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Aim: To estimate effect of combined perindopril/amlodipine therapy on structural and functional characteristics of the heart and blood vessels, intrarenal hemodynamics in patients with essential arterial hypertension (AH) depending on the degree of renal dysfunction., Material and Methods: 112 patients (63 men and 49 women) were included in the study; 35 of them (group 1) had the glomerular filtration rate (GFR) 90 ml/min/1.73 m2 or higher, 43 (group 2)--60-89 ml/min/1.73 m2 and 34 (group 3)--9-45 ml/min/i1.7 mi. The patients were treated with a fixed combination of dosage forms ofp erindopril and amlodipine at 10/5 mg/days or 10/10 mg/days for 24 weeks., Results: Pronounced antihypertensive effect of therapy was comparable in all groups. However dynamics of structural and functional indicators of the left ventricle (LV) and a brachial artery was apparent only in group 3. Endothelium-dependent vasodilation, cardiac index and LV ejectionf raction increased significantly whereas myocardiumnmass index of L decreased .A reduction of resistance andpulsation indices was recorded in interlobar renal arteries especially in groups 2 and 3. Serunmcreatinine level and urinary albumin excretion were significantly decreased while GFR increased ., Conclusion: Manifestations ofr emodeling ofc ardiovascular system and protective efficiencvyof the fixed combination ofp erin.opril and amlodipine correlate with the degree ofr enal dysfunction.

Objective: To investigate the changes of myocardial energy expenditure in patients with heart failure following myocardial infarction after treatment with different doses of perindopril., Methods: Sixty-three patients with heart failure after myocardial infarction were treated with perindopril for 12 months at the doses of 4 mg (group N) and 8 mg (group H). Doppler imaging was used to measure the structural and systolic functional parameters before and after the treatment, and the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated. The biochemical indicators including serum creatinine and plasma NT-proBNP were detected before and after the treatment., Results: The two groups had similar measurements before treatment. After 12 months of perindopril treatment, the patients in group N showed higher LA, LV, RA, RV, LVIDs, AD, cESS, lgNT-proBNP, and MEE with lower LVFS and LVEF than those in group H. Compared to those before treatment, LVFS and LVEF were increased and LA, LV, RA, RV, AD, LVIDs, LVMI, lgNT-proBNP and MEEm lowered after the 12-month treatment in group H. Significant changes were also found in the measured parameters except for PWTs, LVET, LVSV and LVFS in group N after the treatment. Bivariate analysis showed a significant positive correlation between MEE and lgNT-proBNP (r=0.513, P<0.01)., Conclusion: A 12-month treatment with perindopril can suppress myocardial remodeling, improve left ventricular systolic function, and lower NT-proBNP and myocardial energy expenditure in patients with heart failure after myocardial infarction, and a higher dose can produce better results.

Aims: To asses differences in treatment effects of a fixed combination of perindopril-indapamide on major clinical outcomes in patients with type 2 diabetes across subgroups of cardiovascular risk., Methods: 11,140 participants with type 2 diabetes, from the ADVANCE trial, were randomized to perindopril-indapamide or matching placebo. The Framingham equation was used to calculate 5-year CVD risk and to divide participants into two risk groups, moderate-high risk (<25% and no history of macrovascular disease), very high risk (>25% and/or history of macrovascular disease). Endpoints were macrovascular and microvascular events., Results: The mean age of participants was 66 years (42.5% female). 1000 macrovascular and 916 microvascular events were recorded over follow-up of 4.3 years. Relative treatment effects were similar across risk groups, (all P-values for heterogeneity ≥0.38). Hazard ratios for combined macro- and microvascular events were 0.89 (0.77-1.03) for the moderate-high risk and 0.92 (0.81-1.03) for the very high risk. Absolute treatment effects tended to be greater in the high risk groups although differences were not statistically significant (P>0.05)., Conclusions: Relative effects of blood pressure lowering with perindopril-indapamide on cardiovascular outcomes were similar across risk groups whilst absolute effects trended to be greater in the high risk group., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Antihypertensive and renoprotective treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker is indicated in almost all chronic renal failure patients. However, this treatment is not widely used for renal allograft recipients mainly because of the potential side effects, including a decrease in renal function as well as onset of hyperkalemia or anemia. Herein we investigated the effects of ACEI introduction to hypertensive renal transplantation patients who did not display renal artery stenosis. At least 2 months after transplantation, we exchanged amlodipine (5 mg) for either ramipril or perindopril (5 mg) in 25 patients who were free of renal artery stenosis as determined indirectly by measuring the renal arterial resistance index with the noninvasive, inexpensive Doppler ultrasound method. The resistance index was evaluated again at 2 weeks. Systolic and diastolic blood pressure, serum creatinine, calculated creatinine clearance, serum potassium, hemoglobin and hematocrit were also measured before as well as at 2, 4, and 12 weeks after conversion to ACEI. The conversion did not change the mean renal arterial resistance index, nor did it influence renal function or blood count, and it was equally effective for controlling blood pressure. The serum potassium level increased at 2 and 4 weeks; however, it was within the normal range in all patients. Our data suggested that measurement of the renal arterial resistance index is a noninvasive, inexpensive, and reliable preselection method before introduction of ACEI in renal allograft recipients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Fixed-dose combination treatments using an angiotensin-converting enzyme (ACE) inhibitor, such as perindopril, plus a calcium channel blocker (CCB), such as amlodipine, have been endorsed by guidelines because they improve blood pressure control and cardiovascular outcomes in hypertensive patients, while being well tolerated and well adhered to by patients., Objective: This study aimed to assess the blood pressure-lowering effects of fixed-combination perindopril/amlodipine in patients previously treated with an ACE inhibitor and/or a CCB., Methods: This was a prospective, real-life, open-label, longitudinal, phase IV study conducted in 223 outpatient medical centres across Slovakia. 2132 previously treated patients whose hypertension was insufficiently controlled at baseline or who tolerated treatment poorly were included. Patients were treated for 3 months with fixed-combination perindopril/amlodipine 5 mg/5 mg, 5 mg/10 mg, 10 mg/5 mg and 10 mg/10 mg. The main outcome measure was a reduction in mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) and achievement of blood pressure targets (SBP/DBP <140/90 mmHg or <130/80 mmHg for patients with type 2 diabetes mellitus or high cardiovascular risk)., Results: After 3 months of treatment, mean ± SD SBP/DBP had decreased from 158.5 ± 17.5/93.6 ± 9.8 mmHg to 132.9 ± 10.6/80.7 ± 6.2 mmHg (p < 0.0001). In patients with grade 3 hypertension, mean ± SD changes from baseline in SBP/DBP were -45.4 ± 16.4/-20.0 ± 11.5 mmHg after 3 months (p < 0.0001). Blood pressure targets were reached by 74% of the overall patient population, 84% of patients with grade 1 hypertension, and 52% of difficult-to-treat patients with grade 3 hypertension. This treatment was associated with a 58% reduction in the number of patients with amlodipine-related ankle oedema compared with baseline., Conclusion: Fixed-combination perindopril/amlodipine was well tolerated and resulted in statistically significant and clinically meaningful decreases in blood pressure.

