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Sarcopenia is a pertinent challenge in the super-aged societies causing reduced functional performance, poor quality of life and increased morbidity. In this study, the potential of perindopril erbumine-loaded ultradeformable liposomes (PE-UDLs) against sarcopenia was investigated. PE-UDLs were prepared by thin-film hydration and extrusion method using egg yolk L-α-phosphatidylcholine (EPC) as a lipid bilayer former and Tween 80 or sodium deoxycholate as an edge activator. Owing to the smallest particle size (75.0 nm) and the highest deformability (54.2) and entrapment efficiency (35.7 %), PE-UDLs with EPC to Tween 80 ratio of 8:2 was selected as the optimized formulation. The optimized PE-UDLs showed substantially higher cumulative amount of drug permeated and permeation rate across the rat skin compared to PE solution (485.7 vs. 50.1 µg and 13.4 vs. 2.3 µg/cm 2 /h, respectively). Topically applied PE-UDLs successfully ameliorated the effects of lipopolysaccharide (LPS)-induced sarcopenia in mice by improving body weight changes, grip strength and muscle weight. Furthermore, PE-UDLs reduced the shrinkage of muscle fibers as demonstrated by higher cross-sectional area than PE solution. PE-UDLs also increased the expression of myosin heavy chain (MHC) protein and reduced the expression of muscle atrophy F-box (Atrogin-1) and muscle ring-finger protein-1 (MuRF1), thereby improving muscles atrophy. In conclusion, these results demonstrate the therapeutic potential of PE-UDLs against sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Action in Diabetes and Vascular disease: preterAx and diamicroN Controlled Evaluation (ADVANCE) trial investigated the effects of intensive blood pressure (BP) lowering using a fixed combination of perindopril-indapamide versus placebo in type 2 diabetes (T2D). The study showed that combination perindopril-indapamide had significant benefits in reducing cardiovascular, renal, and mortality events, with consistent relative risk reductions across different patient subgroups. Secondary analyses of ADVANCE have identified novel risk markers in T2D including cessation of BP lowering therapy, absent peripheral pulses and cardiac biomarkers to name a few. ADVANCE also shed light on practical aspects of hypertension management, including the limitations of office BP, tolerability of combination BP lowering therapy across the range of BP levels and the interpretation of changes in serum creatinine after treatment initiation. This review article summarizes the findings of ADVANCE and its subsequent substudies, which have been foundational in our understanding of BP management and the use of combination BP lowering therapy in T2D., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy., Methods: A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer's perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates., Results: A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy., Conclusions: The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.

