Efficacy of Zofenopril vs. Irbesartan in Combination with a Thiazide Diuretic in Hypertensive Patients with Multiple Risk Factors not Controlled by a Previous Monotherapy: A Review of the Double-Blind, Randomized "Z" Studies.

Combinations between an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ) are among the recommended treatments for hypertensive patients uncontrolled by monotherapy. Four randomized, double-blind, parallel group studies with a similar design, including 1469 hypertensive patients uncontrolled by a previous monotherapy and with ≥1 cardiovascular risk factor, compared the efficacy of a combination of a sulfhydryl ACE inhibitor (zofenopril at 30 or 60 mg) or an ARB (irbesartan at 150 or 300 mg) plus HCTZ 12.5 mg. The extent of blood pressure (BP)-lowering was assessed in the office and over 24 h. Pleiotropic features of the treatments were evaluated by studying their effect on systemic inflammation, organ damage, arterial stiffness, and metabolic biochemical parameters. Both treatments similarly reduced office and ambulatory BPs after 18-24 weeks. In the ZODIAC study a larger reduction in high sensitivity C reactive protein (hs-CRP) was observed under zofenopril (-0.52 vs. +0.97 mg/dL under irbesartan, p = 0.001), suggesting a potential protective effect against the development of atherosclerosis. In the ZENITH study the rate of carotid plaque regression was significantly larger under zofenopril (32% vs. 16%; p = 0.047). In the diabetic patients of the ZAMES study, no adverse effects of treatments on blood glucose and lipids as well as an improvement of renal function were observed. In patients with isolated systolic hypertension of the ZEUS study, a slight and similar improvement in renal function and small reductions in pulse wave velocity (PWV), augmentation index (AI), and central systolic BP were documented with both treatments. Thus, the fixed combination of zofenopril and HCTZ may have a relevant place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive, and sustained BP reduction, in line with the recommendations of current guidelines.

Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double-blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines.

In this paper, we present the results of a reanalysis of the data of two large randomized, double-blind, parallel group studies with a similar design, comparing the efficacy of an angiotensin-receptor blocker (olmesartan medoxomil) with that of an angiotensin-converting enzyme inhibitor (ramipril), by applying two different blood pressure targets recently recommended by hypertension guidelines for all patients, irrespective of the presence of diabetes (<140/90 mmHg), and for elderly hypertensive patients (<150/90 mmHg). The efficacy of olmesartan was not negatively affected by age, sex, hypertension type, diabetes status or other concomitant clinical conditions, or cardiovascular risk factors. In most cases, olmesartan provided better blood pressure control than ramipril. Olmesartan was significantly more effective than ramipril in male patients, in younger patients (aged 65-69 years), in those with metabolic syndrome, obesity, dyslipidemia, preserved renal function, diastolic ± systolic hypertension, and, in general, in patients with a high or very high cardiovascular risk. Interestingly, patients previously untreated or treated with two or more antihypertensive drugs showed a significantly larger response with olmesartan than with ramipril. Thus, our results confirm the good efficacy of olmesartan in elderly hypertensives even when new blood pressure targets for antihypertensive treatment are considered. Such results may be relevant for the clinical practice, providing some hint on the possible different response of elderly hypertensive patients to two different drugs acting on the renin-angiotensin system, when patients are targeted according to the blood pressure levels recommended by recent hypertension guidelines.

Blood Pressure Response to Zofenopril or Irbesartan Each Combined with Hydrochlorothiazide in High-Risk Hypertensives Uncontrolled by Monotherapy: A Randomized, Double-Blind, Controlled, Parallel Group, Noninferiority Trial.

In this randomized, double-blind, controlled, parallel group study (ZENITH), 434 essential hypertensives with additional cardiovascular risk factors, uncontrolled by a previous monotherapy, were treated for 18 weeks with zofenopril 30 or 60 mg plus hydrochlorothiazide (HCTZ) 12.5 mg or irbesartan 150 or 300 mg plus HCTZ. Rate of office blood pressure (BP) response (zofenopril: 68% versus irbesartan: 70%; p = 0.778) and 24-hour BP response (zofenopril: 85% versus irbesartan: 84%; p = 0.781) was similar between the two treatment groups. Cardiac and renal damage was equally reduced by both treatments, whereas the rate of carotid plaque regression was significantly larger with zofenopril. In conclusion, uncontrolled monotherapy treated hypertensives effectively respond to a combination of zofenopril or irbesartan plus a thiazide diuretic, in terms of either BP response or target organ damage progression.

Olmesartan vs. ramipril in elderly hypertensive patients: review of data from two published randomized, double-blind studies.