Introduction: We investigated the effect of perindopril on pulse-wave velocity (as indicator of arterial elasticity) and endothelin-1 (ET-1) levels in black hypertensive patients., Methods: Forty-four newly diagnosed hypertensive patients who received 4 mg perindopril daily were monitored for nine months. Pulse-wave velocity (PWV) was measured noninvasively along the carotid-femoral arterial segment (high elastic content) and the brachial-ulnar segment (low elastic content)., Results: There was a significant increase in arterial elasticity, as indicated by a slower PWV in the carotid-femoral segment of the treatment group, from 11.6 to 7.5 m/s after nine months. The PWV of the treatment group (7.5 m/s) after nine months was lower than that of the healthy volunteer group (8.2 m/s) but it was not statistically significant. No correlation between ET-1 and PWV could be found., Conclusion: In addition to its blood pressure-lowering effect, our study confirmed the improvement in arterial elasticity in patients on perindopril therapy, without involvement of ET-1.

Evidences indicate that inhibition of central Renin angiotensin system (RAS) ameliorates memory impairment in animals and humans. Earlier we have reported involvement of central angiotensin converting enzyme (ACE) in streptozotocin induced neurodegeneration and memory impairment. The present study investigated the role of central ACE in cholinergic neurotransmission, brain energy metabolism and cerebral blood flow (CBF) in model of memory impairment induced by injection of scopolamine in mice. Perindopril (0.05 and 0.1 mg/kg, PO) was given orally for one week before administration of scopolamine (3mg/kg, IP). Then, memory function was evaluated by Morris water maze and passive avoidance tests. CBF was measured by laser Doppler flowmetry. Biochemical and molecular parameters were estimated after the completion of behavioral studies. Scopolamine caused impairment in memory which was associated with reduced CBF, acetylcholine (ACh) level and elevated acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level. Perindopril ameliorated scopolamine induced amnesia in both the behavioral paradigms. Further, perindopril prevented elevation of AChE and MDA level in mice brain. There was a significant increase in CBF and ACh level in perindopril treated mice. However, scopolamine had no significant effect on ATP level and mRNA expression of angiotensin receptors and ACE in cortex and hippocampus. But, perindopril significantly decreased ACE activity in brain without affecting its mRNA expression. The study clearly showed the interaction between ACE and cholinergic neurotransmission and beneficial effect of perindopril can be attributed to improvement in central cholinergic neurotransmission and CBF., (Copyright © 2012. Published by Elsevier B.V.)

Background and Purpose: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy., Methods: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding., Results: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%-69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg)., Conclusions: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy.

Background Aims: We investigated bone marrow stromal cell (BMSC) transplantation combined with angiotensin-converting enzyme inhibitor (ACEI) treatment in acute myocardial infarction (AMI) and the role of insulin-like growth factor-1 (IGF-1)., Methods: AMI models were established in Sprague-Dawley rats by ligation of the left anterior descending coronary artery and grouped into blank control (BC), ACEI treatment (ACEI), BMSC transplantation (BMSC) and BMSC transplantation plus ACEI (combined). Perindopril (2.5 mg/kg) was administered by gavage to ACEI and combined groups from the day after AMI. BMSC (2 × 10(8)) were injected into the border of the MI area a week later in the BMSC and combined groups., Results: After 4 weeks, hemodynamics in the BMSC and combined groups were significantly improved (P < 0.05 versus BC), with the greatest improvement in the combined group (P < 0.05). In addition, an increased number of BMSC survived in the combined group (P < 0.05 versus BMSC). A proportion of BMSC was positive for troponin T, as detected by immunofluorescence. The number of apoptotic cardiomyocytes was decreased in the BMSC and ACEI groups, and even further in the combined group (P < 0.05). IGF-1 expression was up-regulated in the BMSC and combined groups (P < 0.05 versus BC), but not in the ACEI group. B cell lymphoma-2 (Bcl-2) expression was up-regulated in the ACEI, BMSC and combined groups, with the highest expression in the combined group (P < 0.05)., Conclusions: Our results show that BMSC engrafted in AMI can survive well and secrete IGF-1 and preserve cardiac function significantly. These data suggest that BMSC transplantation inhibits apoptosis of cardiomyocytes by up-regulation of Bcl-2 expression in the myocardium, and this effect might be sensitized by ACEI.

Introduction: There is a growing body of data concerning significant interactions between markers of inflammation and cardiovascular diseases such as hypertension accompanied by elevated levels of plasma C-reactive protein (CRP). Therefore CRP is thought to be an independent risk factor of cardiovascular diseases., Material/methods: The aim of this study was to evaluate the effects of antihypertensive therapy (perindopril, bisoprolol and combined therapy) on plasma CRP concentration in 67 subjects with mild or moderate hypertension who have been treatment-naive and otherwise healthy., Results: The results show a correlation between CRP level and blood pressure values. BP reduction was associated with a decrease in CRP concentration. The CRP-lowering effect of perindopril and bisoprolol was comparable and the degree of reduction might reflect their similar influence on blood pressure. Combined treatment influenced the CRP level to a greater extent than both monotherapies., Conclusions: Plasma CRP level was lowered by antihypertensive therapy independently of the drug applied. The CRP level did not normalize completely in moderate hypertensive patients.

Background: The intercalation of perindopril erbumine into Zn/Al-NO(3)-layered double hydroxide resulted in the formation of a host-guest type of material. By virtue of the ion-exchange properties of layered double hydroxide, perindopril erbumine was released in a sustained manner. Therefore, this intercalated material can be used as a controlled-release formulation., Results: Perindopril was intercalated into the interlayers and formed a well ordered, layered organic-inorganic nanocomposite. The basal spacing of the products was expanded to 21.7 Å and 19.9 Å by the ion-exchange and coprecipitation methods, respectively, in a bilayer and a monolayer arrangement, respectively. The release of perindopril from the nanocomposite synthesized by the coprecipitation method was slower than that of its counterpart synthesized by the ion-exchange method. The rate of release was governed by pseudo-second order kinetics. An in vitro antihypertensive assay showed that the intercalation process results in effectiveness similar to that of the antihypertensive properties of perindopril., Conclusion: Intercalated perindopril showed better thermal stability than its free counterpart. The resulting material showed sustained-release properties and can therefore be used as a controlled-release formulation.