Background: In China, the prevalence of hypertension is high and the use of combination antihypertensive therapy is low, which contributes to inadequate blood pressure (BP) control. The availability of simplified treatments combining complementary BP-lowering agents may help more patients achieve their goals., Methods: This Phase III, multicenter, randomized, double-blind, noninferiority study included Chinese adults with mild-to-moderate hypertension. Following a 1-month run-in on perindopril/indapamide bi-therapy, patients with uncontrolled systolic/diastolic BP (≥140/90 mmHg) were randomized to perindopril 5 mg/indapamide 1.25 mg/amlodipine 5 mg (Per/Ind/Aml) single-pill combination (SPC) or perindopril 4 mg/indapamide 1.25 mg plus amlodipine 5 mg (Per/Ind + Aml) for 6 months. Uptitration was permitted from month 2 onwards. The primary efficacy objective was the noninferiority of Per/Ind/Aml in lowering office systolic BP at 2 months. The secondary objectives included the effectiveness of SPC on diastolic BP, uptitration efficacy, and office BP control (systolic/diastolic <140/90 mmHg). A subgroup of patients participated in 24-h ambulatory BP monitoring (ABPM)., Results: A total of 532 patients were randomized: Per/Ind/Aml ( n  = 262) and Per/Ind + Aml ( n  = 269). Overall, the mean (±SD) age was 55.7 ± 8.8 years, 60.7% were male, and the mean office systolic/diastolic BP at baseline on Per/Ind was 150.4/97.2 mmHg. Systolic BP decreased in both groups at 2 months from baseline: -14.99 ± 14.46 mmHg Per/Ind/Aml versus -14.49 ± 12.87 mmHg Per/Ind +Aml. A predefined noninferiority margin of 4 mmHg was observed ( P  < 0.001). The effectiveness of the Per/Ind/Aml SPC was also demonstrated for all secondary endpoints. ABPM demonstrated sustained BP control over 24 h. Both treatments were well tolerated., Conclusions: Per/Ind/Aml is an effective substitute for Per/Ind + Aml, providing at least equivalent BP control over 24 h in a single pill, with comparable safety., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1-5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55-65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55-65: 2.8 mmHg [95% CI = 1.8-3.7], p < 0.001, >65: 3.7 mmHg [95% CI = 2.7-4.7], p < 0.001). A trend of less blood pressure reduction was seen with ageing in both men and women (p < 0.001). To conclude, we observed that in both women and men the perindopril leads to less SBP reduction with increasing age, whereas the DBP reduction increases with age. More research is needed to determine whether it would be beneficial to use age-adjusted perindopril dosages., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lots of studies showed the combination therapy of perindopril, indapamide and amlodipine could increase BP lowering efficacy and the benefits of high-risk patients. To evaluate potential pharmacokinetic interaction, a simultaneous UPLC-MS/MS quantification method of perindopril, perindoprilat and indapamide in human plasma was developed and validated. The plasma samples were prepared by solid phase extraction, and then separated on an X-terra MS C 18 (2.1 mm × 150 mm, 3.5 μm) with isocratic elution. The ion transitions at m/z 369.165 → 172.000 (perindopril), m/z 341.146 → 170.112 (perindoprilat), m/z 366.010 → 132.100 (indapamide), m/z 389.120 → 206.200 (S10211-1, IS1) and m/z 394.080 → 160.200 (S1641, IS2) were monitored under the positive ion mode of electrospray ionization with multiple reaction monitoring. This method exhibited great sensitivity, linearity, accuracy, and precision for the determination of perindopril, perindoprilat and indapamide over the range of 0.250-50.0 ng/mL. The average extraction recovery of perindopril, perindoprilat and indapamide samples at low, medium, and high concentration levels were between 85.9% and 93.6%, respectively. The stability of analytes over different storage and processing conditions in the whole study was also validated. The method is fast, accurate, sensitive and reproducible, which is suitable for the detection of the concentration of perindopril, perindoprilat and indapamide in human plasma., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles., Method: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for C max , AUC 0-t , and AUC 0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented., Results: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for C max , AUC 0-t, and AUC 0-∞ , respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials., Conclusions: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In the care of a cardiovascular risk patient there is certainly a more frequent situation in which we try to influence several risk factors at the same time. Treatment of a single self-occurring risk factor is rather an exception. In most cases, we need to intervene with more risk factors, often involving combination therapy, which can achieve the desired goals more quickly and reliably. However, with the number of tablets taken by the patient, the patients willingness to take long-term and correct use decreases, which has a significant impact on the effectiveness of therapy and the development of individual cardiovascular risk. In an effort to control all risk factors for cardiovascular disease, there is a growing need to extend the availability of fixed drug formulations to suit the patients ease of use and suitably formulated with varying dose grades to meet the needs of our attending physicians. With regard to the fact that early intervention of risk factors brings greater benefits than deferred, we are looking for appropriate ways to manage it. The current intervention of arterial hypertension and dyslipidemia with safe and proven drugs seems to be one of the ways to further improve the results of the prevention of cardiovascular diseases. The new fixed combination of atorvastatin with perindopril, which is entering the Czech market right now, appears to be in many ways an ideal &#8220;tablet for cardiovascular prevention&#8221;.

Competing Interests: Competing interests: None declared.

