Twenty-four-hour ambulatory blood pressure monitoring efficacy of perindopril/indapamide first-line combination in hypertensive patients: the REASON study

BACKGROUND: Circadian blood pressure (BP) measurements provide more information on hypertensive complications than office BP measurements. The purpose of this study was to analyze the efficacy of the first-line combination of perindopril 2 mg plus indapamide 0.625 mg versus atenolol 50 mg on BP parameters and variability over 24 h in patients with hypertension. METHODS: A double-blind, randomized, controlled, 12-month study comparing perindopril/indapamide and atenolol was performed in 201 patients (age 55.0 years) with uncomplicated sustained essential hypertension. Ambulatory BP measurements (ABPM) were done every 15 min over 24 h. RESULTS: After 1 year of treatment, the decrease in systolic BP was significantly greater for perindopril/indapamide than for atenolol during the entire 24-h period (-13.8 v -9.2 mm Hg), the daytime and the nighttime periods (P <.01). Diastolic blood pressure (DBP) variations were comparable for the two groups (-7.2 v -8.3 mm Hg, NS). Pulse pressure (PP) reduction was also significantly greater for perindopril/indapamide than for atenolol (for the whole 24 h, -6.6 v -0.9 mm Hg, P <.001). The through to peak (T/P) BP ratio and the smoothness index were comparable in the two groups for DBP. For systolic blood pressure (SBP), higher values of the T/P ratio (0.80 v 0.59) and the smoothness index (1.45 v 0.98; P <.02) were achieved for the perindopril/indapamide combination than for atenolol. CONCLUSIONS: The perindopril/indapamide first-line combination decreased SBP and PP more effectively than atenolol. Moreover, the BP control effect was smooth and consistent throughout the 24-h dosing interval and BP reduction variability was lower than the one induced by atenolol.     

The impact of one or two missed doses on the duration of action of combined perindopril and indapamide

To evaluate the persistence of the antihypertensive effect of perindopril 4 mg+indapamide 1.25 mg once daily for up to 72 h using the 'missed-dose' technique. Hypertensive patients were initially treated with perindopril 2 mg+indapamide 0.625 mg once daily. After 4 weeks, the 135 of 216 patients who still had a diastolic BP> or =85 mm Hg went on to receive perindopril 4 mg+indapamide 1.25 mg daily for a further 8 weeks. During either week 9 or 11, placebo was substituted for perindopril 4 mg+indapamide 1.25 mg on either one or two consecutive days to simulate BP changes, which might occur after one or two missed doses. A 24-h ambulatory BP recording was performed at baseline, after 9 or 11 weeks of perindopril+indapamide therapy and during the simulated missed doses, 24- 48 and 48-72 h after the administration of perindopril 4 mg+indapamide 1.25 mg. Significant (P<0.001) reductions in mean (+/-s.d.) 24-h ambulatory BP (mm Hg) during the first 24 h after perindopril 4 mg+indapamide 1.25 mg therapy versus baseline were noted for patients later randomized to the one missed dose (-15.9+/-10.5/-9.4+/-7.6) or two missed dose (-17.4+/-8.7/-10.3+/-5.1) sub-groups. A significant reduction in BP (P<0.001 versus baseline) was still present on the days when placebo was substituted for perindopril 4 mg+indapamide 1.25 mg with decreases in mean 24-h ambulatory BP from 24 to 48 h and 48 to 72 h after dosing being -11.9+/-10.1/-6.9+/-6.2 and -10.6+/-9.9/-5.8+/-5.7, respectively. Use of the 'missed-dose' technique has demonstrated a prolonged antihypertensive effect for perindopril 4 mg+indapamide 1.25 mg for up to 72 h, supporting the use of this combination as therapy for hypertension.     