Aim: To investigate the effects of ivabradine in combination with perindopril on cerebral blood flow and endothelial functional activity., Subjects and Methods: Sixty-four patients with coronary heart disease (CHD) and arterial hypertension (AH) were examined. Group 1 (n = 38) patients took ivabradine in combination with perindopril and Group 2 (n = 26) received metoprolol. At baseline and 8 weeks after therapy, 24-hour blood pressure (BP) monitoring and electrocardiography were done, cerebral blood flow was estimated by Doppler ultrasound, reactive hyperemia and nitroglycerin tests were performed, and plasma nitrite levels were determined., Results: With a comparable decrease in BP and heart rate in the internal carotid artery basin in both groups over time, there was a fall in peak systolic blood flow velocity; Group 1 showed a reduction in pulsatility index (PI) and systolic/diastolic ratio (ISP). After 8 weeks, there was an increase in endothelium-independent vasodilation and baseline blood flow velocity in the brachial artery in Group 1 and a rise in endothelium-dependent vasodilation in Group 2; in both groups, reactive hyperemia were higher in the brachial artery basin. No changes in nitrite levels were recorded during therapy. There was an inverse correlation between PG and PI in Group 1 and between PG and ISP in Group 2., Conclusion: By unidirectionally affecting the vasomotor function of the endothelium, ivabradine in combination with perindopril versus metoprolol has a more favorable effect on circulatory resistance and blood flow velocity in the brachiocephalic arteries of patients with CHD and AH.

Angiotensin-converting enzyme inhibitors are widely prescribed to regulate blood pressure. High doses of orally administered perindopril have previously been shown to improve fracture healing in a mouse femur fracture model. In this study, perindopril was administered directly to the fracture area with the goal of stimulating fracture repair. Three months after being ovariectomized (OVX), tibial fractures were produced in Sprague-Dawley rats and subsequently stabilized with intramedullary wires. Perindopril (0.4 mg/kg/day) was injected locally at the fractured site for a treatment period of 7 days. Vehicle reagent was used as a control. Callus quality was evaluated at 2 and 4 weeks post-fracture. Compared with the vehicle group, perindopril treatment significantly increased bone formation, increased biomechanical strength, and improved microstructural parameters of the callus. Newly woven bone was arranged more tightly and regularly at 4 weeks post-fracture. The ultimate load increased by 66.1 and 76.9% (p<0.01), and the bone volume over total volume (BV/TV) increased by 29.9% and 24.3% (p<0.01) at 2 and 4 weeks post-fracture, respectively. These findings suggest that local treatment with perindopril could promote fracture healing in ovariectomized rats.

The aim of the study was to investigate the dynamics of arterial stiffness and endothelial function parameters under the influence of perindopril arginine and indapamide fixed combination in arterial hypertension (AH) patients. 30 persons with 1-3 degree AH were included into the study. The treatment duration was 24 weeks. Central aortic blood pressure (BP), augmentation pressure and index (AIx), carotid-femoral and carotid-radial pulse wave velocity (PWV), brachial artery endothelium-dependent vasodilatation (EDVD), office and ambulatory BP as well as orthostatic BP falls were evaluated under the influence of selected therapy. 27 patients completed the study protocol. Results showed that aortic systolic BP was significantly reduced by 10.7 mmHg, augmentation pressure - by 3.6 mmHg and AIx - by 6.5%. Carotid-radial PWV decreased by 0.8 m/s. Carotid-femoral PWV did not change. We also revealed the EDVD increase by week 12. The EDVD growth was correlated with degree of aortic systolic BP reduction (r=-0.48, p=0.02). Office and ambulatory BP declined by 15.8/10.0 and 10.0/7.5 mmHg respectively. The target BP &lt;140/90 mmHg was achieved in 20 (74.1%) persons. At the same time the orthostatic hypotension did not rise. Conclusion. We concluded that perindopril arginine/indapamide fixed combination improved vascular function in hypertensive patients by wave reflection reduction, peripheral arterial stiffness lowering and endothelial function improvement.

This review provides an analysis of the results of Russian and foreign clinical trials that have shown a high antihypertensive efficacy and tolerability of combined medications containing fixed doses of perindopril and indapamide.

Arterial hypertension determines the remodeling of the vascular bed at all levels, resulting in a high risk of developing cardiovascular complications. Recent studies performed on the basis of evidence-based medicine, demonstrated the high efficiency of the combination drug therapy with perindopril and amlodipine in preventing such complications. This may be due to the positive influence of a fixed combination of these drugs on the parameters of the state of the microcirculatory level of the vascular bed.

Aim: To estimate the time course of changes in brachial artery (BA) functional parameters in patients with unstable angina (UA) treated with angiotensin-converting enzyme inhibitors., Subjects and Methods: After examination, 30 patients with Braunwald Classes IB and IIB UA were randomized to two groups to receive perindopril or enalapril as part of combination therapy (Group 1 and Group 2, respectively). The authors carried out BA duplex scanning with a reactive hyperemia test, calculated the values of its viscoelastic properties, and determined pulse wave velocity (PWV) at baseline and after 3 months., Results: The patients of both groups did not differ in BA functional parameters at baseline. Following 3 months, Group 1 showed a reduction in Young's (p = 0.046) and Peterson's (p = 0.049) modules, an increase in compliance (p = 0.016) and distensibility (p = 0.02) coefficients, and a decrease in PWV (p = 0.23). Estimation of endothelium-dependent vasodilation of BA revealed a significant increase in its diameter increment both at testing minutes 1 (p = 0.047) and 2 (p = 0.049). In Group 2, only did the distensibility coefficient change significantly (p = 0.041). After the reactive hyperemia test, there was a significant rise in BA diameter increment at minute 1 (p = 0.047) and no change in this indicator at minute 2., Conclusion: After 3-month treatment, the viscoelastic properties of BA improved in all indicators in the patients taking perindopril as part of combination therapy. The use of enalapril improved only an arterial distensibility index. The BA endothelial function estimated by its diameter increment also displayed better changes in the patients receiving perindopril.