Aims: To evaluate 1,5-anhydroglucitol (1,5-AG) according to clinical outcomes and assess the effects of glucose- and blood pressure-lowering interventions on change in 1,5-AG levels in people with type 2 diabetes., Methods: We measured 1,5-AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1-year follow-up visit in the ADVANCE trial. We examined baseline 1,5-AG [< 39.7, 39.7-66.2, ≥ 66.2 μmol/L (<6, 6-10, ≥10 μg/mL)] and microvascular and macrovascular events and mortality using Cox regression models during 5 years of follow-up. Using an intention-to-treat approach, we examined 1-year change in 1,5-AG (mean and percent) in response to the glucose- and blood pressure-lowering interventions in the subsample., Results: Low 1,5-AG level [<39.7 μmol/L vs ≥ 66.2 μmol/L (<6 μg/mL vs ≥10 μg/mL)] was associated with microvascular events (hazard ratio 1.28, 95% confidence interval 1.03-1.60) after adjustment for risk factors and baseline glycated haemoglobin (HbA1c); however, the associations for macrovascular events and mortality were not independent of HbA1c. The glucose-lowering intervention was associated with a significant 1-year increase in 1,5-AG (vs standard control) of 6.69 μmol/L (SE 2.52) [1.01 μg/mL (SE 0.38)], corresponding to an 8.26% (SE 0.10%) increase from baseline. We also observed an increase in 1,5-AG of similar magnitude in response to the blood pressure intervention independent of the glucose-lowering effect., Conclusions: Our results suggest that 1,5-AG is a marker of risk in adults with type 2 diabetes, but only for microvascular events independently of HbA1c. We found that 1,5-AG was improved (increased) in response to an intensive glucose-lowering intervention, although the independent effect of the blood pressure-lowering intervention on 1,5-AG suggests potential non-glycaemic influences., (© 2019 John Wiley & Sons Ltd.)

Poor blood pressure (BP) control contributes to complications in sub-Saharan African (SSA) type 2 diabetic individuals. Experts have advocated the use of combination therapies for effective BP control in these patients. The suggested combinations should include a RAAS antagonist and either a CCB or a thiazide diuretic; however, their efficacy is yet to be established in SSA. We investigated the short-term effects of two combination therapies on BP control in SSA type 2 diabetic individuals. This was a double-blinded randomized controlled trial conducted at the Yaoundé Central Hospital (Cameroon) from October 2016 to May 2017. We included type 2 diabetic patients, newly diagnosed for hypertension. After baseline assessment and 24-hour ABPM, participants were allocated to receive either a fixed combination of perindopril + amlodipine or perindopril + indapamide for 42 days. Data analyses followed the intention-to-treat principle. We included fifteen participants (8 being females) in each group. Both combinations provided good circadian BP control after 6 weeks with similar efficacy. Twenty-four-hour SBP dropped from 144 to 145 mm Hg vs 128 to 126 mm Hg with perindopril-amlodipine and perindopril-indapamide, respectively (P = 0.003 for both groups). Twenty-four-hour DBP dropped from 85 to 78 mm Hg (P = 0.013) vs 89 to 79 mm Hg (P = 0.006) in the same respective groups. No significant adverse effect was reported. A fixed initial combination of perindopril-amlodipine or perindopril-indapamide achieved similar effective BP control after 6 weeks in SSA type 2 diabetic individuals with newly diagnosed hypertension. Therefore, these combinations can be used interchangeably in this indication., (©2019 Wiley Periodicals, Inc.)

Background: The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established., Methods: In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or was taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months., Results: The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, -3.14 mm Hg; 95% confidence interval [CI], -5.90 to -0.38; P = 0.03; and -3.00 mm Hg; 95% CI, -5.8 to -0.20; P = 0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was -0.14 mm Hg (95% CI, -2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups., Conclusions: These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months. (Funded by GlaxoSmithKline Africa Noncommunicable Disease Open Lab; CREOLE ClinicalTrials.gov number, NCT02742467.)., (Copyright © 2019 Massachusetts Medical Society.)

Purpose: Endoglin is a transmembrane glycoprotein which plays an important role in maintaining cardiovascular homeostasis. One of its forms, soluble endoglin (sEng), a molecule with antiangiogenic properties, has been found overexpressed in patients suffering from hypercholesterolemia, diabetes mellitus and hypertension, and is proposed as a marker of endothelial damage. Accordingly, we aimed to quantify the efficacy of various antihypertensive regimens on sEng levels, in hypertensive patients with endothelial dysfunction. Patients and methods: 323 patients were enrolled, and there were 99 patients with normal blood pressure values, 106 hypertensive patients under chronic treatment with different types of antihypertensive molecules (beta blockers, calcium channel blockers, and diuretics) in monotherapy, and 118 hypertensive patients under chronic treatment with perindopril. sEng plasma levels were quantified and were correlated with classical methods of assessing the endothelial damage. Results: Patients under chronic treatment with perindopril had lower sEng plasma levels compared with the other group of hypertensive patients under different regimens of antihypertensive treatment (sEng: 4.73±1.39 versus 5.63±2.33, p <0.01). Conclusion: Decreased sEng plasma levels were found in patients under chronic treatment with perindopril, when compared with other antihypertensive regimens of treatment (beta blockers, calcium channel blockers, and/or diuretics)., Competing Interests: The authors report no conflicts of interest in this work.

