Efficacy and tolerability of a switch to fixed-dose combination therapy with amlodipine besylate/benazepril hydrochloride after monotherapy with amlodipine besylate: Data from the African-American subpopulation of a practice-based, open-label study (the LOGIC study)

Background: The LOGIC (LOtrel: Gauging Improved Control) study assessed the efficacy and tolerability of switching from amlodipine besylate monotherapy to fixed-dose combination therapy with amlodipine besylate/benazepril hydrochloride (HCI) in patients who were experiencing uncontrolled blood pressure (BP) or edema with monotherapy.Objective: This article reports the efficacy and tolerability of amlodipine besylate/benazepril HCI combination therapy in the predefined African-American population of the LOGIC study.Methods: This multicenter (1518 centers across the United States), practice-based, open-label, clinical trial enrolled patients with mild to moderate essential hypertension. Patients in group 1 had uncontrolled BP (sitting diastolic BP [DBP] ≥90 mm Hg and ≤110 mm Hg) during treatment with amlodipine besylate monotherapy 5 or 10 mg/d, and those in group 2 had controlled BP (sitting DBP ⩽90 mm Hg), but also had experienced edema during amlodipine besylate monotherapy. Participants were instructed to discontinue amlodipine besylate and were given amlodipine besylate/benazepril HCl 5/10 mg/d or 5/20 mg/d for 4 weeks. For group 1, the primary efficacy outcome was the change in mean sitting DBP (MSDBP) from baseline to week 4; a secondary efficacy outcome was the change in mean sitting systolic BP (MSSBP) from baseline to week 4. The primary efficacy outcome for group 2 was the percentage of patients whose edema improved with the switch to combination therapy. The secondary efficacy variables in group 2 were the changes in MSDBP and MSSBP from baseline to week 4. Patients in groups 1 and 2 were questioned about any adverse events that may have occurred since the previous visit. At both study visits, medications were reviewed, and the level of edema was assessed.Results: A total of 2055 African-American patients were enrolled in the study. At study end, African-American patients in group 1 (n = 1422 assessable patients) experienced significant reductions in MSSBP (13.9 mm Hg) and MSDBP (10.4 mm Hg) from those achieved during amlodipine besylate monotherapy (both P < 0.001). In group 2 (n = 266 assessable patients), 81% of African-American patients reported improvement in edema, and BP remained well controlled.Conclusions: In this study of an African-American subpopulation of patients with mild to moderate essential hypertension who had uncontrolled BP while receiving amlodipine besylate monotherapy, switching from amlodipine besylate monotherapy to fixed-dose amlodipine besylate/benazepril HCl combination therapy reduced BP to a greater extent than with amlodipine besylate alone, and reduced the incidence of edema in patients who were edematous but who had controlled BP. Fixed-dose combination therapy with amlodipine besylate/benazepril HCI has the potential to improve BP control, leading to improved clinical outcomes and enhanced treatment compliance.     

When antihypertensive monotherapy fails: fixed-dose combination therapy

BACKGROUND: Antihypertensive monotherapy fails to control blood pressure in many patients. METHODS: Data on the efficacy and tolerance of fixed dose angiotensin-converting enzyme (ACE) inhibitor/calcium antagonist combinations were reviewed, since they are the most widely prescribed medications for hypertension. RESULTS: A fixed-dose combination of two drug classes is an option for hypertension treatment. Four fixed-dose ACE inhibitor/calcium antagonist combinations are available. They achieve superior blood pressure control with no increase in adverse events compared with their monotherapy components. In addition, they antagonize some class-specific adverse effects and may exhibit beneficial effects on target organ disease, such as renal dysfunction and left ventricular hypertrophy. CONCLUSIONS: Fixed-dose combination therapy is an attractive option when reasonable doses of initial antihypertensive monotherapy fail. Use of such combinations could increase patient compliance, by virtue of better tolerance compared with increased-dose monotherapy and simplicity of administration.     