This comparative ultrasound study included 210 patients aged 65-80 years with non-valvular atrial fibrillation treated with the use of 4 different therapeutic modalities. Intake of perindopril, valsartan, valsartan + rozuvastatin, and lercanidipine resulted in a rise in distension index of common carotid artery, decrease of rigidity coefficient of the aortic wall and increase of the pulsed wave propagation speed. Combination of valsartan (80-160 mg/d) and rozuvastatin (10 mg/d) had the most pronounced effect on the vascular wall compliance compared with other modalities and reduced the frequency of ischemic stroke, myocardial infarction, and mortality. It is concluded that therapy of non-valvular atrial fibrillation in elderly patients with valsartan + rozuvaststin is the optimal strategy for the improvement of elastic properties of the vascular wall and reduction of the frequency of cardiovascular complications.

Objective: Participants in ADVANCE were drawn from many countries. We examined whether the effects of intensive glycemic control on major outcomes in ADVANCE differ between participants from Asia, established market economies (EMEs), and eastern Europe., Research Design and Methods: ADVANCE was a clinical trial of 11,140 patients with type 2 diabetes, lasting a median of 5 years. Demographic and clinical characteristics were compared across regions using generalized linear and mixed models. Effects on outcomes of the gliclazide modified release-based intensive glucose control regimen, targeting an HbA(lc) of ≤6.5%, were compared across regions using Cox proportional hazards models., Results: When differences in baseline variables were allowed for, the risks of primary outcomes (major macrovascular or microvascular disease) were highest in Asia (joint hazard ratio 1.33 [95% CI 1.17-1.50]), whereas macrovascular disease was more common (1.19 [1.00-1.42]) and microvascular disease less common (0.77 [0.62-0.94]) in eastern Europe than in EMEs. Risks of death and cardiovascular death were highest in eastern Europe, and the mean difference in glycosylated hemoglobin between the intensive and standard groups was lowest in EMEs. Despite these and other differences, the effects of intensive glycemic control were not significantly different (P ≥ 0.23) between regions for any outcome, including mortality, vascular end points, and severe hypoglycemic episodes., Conclusions: Irrespective of absolute risk, the effects of intensive glycemic control with the gliclazide MR-based regimen used in ADVANCE were similar across Asia, EMEs, and eastern Europe. This regimen can safely be recommended for patients with type 2 diabetes in all of these regions.

Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Since neovascularization plays an important role in hepatocarcinogenesis and IR, an angiostatic therapy may be considered as one of the promising approaches for chemoprevention against HCC. The aim of the current study was to examine the combination effect of a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I), both reportedly possess anti-angiogenic and IR-improving activities, on the cumulative recurrence after curative therapy. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered after the curative therapy for HCC, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly inhibited the cumulative recurrence of HCC under IR conditions, whereas neither single treatment exerted a significant inhibition. The soluble form of the vascular endothelial growth factor (VEGF; a central angiogenic factor) receptor-2 (sVEGFR2) was significantly decreased only three months after the treatment without recurrence. We also observed that IR, determined by the homeostasis model assessment (HOMA-IR), was significantly improved by this regimen, indicating that an inhibitory effect was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. In conclusion, since both BCAA and ACE-I are widely used in clinical practice with safety, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC recurrence in the future. Moreover, sVEGFR2 may become a useful clinical predictive marker of this combination treatment.

Introduction: Hypertension is an important risk factor for cardiovascular complications and the need to treat this condition has been well established. Despite the availability of many antihypertensive drugs, it is often necessary to combine several of these drugs. The compound perindopril/indapamide offers the opportunity to start with a fixed combination of two effective agents as first-line treatment. Large outcome trials so far show that the perindopril/indapamide compound has favourable prognostic effects in elderly hypertensives as well as in patients with high cardiovascular risks, regardless of their level of blood pressure., Areas Covered: This review examines the prevalence of hypertension, the major risk factors, its pharmacodynamics, pharmacokinetics and clinical efficacy, and also looks at the results of large outcome trials. This review will allow the reader to put the role of the perindopril/indapamide combination in perspective, at least from a clinical point of view., Expert Opinion: Despite the positive trial results, there are still issues that deserve attention, for example safety with respect to drug levels in special patient groups. Also, in the large outcome trials placebo treatment (whether or not in addition to other medication) was taken as the comparator, and it is uncertain whether the combination of perindopril and indapamide performs better than established modes of treatment. More studies are needed to establish whether the combination drug has similar positive effects in the long run in 'ordinary' patients and those with comorbid conditions or those who are treated with other drugs as well. Nevertheless, it is fair to state that the low-dose perindopril/indapamide combination adds to our pharmaceutical arsenal and can be applied as first-line treatment by physicians who care for patients with elevated blood pressure or, more broadly, those with cardiovascular disease.

Background: The Action in Diabetes and Vascular Disease (ADVANCE) Study demonstrated that a fixed combination of perindopril and indapamide reduced the risk of major vascular events and mortality in patients with type 2 diabetes. This Echocardiographic Substudy was designed to determine the effects of this treatment on left ventricular diastolic function and left ventricular mass., Methods: Five hundred and fifty-five patients entering ADVANCE underwent quantitative echocardiography prior to randomization and after 6 months and 4 years of treatment with perindopril-indapamide or placebo. Main end points were left ventricular diastolic function (ratio of mitral E velocity/early medial mitral annular tissue Doppler velocity, E/Em, and left atrial volume index) and left ventricular mass index., Results: Overall, blood pressure was reduced in the perindopril-indapamide group compared with placebo. E/Em and left atrial volume index both increased over the 4 years. There was no effect of perindopril-indapamide on E/Em, although there was a small attenuation of the increase in left atrial volume index with active treatment. Left ventricular mass index was reduced by 2.7 g/m with active treatment (95% confidence interval -5.0 to -0.1, P = 0.04)., Conclusion: Compared with placebo, the perindopril-indapamide combination reduced blood pressure and left ventricular mass in patients with diabetes, but did not improve left ventricular diastolic function. Left ventricular diastolic function worsened in both groups over 4 years, despite blood pressure reduction and reduction in left ventricular mass. Improving left ventricular diastolic function remains a challenge in patients with diabetes.