Hypertension is a frequent condition among individuals over 65 years of age worldwide and is one of the most important risk factors for cardiovascular (CV) disease. Effective drug treatment of elderly hypertensives is usually associated with a marked reduction in CV morbidity and mortality. Among the different classes of antihypertensive agents, angiotensin receptor blockers (ARBs) and ACE-inhibitors are supposed to provide the best efficacy in lowering blood pressure (BP) and protecting target organ damage while featuring a good tolerability profile. However, up to date, few randomized clinical studies have directly compared the activity and safety of ARBs and ACE-inhibitors in elderly hypertensive patients. Aim of this review of published and unpublished pooled data from two recent randomized, double-blind, controlled trials, is to offer a comprehensive head-to-head comparison of the antihypertensive efficacy of the ARB olmesartan medoxomil vs. the ACE-inhibitor ramipril in a large study population including more than 1,400 hypertensive subjects aged 65-89 years with mild-to-moderate essential hypertension. The efficacy of the two drugs was separately evaluated in subgroups of patients classified according to the presence of metabolic syndrome, reduced renal function, CV risk level, gender, class of age, type of arterial hypertension and previous antihypertensive treatments. Olmesartan showed a greater efficacy than ramipril both in terms of clinic BP reduction and rate normalization. Olmesartan appeared significantly superior to ramipril in providing a more homogeneous and long-lasting 24-h BP control and maintaining an effective antihypertensive action in the last 6-h period from drug intake. In subgroups of patients with additional clinical conditions, olmesartan gave comparable, and in some cases greater, BP responses than those achieved with the ACE-inhibitor. The incidence of adverse events was similar for both drugs. Olmesartan may thus represent an effective alternative to ACE-inhibitors among first-line drug treatments for hypertension in older people.

Antihypertensive efficacy and safety of olmesartan medoxomil and ramipril in elderly mild to moderate essential hypertensive patients with or without metabolic syndrome: a pooled post hoc analysis of two comparative trials.

BACKGROUND: Two recent identically designed trials (one Italian and one European multinational) have compared the head-to-head efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil and the angiotensin converting enzyme inhibitor ramipril, in elderly patients with essential hypertension. OBJECTIVE: The aim of the present study was to assess the antihypertensive efficacy of olmesartan and ramipril in elderly patients with hypertension, with or without metabolic syndrome, by performing a pooled analysis of data from the two head-to-head trials. METHODS: After a 2-week, placebo wash-out, 1,453 treated or untreated elderly hypertensive patients aged 65-89 years [with sitting office diastolic blood pressure (DBP) 90-109 mmHg and/or sitting office systolic BP (SBP) 140-179 mmHg] were randomized to 12-weeks of double-blind treatment with olmesartan 10 mg or ramipril 2.5 mg once daily. Treatment could be up-titrated to 20 and 40 mg for olmesartan, and 5 and 10 mg for ramipril, after the first 2 and 6 weeks, respectively, in patients with inadequately controlled BP (BP ≥ 140/90 mmHg for non-diabetics and ≥ 130/80 mmHg for diabetics). Office BP was measured at randomization and after 2, 6 and 12 weeks of treatment. 24-h ambulatory BP recordings were obtained at randomization and after 12 weeks. RESULTS: Of the 1,426 patients in the intent-to-treat analysis, 735 (51.5 %) had metabolic syndrome (olmesartan, n = 372; ramipril, n = 363). After 12 weeks of treatment, baseline-adjusted office BP reductions were greater (p < 0.05) with olmesartan (SBP 17.0 mmHg; 95% CI 18.4, 15.6; DBP 9.6 mmHg; 95% CI 10.4, 8.8) than with ramipril (SBP 14.7 mmHg; 95% CI 16.1, 13.2; DBP 8.4 mmHg; 95% CI 9.2, 7.6) in patients with metabolic syndrome. In these patients, BP normalization rates were also greater with olmesartan than with ramipril (46.0 vs. 35.8%, p < 0.01). Similarly, in patients without metabolic syndrome, the antihypertensive efficacy of olmesartan was also significantly (p < 0.05) better than that of ramipril. In the subgroup of patients with valid ambulatory BP (ABP) recordings and metabolic syndrome (olmesartan, n = 182; ramipril, n = 170), the reduction in mean 24-h ABP was greater with olmesartan (SBP 10.2 mmHg; 95% CI 11.8, 8.6; DBP 6.6 mmHg; 95% CI 7.5, 5.6) than with ramipril (SBP 8.5 mmHg; 95% CI 10.2, 6.9; DBP 4.7 mmHg; 95% CI 5.7, 3.7), with a statistically significant (p < 0.01) difference for the DBP comparison. The proportion of patients experiencing drug-related adverse events was comparable in patients with (olmesartan 2.4 % vs. ramipril 2.8 %) and without (3.5 vs. 3.7 %) metabolic syndrome. CONCLUSIONS: Olmesartan provides more effective BP control than ramipril in elderly hypertensive patients with and without metabolic syndrome.