I-ADD Study: Assessment of Efficacy and Safety Profile of Irbesartan/Amlodipine Fixed-Dose Combination Therapy Compared With Irbesartan Monotherapy in Hypertensive Patients Uncontrolled With Irbesartan 150 mg Monotherapy: A Multicenter, Phase III, Prospective, Randomized, Open-Label With Blinded-End Point Evaluation Study

BackgroundHypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker.ObjectiveThe I-ADD study aimed to demonstrate whether the antihypertensive efficacy of fixed-dose combination irbesartan 300 mg/amlodipine 5 mg (I300/A5) was superior to that of irbesartan (I300) monotherapy in lowering home systolic blood pressure after 10 weeks' treatment.MethodsThe I-ADD study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded–end point study. The main inclusion criterion was essential uncontrolled hypertension (systolic blood pressure ≥145 mm Hg at office after at least 4 weeks of irbesartan 150 mg [I150] monotherapy administered once daily). Patients continued to receive I150 for 7 to 10 days and were randomized to either monotherapy with I150 for 5 weeks then I300 for the next 5 weeks, or to a fixed-dose combination therapy (I150/A5, then I300/A5). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator.ResultsFollowing enrollment, 325 patients were randomized to treatment, and 320 (mean [SD] age, 56.7 [11.4] years; 41% male) were included in the intention-to-treat analysis: 155 patients treated with I150/A5 then I300/A5, and 165 patients treated with I150 then I300. At randomization, mean home systolic blood pressure was similar in both groups: 152.7 (11.8) mm Hg in the I150/A5 group and 150.4 (10.1) mm Hg in the I150 group. At week 10, the adjusted mean difference in home systolic blood pressure between groups was –8.8 (1.1) mm Hg (P < 0.001). The percentage of controlled patients (mean home blood pressure <135 and 85 mm Hg) was nearly 2-fold higher in the I300/A5 group versus the I300 group (P < 0.001). Treatment-emergent adverse events were experienced by 10.5% of I300/A5-treated patients and 6.6% of I300-treated patients during the second 5-week period. Three serious adverse events were reported; 2 with monotherapy (1 with I150 and 1 with I300) and 1 with fixed-dose combination I300/A5. All patients affected by serious adverse events made a full recovery.ConclusionsThese 10-week data from this patient population suggest a greater antihypertensive efficacy of the fixed-dose combination I300/A5 over I300 alone in lowering systolic blood pressure. Both treatments were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00957554.     

Review: a single-pill combination of telmisartan plus amlodipine for the treatment of hypertension

Despite an increased proportion of patients with hypertension achieving recommended blood pressure (BP) targets, BP control remains suboptimal in many patients. A range of combination therapies utilizing medications with differing mechanisms of action have been shown to provide superior BP-lowering efficacy than monotherapy with individual components. Single-pill combinations deliver improved convenience and may help to improve patient compliance. A single-pill combination of the angiotensin receptor blocker (ARB) telmisartan and the calcium channel blocker (CCB) amlodipine has recently been approved in 4 different doses (telmisartan/amlodipine 40 mg/5 mg, 40 mg/10 mg, 80 mg/5 mg, and 80 mg/10 mg) for antihypertensive use in the United States. In an 8-week clinical study (N = 1461), these combinations were superior to monotherapy with telmisartan or with amlodipine with respect to the primary endpoint, change in diastolic BP (DBP) from baseline (mean baseline BP, 153.2 [± 12.1]/101.7 [± 4.3] mm Hg) to study end (placebo-corrected reductions of 10.3, 14.0, 12.0, and 13.9 mm Hg, respectively), as well as in multiple secondary endpoints, including change in systolic BP (SBP), DBP response, SBP response, BP control (< 140/< 90 mm Hg), and DBP control (< 90 mm Hg). The telmisartan plus amlodipine combinations were well tolerated, with the incidence of adverse events similar to placebo; the incidence of peripheral edema was lower with the 40 mg/10 mg and 80 mg/10 mg combinations than with amlodipine 10 mg alone. In another study (N = 858), the highest-dose combination (80 mg/10 mg) demonstrated superior BP-lowering efficacy than same-dose monotherapy with either telmisartan or amlodipine in patients with severe hypertension (SBP ≥ 180 and DBP ≥ 95 mm Hg). Single-pill telmisartan plus amlodipine combination therapy appears to be an effective and well-tolerated treatment as initial therapy for patients likely to require > 1 antihypertensive agent to reach BP targets.     