To determine whether the persistent antihypertensive effect observed after withdrawal of angiotensin-converting enzyme inhibition was specific and whether it was associated with durable improvement of renal function. Lyon hypertensive (LH) rats were treated from 3 and 12 weeks of age with perindopril at the dose of 0.4 (P0.4) or 1.5 (P1.5) mg·kg(-1)·d(-1), with double (hydralazine 75 mg·kg(-1)·d(-1) and hydrochlorothiazide 15 mg·kg(-1)·d(-1)), or triple antihypertensive therapy (reserpine 0.75 mg·kg(-1)·d(-1) was added). Blood pressure (BP) was recorded by telemetry, and renal functions were evaluated in freely moving rats. Despite similar BP reduction after perindopril withdrawal in P0.4 and P1.5 groups, greater decrease in proteinuria was observed in P1.5 group. Double or triple therapy prevented the hypertension of LH rats, but without any persistent antihypertensive or antiproteinuric effect after its withdrawal. Salt load elicited an increase in BP that was similar in untreated LH and both perindopril-pretreated groups (+30 mm Hg), but more pronounced in double therapy–pretreated or triple therapy–pretreated groups (+50 mm Hg). The pressure–natriuresis curve shifted to lower BP levels in P0.4 and P1.5 groups, whereas it was blunted in double and triple therapy groups. Angiotensin-converting enzyme inhibition has a durable renoprotection after treatment withdrawal that is independent of BP lowing.

The results of observational investigation by prescription of the fixed combination perindopril + amlodipin produced by to the uncontrollable hypertension patients by the previous therapy are described in the given article. In Kazan population 50 patients at the age of 32 to 92 with essential hypertension having blood pressure level of 140/90 mm/hg. Were included into the investigation. Before these patients took different groups of antihypertension preparation (including perindopril). The preparation was prescribed in different fixed dosage depending on duration of hypertension, quantity of taken hypertension groups of preparations and blood pressure level. Then during 1, 2, 3 months of treatment the physician had the possibility to determine the dosage necessary to prescribe. The prescription of perindopril in combination with amlodipin during 3 months led to certain lowering of systolic and diastolic arterial pressure for 38.2 and 11.6 mm/hg accordingly and 80% of patients had the required pressure level of (<140/90 mm/hg). Moreover, the frequency of heart beat reduced and necessary increase of patient compliance for treatment took place. Taking the preparation only 31% of patients had unwilling effects but it didnt require the abolition of the antihypertension therapy till the end of observation. As a result, the investigation confirmed the high efficiency, good perception, improvement of patient compliance for treatment by prescribing the fixed combination perindopril + amlodipin.

Based on the results of the ADVANCE study, the article considers the issues of medication nephroprotection in patients with type 2 diabetes mellitus, including patients with uncontrolled arterial hypertension. Potentials for use of fixed combination of perindopril + indapmide, which provides therapeutic effect at all stages of renal continuum, are discussed. It is established that improved control of blood pressure by combination of perindopril + indapmide leads to a significant decrease in mortality in DM 2 patients.

Aim: To study ways of realization of pleiotropic effects of treatment with low-dose combination of perindopril arginine with indapamide in hypertensive patients with metabolic syndrome (MS)., Material and Methods: Thirty hypertensive patients with MS received low-dose combined drug noliprel A (Servier, France). In weak hypotensive effect noliprel A forte was used. An antihypertensive (by the data of 24-h blood pressure monitoring), sympatholytic (by the levels of ACTH and cortisol in blood plasma, by variability of the heart rate)and metabolic effects of the drug were assessed after 3 weeks, 3 and 6 months of treatment. Carbohydrate metabolism was studied by glucose and insulin blood levels before meal and after it. Lipid and purin metabolism were assessed by enzyme method, leptin levels - by enzyme immunoassay., Results: 24-h blood pressure monitoring registered a stable regular blood pressure lowering, target blood pressure was achieved in 78.6% patients. Blood ACTH concentration significantly reduced showing a sympatholytic action of the drug. Parameters of lipid, carbohydrate and purin metabolism changed insignificantly. Positive changes were seen in anthropometric indices, leptin tended to decrease. Changes in these parameters, sympatholytic and hypotensive effects depended on plasmic levels of leptin., Conclusion: A fixed low-dose combination of perindopril arginine with indapamide in a stable hypotensive effect and metabolic neutrality influences some key components of MS including hyperactivity of sympathic autonomic nervous system component and hyperleptinemia.

We gave perindopril (10 mg/day) for 24 weeks to 30 patients with arterial hypertension and obesity and proved its ability to effectively lower arterial pressure, exert cardio-, angio-, and nephro-protection, improve parameters of lipid, carbohydrate and purine metabolisms in these patients. Moreover perindopril in these patients diminished manifestations of insulin resistance, hyperleptinemia, and inflammation; it also exerted pronounced positive effect on anthropometric parameters and percent of fat deposits. Basing on the aggregate of clinical and pharmacodynamics effects perindopril can be considered the drug of choice for treatment of arterial hypertension at the background of obesity.

We have recently reported favorable responses to a combination treatment comprising cimetidine, a cyclooxygenase-2 inhibitor and a renin-angiotensin-system inhibitor in metastatic renal cell carcinoma (RCC). In view of the potential synergistic effects of these three agents and interferon-α (I-CCA therapy), we conducted a phase-II trial to examine the efficacy and toxicity of I-CCA as first-line treatment. Fifty-one patients with advanced RCC received natural interferon-α (3-6 million U thrice/week) and cimetidine (800 mg), cyclooxygenase-2 inhibitor meloxicam (10 mg), and renin-angiotensin-system inhibitor candesartan (4 mg) or perindopril (4 mg) orally daily. Memorial Sloan-Kettering Cancer Center prognostic categories were favorable, intermediate and poor in 10 (20%), 31 (61%) and 10 (20%) patients, respectively. The primary end-point was the objective response rate (ORR) and the secondary end-points included clinical benefit, progression-free survival (PFS), overall survival (OS) and safety. Median follow-up was 19 months. Complete response (CR) was observed in four patients (8%) and partial response in seven (14%), yielding an ORR of 22%. None of the four patients who achieved CR relapsed during the 16- to 81-month follow up. The ORR were 17% in the favorable- or intermediate-risk group and 40% in the poor-risk group. The other 24 patients (45%) had stable disease for at least 6 months, resulting in a clinical benefit rate of 67%. The median PFS and OS were 12 and 30 months, respectively. Grade 3/4 toxicities were never observed. The I-CCA therapy, providing favorable responses and low toxicity profiles, is worthy of further consideration as a first-line therapy for metastatic RCC., (© 2010 Japanese Cancer Association.)