Background: Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension., Objective: This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension., Methods: Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP < 140/90 mmHg (< 130/80 mmHg in patients with diabetes). The primary endpoint (proportion with controlled BP at each uptitrated dose) was evaluated at 6 months, and safety was evaluated at 9 months; 24-h ambulatory BP measurement and BP variability were also investigated. Control-arm participants (n = 1653) were randomized to irbesartan 150 mg daily, uptitrating over 3 months to irbesartan/hydrochlorothiazide 300/25 mg., Results: Significant increases in BP control were observed with each dosage increment of perindopril/amlodipine, which was well tolerated, rising from 21% (3.5/2.5 mg) to 30% (7/5 mg), 37% (14/5 mg), and 42% (14/10 mg) after 1, 2, 3, and 6 months, respectively. Reductions in mean systolic and diastolic BP occurred with each incremental dose of perindopril/amlodipine. After 6 months, mean BP had fallen by 24.8/10.8 mmHg. Irbesartan-based therapy reduced clinic and 24-h BP similarly to perindopril/amlodipine, but perindopril/amlodipine reduced BP variability more in comparison., Conclusions: Incremental uptitration with dosage-adapted perindopril/amlodipine SPC is a safe and effective strategy for managing hypertension., Trial Registration: EudraCT (No. 2006-005799-42).

The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Cox models were used to determine whether baseline BP category or CVD risk modified the outcomes of combination perindopril-indapamide treatment, compared with placebo. During 4.3 years of follow-up, treatment with perindopril-indapamide versus placebo reduced mortality and major vascular (macrovascular or microvascular) events. There was no evidence of differences in these effects, regardless of baseline systolic BP (evaluated down to <120 mm Hg; P for heterogeneity, 0.85), diastolic BP (evaluated down to <70 mm Hg; P=0.49), or whether 10-year CVD risk was ≥20% or <20% ( P=0.08). The effects of randomized treatment on discontinuation of treatment because of cough or hypotension/dizziness were also statistically consistent across subgroups defined by baseline BP and CVD risk (all P ≥0.08). Adults with diabetes mellitus appear to benefit from more intensive BP treatment even at levels of BP and CVD risk that some guidelines do not currently recommend for intervention. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00751972.

Current research work was conducted to synthesize Thiol modified arabinoxylan and its application in fabrication of hydrogel. Thioglycolic acid was esterified with arabinoxylan to prepare Thiolatedarabinoxylan. Appearance of peak at 2533.34 cm -1 in FTIR and thiol content showed successful thiolation. The pH-dependent Thiolatedarabinoxylan/acrylic acid (TAX/AA) hydrogels of perindopril erbumine were prepared via free-radical co-polymerization. Perindopril erbumine (PE) was employed as model drug. Different batches with different feed ratio of TAX, AA, and MBA were prepared and their influence on swelling, solvent penetration, and consequent drug release was investigated. Swelling coefficients increased with increase in pH. TAX/AA hydrogels were characterized by Fourier-transform infrared spectroscopy (FT-IR), Thermal Analysis (TA), X-Ray diffraction (XRD), and scanning electron microscope (SEM). Dissolution studies were performed at pH 1.2 and 7.4 in which drug release showed direct correlation with TAX and AA ratio. In vivo studies showed that C max of TAX-co-AA based hydrogel was 81.57 ± 0.35 ng/ml which was maintained for a longer time after its administration. All the results of in vivo studies were significant and TAX-co-AA based hydrogel enhances the bioavailability of perindopril erbumine.