Rational pharmacotherapy of hypertension in the elderly: analysis of the choice and dosage of drugs

OBJECTIVES: To determine in older people with uncomplicated hypertension: (a) the pattern of prescribing of antihypertensives; (b) the extent of physicians' adherence to recommendations on dosage for antihypertensive combinations; (c) whether prescribing practice conforms with recommended therapeutic guidelines; and (d) the frequency of prescribing of other drugs which have the potential to alter the efficacy of antihypertensive agents. METHODS: A survey of prescribing in older patients with uncomplicated hypertension in primary care setting of Bahrain was conducted. RESULTS: Of the 432 (56.5%) patients on monotherapy, 192 (44.4%) were treated with beta-blockers, 87 (20.1%) with calcium channel blockers (CCBs), 53 (12.3%) with alpha-methyldopa, 47 (10.9%) with diuretics, 46 (10.6%) with angiotensin converting enzyme (ACE) inhibitors, and 7 (1.6%) with hydralazine. Of the 1146 patients on mono- or combination therapies, 434 (56.8%) were treated with beta-blockers, 244 (31.9%) with diuretics, 211 (27.6%) with CCBs, 139 (18.2%) with ACE inhibitors, 103 (13.5%) with alpha-methyldopa 8 (1.0%) with brinerdine and 7 (0.9%) with hydralazine. In the 332 (43.5%) patients on combination therapy, 15 different two- and three-antihypertensive drug combinations were prescribed: a diuretic with a beta-blocker (37.2%) and a beta-blocker with either a CCB (20.9%) or an ACE inhibitor (12.4%) were the most popular two-drug regimens. The most commonly prescribed triple drug regimens were a diuretic and a beta-blocker plus either a CCB (26.1%) or an ACE inhibitor (17.4%) and diuretic plus an ACE inhibitor and a CCB (15.2%). Daily dosage of beta-blockers, ACE inhibitors and alpha-methyldopa were somewhat high in a considerable proportion of patients on both mono- and combined therapies. A substantial proportion (9.7%) of patients on monotherapy were treated with immediate release nifedipine. CONCLUSION: The pharmacotherapy of hypertension in elderly patients was found in some instances not to conform to recommended guidelines. For certain classes of antihypertensive agent such as beta-blockers, ACE inhibitors and alpha-methyldopa, neither the principles of geriatric pharmacology nor of antihypertensive combination therapy, and in particular, the need to reduce daily dosage, were followed. The use of immediate release nifedipine in the elderly is irrational, and instead, the use of long-acting dihydropyridine CCBs should be considered. The results of long-term randomized clinical trials published during the last decade have had a minimal impact on clinical practice of primary care physicians in Bahrain.     

Treatment with aliskiren/amlodipine combination in patients with moderate-to-severe hypertension: a randomised, double-blind, active comparator trial

Aims: To assess the extent of reduction in blood pressure (BP) of aliskiren/amlodipine combination therapy compared with amlodipine monotherapy in moderate‐to‐severe hypertensive patients. Methods: This was an 8‐week multicentre, randomised, double‐blind study. After a 1‐to 4‐week washout period, eligible patients [mean sitting systolic blood pressure (msSBP) ≥ 160 to < 200 mmHg] were randomised to receive a once‐daily dose of aliskiren/amlodipine 150/5 mg (n = 244) or amlodipine 5 mg (n = 241) for 1 week, followed by up‐titration to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. Efficacy outcome measures included change from baseline to week 8 endpoint in msSBP (primary endpoint), mean sitting diastolic blood pressure (msDBP), and BP control rate (< 140/90 mmHg). Safety was assessed by monitoring and recording all adverse events (AEs) and laboratory abnormalities. Results: Patients’ demographic characteristics were balanced between the two groups, mean baseline BP being 171.0/94.3 mmHg for aliskiren/amlodipine and 171.8/95.6 mmHg for amlodipine. Of 485 randomised patients, 433 (89.3%) completed the study. At week 8 endpoint, combination therapy resulted in significantly greater msSBP/msDBP reductions and BP control rate, compared with monotherapy (all: p ≤ 0.0001). The overall incidence of AEs was similar between the two groups. The most commonly reported AE was peripheral oedema with the incidence lower for combination therapy (14.4%) than for monotherapy (18.3%). Conclusion: In this population with considerably elevated BP, use of aliskiren/amlodipine combination showed significantly greater BP reductions and allowed more patients to achieve BP control compared with amlodipine monotherapy, with no additional safety concerns.     