Twenty-four hour and early morning blood pressure control of olmesartan vs. ramipril in elderly hypertensive patients: pooled individual data analysis of two randomized, double-blind, parallel-group studies.

OBJECTIVE: To assess the antihypertensive efficacy of olmesartan medoxomil and ramipril on 24-h ambulatory blood pressure (ABP) in elderly hypertensive patients by pooled data analysis of two studies with identical designs (one Italian, one European). METHODS: After a 2-week placebo wash-out 1453 elderly hypertensive patients (65-89 years; sitting office DBP 90-109 mmHg and/or sitting office SBP 140-179 mmHg) were randomized to a 12-week double-blind treatment with olmesartan medoxomil 10 mg or ramipril 2.5 mg once-daily, up-titrated (20 and 40 mg olmesartan medoxomil; 5 and 10 mg ramipril) after 2 and 6 weeks in patients without normalized office BP. 24-h ABP was recorded at randomization and after 12 weeks. RESULTS: In 715 patients with valid baseline and end-of-treatment recordings baseline-adjusted 24-h SBP and DBP reductions were greater with olmesartan medoxomil (n = 356) than with ramipril (n = 359) [between-treatment differences and 95% confidence interval (CI), SBP: 2.2 (3.8, 0.6), P = 0.006; DBP: 1.3 (2.2, 0.3), P = 0.009]. Olmesartan medoxomil showed larger BP reductions in the last 6 h from the dosing interval and higher smoothness indices than ramipril. Olmesartan medoxomil reduced the SBP morning rise [-2.8 (-4.9, -0.8) mmHg], whereas ramipril did not [+1.5 (-0.6, +3.6) mmHg; P = 0.004 between-treatments]. Five hundred and eighty-two patients with sustained hypertension (office and 24-h ambulatory hypertension) showed the largest antihypertensive effect, with between-treatment differences still in favor of olmesartan medoxomil [SBP: 2.1 (3.9, 0.4), P = 0.019; DBP: 1.2 (2.3, 0.1), P = 0.032]. CONCLUSIONS: Olmesartan medoxomil provides a more effective and sustained 24-h BP control than ramipril in elderly hypertensive patients, particularly in the hours farthest from last intake.

Antihypertensive efficacy of olmesartan medoxomil and ramipril in elderly patients with mild to moderate hypertension grouped according to renal function status : a retrospective analysis.

AIM: The objective of this study was to compare the antihypertensive efficacy and safety of the angiotensin II antagonist olmesartan medoxomil and the ACE inhibitor ramipril in elderly patients with mild to moderate essential hypertension, grouped according to renal function. METHODS: We performed a post hoc analysis of pooled data from two randomized, double-blind, parallel-group, multicentre studies. After a 2-week placebo wash-out period, 1453 mild to moderate hypertensive subjects were randomized to a 12-week treatment with olmesartan medoxomil 10 mg/day or ramipril 2.5 mg/day. After 2 and 6 weeks, doses were increased up to a maximum of 40 mg/day (olmesartan medoxomil) and 10 mg/day (ramipril) in non-normalized subjects (office systolic blood pressure [SBP] ≥ 140 mmHg or diastolic blood pressure [DBP] ≥90 mmHg in non-diabetic subjects and office SBP ≥ 130 mmHg or DBP ≥80 mm Hg in diabetic patients). Office blood pressure (BP) was measured at 0, 2, 6 and 12 weeks, 24-hour ambulatory BP at 0 and 12 weeks. 284 patients treated with olmesartan medoxomil 40 mg/day at the end of the double-blind period entered a 36-week, open-label follow-up. Renal function (Cockroft-Gault equation) was evaluated as normal or increased estimated glomerular filtration rate (eGFR) [≥90 mL/min/1.73 m(2)], mild eGFR reduction (60-90 mL/min/1.73 m(2)) and moderate or severe eGFR reduction (<60 mL/min/1.73 m(2)). RESULTS: 181 (12.7%) subjects had normal or increased eGFR, 840 (58.9%) mild eGFR reduction, and 405 (28.4%) moderate or severe eGFR reduction. Baseline-adjusted office BP reductions were superior with olmesartan medoxomil than with ramipril in normal or increased (olmesartan medoxomil - ramipril difference SBP: 5.0 mmHg [95% CI 9.1, 0.9], p = 0.018; DBP: 2.7 mmHg [4.8, 0.6], p = 0.011) and mildly reduced eGFR patients (SBP: 1.6 mmHg [3.5, 0.2], p = 0.080; DBP: 1.2 mmHg [2.3, 0.2], p = 0.022). In the group with moderately or severely reduced eGFR the two treatments were comparable (SBP: 1.9 mmHg [4.6, 0.9], p = 0.185; DBP: 0.8 mmHg [2.3, +0.7]; p = 0.296). At 12 weeks, the rate of normalized patients was 46.1 % with olmesartan medoxomil versus 23.9% with ramipril (p = 0.002) in the normal, and 49.9% versus 42.7% (p = 0.037) in the mild eGFR reduction group. No significant differences in normalization rate were observed in the moderately or severely reduced eGFR group (olmesartan medoxomil 49.5% vs ramipril 46.3%, p = 0.519). eGFR did not show any significant change during treatment. CONCLUSIONS: Olmesartan medoxomil provides a more effective BP control, similar if not superior to that of ramipril, independently from the patient's renal function status.