Background: Despite the overwhelming evidence and the established benefits of antihypertensive treatment, adherence to treatment remains low., Objective: To assess the adherence to treatment with a perindopril/indapamide/amlodipine single-pill combination (SPC), its effectiveness on blood pressure (BP) reduction, as well as the safety and tolerability of this SPC over a 4-month treatment period., Methods: This multicenter, non-interventional study prospectively included 2285 hypertensive patients on perindopril/indapamide/amlodipine SPC. The data were recorded at baseline, 1 month, and 4 months., Results: Of the 2285 hypertensive patients included in the study, 50.5% were at "high/very high risk". Mean systolic (SBP)/diastolic (DBP) decreased from 162.3 ± 13.3/93.1 ± 9.3 mmHg at baseline to 129.7 ± 8.3/78.6 ± 7.1 mmHg at 4 months (p < 0.001). Patients with higher baseline BP levels showed greater BP reduction. Patients with hypertension stages 1, 2, and 3 showed mean SBP/DBP reductions of 21.5/10.4 mmHg, 34.2/14.7 mmHg, and 51.2/22.5 mmHg, respectively, at study end (p < 0.001). Only 26 patients (1.1%) prematurely discontinued treatment (0.58% due to an adverse reaction or event)., Conclusions: Perindopril/indapamide/amlodipine SPC decreased BP levels rapidly and significantly. The degree of BP reduction was associated with the severity of hypertension and/or with total cardiovascular risk at baseline. Simplifying the drug regimen by using this SPC improved adherence and showed excellent tolerability.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg -1 ·wk -1 ), or 3) SNT (40 mg·kg -1 ·day -1 ) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Purpose: Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237-246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR., Patients and Methods: In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03., Results: A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%)., Conclusion: The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

Background and Purpose: The endocannabinoid (EC) system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effects of peripheral blockade of the cannabinoid CB 1 receptor as an add-on treatment to ACE-inhibition in type 1 diabetic mice (DM) with established albuminuria., Experimental Approach: Renal functional parameters (albumin excretion rate, creatinine clearance), tubular injury, renal structure, both EC and CB receptor levels and markers of podocyte dysfunction, fibrosis and inflammation were studied in streptozotocin-induced DM treated for 14 weeks with vehicle, the ACE-inhibitor perindopril (2 mg·kg -1 ·day -1 ), peripherally-restricted CB 1 receptor antagonist AM6545 (10 mg·kg -1 ·day -1 ) or both. Treatments began at 8 weeks after diabetes onset, when early DN is established., Key Results: CB 1 receptors were overexpressed in DM and neither perindopril nor AM6545 altered this effect, while both drugs abolished diabetes-induced overexpression of angiotensin AT 1 receptors. Single treatment with either AM6545 or perindopril significantly reduced progression of albuminuria, down-regulation of nephrin and podocin, inflammation and expression of markers of fibrosis. However, reversal of albuminuria was only observed in mice administered both treatments. The ability of the combination therapy to completely abolish slit diaphragm protein loss, monocyte infiltration, overexpression of inflammatory markers and favour macrophage polarization towards an M2 phenotype may explain this greater efficacy. In vitro experiments confirmed that CB 1 receptor activation directly inhibits retinoic acid-induced nephrin expression in podocytes and IL-4-induced M2 polarization in macrophages., Conclusion and Implications: Peripheral CB 1 receptor blockade used as add-on treatment to ACE-inhibition reverses albuminuria, nephrin loss and inflammation in DM., (© 2018 The British Pharmacological Society.)

Background and Objectives: Management of hypertension and dyslipidemia is important when considering cardiovascular disease risk; however, achievement of optimal lipid and blood pressure (BP) targets in clinical practice remains inadequate. This analysis sought to estimate the frequency, effectiveness, and safety of co-administrated atorvastatin and perindopril in routine care., Methods: We conducted a post hoc analysis of four Canadian, prospective, multi-center, observational studies assessing real-life effectiveness and safety of perindopril + atorvastatin in mild-to-moderate hypertensive patients with concomitant dyslipidemia over 16 weeks. The safety population comprised patients receiving one or more doses of free combination perindopril + atorvastatin; the full analysis set (FAS) received perindopril + atorvastatin at baseline, with one or more post-baseline systolic BP measurements while on treatment., Results: A total of 3541 and 3172 patients were included in the safety population and FAS, respectively. At the last observation carried forward, significant reductions in mean systolic BP (- 18.0 mmHg; p < 0.001) and diastolic BP (- 8.9 mmHg; p < 0.001) were observed; target BP was achieved by 73.1% of patients. Emergent adverse events (AEs) were reported in 8.0% of patients, the most common being cough (4.5% of patients), headache (0.9%), and dizziness (0.8%). Four serious AEs were reported among three (0.1%) patients. No differences were observed in effectiveness or safety between studies., Conclusions: Concomitant perindopril + atorvastatin therapy demonstrated similar efficacy across all studies, with significant reductions in BP and achievement of target BP levels observed in a real-world setting. Results align with known safety profiles of atorvastatin and perindopril, with no unexpected AEs observed when compared with data from treatment with the individual drugs.