Efficacy and safety of angiotensin II type 1 receptor blocker/calcium channel blocker combination therapy for hypertension: focus on a single-pill fixed-dose combination of valsartan and amlodipine

Adequate lowering of blood pressure reduces the risk of hypertension-induced cardiovascular events. Worldwide, blood pressure is not optimally controlled and more effective management is needed. The efficacy and tolerability of angiotensin II type 1 receptor blockers (ARBs) have led to their widespread use. Calcium channel blockers (CCBs) are highly effective antihypertensives and amlodipine has a long half-life in the circulation. The combination of an ARB with a CCB as a single-pill, fixed-dose treatment is emerging as possibly the best therapy for preventing cardiovascular disease. Although many kinds of ARB are used in such combinations, amlodipine is mainly used as the CCB. Thus, differences in safety and efficacy among single-pill ARB/CCBs depend mainly on the ARB. Not all ARBs have the same effects and some of these may be molecular (or differential) rather than class (or common) effects. This review discusses the safety and efficacy of ARB/CCB combination therapy, with particular focus on a single-pill, fixed-dose combination of valsartan/amlodipine.     

Antihypertensive therapy and incidence of type 2 diabetes in an elderly cohort

OBJECTIVE: The aim of this study was to determine whether the incidence of type 2 diabetes differed among elderly users of four major antihypertensive drug classes. RESEARCH DESIGN AND METHODS: This was a retrospective, observational cohort study of previously untreated elderly patients (aged > or = 66 years) identified as new users of an antihypertensive drug class between April 1995 and March 2000. Using a Cox proportional hazards model, the primary analysis compared diabetes incidence in users of ACE inhibitors, beta-blockers, and calcium channel blockers (CCBs), with thiazide diuretics allowed as second-line therapy. In the secondary analysis, thiazide diuretics were added as a fourth study group. RESULTS: In the multivariable-adjusted primary analysis (n = 76,176), neither ACE inhibitor use (hazard ratio 0.96 [95% CI 0.84-1.1]) nor beta-blocker use (0.86 [0.74-1.0]) was associated with a statistically significant difference in type 2 diabetes incidence compared with the CCB control group. In the secondary analysis (n = 100,653), compared with CCB users, type 2 diabetes incidence was not significantly different between users of ACE inhibitors (0.97 [0.83-1.1]), beta-blockers (0.84 [0.7-1.0]), or thiazide diuretics (1.0 [0.89-1.2]). CONCLUSIONS: Type 2 diabetes incidence did not significantly differ among users of the major antihypertensive drug classes in this elderly, population-based administrative cohort. These results do not support the theory that different antihypertensive drug classes are relatively more or less likely to cause diabetes.     