Regression of left ventricular mass in hypertensive patients treated with perindopril/indapamide as a first-line combination: the REASON echocardiography study

BACKGROUND: Increase in left ventricular mass (LVM) may be linked to morbidity and mortality in hypertensive patients. Arterial stiffness, systolic blood pressure (BP), and pulse pressure (PP) seem to be the main determinants of LVM. The perindopril/indapamide combination normalizes systolic BP, PP, and arterial function to a greater extent than atenolol. The aim of this study was to compare the effects of perindopril (2 mg)/indapamide (0.625 mg) first-line combination with atenolol (50 mg) on LVM reduction in hypertensive patients. METHODS: Two hundred fourteen patients with essential hypertension participating in the PREterax in Regression of Arterial Stiffness in a ContrOlled Double-BliNd (REASON), randomized, double-blind, parallel-group study, underwent M-mode two-dimensional-guided echocardiography. RESULTS: Perindopril/indapamide and atenolol were both effective at brachial BP reduction during the 12-month period. The systolic BP reduction was significantly greater with perindopril/indapamide than with atenolol (-21.2 v -15.3 mm Hg), whereas the reduction in diastolic BP was similar between treatment groups (-12.1 v -11.3 mm Hg). Reduction in LVM was higher with perindopril/indapamide than with atenolol. The between-group difference was significant for LVM (-13.6 v -4.3 g, P = .027), LVM/body surface area (LVMI1, P = .032), and LVM/body height2.7 (LVMI2, P = .013). The 124 patients with LV hypertrophy at baseline showed greatest LVM regression (LVM: -22.5 v -8.9 g, P = .009; LVMI1, P = .031; LVMI2, P = .028). The reduction in LVM adjusted for brachial systolic BP and heart rate was still significantly greater with perindopril/indapamide than with atenolol. CONCLUSIONS: Treatment, based on a first-line perindopril/indapamide combination in hypertensive patients, was more effective than atenolol on regression of echocardiographic indices of LVM and LV hypertrophy.     

Effect of twelve-month combined therapy with perindopril and indapamide on the level of blood pressure and left ventricular hypertrophy in patients with hypertensive disease

Left ventricular hypertrophy (LVH) in patients with hypertensive disease is associated with unfavorable prognosis. Long term and effective antihypertensive therapy is capable to cause reverse development of LVH. We included in this study 72 patients (27 men, 45 women, age from 34 to 72 years) with untreated 1st and 2nd degree arterial hypertension (systolic blood pressure 140-179 mm Hg and/or diastolic blood pressure 99-109 mm Hg) and echocardiographical signs of LVH (left ventricular myocardial mass index >120 g/m2 in men and >100 g/m2 in women). After that the patients were randomized into 2 groups: the study group (39 patients, mean age 53.0+/-11.6 years) received combination of perindopril and indapamide in initial dose of 2 mg/0.625 mg, and comparison group (33 patients, mean age 54.4+/-8.2 years) received monotherapy with enalapril (10 mg). Once daily dosing of the preparation provided high level of compliance of patients with treatment. During 12-month therapy with combination of perindopril and indapamide target blood pressure (<140/90) was achieved in 74.4% of patients, during monotherapy with enalapril--in 27.3% of patients. Significant decrease of left ventricular myocardial mass index (LVMMI) with combination therapy was observed by 6th month of treatment (from 260 to 234 g), with monotherapy within same period of time--from 267 to 260 g. As a result of 12 months therapy of patients with I-II degree of hypertension with perindopril and indapamide LVMMI decreased by 17.5% while monotherapy with enalapril was associated with 5.6% decrease of LVMMI. Lowering of LVMMI occurred mainly at the account of decrease of left ventricular wall thickness.     

Fixed low-dose perindopril-indapamide combination in hypertensive patients with chronic renal failure

The angiotensin converting enzyme inhibitor perindopril and the diuretic indapamide have been shown to be effective antihypertensive agents in patients with chronic renal failure. A fixed low-dose combination of these two agents has been proposed in the treatment of hypertension. We evaluated this combination in 26 patients with mild to moderate essential hypertension and mild to severe chronic renal failure that did not require dialysis. This was a multicenter, open trial consisting of a 2-week single-blind placebo washout period followed by 12 weeks of active treatment. At week 0, the patients received 2 mg perindopril/0.625 mg indapamide once a day or every other day, with the possibility of dosage adjustment to perindopril 4 mg/indapamide 1.25 mg at week 2, week 4, or week 8. A pharmacokinetic analysis using a population pharmacokinetic approach was performed at week 8. Twenty-three patients completed the 12-week study, at which time 14 patients were receiving 2 mg perindopril/0.625 mg indapamide daily, three were receiving 2 mg perindopril/0.625 mg indapamide every other day, and six perindopril 4 mg/indapamide 1.25 mg. Blood pressure readings (supine) decreased from 170.4 ± 19.2/101.5 ± 6.7 mm Hg before active treatment to 146.5 ± 19.7/86.5 ± 10.6 mm Hg at the end of treatment (P < .0001). Pharmacokinetic analysis showed that for indapamide and perindoprilat (the active metabolite of perindopril) the area under the curve (AUC₂₄) increased with the severity of renal failure. No interaction was noted between the two drugs. Mean serum creatinine and sodium and serum potassium levels remained stable during the study. Impairment of renal function occurred in one patient and was considered unrelated to treatment. We conclude that a fixed low-dose perindopril-indapamide combination as first-line treatment has a good safety/efficacy ratio in hypertensive patients with chronic renal failure.     