Antihypertensive efficacy and safety of olmesartan medoxomil and ramipril in elderly patients with mild to moderate essential hypertension: the ESPORT study.

OBJECTIVE: To compare the efficacy and safety of the angiotensin II antagonist olmesartan medoxomil (O) and the ACE inhibitor ramipril (R) in elderly patients with essential arterial hypertension. METHODS: After a 2-week placebo wash-out 1102 treated or untreated elderly hypertensive patients aged 65-89 years (office sitting diastolic blood pressure, DBP, 90-109 mmHg and/or office sitting systolic blood pressure, SBP, 140-179 mmHg) were randomized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once-daily. After the first 2 and 6 weeks doses could be doubled in non-normalized [blood pressure (BP) < 140/90 mmHg for nondiabetic and < 130/80 mmHg for diabetic) individuals, up to 40 mg for O and 10 mg for R. Office BPs were assessed at randomization, after 2, 6 and 12 weeks of treatment, whereas 24-h ambulatory BP was recorded at randomization and after 12 weeks. RESULTS: In the intention-to-treat population (542 patients O and 539 R) after 12 weeks of treatment baseline-adjusted office SBP and DBP reductions were greater (P < 0.01) with O [17.8 (95% confidence interval: 16.8/18.9) and 9.2 (8.6/9.8) mmHg] than with R [15.7 (14.7/16.8) and 7.7 (7.1/8.3) mmHg]. BP normalization rate was also greater under O (52.6 vs. 46.0% R, P < 0.05). In the subgroup of patients with valid ambulatory BP recording (318 O and 312 R) the reduction in 24-h average BP was larger (P < 0.05) with O [SBP: 11.0 (12.2/9.9) and DBP: 6.5 (7.2/5.8) mmHg] than with R [9.0 (10.2/7.9) and 5.4 (6.1/4.7) mmHg]. The larger blood pressure reduction obtained with O was particularly evident in the last 6 h from the dosing interval; a better homogeneity of the 24-h BP control with O was confirmed by higher smoothness indices. The proportion of patients with drug-related adverse events was comparable in the two groups (3.6 O vs. 3.6% R), as well as the number of patients discontinuing study drug because of a side effect (14 O vs. 19 R). CONCLUSION: In elderly patients with essential arterial hypertension O provides an effective, prolonged and well tolerated BP control, representing a useful option among first-line drug treatments of hypertension in this age group.

Zofenopril plus hydrochlorothiazide fixed combination in the treatment of hypertension and associated clinical conditions.

Zofenopril, is a highly lipophilic ACE inhibitor, characterized by long-lasting tissue penetration and sustained cardiac ACE inhibition, indicated for the treatment of hypertension and myocardial infarction. Comparative studies with different antihypertensive drug classes have demonstrated the good efficacy and tolerability of this compound in the management of the patient with mild-moderate hypertension. Zofenopril may also be combined with hydrochlorothiazide, a combination which has proved to be effective and safe as compared with monotherapy with either agent in three studies, including more than 600 patients. In addition, recent post hoc analyses in high-risk patients, such as those with the metabolic syndrome, impaired fasting glucose or diabetes, atherogenic dyslipidemia, and impaired renal function, have confirmed the superiority of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once-daily combination as compared with zofenopril monotherapy also in these high-risk populations of patients with hypertension. These data suggest the usefulness of this fixed combination in the treatment of patients with hypertension requiring more prompt, intensive, and sustained blood pressure reduction, according to guidelines recommendation.

