1次）、缬沙坦组（缬沙坦80mg,每天1次）及联合用药组（氨氯地平5mg,缬沙坦80mg,每天1次）,比较3组的临床疗效及不良反应。结果：治疗后,联合用药组显效率及总有效率分别为63.4%、93.0%,均显著高于苯磺酸氨氯地平组（43.7%、78.9%）及缬沙坦组（40.8%、77.5%）（P〈0.05）。治疗期间,3组均出现头痛,患者均能耐受,继续服药头痛缓解,未停药。结论：苯磺酸氨氯地平联合缬沙坦治疗高血压,临床疗效显著优于单一用药,患者耐受性好,并发症少,值得临床推广应用。     

社区门诊非洛地平联合缬沙坦治疗高血压83例临床分析

目的：观察非洛地平联合缬沙坦治疗高血压的临床疗效。方法：选取2008年1月～2009年12月本社区内科门诊的高血压患者166例,将其按双盲随机法分为对照组和观察组,观察组（83例）应用非洛地平联合缬沙坦治疗,对照组（83例）单纯应用非洛地平治疗。观察治疗前及治疗8周后血压的变化。结果：对照组和观察组的总有效率分别为61.4%和95.2%,观察组的临床疗效明显高于对照组,两组差异有统计学意义（P〈0.05）。结论：非洛地平联合缬沙坦治疗高血压疗效显著,值得在社区门诊临床中予以推广应用。     

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.     

Evaluation of compliance and health care utilization in patients treated with single pill vs. free combination antihypertensives

Abstract

Objectives:

To compare compliance/persistence, health care resource utilization, and costs associated with single-pill combination (SPC) vs. free-combination (FC) therapies among adult hypertension patients at the national and state level. Combination therapies with angiotensin receptor blocker (ARB)?+?calcium channel blocker, ARB?+?hydrochlorothiazide, and angiotensin-converting enzyme inhibitor?+?hydrochlorothiazide were evaluated.     

Efficacy of zofenopril in combination with amlodipine in patients with acute myocardial infarction: a pooled individual patient data analysis of four randomized,double-blind,controlled, prospective studies

Objective: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients.

Methods: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes.

Results: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR?=?0.66; and 95% confidence interval, CI?=?0.44–0.98; p?=?.039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR?=?0.78; 95% CI?=?0.63–0.97; p?=?.026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR?=?0.76; 95% CI?=?0.61–0.94); p?=?.013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering.

Conclusions: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1?year.     

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.     

缬沙坦联用依那普利对高血压患者心功能及左心室肥厚的影响

目的探讨缬沙坦联用依那普利,对高血压患者心功能及左心室肥厚的影响。方法45例高血压患者随机分为治疗组23例和对照组22例,观察2组血压,采用彩色超声心动图测定治疗前及治疗12个月后左心功能及左心室参数变化,观察临床疗效及不良反应。结果治疗组治疗后每搏输出量（SV）、每分输出量（CO）、左室射血分数（LVEF）均高于治疗前和对照组（P〈0.05）;左室舒张未期内径（LVDd）、左室收缩未期内径（LVSd）、左室质量指数（LVMI）均下降,与治疗前及对照组比较,差异有统计学意义（P〈0.05）。结论缬沙坦联用依那普利,改善高血压患者心功能及左室肥厚作用优于单独应用依那普利。     

Long-term safety and efficacy of aliskiren and valsartan combination with or without the addition of HCT in patients with hypertension

Abstract

Objective:

To assess the long-term safety and antihypertensive efficacy of aliskiren/valsartan 300/320?mg combination.     

Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease: results of a pooled analysis of two randomized,double-blind,placebo-controlled trials in Japan

Background: With the increase in the aging population, there is a pressing need to provide effective treatment options for individuals with Alzheimer's disease (AD). Memantine is an N-methyl-D-aspartate receptor antagonist used to treat AD in > 80 countries worldwide, and studies in the USA and Europe have shown it to be effective in improving language deficits; however, there are currently no data on language improvements in Japanese patients treated with memantine.

Objectives: To clarify the efficacy and safety of memantine in Japanese outpatients with moderate to severe AD, using a pooled analysis of two multicenter randomized placebo-controlled trials, a phase 2 dose-finding study and a phase 3 study.

Results: The final analysis comprised 633 patients (318 receiving memantine and 315 placebo). Memantine produced better outcomes in terms of Severe Impairment Battery-Japanese version, Clinician's Interview-Based Impression of Change plus-Japanese version, Behavioral Pathology in AD Rating Scale, and language scores, versus placebo. The overall incidence of adverse events and adverse reactions was similar between groups.

Conclusion: In this pooled analysis of Japanese patients, memantine achieved better outcomes than placebo in terms of cognition, including attention, praxis, visuospatial ability and language, and behavioral and psychological symptoms, including activity disturbances and aggressiveness.     

Antihypertensive efficacy of olmesartan medoxomil alone and in combination with hydrochlorothiazide

Angiotensin receptor blockers (ARBs) are highly effective antihypertensive agents with excellent safety profiles. ARBs have been shown to improve cardiovascular morbidity and mortality in hypertensive patients with heart failure or diabetic nephropathy. For this later class of patients, the American Diabetes Association recommends ARBs as the primary treatment option. The ARBs function by blocking the binding of angiotensin-II (A-II) to its receptor, thereby inhibiting the action of A-II. Unlike the angiotensin-converting enzyme (ACE) inhibitors, which block the production of A-II through the ACE pathway, the ARBs effectively inhibit A-II regardless of whether it is produced through ACE or some alternate enzyme pathway. This difference in action offers a distinct advantage of ARBs over ACE inhibitors. Olmesartan medoxomil, the latest addition to the ARB class, is a long-acting, safe and well-tolerated antihypertensive drug. The combination of olmesartan medoxomil with a low-dose diuretic, potentiates the blood pressure lowering effect of either agent alone and is highly effective in achieving the recommended blood pressure goals in the majority of patients treated.     

Effects of demographics on the antihypertensive efficacy of triple therapy with amlodipine,valsartan, and hydrochlorothiazide for moderate to severe hypertension

Abstract

Objective:

To compare the antihypertensive efficacy and safety of once-daily triple therapy with amlodipine (Aml) 10?mg, valsartan (Val) 320?mg, and hydrochlorothiazide (HCTZ) 25?mg versus dual-therapy combinations of these components in patients with moderate to severe hypertension.     

Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: a pooled analysis of two 6-week, double-blind, placebo-controlled studies

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD. The primary endpoint was Montgomery-?sberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330). The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%). Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.