Efficacy of indapamide SR compared with enalapril in elderly hypertensive patients with type 2 diabetes

BACKGROUND: Blood pressure control is the main influential variable in reducing microalbuminuria in patients with type 2 diabetes. In this subanalysis of the Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetics with micrOalbuminuRia (NESTOR) study, we have compared the effectiveness of indapamide sustained release (SR) and enalapril in reducing blood pressure and microalbuminuria in patients > or =65 years of age. METHODS: Of the 570 hypertensive patients with type 2 diabetes and persistent microalbuminuria in the NESTOR study, 187 (33%) individuals > or =65 years of age were included in this analysis. Of these, 95 patients received indapamide SR 1.5 mg and 92 patients received enalapril 10 mg, taken once daily in both cases. Adjunctive amlodipine and/or atenolol was added if required. RESULTS: The urinary albumin-to-creatinine ratio decreased by 46% in the indapamide SR group and 47% in the enalapril group. Noninferiority of indapamide SR over enalapril was demonstrated (P = .0236; 35% limit of noninferiority) with a ratio of 0.95 (95% CI: 0.68, 1.34). Mean arterial pressure decreased by 18 mm Hg and 15 mm Hg in the indapamide SR and the enalapril groups, respectively (P = .1136). The effects of both treatments seen in these elderly patients were similar to those observed in the main population, although the extent of the reduction in microalbuminuria was slightly higher. Both treatments were well tolerated, and no difference between groups was observed regarding glucose or lipid profiles. CONCLUSION: Indapamide SR is not less effective than enalapril in reducing microalbuminuria and blood pressure in patients aged >65 years of age with type 2 diabetes and hypertension.     

Effect of two antihypertensive combinations on metabolic control in type-2 diabetic hypertensive patients with albuminuria: a randomised, double-blind study.

The objective of this study was to compare, at equal blood pressure (BP) reduction, the effect of two different combinations on metabolic control and albuminuria in type 2 diabetic hypertensive patients with albuminuria. This was a prospective, randomised, double-blind, parallel, controlled trial carried out in 11 Spanish hospitals. A total of 103 type 2 diabetic patients with stable albuminuria and BP not controlled on monotherapy were randomised of which 93 finished the study. After a 4-week single-blind placebo period, patients were randomised to verapamil SR/trandolapril 180/2 mg (VT) or to enalapril/hydroclorothiazide 20/12.5 mg (EH). Treatment duration was 6 months. The main outcome measures were changes in BP, 24-h albuminuria, blood glucose and glycated haemoglobin. Overall BP was significantly reduced from 157.3 +/- 12.0/98.3 +/- 6.4 mm Hg to 140.5 +/- 14.5/86.1 +/- 8.2 mm Hg (P < 0.001) and albuminuria significantly decreased from 508.6 +/- 693.8 mg/24 h to 253.4 +/- 517.2 mg/24 h (P < 0.001), both without significant differences between treatments. Glycated haemoglobin was not modified on VT: baseline, 5.91 +/- 1.43%; end of treatment, 5.94 +/- 1.62%, but increased on EH: baseline, 5.96 +/- 1.25%; final, 6.41 +/- 1.51%, (ANOVA interaction P = 0.040). At the end of the study, a blood glucose <126 mg/dL was attained in 72.7% of the VT group-improving in 29.5% and worsening in 6.8% of patients (P = 0.021)-and in 50% of the EH group, 13.6% of patients improved and 11.4% worsened (P = 1.000). There were no changes in body weight, serum creatinine, uric acid, potassium, cholesterol, tryglicerides and serum albumin. In hypertensive type 2 diabetic patients not controlled on monotherapy, both treatments similarly reduced albuminuria. The combination verapamil/ trandolapril seems to allow a better metabolic control than enalapril/hydroclorothiazide.     