Nebivolol/Hydrochlorothiazide : a new fixed-dose combination for effective simplified antihypertensive therapy.

Hypertension is a major independent risk factor for cardiovascular (CV) morbidity and mortality and is combined with additional CV risk factors, such as diabetes mellitus, dyslipidaemia, heart disease, metabolic syndrome, smoking and obesity in many hypertensive individuals. The prevention of CV disease with antihypertensive therapy has been widely demonstrated, with a 30-40% reduction in stroke and a 20% reduction in coronary events in patients receiving antihypertensive drugs compared with untreated hypertensive individuals. Even small decreases in blood pressure (BP) correlate with a significantly lower incidence of CV events; this is independent of drug class used, but dependent on the extent of BP reduction achieved. All antihypertensive drugs lower BP to a similar extent and are suitable for long-term therapy. Treatment guidelines recommend that antihypertensive treatment should be initiated early to reach a target BP value of ≤140/90 mmHg, or lower in high-risk patients, in order to maximize the long-term benefits in CV mortality and morbidity reduction. However, the proportion of patients responding to monotherapy is generally low; therefore, first-line therapy with a combination of antihypertensive drugs is recommended in non-responders and those with multiple risk factors or subclinical organ damage. The combination of ß-blocker/thiazide diuretic is frequently used in clinical practice and as reference treatment in clinical trials. Nebivolol, a third-generation cardioselective vasodilatory ß-blocker, shows an additive effect in reducing systolic and diastolic BP when combined with hydrochlorothiazide (HCTZ). In monotherapy non-responders, the combination improves response and BP normalization rates compared with monotherapy. Since pharmacokinetic studies have shown that fixed-dose nebivolol-HCTZ therapy is bioequivalent to the two agents administered concomitantly, this combination is useful in monotherapy non-responders and for those who require rapid BP control to prevent end-organ damage. In addition, a simplified regimen improves patient compliance - a major obstacle to achieving target BP levels. In addition to providing enhanced BP reduction and control, nebivolol-HCTZ is well tolerated, with a similar incidence of adverse events to that observed with either monotherapy, and a neutral impact on lipid and glucose metabolism.

Antihypertensive effect of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension according to their cardiovascular risk level: A post hoc analysis.

BACKGROUND: International guidelines recommend the use of angiotensin-converting enzyme inhibitors, possibly in combination with other antihypertensive drugs, to treat hypertension with associated risk factors. OBJECTIVE: The aim of this study was to compare the antihypertensive effect of the combination of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension, according to their cardiovascular risk level. METHODS: This was a post hoc analysis of a previously published efficacy and tolerability study. After a 4-week placebo washout, patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] 95-115 mm Hg), aged 18 to 75 years, were randomized at a ratio of 2:1:1 to treatment with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or monotherapy with zofenopril 30 mg or hydrochlorothiazide 12.5 mg for 12 weeks in an international, multicenter, double-blind study. This period was followed by 24 weeks of open-label treatment. Systolic BP [SBP] and DBP were measured by mercury sphygmomanometry, and changes associated with treatment were calculated. Patients' cardiovascular risk was computed using the Heart Score algorithm. Patients were classified in quartiles according to distribution of cardiovascular risk level, and comparisons were limited to the zofenopril plus hydrochlorothiazide and zofenopril monotherapy treatment groups. The primary end point was change in office DBP. RESULTS: Two hundred forty-six patients (139 men, 107 women; mean [SD] age, 54 [11] years) were included in the analysis. Mean baseline cardiovascular risk was similar in the zofenopril plus hydrochlorothiazide group and the zofenopril monotherapy group (7% vs 9%). DBP and SBP reductions with treatment were significantly greater (both, P < 0.01) with combination treatment than with monotherapy for each quartile of cardiovascular risk. Cardiovascular risk reduction at the end of the 12 weeks of double-blind treatment was greater in the zofenopril plus hydrochlorothiazide group than in the zofenopril monotherapy group (1.9% vs 0.2%; P < 0.01), particularly in the group of patients with the highest cardiovascular risk at baseline (5.2% vs 2.0%). At the end of the 24-week open-label treatment period, the mean reduction in cardiovascular risk was also significantly greater in the combination treatment group than in the monotherapy group (1.4% vs 0.5%; P < 0.01). CONCLUSIONS: In these hypertensive patients, combination treatment with zofenopril plus hydrochlorothiazide was associated with a significantly greater decrease in BP compared with zofenopril monotherapy, regardless of the patient's cardiovascular risk. The difference between combination treatment and monotherapy was particularly evident for the group of patients at highest risk.