The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.

Aims: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for cardiovascular disease. In these analyses of the ADVANCE trial, we assessed the effects of a fixed combination of perindopril-indapamide on renal and cardiovascular outcomes in patients with type 2 diabetes according to baseline CKD stage., Methods and Results: Patients with type 2 diabetes were randomized to perindopril-indapamide (4 mg/1.25 mg) or placebo. Treatment effects on cardiovascular (cardiovascular death, myocardial infarction, or stroke) and renal outcomes were compared in subgroups defined by baseline Kidney Disease Outcome Quality Initiative CKD stage. Homogeneity in treatment effect was tested by adding interaction terms to the relevant Cox models. The study included 10 640 participants with known CKD status, of whom 6125 did not have CKD, 2482 were classified as CKD stage 1 or 2, and 2033 as CKD stage ≥3. The relative treatment effects on major cardiovascular events were similar across all stages of CKD, with no heterogeneity in the magnitude of the effects for any outcome. In contrast, the absolute treatment effects approximately doubled in those with CKD stage ≥3 when compared to those with no CKD. For every 1000 patients with CKD stage ≥3 treated for 5 years, active treatment prevented 12 cardiovascular events when compared with six events per 1000 patients with no CKD., Conclusion: The treatment benefits of a routine administration of a fixed combination of perindopril-indapamide to patients with type 2 diabetes on cardiovascular and renal outcomes, and death, are consistent across all stages of CKD at baseline. Absolute risk reductions are larger in patients with CKD highlighting the importance of blood pressure-lowering in this population.

Objectives: The aim of this study was to examine the relationship between erectile problems in men and cardiovascular disease (CVD) mortality., Background: Although there are plausible mechanisms linking erectile dysfunction (ED) with coronary heart disease (CHD) and stroke, studies are scarce., Methods: In a cohort analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) trial population, 6,304 men age 55 to 88 years with type 2 diabetes participated in a baseline medical examination when inquiries were made about ED. Over 5 years of follow-up, during which study members attended repeat clinical examinations, the presence of fatal and nonfatal CVD outcomes, cognitive decline, and dementia was ascertained., Results: After adjusting for a range of covariates, including existing illness, psychological health, and classic CVD risk factors, relative to those who were free of the condition, baseline ED was associated with an elevated risk of all CVD events (hazard ratio: 1.19; 95% confidence interval: 1.08 to 1.32), CHD (hazard ratio: 1.35; 95% confidence interval: 1.16 to 1.56), and cerebrovascular disease (hazard ratio: 1.36; 95% confidence interval: 1.11 to 1.67). Men who experienced ED at baseline and at 2-year follow-up had the highest risk for these outcomes., Conclusions: In this cohort of men with type 2 diabetes, ED was associated with a range of CVD events., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Angiotensin-converting enzyme (ACE) inhibitors differ in their lipophilic/hydrophilic index that determines their tissue bioavailability and affinity to ACE, which may result in major differences in the degree of blockade of cardiac ACE. We evaluated the hypothesis that in patients with chronic heart failure (CHF) and activated cardiac renin-angiotensin-aldosterone system (RAAS), lipophilic ACE inhibitors with high affinity for ACE (perindopril and quinapril) will cause marked blockade of cardiac angiotensin (Ang) II and aldosterone generation, but not a hydrophilic ACE inhibitor with low affinity for ACE (lisinopril)., Methods: Patients were randomized to receive perindopril (8 mg/day), quinapril (40 mg/day), or lisinopril (20 mg/day) for 3-4 weeks before cardiac catheterization. The coronary sinus-aortic root gradients for Ang I and II, and aldosterone were determined., Results: A total of 19 patients completed the study. Compared to a healthy control group, all three ACE inhibitors decreased circulating Ang II and aldosterone to a similar extent. There were only minor differences between the three ACE inhibitors for the Ang II gradient between the coronary sinus and aortic root. The gradient for aldosterone tended to be positive in the quinapril group and absent/negative in the lisinopril and perindopril groups. Despite the lowest pulmonary capillary wedge pressure (PCWP), gradients between the coronary sinus and aortic root for Ang II and aldosterone were actually the highest in the quinapril group., Conclusions: These findings do not support the concept that a hydrophilic ACE inhibitor is less effective in blocking the cardiac RAAS as compared to lipophilic ACE inhibitors.

The ACCESS (Acute Candesartan Cilexetil Therapy in Stroke Survivors) study found that administration of candesartan in the acute phase of stroke confers a long-term benefit in patients who have sustained acute ischemic stroke. This treatment did not significantly reduce blood pressure (BP) during the acute phase, however. We assessed the short-term safety of reducing BP with renin-angiotensin system blockade in hypertensive patients who sustained acute ischemic stroke. Our randomized study compared the effects of 14 days of oral candesartan (4 mg/day), perindopril (4 mg/day), or conventional therapy (topical nitrate only when systolic BP (SBP) was ≥220 mm Hg or diastolic BP (DBP) was ≥120 mm Hg) administered to hypertensive patients within 72 hours of the onset of minor ischemic stroke. We assessed neurologic symptoms using the National Institutes of Health Stroke Scale and the modified Rankin Scale within 72 hours of stroke onset before and after drug therapy. A total of 40 patients completed the protocol. Therapy with candesartan and perindopril reduced SBP/DBP values by 23/11 mm Hg (SBP, P<.01; DBP, P=.07) and 14/0 mm Hg (SBP, P=.07), respectively, compared with conventional treatment. Neurologic symptoms worsened in 2 patients who received perindopril, which has no statistical significance, despite the BP reduction in patients given candesartan or perindopril. Our findings indicate that low doses of candesartan or perindopril safely reduce SBP in hypertensive patients with acute ischemic stroke., (Copyright © 2010 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors.

Objective: To determine the cost-effectiveness of routine administration, irrespective of blood pressure (BP), of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus., Design, Setting and Participants: Prospective cost-effectiveness analysis within the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, an international, multicentre, randomised controlled trial of 11,140 participants with type 2 diabetes randomly allocated to receive perindopril plus indapamide (4 mg-1.25 mg/day) or placebo., Main Outcome Measures: Health-related quality-of-life measured by the EuroQol-5D, resource utilisation, and cost-effectiveness (cost per death averted at 4.3 years' average follow-up, and estimated cost per life-year gained, by extrapolation)., Results: The mean health-related quality-of-life score of survivors was 0.80 (on a 0-1 scale [death to full health]), with no difference between treatment groups. Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5%. For the Australian participants, perindopril-indapamide cost A$1368 per patient during the trial period, but reduced total hospitalisation costs by A$410 and other medication costs (mainly other BP-lowering drugs) by A$332. The absolute reduction in all-cause mortality for the active treatment group was 1.1%, giving a cost per life saved of A$49,200. Lifetime extrapolation gave an estimated cost per life-year saved of A$10,040 (discounted at 5% per year)., Conclusion: The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective., Trial Registration: United States National Library of Medicine NCT00145925.