Efficacy and safety of an oral fixed low-dose perindopril 2 MG/indapamide 0.625 MG combination: a randomized, double-blind, placebo-controlled study in elderly patients with mild to moderate hypertension.

The efficacy and safety of 12 weeks treatment with an oral fixed low-dose perindopril 2 mg + indapamide 0.625 mg (Per/Ind) combination in elderly and very elderly patients (65-85 years) with mild to moderate systolic and diastolic hypertension (SDH) or isolated systolic hypertension (ISH) were investigated vs placebo. This trial was a multinational randomized double-blind study with doubling of active drug dosage in nonresponders. Intention to treat analysis was performed in 383 patients (age 72.4 years; ISH 32%). 58.5% remained on their initial dosage. Per/Ind decreased supine diastolic and systolic blood pressure (sDBP/sSBP) by 13.2+/-8.0 mm Hg and 22.5+/-13.9 mm Hg (P <.0001) versus placebo -7.3+/-9.0 mm Hg and -12.3+/-15.2 mm Hg, respectively. In ISH (n = 123), Per/Ind decreased sSBP by 23.0+/-11.8 mm Hg (P <.0001). Overall response and normotension rates was 81.3% with Per/Ind (P <.0001). Adverse event rates (including hypokalemia) were similarly low in both groups. Analysis in the over-75 year subgroup showed similar safety and efficacy results. Fixed low-dose Per/Ind is a safe and effective treatment of hypertension including isolated systolic hypertension in the elderly.     

Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension

This study compared the efficacy and tolerability of eplerenone and enalapril in 499 patients with stage 1 or 2 hypertension who were randomized to receive eplerenone or enalapril for 6 months in a 3-step titration-to-effect study. After 6 months, patients whose diastolic blood pressure (BP) was <90 mm Hg had their dosages down-titrated were followed for an additional 6 months. Diastolic BP was the primary end point. Eplerenone was as effective as enalapril in reducing both systolic BP (eplerenone, -14.5 mm Hg; enalapril, -12.7 mm Hg; p = 0.199) and diastolic BP (eplerenone, -11.2 mm Hg; enalapril, -11.3 mm Hg; p = 0.910) at 6 months. BP reductions at 12 months were also similar between groups (-16.5/-13.3 mm Hg for eplerenone, -14.8/-14.1 mm Hg for enalapril; p = 0.251 and 0.331, respectively). Withdrawal rates for adverse events (eplerenone 7.9%, enalapril 9.3% at 6 months) and treatment failures (eplerenone 23.3%, enalapril 22.8% at 6 months) were also equivalent. Approximately 2/3 of each group had normal BP with monotherapy treatment at 6 months. BP response was independent of renin levels in the eplerenone group, but not in the enalapril group. Both agents reduced albuminuria in patients who had an elevated value at baseline, with significantly greater improvement in patients treated with eplerenone versus enalapril (-61.5% vs -25.7%; p = 0.01). Both agents were similarly well tolerated, and there was no increased incidence of any sexual adverse events in the eplerenone group. Patients taking enalapril had a higher rate of cough. Both agents increased serum potassium levels, but <1% in each group reported adverse events from hyperkalemia. Eplerenone was as effective as enalapril as monotherapy in patients with stage 1 or 2 hypertension, was more effective in reducing albuminuria, and was well tolerated for 12 months.     

Effect of fixed low dose combination of perindopril and indapamide on processes of cardiovascular remodeling in previously untreated patients with hypertension