Renoprotective effects of benazepril: current perspective

Cardiovascular (CV) disease, its associated risk factors and continued progression run in parallel with renal deterioration (cardio–renal syndrome). Most guidelines promote early treatment, including the use of ACE inhibitors to control CV risk in patients with chronic renal failure. The renoprotective effects of the ACE inhibitor, benazepril, independent of blood pressure control, have been demonstrated, as monotherapy or in combination with amlodipine or hydrochlorothiazide, in large clinical trials: Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) and Gauging Albuminuria Reduction with Lotrel in Diabetic Patients with Hypertension (GUARD) in patients with mild-to-severe chronic kidney disease. In the ACCOMPLISH trial, CV outcomes and renoprotective effects were greater in patients receiving benazepril in combination with amlodipine; the GUARD trial demonstrated that combined benazepril/hydrochlorothiazide was more effective than amlodipine combined with benazepril in reducing baseline urinary albumin:creatinine ratio and normalizing urinary albumin:creatinine ratio in patients with baseline microalbuminuria, although this effect was accompanied with a greater decrease in glomerular filtration rate than with benazepril/amlodipine. While this is not a study in patients with overt renal disease (patients had severe CV diseases), the ACCOMPLISH trial is the first large study to date to show the added benefit of combining ACE inhibitors and calcium-channel blockers in renal protection. Future large, well-controlled trials, designed to evaluate hard renal outcomes, are required to identify which patients will benefit most from particular combination treatment strategies in renoprotection.     

Renoprotective effects of benazepril: current perspective

Cardiovascular (CV) disease, its associated risk factors and continued progression run in parallel with renal deterioration (cardio-renal syndrome). Most guidelines promote early treatment, including the use of ACE inhibitors to control CV risk in patients with chronic renal failure. The renoprotective effects of the ACE inhibitor, benazepril, independent of blood pressure control, have been demonstrated, as monotherapy or in combination with amlodipine or hydrochlorothiazide, in large clinical trials: Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) and Gauging Albuminuria Reduction with Lotrel in Diabetic Patients with Hypertension (GUARD) in patients with mild-to-severe chronic kidney disease. In the ACCOMPLISH trial, CV outcomes and renoprotective effects were greater in patients receiving benazepril in combination with amlodipine; the GUARD trial demonstrated that combined benazepril/hydrochlorothiazide was more effective than amlodipine combined with benazepril in reducing baseline urinary albumin:creatinine ratio and normalizing urinary albumin:creatinine ratio in patients with baseline microalbuminuria, although this effect was accompanied with a greater decrease in glomerular filtration rate than with benazepril/amlodipine. While this is not a study in patients with overt renal disease (patients had severe CV diseases), the ACCOMPLISH trial is the first large study to date to show the added benefit of combining ACE inhibitors and calcium-channel blockers in renal protection. Future large, well-controlled trials, designed to evaluate hard renal outcomes, are required to identify which patients will benefit most from particular combination treatment strategies in renoprotection.     

Untoward effects of blood transfusion

Abstract

Hypertension affects approximately 73 million individuals in the United States. Clinical studies have shown that antihypertensive therapy can reduce blood pressure (BP) and the risk of cardiovascular events. However, the majority of patients with hypertension do not achieve the recommended BP goal of < 140/90 mm Hg (or < 130/80 mm Hg for patients with diabetes) with antihypertensive monotherapy, and require therapy with 2 or more antihypertensive agents. Combination therapy utilizes antihypertensive agents from different drug classes, which act via distinct pharmacologic mechanisms to improve overall efficacy and tolerability. Although combination therapy is superior to monotherapy in achieving BP goals across the entire spectrum of hypertension, the proportion of patients achieving the recommended BP goal can be further improved by the use of new antihypertensive drug combinations. The beneficial antihypertensive characteristics of both angiotensin receptor blockers and calcium channel blockers suggest that combining these classes may result in a highly efficacious antihypertensive therapy with regard to both activity and safety when used as a fixed-dose combination. In particular, a fixed-dose combination of olmesartan medoxomil plus amlodipine besylate has been demonstrated to be an efficacious antihypertensive combination due in part to the benefits associated with each of these agents within their respective drug classes.     