Antihypertensive efficacy of zofenopril plus hydrochlorothiazide fixed combination for treatment in metabolic syndrome.

This study was undertaken to compare the antihypertensive efficacy of zofenopril 30 mg + hydrochlorothiazide 12.5 mg fixed combination versus zofenopril alone in patients with essential hypertension with and without the metabolic syndrome, according to National Cholesterol Education Program-Adult Treatment Panel III criteria. After a 4-wk placebo washout period, 463 patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] 95-115 mm Hg) aged 18 to 75 y were randomly assigned 2:1:1 to treatment with zofenopril+hydrochlorothiazide, zofenopril, or hydrochlorothiazide for 12 wk in an international, multicenter, double-blind, parallel-group study. DBP and systolic blood pressure changes with treatment were calculated. The first 12 wk of treatment were followed by a 24-wk open-label period during which only safety was assessed. Reported here is a subanalysis of the main study results, performed in patients with and without metabolic syndrome, limited to a zofenopril+hydrochlorothiazide versus zofenopril comparison. The antihypertensive effect of zofenopril+hydrochlorothiazide or zofenopril was similar in patients with (77%) and without metabolic syndrome. In patients with and without metabolic syndrome, however, DBP and systolic blood pressure reductions were significantly greater with zofenopril+hydrochlorothiazide (with metabolic syndrome: 14+/-8/21+/-14 mm Hg; without metabolic syndrome: 15+/-7/23+/-14 mm Hg) than with zofenopril alone (with metabolic syndrome: 10+/-9/11+/-15; without metabolic syndrome: 12+/-10/14+/-18 mm Hg). The safety of the 2 treatments was similar in patients with and without metabolic syndrome. The fixed combination of zofenopril+hydrochlorothiazide improved the efficacy of zofenopril alone. This effect was particularly evident in patients with metabolic syndrome, in whom blood pressure control is more difficult to achieve and who are at greater risk for cardiovascular events.

Zofenopril plus hydrochlorothiazide: Combination therapy for the treatment of mild to moderate hypertension.

Achieving target blood pressure (BP) levels in clinical practice is one of the main challenges for physicians in the management of patients with hypertension. It is now recognised that the majority of patients will require at least two antihypertensive drugs to achieve optimal BP control; the use of combination therapy as first-line treatment is also increasing as BP goals of antihypertensive therapy become more ambitious. The fixed combination of zofenopril/hydrochlorothiazide (HCTZ) 30/12.5 mg/day is approved in Italy, France, Switzerland and Greece for the management of mild to moderate hypertension. In clinical trials comparing zofenopril/HCTZ with each agent administered as monotherapy, combination therapy was more effective in normalising BP. This effect was particularly evident in one trial in which patients who were nonresponsive to zofenopril monotherapy were studied. In addition, in clinical trials to date, combination therapy provided sustained and consistent BP control over the entire 24-hour dose interval. Despite the greater efficacy of zofenopril/HCTZ 30/12.5 mg/day, when directly compared with each agent administered as monotherapy, there were no significant differences in the nature, severity or incidence of treatment-related adverse events; headache, dizziness, cough and polyuria were most frequently reported. Notably, in one study, fewer patients discontinued treatment with combination therapy than with zofenopril monotherapy due to adverse events. In conclusion, zofenopril/HCTZ 30/12.5 mg/day provides more optimal BP control in a larger proportion of patients than would be achievable with monotherapy, while maintaining the tolerability profile observed with each individual agent, and thereby potentially enhancing patient compliance. The efficacy and safety profiles of this combination shown in clinical trials to date indicate that it will be a useful addition to currently available therapy for patients who have mild to moderate hypertension that is not adequately controlled by monotherapy, as well as for patients who require more rapid, intensive BP control.

Treatment of hypertension and adherence to treatment guidelines in clinical practice: an Italian study.

Despite the results from clinical trials in patients with hypertension and the development of a long list of guidelines for the management of hypertension, many physicians and other healthcare professionals still manage hypertension using approaches that clearly diverge at least partially from the recommendations of these guidelines. Whatever the underlying reasons for physicians' failure to adhere to these guidelines, it is one of the main causes of the high percentage of treated patients with uncontrolled hypertension. This article is a report of the outcomes of a project designed to identify specific discrepancies between hypertension guidelines and clinical practice in Italy then guide the physicians to reach a consensus on hypertension management through discussions with their peers. A total of 1120 internists from all 20 regions in Italy were recruited to participate in workshops conducted between June 2002 and July 2004. They were divided into 57 groups to discuss at least 7 key topics, including the blood pressure level at which to start drug therapy, target-organ damage, isolated systolic hypertension, pulse pressure, clinical trials, generic drugs, and fixed combination drug therapy. The project findings confirmed that the vast majority of internists agree with the guidelines but do not adhere to them completely in clinical practice. Through open discussions that allowed them to identify common viewpoints, the participants may have developed a better awareness of and insight into the guidelines for hypertension management. Hopefully this strategy for group participation will lead to improvements in the management of hypertension throughout Italy.