AIM: To assess changes of blood pressure (BP) and processes of cardiovascular remodeling during treatment of previously untreated patients with hypertension with fixed low dose combination of perindopril and indapamide. MATERIAL: Patients with untreated hypertension (n=30, mean age 46.7+/-1.8 years, 16 men, 14 women) received low-dose perindopril (2 mg) - indapamide (0.625 mg) combination for 6 months. METHODS: Twenty four-hour BP monitoring, measurement of left ventricular (LV) mass index and wall and interventricular septal thickness, carotid artery intima-media thickness, pulse wave velocity and cerebral blood flow velocity. RESULTS: Target BP level was reached in 83.3% of patients. BP monitoring revealed significant lowering of daytime and nocturnal systolic BP (-13.2%, p<0.0001 and -14.5%, p<0.0001, respectively), daytime and nocturnal diastolic BP (- 14.3%, p<0.0001 and -15.3%, p<0.0001, respectively). Significant reduction of LV mass index (-12%, p=0.0002) was also observed. Both LV posterior wall and interventricular septal thicknesses were reduced as well (-5.1%, p<0,01). This was accompanied by decreases of intima-media thickness of right and left carotid arteries (-5,4%, p=0.04 and -5,3%, p=0.01, respectively), reduction of stiffness of elastic arteries (carotid-femoral pulse wave velocity decreased by 8%, p=0.003), and increase of cerebral blood flow velocity. CONCLUSION: The use of perindopril/indapamide combination in hypertensive patients was associated BP lowering and positive effects on remodeling both of the heart and large and medium arteries.     

Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study

OBJECTIVES: To test whether microalbuminuria in patients with type 2 diabetes and hypertension is primarily dependent on the severity of hypertension, and to compare the effectiveness of two antihypertensive drugs with opposite effects on the renin-angiotensin system [the diuretic, indapamide sustained release (SR), and an angiotensin-converting enzyme inhibitor, enalapril] in reducing microalbuminuria. DESIGN: A multinational, multicentre, controlled, double-blind, double-dummy, randomized, two-parallel-groups study over 1 year. METHODS: After a 4-week placebo run-in period, 570 patients (ages 60.0 +/- 9.9 years, 64% men) with type 2 diabetes, essential hypertension [systolic blood pressure (SBP) 140-180 mmHg, and diastolic blood pressure (DBP) < 110 mmHg], and persistent microalbuminuria (20-200 microg/min) were allocated randomly to groups to receive indapamide SR 1.5 mg (n = 284) or enalapril 10 mg (n = 286) once a day. Amlodipine, atenolol, or both were added, if necessary, to achieve the target blood pressure of 140/85 mmHg. RESULTS: There was a significant reduction in the urinary albumin : creatinine ratio. Mean reductions were 35% [95% confidence interval (CI) 24 to 43] and 39% (95% CI 30 to 47%) in the indapamide SR and enalapril groups, respectively. Equivalence was demonstrated between the two groups [1.08 (95% CI 0.89 to 1.31%); P = 0.01]. The reductions in mean arterial pressure (MAP) were 16.6 +/- 9.0 mmHg for the indapamide SR group and 15.0 +/- 9.1 mmHg for the enalapril group (NS); the reduction in SBP was significantly greater (P = 0.0245 ) with indapamide SR. More than 50% of patients in each group required additional antihypertensive therapy, with no differences between groups. Both treatments were well tolerated. CONCLUSIONS: Indapamide-SR-based therapy is equivalent to enalapril-based therapy in reducing microalbuminuria with effective blood pressure reduction in patients with hypertension and type 2 diabetes.     

Long-term efficacy of a new, fixed, very-low-dose angiotensin-converting enzyme-inhibitor/diuretic combination as first-line therapy in elderly hypertensive patients

OBJECTIVE: To determine the long-term efficacy and safety of a fixed, very-low-dose tablet combining one-half the standard dose of perindopril with one-quarter the standard dose of indapamide as first-line treatment in elderly patients. DESIGN: Double-blind, randomized, placebo-controlled study in an outpatient setting. PATIENTS AND INTERVENTIONS: Following a single-blind, placebo run-in period of 4 weeks, patients [65-85 years, with mild-to-moderate essential hypertension or isolated systolic hypertension (ISH)] were randomized to receive one tablet of perindopril 2 mg/indapamide 0.625 mg (Per/ Ind) (n=193) or placebo (n=190), daily for 12 weeks. After this first 12-week period, all patients on Per/Ind (n=138) and patients responding to placebo (n=61) were maintained on their previous regimen for a further 48 weeks. Patients in the placebo group whose blood pressure was not normalized, were switched to Per/Ind (n=60). MAIN OUTCOME MEASURE: The primary endpoint was the proportion of patients with blood pressure that normalized between weeks 0 and 60. RESULTS: After 1 year of treatment (intention-to-treat) supine systolic and diastolic blood pressure decreased by 23.0 +/- 15.3 mmHg and 13.3 +/- 94 mmHg with Per/Ind (n=253: 193 from randomized Per/Ind group and 60 from the placebo group switched at week 12). The mean decreases in systolic blood pressure were similar in essential hypertension and ISH (systolic blood pressure 23.2 versus 22.7 mmHg, respectively). Per/Ind treatment (n=253) achieved an initial normalization of blood pressure in 96.2% [95% confidence interval (CI) 93.6-98.9%; Kaplan-Meier estimate] of Per/Ind-treated patients; 79.8% (95% CI 74.1-85.5%) of these maintained a normalized blood pressure throughout the 1 -year follow-up. The incidence of adverse events was similarly low in the placebo and active therapy groups. Efficacy and safety results for the over 75 years subgroup were similar to those for the younger elderly subjects CONCLUSIONS: The fixed, very low-dose combination of perindopril 2 mg/indapamide 0.625 mg results in sustained blood pressure control when used as first line treatment of elderly hypertensive patients over 1-year, and is well-tolerated.     