Calcium channel blockers in the treatment of hypertension and prevention of cardiovascular disease: results from major clinical trials

The ability of antihypertensive agents such as ss-blockers and thiazide and thiazide-like diuretics to reduce the risk of cardiovascular disease is well documented. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was undertaken to determine whether the newer classes of antihypertensive drugs-namely, calcium channel blockers (CCBs), alpha-1 blockers, and angiotensinconverting enzyme (ACE) inhibitors-were as effective as the older agents in preventing cardiovascular events. The results of ALLHAT showed that the diuretic chlorthalidone, the CCB amlodipine, and the ACE inhibitor lisinopril were equally effective in preventing the primary outcome-fatal coronary heart disease or nonfatal myocardial infarction. However, chlorthalidone and lisinopril were more effective at preventing heart failure, whereas amlodipine and chlorthalidone were more effective than lisinopril at preventing stroke. The ALLHAT findings, as well as those of other large, randomized, controlled antihypertensive trials, confirm the value of lowering blood pressure as an approach to reducing the risk, incidence, and economic burden of cardiovascular disease.     

An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study

BACKGROUND: A combination of antihypertensive agents of different drug classes in a fixed-dose combination (FDC) may offer advantages in terms of efficacy, tolerability, and treatment compliance. Combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor may act synergistically to reduce blood pressure (BP). OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of an amlodipine/ramipril FDC with those of amlodipine monotherapy. METHODS: This 18-week, prospective, randomized, double-blind study was conducted at 8 centers across Brazil. Patients with stage 1 or 2 essential hypertension were enrolled. After a 2-week placebo run-in phase, patients received amlodipine/ramipril 2.5/2.5 mg or amlodipine 2.5 mg, after which the doses were titrated, based on BP, to 5/5 then 10/10 mg (amlodipine/ramipril) and 5 then 10 mg (amlodipine). The primary end point was BP measured in the intent-to-treat (ITT) population. Hematology and serum biochemistry were assessed at baseline and study end. Tolerability was assessed using patient interview, laboratory analysis, and physical examination, including measurement of ankle circumference to assess peripheral edema. RESULTS: A total of 222 patients completed the study (age range, 40-79 years; FDC group, 117 patients [mean dose, 7.60/7.60 mg]; monotherapy, 105 patients [mean dose, 7.97 mg]). The mean (SD) changes in systolic BP (SBP) and diastolic BP (DBP), as measured using 24-hour ambulatory blood pressure monitoring (ABPM) and in the physician's office, were significantly greater with combination therapy than monotherapy, with the exception of office DBP (ABPM, -20.76 [1.25] vs -15.80 [1.18] mm Hg and -11.71 [0.78] vs -8.61 [0.74] mm Hg, respectively [both, P = 0.004]; office, -27.51 [1.40] vs -22.84 [1.33] mm Hg [P = 0.012] and -16.41 [0.79] vs -14.64 [0.75] mm Hg [P = NS], respectively). In the ITT analysis, the mean changes in ambulatory, but not office-based, BP were statistically significant (ABPM: SBP, -20.21 [1.14] vs -15.31 [1.12] mm Hg and DBP, -11.61 [0.72] vs -8.42 [0.70] mm Hg, respectively [both, P = 0.002]; office: SBP, -26.60 [1.34] vs -22.97 [1.30] mm Hg and DBP, -16.48 [0.78] vs -14.48 [0.75] mm Hg [both, P = NS]). Twenty-nine patients (22.1%) treated with combination therapy and 41 patients (30.6%) treated with monotherapy experienced > or =1 adverse event considered possibly related to study drug. The combination-therapy group had lower prevalence of edema (7.6% vs 18.7%; P = 0.011) and a similar prevalence of dry cough (3.8% vs 0.8%; P = NS). No clinically significant changes in laboratory values were found in either group. CONCLUSIONS: In this population of patients with essential hypertension, the amlodipine/ramipril FDC was associated with significantly reduced ambulatory and office-measured BP compared with amlodipine monotherapy, with the exception of office DBP. Both treatments were well tolerated.     