Introduction: The objective of this study was to assess the impact of a single-pill combination (SPC) of perindopril/indapamide (PER/IND) at full doses (10/2.5 mg) on endothelial and cognitive function as a clinical intermediate marker of vascular improvement., Methods: This open-label, uncontrolled, observational study enrolled 30 patients (20 females and 10 males) with grade II-III uncontrolled arterial hypertension (SBP/DBP ≥ 160/100 mmHg) and no evidence of cerebrovascular disease. All patients underwent assessment of macro- and microvascular endothelial function parameters at baseline and after 12 months of treatment with SPC PER/IND using photoplethysmography and video capillaroscopy. Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA)., Results: All patients (mean age 60.06 ± 10.19 years) were at high risk for cardiovascular events: mean body mass index (BMI) 31.2 ± 3.9 kg/m 2 , 33% diagnosed with coronary artery disease angina class I, 30% with impaired glucose tolerance, and 7% with type 2 diabetes. Impaired endothelial function was observed at the both micro- and macrovascular levels. Endothelial function parameters improved after 12-month treatment with SPC PER/IND with an increase in occlusion index from 1.4 to 1.8 (P < 0.00005) and phase shift from 5.0 to 10.8 (P < 0.00001); all values achieved levels in the normal range. Resting capillary network density (CND) increased from 44.8 to 52 cap/mm 2 (P < 0.00007), and CND after a venous occlusion test increased from 55 to 61 cap/mm 2 (P < 0.006). Signs of cognitive impairment were present at baseline with a mean MoCA score of 23 (normal cognitive function score ≥ 26), but improved after 12-month treatment with a mean MoCA score of 27 (P< 0.0001). Treatment was well tolerated., Conclusion: SPC PER/IND at full doses for 12 months improves endothelial function, structural and functional parameters of the microcirculation, as well as cognitive function in patients with arterial hypertension at high cardiovascular risk., Funding: Les Laboratoires Servier.

Objective: The purpose of this study was to assess the changes in adherence to treatment, in patients who switched from perindopril and/or amlodipine as a monotherapy (single-pill therapy, SPT) or two-pill combinations to fixed-dose combination (FDC) therapy., Methods: A large retrospective cohort study, in three Italian Local Health Units, was performed. All adult subjects who received at least one prescription of anti-hypertensive drugs between January 1, 2010 and December 31, 2014 were selected. The date of the first anti-hypertensive prescription was defined as the index-date (ID). For each patient, we evaluated the anti-hypertensive therapy and the adherence to treatment during the two 12-month periods preceding and following the ID. Changes in the level of adherence have been compared in patients who switched to the FDC of perindopril/amlodipine after the ID, as well as in patients who did not., Results: A total of 24,020 subjects were initially included in the study. Subjects treated with the free dose combination switched more frequently to FDC of perindopril/amlodipine than subjects treated with SPT (p < .001). Adherence to treatment was found to be higher in the 3,597 subjects who switched to the perindopril/amlodipine FDC therapy, than in the 20,423 subjects who did not. A significant decrease in the number of concomitant anti-hypertensive drugs has been observed in patients treated with the same FDC., Conclusions: The results show that perindopril/amlodipine FDC increases the rate of stay-on-therapy and reduces the number of concomitant anti-hypertensive drugs in subjects previously treated with the same drugs as a two-pill combination or as SPT.