Persistence of the antihypertensive effect of low-dose combination therapy in mild hypertension

The persistence of the antihypertensive effect of perindopril 2 mg + indapamide 0.625 mg once daily for up to 72 h was evaluated using the "missed-dose" technique. After 4 weeks on perindopril 2 mg+indapamide 0.625 mg, 79 of 216 hypertensive patients at goal (diastolic blood pressure < 85 mmHg) continued on perindopril 2 mg+indapamide 0.625 mg for a further 8 weeks. During either week 9 or 11, placebo was substituted for perindopril 2 mg+indapamide 0.625 mg on either 1 day or on 2 consecutive days. Twenty-four-hour ambulatory blood pressure was recorded at baseline, after 9 or 11 weeks of perindopril 2 mg+indapamide 0.625 mg and during the simulated missed doses, 24-48 and 48-72 h after perindopril 2 mg+indapamide 0.625 mg. Significant (p < 0.001) reductions in mean (+/- SD) 24-h blood pressure (mmHg) during the first 24 h after perindopril 2 mg+indapamide 0.625 mg vs baseline were noted for the two sub-groups subsequently allocated to one missed dose (-13.5 +/- 10.4/-8.0 +/- 6.6) or two missed doses (-12.2 +/- 7.4/-6.9 +/- 4.2). The antihypertensive effect persisted (p < 0.001 to p < 0.05 vs baseline) on the days when placebo was substituted for perindopril 2 mg+indapamide 0.625 mg with reductions in mean 24-h blood pressure from 24-48 h and 48-72 h after dosing being -11.6 +/- 9.6/-6.3 +/- 6.4 and -6.4 +/- 6.0/-3.9 +/- 4.2, respectively. Use of the "missed-dose" technique demonstrated persistence of an antihypertensive effect for perindopril 2 mg + indapamide 0.625 mg for up to 72 h after dosing.     

Blood pressure–lowering efficacy of indapamide SR/amlodipine combination in older patients with hypertension: A post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria)

To examine the antihypertensive efficacy and safety of indapamide sustained‐release (SR)/amlodipine compared with enalapril/amlodipine in patients 65 years and older with uncontrolled blood pressure (BP) on monotherapy, a post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria) was conducted. NESTOR randomized 570 patients (n=197, aged ≥65 years) with hypertension (systolic BP 140–180/diastolic BP <110 mm Hg) to indapamide SR 1.5 mg or enalapril 10 mg. If target BP (<140/85 mm Hg) was not achieved at 6 weeks, amlodipine 5 mg was added with uptitration to 10 mg if required. A total of 107 patients aged 65 years and older received dual therapy (53 indapamide SR/amlodipine and 54 enalapril/amlodipine). Amlodipine uptitration occurred in 22 and 24 patients, respectively. At 52 weeks, mean systolic BP (±SE) reduction was significantly greater with indapamide SR/amlodipine vs enalapril/amlodipine 6.2±2.7 mm Hg (P=.02). Indapamide SR/amlodipine was also associated with a greater BP response rate (88% vs 75%, respectively). Both regimens were well tolerated. Indapamide SR/amlodipine may be more effective than enalapril/amlodipine for lowering systolic BP in patients with hypertension aged 65 years and older.     