Long-term effects of candesartan and amlodipine on cardiovascular mortality and morbidity in Japanese high-risk hypertensive patients: rationale, design, and characteristics of candesartan antihypertensive survival evaluation in Japan extension (CASE-J Ex)

Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of the angiotensin II receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine on the incidence of cardiovascular (CV) events in Japanese high-risk hypertensive patients. After 3.2years follow-up, CV events rate was 17.6-17.7 per 1000 person-years in each group, which was much lower than we expected. Since it has not been known whether the same efficacy of two drugs is sustained beyond the current trial, a longer follow-up period will be needed. The Steering Committee of CASE-J trial decided to extend the trial for 3years as an observational study (CASE-J Ex). In CASE-J Ex, the primary end point is a composite of CV events and the secondary endpoints are all-cause death and new-onset diabetes. After Committee's decision, 245 doctors agreed to participate in CASE-J Ex and 2236 patients (1141 with candesartan-based regimens and 1095 with amlodipine-based regimens) were re-enrolled. The baseline characteristics of CASE-J Ex participants were similar to CASE-J participants and still balanced well between candesartan and amlodipine. Recently, the interest of antihypertensive treatment has focused to differentiation of the effects of antihypertensive agents on the incidence of CV events as well as blood pressure lowering effect. CASE-J Ex will clarify the long-term effects of ARB and CCB on CV mortality and morbidity. Additionally, because the number of diabetic patients is increased, the evidences from CASE-J Ex will be valuable.     

ARB candesartan and CCB amlodipine in hypertensive patients: the CASE-J trial

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was a comparative study of the angiotensin II receptor blocker (ARB), candesartan, and a calcium channel blocker (CCB), amlodipine, regarding the incidence of cardiovascular events in high-risk Japanese hypertensive patients. The study design was a prospective, multicenter, randomized, open-label, active-controlled, two-arm, parallel-group comparison study with a response-dependent dose titration and blinded assessment of the end point. The CASE-J trial enrolled 4728 patients, with a mean age of 63.8 years and a mean BMI of 24.6 kg/m(2), who were randomly assigned to either candesartan- or amlodipine-based treatment regimens. Blood pressure was well controlled to the level of less than 140/80 mmHg in both of the treatment regimens. During 3.2 years of follow-up, primary cardiovascular events occurred in 134 patients in each of the two treatment-based regimens, resulting in no significant difference in the incidence of cardiovascular events between them (hazard ratio: 1.01; 95% confidence interval: 0.79-1.28; p = 0.969). In 404 patients with left ventricular hypertrophy, a significantly larger decrease in left ventricular mass index 3 years after enrollment was observed in candesartan-based (n = 205) than amlodipine-based (n = 199) regimens (-22.9 vs -13.4 g/m(2), respectively; p = 0.023). Furthermore, new-onset diabetes occurred in fewer patients taking candesartan than in those taking amlodipine, resulting in a 36% relative risk reduction (p = 0.030). The CASE-J trial demonstrated that both an ARB, candesartan, and a CCB, amlodipine, equally suppressed the incidence of cardiovascular events. The ARB may confer more beneficial effects to hypertensive patients with left ventricular hypertrophy or for those at-risk of diabetes than CCB.     

Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study

BACKGROUND: Recent antihypertensive treatment guidelines recommend greater use of combination therapies. OBJECTIVES: The primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and > or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation. METHODS: This was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP <140 mm Hg or a reduction in mean sitting SBP of > or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP <90 mm Hg or a reduction in mean sitting DBP of > or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL). RESULTS: The study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged > or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P < 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P < 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P < 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P < 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P < 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P < 0.05). CONCLUSION: In this group of patients with moderate hypertension and > or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.     

Antihypertensive and organ-protective effects of benazepril

Benazepril is a nonsulfhydryl ACE inhibitor with favorable pharmacodynamic and pharmacokinetic properties, well-established antihypertensive effects and a good tolerability profile. Recent clinical studies have demonstrated that patients treated with benazepril alone or in combination with hydrochlorothiazide or amlodipine may achieve beneficial renal outcomes that extend beyond blood pressure control. Furthermore, the recent Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed decreased cardiovascular morbidity and mortality with benazepril when administered as a cotreatment. An additional novel therapeutic area for benazepril is atrial fibrillation. Differences between combination therapies have implications for which patients may be best suited to particular interventions, and further studies are required to fully ascertain this potential.