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.

Zofenopril versus Lisinopril in the Treatment of Essential Hypertension in Elderly Patients : A Randomised, Double-Blind, Multicentre Study.

BACKGROUND: Angiotensin-converting enzyme inhibitors have been proposed as first-choice drugs for antihypertensive therapy in elderly subjects because of their demonstrated efficacy and safety. However, no information is currently available on the use of zofenopril in elderly hypertensive patients. OBJECTIVE: To assess the efficacy and safety of zofenopril (30 or 60mg once daily) compared with lisinopril (10 or 20mg once daily). PATIENTS AND METHODS: Patients aged >/=65 years with mild to moderate essential hypertension (sitting diastolic blood pressure [DBP] >/=90mm Hg and /=90mm Hg. The primary endpoint was to achieve sitting DBP values <90mm Hg or a reduction of sitting DBP >10mm Hg after 12 weeks of treatment. RESULTS: 181 patients were randomised to treatment and 164 patients completed the study. Thirty-three patients were included in the analysis of 24-hour blood pressure monitoring. The percentage of patients with normalised sitting DBP (<90mm Hg) and the rate of treatment responders (reduction of sitting DBP >/=10mm Hg) were not significantly different between the two treatment groups (normalised: zofenopril 81.3% vs lisinopril 76.7%; responders: zofenopril 74.7% vs lisinopril 77.8%). At the end of the treatment sitting DBP was not significantly different between the two treatment groups (zofenopril 82.2 +/- 6.6mm Hg vs lisinopril 82.0 +/- 7.8mm Hg). Eight percent of patients experienced adverse events in the zofenopril group and 9% in the lisinopril group. A small percentage of adverse events (4%) was related to treatment and reported in the zofenopril group. CONCLUSIONS: In elderly hypertensive patients, treatment with zofenopril was effective and well tolerated. Efficacy and safety were comparable with those of lisinopril.

Effects of valsartan/hydrochlorothiazide and amlodipine on ambulatory blood pressure and plasma norepinephrine levels in high-risk hypertensive patients.

The efficacy and tolerability of the combination of valsartan and hydrochlorothiazide (HCTZ) were compared with that of amlodipine in reducing ambulatory blood pressure and plasma norepinephrine levels in patients with mild to moderate hypertension and at least 1 cardiovascular risk factor. At the end of a 2-week washout period, 92 outpatients with a sitting diastolic blood pressure > or =95 and <110 mm Hg, associated with at least 1 additional risk factor, were randomly assigned to receive either valsartan 160 mg and HCTZ 12.5 mg once daily (n=46) or amlodipine 10 mg alone once daily (n=46) for 12 weeks, according to a prospective, randomized, open-label, blinded end point, parallel-group design. At the end of the washout period and after 6 and 12 weeks of active treatment, 24-hour ambulatory blood pressure monitoring was performed, and clinical blood pressure and heart rate and plasma norepinephrine levels were assessed (by high-performance liquid chromatography). Both the valsartan/HCTZ combination and amlodipine had a demonstrable antihypertensive effect, but the combination showed an antihypertensive effect significantly greater than that of amlodipine, as demonstrated by the 24-hour (P<.001), daytime (P<.001), and nighttime ambulatory blood pressure values (P<.01) and by the clinical blood pressure values at trough, which were all significantly lower. Although the trough-to-peak ratios were similar in both groups, the smoothness indexes pertaining to both systolic and diastolic pressures were significantly higher (P<.05 and P<.001, respectively) in patients receiving valsartan/HCTZ, suggesting the combination produces a more homogeneous anti-hypertensive effect. A significant increase in plasma norepinephrine levels was associated with amlodipine (+9% at 6 weeks, +15% at 12 weeks) but not with the valsartan/HCTZ combination. The valsartan/HCTZ combination was better tolerated than amlodipine, which was associated with a higher frequency of ankle edema. These results indicate that the combination of valsartan 160 mg and HCTZ 12.5 mg provides more sustained and homogeneous control of blood pressure than does amlodipine 10 mg in high-risk hypertensive patients, without producing reflex sympathetic activation.

Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study.