Blood pressure control in the Hypertension in the Very Elderly Trial (HYVET)

To report blood pressure control in the Hypertension in the Very Elderly Trial, a placebo-controlled trial of hypertensive (systolic blood pressure (SBP) 160-199?mm?Hg, diastolic blood pressure (DBP) <110?mm?Hg) participants over the age of 80 years, given treatment in three steps: indapamide slow release 1.5?mg alone, indapamide plus 2?mg perindopril and indapamide plus 4?mg perindopril. The difference in control between participants with combined systolic and diastolic hypertension (SDH, DBP90?mm?Hg) and those with isolated systolic hypertension (ISH, DBP<90?mm?Hg) is determined together with the effects of increments in the treatment regimen. At 2 years, the active treatment lowered blood pressure by 16.5/6.9?mm?Hg more than that on placebo in participants with SDH and by 19.3/4.8?mm?Hg more in those with ISH. The 2-year falls in pressure on placebo alone were 13.2/8.5?mm?Hg in SDH and 8.2/1.5?mm?Hg in ISH participants. With full titration of active treatment, 62% of SDH participants achieved goal SBP (<150?mm?Hg) by 2 years and 71% of those with ISH. The corresponding results for DBP control (<80?mm?Hg) were 40 and 78%. The addition of active perindopril 2?mg roughly doubled the percentage controlled, as did increasing to 4 from 2?mg. Blood pressure control was good with ISH and better than with SDH. The fall in SBP accounted for the observed 30% reduction in strokes, but the 21% reduction in total mortality and 64% reduction in heart failure were greater than predicted.     

Low-dose diuretic and/or dietary sodium restriction when blood pressure is resistant to ACE inhibitor.

AIM: To compare the efficacy of indapamide (1.25 mg daily) and low-salt diet (<100 mmol/day) separately and in combination in essential hypertensive patients with inadequate BP response to perindopril. DESIGN AND METHODS: Randomized double-blind, double-dummy, crossover design. The randomized treatments were indapamide 1.25 mg daily, sodium chloride 80 mmol daily, the combination of indapamide and sodium chloride and placebo. All patients received perindopril 4 mg daily and maintained a low-sodium diet. RESULTS: 19 patients entered and 17 completed the study. Prior to randomization, average clinic sitting blood pressure was 162/101 mm Hg and average 24-h urine sodium excretion was 157 mmol/day. Compared to the phase in which patients received perindopril with sodium repletion, clinic and ambulatory BPs were significantly reduced (p<0.01) in all the other phases. Indapamide had a greater effect on BP than dietary sodium restriction, and in combination their effects were additive. The effect of indapamide on ambulatory BP persisted throughout 24 h, but the effect of the low-salt diet was predominantly observed during waking hours. CONCLUSIONS: In hypertensives with BP resistant to the angiotensin converting enzyme (ACE) inhibitor perindopril, the diuretic indapamide had greater additional efficacy and longer duration of action than dietary sodium restriction. In combination they had additive effects on BP.     

Valsartan improves arterial stiffness in type 2 diabetes independently of blood pressure lowering

Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (n=66), an ARB, with that of amlodipine (n=65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) >or=60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), -0.9 m/s (-1.4 to -0.3) for valsartan/HCTZ compared to amlodipine (P=0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (P=0.01) with between treatment difference in favor of Val/HCTZ of -15.3mcg/min (P<0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs.     

Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass: the PICXEL study

OBJECTIVE: Few data are available comparing the effects of monotherapy and combination therapy on target organ damage. The PICXEL study compared the efficacy of a strategy based on first-line combination with perindopril/indapamide versus monotherapy with enalapril in reducing left ventricular hypertrophy (LVH) in hypertensive patients. METHODS: In this 1-year multicentre randomized double-blind study, patients received an increasing dosage of perindopril/indapamide (n = 284) or enalapril (n = 272). Changes in blood pressure and echocardiographic measures of LVH were assessed from baseline to the end of treatment. Reading of the echocardiograms was central and blinded for therapy, patient and sequence. RESULTS: Systolic and diastolic blood pressure decreased significantly more in the perindopril/indapamide than in the enalapril group (P < 0.0001 and P = 0.003). The left ventricular mass index decreased by 13.6 +/- 23.9 g/m(2) (mean +/- SD) with perindopril/indapamide (P < 0.0001) and 3.9 +/- 23.9 g/m(2) with enalapril (P < 0.005); these decreases were significantly different (P < 0.0001). The left ventricular internal diameter, posterior and interventricular septal wall thickness decreased significantly with perindopril/indapamide (P < or = 0.0001); the interventricular septal wall thickness decreased significantly with enalapril (P < 0.001). Both treatments were well tolerated. CONCLUSION: A strategy based on first-line combination with perindopril/indapamide achieved better blood pressure decrease with a significantly greater degree of LVH reduction than a strategy based on monotherapy with enalapril in hypertensive patients with LVH.     