Introduction: In everyday medical practice, physicians often need to manage patients whose blood pressure is not well controlled. Those with a history of cerebrovascular disease are a high-risk group in need of rapid blood pressure control., Methods: The PICASSO study was a real-life, observational trial involving 9257 inadequately treated hypertensive patients who were switched from previous therapy to the fixed-dose combination of perindopril 10 mg/indapamide 2.5 mg (PI) for 3 months. A subanalysis of data of 1117 hypertensive patients who met the clinical criteria of previous stroke or transient ischemic attack was performed. Twenty-four hour ambulatory blood pressure measurements (ABPMs) were also done in a small group of patients (n:38)., Results: At baseline, mean systolic/diastolic blood pressure (SBP/DBP) was 161.5 ± 15.2/93.1 ± 9.9 mmHg. After 1 month with the fixed dose of PI, average office SBP/DBP decreased to 140.0 ± 11.9/83.5 ± 7.7 mmHg. After 3 months, SBP/DBP had dropped to 132.9 ± 9.8/80.0 ± 6.2 mmHg, by 28.6 ± 15.5/13.1 ± 10.0 mmHg (p < 0.001). Blood pressure control rate (< 140/90 mmHg) was 67.3% after 3 months. When data were stratified by baseline blood pressure, decreases in SBP/DBP were statistically significant in patients with all grades (1-3) of hypertension. In patients previously treated with an angiotensin-converting enzyme inhibitor ± hydrochlorothiazide (n = 677), blood pressure decreased by 29.8 ± 15.5/13.3 ± 10.2 mmHg (p < 0.001). Decreases in 24-h ABPM values were also significant (n = 38). Treatment was well tolerated; only a few adverse events were recorded., Conclusion: This study suggests that fixed combination perindopril 10 mg/indapamide 2.5 mg is an effective and well-tolerated treatment for patients with a history of stroke or transient ischemic attack., Funding: EGIS Pharmaceuticals Plc.

Aims/hypothesis: Previous studies have suggested that the haemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications in individuals with type 1 and type 2 diabetes. We investigated whether HGI was a predictor of adverse outcomes of intensive glucose lowering and of diabetes-related complications in general, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial., Methods: We studied participants in the ADVANCE trial with data available for baseline HbA 1c and fasting plasma glucose (FPG) (n = 11,083). HGI is the difference between observed HbA 1c and HbA 1c predicted from a simple linear regression of HbA 1c on FPG. Using Cox regression, we investigated the association between HGI, both categorised and continuous, and adverse outcomes, considering treatment allocation (intensive or standard glucose control) and compared prediction of HGI and HbA 1c ., Results: Intensive glucose control lowered mortality risk in individuals with high HGI only (HR 0.74 [95% CI 0.61, 0.91]; p = 0.003), while there was no difference in the effect of intensive treatment on mortality in those with high HbA 1c . Irrespective of treatment allocation, every SD increase in HGI was associated with a significant risk increase of 14-17% for macrovascular and microvascular disease and mortality. However, when adjusted for identical covariates, HbA 1c was a stronger predictor of these outcomes than HGI., Conclusions/interpretation: HGI predicts risk for complications in ADVANCE participants, irrespective of treatment allocation, but no better than HbA 1c . Individuals with high HGI have a lower risk for mortality when on intensive treatment. Given the discordant results and uncertain relevance beyond HbA 1c , clinical use of HGI in type 2 diabetes cannot currently be recommended.

Introduction: We conducted a prospective, non-interventional, multicenter study to examine the effect of a fixed-dose combination of perindopril/amlodipine in patients with arterial hypertension., Methods: Patients who were previously untreated or required a change in medication were treated with a fixed combination of perindopril/amlodipine (3.5/2.5 or 7.0/5.0 mg) for 12 weeks. Changes in office, home and ambulatory blood pressure (BP) were recorded. Adherence was assessed by the Hill-Bone medication adherence scale., Results: Overall, 1814 patients (mean age 60.0 ± 13.4 years) were included in 614 German practices, and data of 1770 patients were analyzed. At study entry, 97.7% of patients received perindopril/amlodipine at a daily dose of 3.5 mg/2.5 mg, and 47.9% of patients remained on this dose during the study period. Treatment with perindopril/amlodipine decreased mean office BP from 163.7/95.4 to 133.6/80.3 mmHg (p < 0.0001), resulting in a hypertension control rate of 69.1%. Blood pressure control was comparable in previously untreated and treated patients (70.3 vs. 68.1%), and in younger and older patients (70.6 < 65 vs. 66.3% ≥ 65 years). Ambulatory BP measurements were available in a subgroup of patients (n = 167), and mean 24 h ambulatory BP decreased from 150.6 ± 12.6/88.9 ± 8.8 to 132.4 ± 11.9/79.4 ± 8.5 mmHg (p < 0.0001). Furthermore, the proportion of patients with severe hypertension European Society of Hypertension/European Society of Cardiology (ESH/ESC) grade II or III decreased from 64.4 to 3.9%, and patients with pre-existing isolated systolic hypertension (n = 284) converted to normal BP in 67.6% of cases. Nearly half of the patients (47.2%) were perfectly adherent during the study. In previously treated patients, the percentage of patients with perfect adherence increased from 20.6% prior to study to 43.5% at final visit (p < 0.0001). Adverse drug reactions were documented for 4.9% of patients., Conclusion: A fixed-dose combination of perindopril/amlodipine shows significant blood pressure reduction and improvement in medication adherence in a primary care setting., Trial Registration: ISRCTN26323538., Funding: Servier Deutschland GmbH.