Background: Combination antihypertensive therapy with an inhibitor of the renin-angiotensin system (RAS) and a calcium channel blocker (CCB) is a rational approach to achieve blood pressure (BP) goals in patients with hypertension, and may provide additional cardiovascular protection compared to other strategies in special populations. This article reviews the rationale for, and evidence supporting, the use of newer fixed-dose combinations of RAS inhibitors and CCBs, with particular emphasis on perindopril/amlodipine., Methods: A literature search was performed in Medline and EMBASE databases to identify articles published up to May 2010 describing the impact of combination treatment with angiotensin receptor blocker (ARB)/CCB or angiotensin-converting enzyme (ACE) inhibitor/CCB based antihypertensive strategies on BP or clinical outcomes., Findings: A substantial body of evidence supports the BP-lowering efficacy of RAS inhibitor/CCB combination therapy in patients with hypertension. RAS inhibitors and CCBs represent two different and complementary mechanisms of actions; their use in combination is associated with effective BP lowering with favourable tolerability and fewer adverse metabolic effects than some other combination therapies. Currently, intervention studies demonstrating the impact of ARB/CCB combinations on cardiovascular mortality and morbidity are lacking. However, evidence from large outcome trials supports the use of ACE inhibitor/CCB combinations for reducing the risk of cardiovascular and renal events, particularly in high-risk patients. There is also evidence that the benefits of ACE inhibitor/CCB combinations may extend beyond those solely associated with brachial BP lowering, by an additional impact on central BP haemodynamics., Conclusions: RAS inhibitor/CCB combination therapy is an effective antihypertensive therapy. Strong evidence supports the antihypertensive efficacy of ACE inhibitor/CCB combinations with cardioprotective and renoprotective properties. In particular, evidence suggests that fixed-dose perindopril/amlodipine effectively decreases BP and currently is the only RAS inhibitor/CCB combination proven to decrease all-cause and cardiovascular mortality as well as major cardiovascular events, and thus is a valuable option for the management of hypertension, especially in high-risk patients.

Background: fractures may have serious implications in an elderly individual, and fracture prevention may include a careful choice of medications., Design: the Hypertension in the Very Elderly Trial (HYVET) was a double-blind placebo-controlled trial of a thiazide-like diuretic (indapamide 1.5 mg SR) with the optional addition of the angiotensin-converting enzyme (ACE) inhibitor (perindopril 2-4 mg). Fracture was a secondary end point of the trial., Setting: HYVET recruited participants from Eastern and Western Europe, China, Australasia, and Tunisia., Subjects: all participants were > or =80 years of age and hypertensive., Methods: participants were randomised to receive a thiazide-like diuretic (indapamide 1.5 mg SR) +/- ACE inhibitor (perindopril 2-4 mg) or matching placebos. Incident fractures were validated and analysed based on time to first fracture., Results: there were 3,845 participants in HYVET and a total 102 reported fractures (42 in the active and 60 in the placebo group). When taking only validated first fractures, 90 were included in the analyses (38 in the active and 52 in the placebo group). Cox proportional hazard regression, adjusted for key baseline risk factors, resulted in a point estimate of 0.58 (95% CI 0.33-1.00, P = 0.0498)., Conclusions: despite the lowering of blood pressure, treatment with a thiazide-like diuretic and an ACE inhibitor does not increase and may decrease fracture rate.

Angiotensin-converting enzyme (ACE) inhibitors are among the most commonly used drugs in stable coronary artery disease as these agents have been proven to be effective for reducing the risk of cardiovascular morbidity and mortality. As with other drugs, individual variation in treatment benefit is likely. Such heterogeneity could be used to target ACE-inhibitor therapy to those patients most likely to benefit from treatment. However, prior attempts to target ACE-inhibitor therapy to those patients who are most likely to benefit of such prophylactic treatment in secondary prevention using clinical characteristics or the level of baseline risk appeared not to be useful. A new approach of 'tailored therapy' could be to integrate more patient-specific characteristics, such as the genetic information of patients. Pharmacogenetic research of ACE inhibitors in coronary artery disease patients is at a formative stage, and studies are limited. The Perindopril Genetic association (PERGENE) study is a large pharmacogenetic substudy of the randomized placebo-controlled European trial On Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery disease (EUROPA) trial, aimed to assess the feasibility of pharmacogenetic profiling of ACE-inhibitor therapy by perindopril. This article summarizes the recent findings of the PERGENE study and pharmacogenetic research of the treatment benefit of perindopril in stable coronary artery disease.

Importance of the Field: The increase in type 2 diabetes mellitus is associated to cardiovascular morbidity and mortality. This review focuses on the benefits of the fixed-dose combination of perindopril and indapamide on cardiovascular and renal end points in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial., Areas Covered in the Review: In the last decade, clinical trials have indicated that blood pressure reduction and glucose lowering were effective in reducing morbidity and morbility. The ADVANCE trial has explored both intensive glucose lowering with gliclazide modified release (MR) and intensive blood pressure lowering using a fixed combination of perindopril/indapamide, on top of current treatments, including renin-angiotensin inhibitors., What the Reader Will Gain: In ADVANCE, perindopril/indapamide reduced a composite of macrovascular and microvascular events, also significantly decreasing cardiovascular mortality and death from any cause and reducing coronary and renal complications. The review discusses the relevance of results and the advantages of this therapeutic strategy in clinical practice., Take Home Message: ADVANCE provides a new, simple and pragmatic treatment algorithm that maximizes clinical benefits and is suitable for all type 2 diabetic patients: intensive blood pressure lowering based on combined perindopril/indapamide with intensive glucose lowering based on gliclazide MR.