BACKGROUND: The goal of antihypertensive therapy is to provide good blood pressure (BP) control without eliciting adverse effects. OBJECTIVE: This study compared the risk-benefit profile of the angiotensin II receptor blocker valsartan with that of the angiotensin-converting enzyme inhibitor lisinopril in patients with mild to severe hypertension. The primary objective was to show that the equipotent BP-lowering effect of the valsartan-based treatment is accompanied by a better tolerability profile. METHODS: This 16-week, randomized, double-blind, parallel-group study was conducted at 88 outpatient centers across Italy. After a 2-week placebo run-in period, patients aged > or = 18 years with mild to severe hypertension (systolic BP [SBP], 160-220 mm Hg; diastolic BP [DBP], 95-110 mm Hg) were eligible. Patients were randomized to receive once-daily, oral, self-administered treatment with valsartan 160-mg capsules or lisinopril 20-mg capsules under double-blind conditions for 4 weeks. Responders continued monotherapy, whereas nonresponders had hydrochlorothiazide 12.5 mg added for the final 12 weeks of the study. The 2 primary variables used to assess the equivalence of therapeutic efficacy of the 2 regimens were sitting SBP and sitting DBP, which were measured at weeks 0 (baseline), 4, 8, and 16. The rate of drug-related adverse events (AEs) was used to assess whether 1 treatment had a better tolerability profile than the other. Tolerability was assessed by collecting information about AEs by means of questioning the patient or physical examination at each visit. RESULTS: A total of 1213 patients were enrolled (635 men, 578 women; mean [SD] age, 54.5 [10.1] years [range, 28-78 years]). The study was completed by 1100 patients (553 receiving valsartan and 547 receiving lisinopril). Fifty-one patients (8.4%) treated with valsartan and 62 (10.2%) [corrected] treated with lisinopril withdrew, mainly because of AEs (9 [1.5%] and 23 patients [3.8%], respectively). The valsartan- and lisinopril-based treatments were similarly effective in reducing sitting BP, with mean SBP/DBP reductions of 31.2/15.9 mm Hg and 31.4/15.9 mm Hg, respectively. At the end of the study, BP was controlled in 82.6% [corrected] of the patients receiving valsartan and 81.6% of those receiving lisinopril. AEs were experienced by 5.1% of the patients treated with valsartan and 10.7% of those treated with lisinopril (P=.0001), with dry cough observed in 1.0% and 7.2% of patients, respectively (P<0.001). CONCLUSIONS: Valsartan and lisinopril were both highly effective in controlling BP in these patients with mild to severe hypertension, but valsartan was associated with a significantly reduced risk for AEs, especially cough.

Comparison of the effects on 24-h ambulatory blood pressure of valsartan and amlodipine, alone or in combination with a low-dose diuretic, in elderly patients with isolated systolic hypertension (Val-syst Study).

OBJECTIVE: The aim of this study was to compare the time-effect profiles of a once-daily administration of valsartan and amlodipine, each given alone or in combination with hydrochlorothiazide, in terms of ambulatory blood pressure (BP) and heart rate in elderly patients with isolated systolic hypertension. METHODS: One hundred and sixty-four elderly outpatients with systolic hypertension received valsartan 80 mg (n=79) or amlodipine 5 mg (n=85) once daily for eight weeks, after which the patients with poorly controlled office BP were up-titrated to valsartan 160 mg or amlodipine 10 mg once daily. If their office systolic BP was still >140 mmHg after eight weeks at these doses, 12.5 mg hydrochlorothiazide was added for a further eight weeks. The hourly BP decreases in all of the patients were calculated on the basis of 24-h ambulatory recordings made after the placebo period and at the end of active treatment. The trough/peak ratio and smoothness index were calculated in the responders. RESULTS: Both the valsartan- and amlodipine-based treatments effectively lowered mean 24-h, daytime and night-time systolic ambulatory BP (all p<0.001) without any significant differences between the two regimens. Ambulatory heart rate decreased in the subjects on valsartan and slightly increased in those on amlodipine (the differences in 24-h and daytime heart rate were significant (p=0.008 and 0.002 respectively). Among the 138 responders, the valsartan-based treatment had a greater anti-hypertensive effect during the daytime hours (p=0.02), a difference that was also significant for average 24-h BP (p=0.02). The mean systolic BP trough/peak ratio was 0.56 in the patients on valsartan, and 0.77 in those on amlodipine (NS). The smoothness index was respectively 1.70 and 1.58 (NS). CONCLUSIONS: The present results show that both the valsartan- and amlodipine-based treatments lead to a similar long-term reduction in 24-h systolic BP. However, in treatment responders, valsartan has a greater anti-hypertensive effect during the daytime.