Indapamide retard and enalapril in patients with arterial hypertension: hypotensive effectiveness and effect on endothelial function

AIM: To find out what type of therapy was better for restoration of 24 hour blood pressure (BP) rhythm and impaired function of vascular endothelium, and to determine preferential therapy for patients with severe endothelial dysfunction. METHODS: We performed ambulatory blood pressure monitoring and assessments of endothelial dependent (flow mediated-FM) and endothelial independent (nitroglycerine) dilatation of forearm artery (DFA) in patients with stage I-III essential hypertension. In a randomized comparative cross-over study 76 patients (mean age 49.2 +/- 6.2 years) received indapamide retard 1.5 mg and enalapril 20 mg for 24 weeks. RESULTS: Hypotensive effect of both drugs was identical (indapamide lowered systolic/diastolic BP by 13.6/12.0% and 12.9/9.9%, enalapril lowered BP by 14/14.6% and 13.2/12.9%). BP rhythm was better transformed by treatment with indapamide: nocturnal fall of mean BP increased on indapamide from 8.1 +/- 6.9% at baseline to 12.8 +/- 5.0% after treatment, p=0.007, and on enalapril from 11.8 +/- 7.9% at baseline to 10.4 +/- 6.2% after treatment, p=0.2. Indapamide and enalapril significantly augmented FM DFA (from 4.7 +/- 2.8% to 9.03 +/- 3.47%, p < 0.001, and from 4.6 +/- 2.2% to 10.9 +/- 3.5%, p < 0.001, respectively). All patients were divided into 2 groups: with baseline FM DFA - 2.5% (group I, n=59) and < 2.5% (group II, n=16). In group II indapamide lowered BP more effectively than enalapril ( - 10.2/ - 9.1% and - 5.5/ - 5.2%, p < 0,01/0.01, respectively). CONCLUSION: Both indapamide retard 1.5 mg and enalapril 20 mg exerted normalizing action on endothelium dependent DFA. However indapamide transformed 24 hour BP profile better than enalapril. Hypotensive therapy with indapamide was more effective than therapy with enalapril in patients with more pronouncedly disturbed FM arterial vasodilatation. This can be used in selection of a preparation in patients with impaired FM vasodilatation.     

Long term reduction of microalbuminuria after 1 year of angiotensin converting enzyme inhibition by perindopril in hypertensive insulin-treated diabetic patients

We studied the effects of perindopril, an angiotensin converting enzyme (ACE) inhibitor administered during 12 months, on creatinine clearance, albuminuria and glycaemic control in diabetic subjects with mild to moderate hypertension. After 1 month placebo, 40 insulin-treated patients were divided into 3 groups based upon their urinary albumin excretion rate (AER). Group I had a normoalbuminuria (AER less than 15 mg/24 h), group II had a microalbuminuria (AER : 15-150 mg/24 h) and group III had a macroproteinuria (AER greater than 150 mg/24 h and Albustix (+)). They were given perindopril, 4 to 8 mg orally once daily, and received a stable diet. Diastolic blood pressure was normalized within the first 3 months in 80% of the patients. From these, 28 (14.7 and 7 from groups I, II and III respectively) were followed during a total active treatment period of 12 months. They were matched for age, duration of diabetes and hypertension, systolic and diastolic blood pressures, daily insulin dose, postprandial plasma C-peptide and quality of glycaemic control. Mean supine diastolic blood pressure was decreased by 15 and 18% at 1 and 12 months respectively. Heart rate was not significantly modified. At 3 months, plasma ACE activity was nearly totally inhibited while plasma renin activity was markedly increased. In patients of group II, microalbuminuria was reduced from 66 +/- 13 (mean +/- SEM after placebo) to 39 +/- 6 mg/24 h after 1 month perindopril and this effect was maintained at 12 months. In group I, albuminuria remained within the normal range. In group III, macroproteinuria was not consistently modified by perindopril.(ABSTRACT TRUNCATED AT 250 WORDS)