Objective: The efficacy and safety of blood pressure lowering in elderly patients have not been sufficiently investigated in patients with diabetes. Using data from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation study, we assessed the efficacy and safety of routine blood pressure lowering to prevent major clinical outcomes in elderly patients with type 2 diabetes., Methods: Eleven thousand one hundred and forty patients aged at least 55 years with type 2 diabetes (mean 66+/-6 years) were randomly assigned to perindopril-indapamide or placebo. The primary endpoint was a composite of major macrovascular and microvascular disease. The effects of active treatment on outcomes were estimated in subgroups according to age: below 65, 65-74 and at least 75 years., Results: During a mean 4.3-year follow-up, 1799 (16.1%) patients experienced a major event. Active treatment produced similar relative risk reductions for the primary outcome, major macrovascular disease, death and renal events across age groups (all P heterogeneity >0.3). Over 5 years, active treatment was estimated to prevent one primary outcome in every 21, 71 and 118 patients of at least 75, 65-74 and below 65 years, respectively. Similar patterns of benefits were observed for secondary outcomes. There were no differences in the tolerability between randomized allocations across age groups (all P heterogeneity >0.6), Conclusion: Routine administration of perindopril-indapamide lowers blood pressure safely and reduces the risk of major clinical outcomes in patients of at least 75 years with type 2 diabetes. The greater absolute benefits in older patients in this age group were not offset by an increased risk of side effects.

We studied the effect of perindopril (1%) on intraocular pressure (IOP) and compared it with the effect of pilocarpine, a therapeutic agent used in experimentally induced acute and chronic models of glaucoma in rabbits. Acute glaucoma was induced by intravenous administration of 5% glucose. Pretreatment with topical perindopril (1%) and pilocarpine (1%) prevented acute rise in IOP induced by intravenous administration of 5% glucose. For inducing chronic ocular hypertension in rabbits, 50 units of freshly prepared alpha-chymotrypsin in 0.1 mL of sterile saline was injected in the posterior chamber of the eye. Perindopril (1%) (35 +/- 1.38 mm Hg to 22.45 +/- 1.42 mm Hg) and pilocarpine (1%) (34.4 +/- 0.81 mm Hg to 20.15 +/- 0.69 mm Hg) produced a significant fall in IOP in these rabbits; pretreatment with indomethacin (prostaglandin synthesis inhibitor) did not affect the IOP-lowering action of perindopril (1%). Perindopril (2.71 x 10(-7) mol/L) and neostigmine (1.49 x 10(-7) mol/L) inhibited true cholinesterase and pseudocholinesterase enzyme activity in blood. The cholinesterase enzyme inhibition by perindopril was comparable with that by neostigmine. In conclusion, our data suggest that perindopril reduced IOP in experimentally induced acute and chronic glaucoma in rabbits. One of the possible mechanisms of perindopril, apart from the inhibition of angiotensin-converting enzyme, may be inhibition of the enzyme cholinesterase.

Background: The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention., Methods: We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB)., Results: Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects., Conclusion: Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality., (2010 Mosby, Inc. All rights reserved.)

Background and Purpose: Patients with cerebral amyloid angiopathy (CAA) are at high risk for intracerebral hemorrhage (ICH), but no effective prevention strategies have been established. The objective is to determine whether lowering of blood pressure (BP) provides protection for this high-risk patient group., Methods: This study is a subsidiary analysis of the PROGRESS trial-a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in patients with cerebrovascular disease; 6105 patients were randomly assigned to either active treatment (perindopril for all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo. Outcomes were probable CAA-related ICH as defined by the Boston criteria, probable hypertension-related ICH, and unclassified ICH., Results: Over a mean follow-up of 3.9 years, 16 probable CAA-related ICH, 51 probable hypertension-related ICH, and 44 unclassified ICH occurred. Active treatment reduced the risk of CAA-related ICH by 77% (95% CI, 19%-93%), that of hypertension-related ICH by 46% (95% CI, 4%-69%), and that of unclassified ICH by 43% (95% CI, -5%-69%). There was no evidence of differences in the magnitude of the effects of treatment among different types of ICH (P homogeneity=0.4)., Conclusions: BP-lowering treatment is likely to provide protection against all types of ICH.

Aims: An international randomized controlled trial has shown that anti-hypertensive therapy using perindopril and indapamide significantly reduces the recurrence of stroke. To evaluate the efficacy and safety of diuretics given as add-on therapy to stroke patients, as needed, to perindopril, we conducted a prospective multicenter observational study., Methods: A total of 3825 hypertensive patients with a history of stroke were enrolled. The patients received a two-step therapy, starting with perindopril alone, and those who failed to achieve the blood pressure target were subsequently given a diuretic. Each group was followed for 6 months., Results: 62.8% of the patients achieved the blood pressure goal. The incidence of adverse events was significantly higher in the perindopril plus diuretic combination therapy group than in the perindopril monotherapy group. Although these results may reflect that severely hypertensive patients were selectively assigned to combination therapy, the observed differences were essentially elevated serum creatinine, triglycerides, blood urea nitrogen and uric acid, whereas no significant inter-group difference was noted in total cholesterol and blood glucose., Conclusions: If adequate care of compromised renal function is taken, perindopril plus diuretic combination therapy exerts potent hypotensive effects without posing significant safety problems in patients with a history of stroke.

Background and Aims: Given the recent observation of a local renin-angiotensin system (RAS) in adipose tissue, and its association with obesity-related hypertension, the metabolic effects of treatment with a low dose angiotensin converting enzyme inhibitor (ACEI) were investigated in a rodent model of diet-induced obesity., Methods and Results: Male Sprague Dawley rats were exposed to either standard laboratory chow (12% calories as fat) or palatable high fat (30% calories as fat) diet for 12 weeks. A subset from both dietary groups was given low dose ACEI in drinking water (perindopril, 0.3 mg/kg/day) throughout the study. The high fat diet increased body weight, adiposity, circulating leptin and insulin and in the liver we observed fat accumulation and increased tissue ACE activity. Treatment with perindopril decreased food intake and circulating insulin in both diet groups, and hepatic ACE activity in high fat fed animals only. Decreased plasma leptin concentration with ACE inhibition was only evident in chow fed animals. These effects were independent of any blood pressure lowering effect of ACE inhibition., Conclusion: Chronic low dose ACEI treatment reduced circulating insulin and leptin levels with some reduction in food intake in chow fed rats. Fewer beneficial effects were observed in obesity, and further work is required to investigate higher ACEI doses. Our data suggest a reduction in hepatic ACE activity may affect lipid accumulation and other inflammatory responses, as well as improving insulin resistance. Our findings may have implications for maximizing the clinical benefit of ACEI in patients without overt cardiovascular complications., (Copyright 2009 Elsevier B.V. All rights reserved.)