Introduction: Controlling blood pressure is a global health priority; single-pill antihypertensive combinations may improve adherence, persistence, and outcomes. Areas covered: A novel combination of perindopril arginine and amlodipine besylate was recently approved. A systematic review of the literature revealed its most common adverse effects as: peripheral edema (depending on the dose of amlodipine, but attenuated by perindopril), cough, dizziness and hypotension. Dose-dependent hyperkalemia, impairment of renal function (especially in renovascular hypertension), angioedema, and teratogenicity were derived from experience with other ACE-inhibitors. Expert opinion: Substantial clinical trial experience with amlodipine or perindopril suggests that these two agents effectively lower blood pressure, and can reduce the risk of major adverse cardiovascular events, as in the Anglo-Scandinavian Cardiac Outcomes Trial. The incidence of adverse effects reported in clinical trials is lower than expected, likely due to exclusion of subjects previously exposed to its components; the nature of open-label, uncontrolled observational studies; and difficulty in recognizing and measuring cough and pedal edema. This new formulation of perindopril arginine protects its ethyl ester, without requiring physical separation from amlodipine in a single tablet, and is less hygroscopic than perindopril erbumine. These and other attributes may make this combination an attractive addition to the antihypertensive armamentarium.

Background: It is well documented in the scientific literature that high blood pressure can lead to cardiovascular disease. Untreated hypertension has clinical consequences such as coronary artery disease, stroke or kidney failure. Diltiazem hydrochloride (DH), a calcium-channel blocker, and perindopril erbumine (PE), an inhibitor of the angiotensin converting enzyme are used for the management of hypertension., Objective: This project will examine the effect of microneedle rollers on the transport of DH and PE across pig ear skin. The use of the transcutaneous route of administration reduces and in sometimes eliminates the trauma and pain associated with injections. Furthermore, there is increased patient compliance. The purpose of this project was to study the effect of stainless steel microneedles on the transdermal delivery of DH and PE., Method: We utilized vertical Franz diffusion cells to study in vitro transport of DH and PE across microneedle- treated pig ear skin. Confocal laser scanning microscopy (CLSM) was used to characterize microchannel depth. Transdermal flux values were determined from the slope of the linear portion of the cumulative amount versus time curve., Results: There was a 113.59-fold increase in the transdermal permeation of DH following the application of microneedle roller compared to passive diffusion., Conclusion: In the case of PE, there was an 11.99-fold increase in the drug transport across pig skin following the application of microneedle rollers in comparison with passive diffusion. Student's t-test and Mann-Whitney's rank sum test were used to determine statistically significant differences between experimental and control groups., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: To study treatment persistence and mortality using a single-pill, fixed-dose combination tablet compared with a two-pill combination for hypertension., Research Design and Methods: We analyzed Australian Pharmaceutical Benefit Scheme records 2011-2014 in a 10% random sample of concessional patients prescribed concomitant amlodipine and perindopril - either as a single-pill, fixed-dose combination tablet (n = 9340) or as two-pill combination therapy (n = 3093). Main outcome measures were: (a) proportions failing to continue amlodipine + perindopril over time, (b) proportions failing to continue any subsequent calcium channel and angiotensin inhibition therapy over time and (c) proportions dying., Results: After 12 months, 34% of single-pill and 57% of two-pill users discontinued amlodipine + perindopril, median persistence time 42 months versus 7 months; 28% and 47% respectively discontinued any calcium channel-angiotensin inhibition therapy. After 48 months, 8% of single-pill and 18% of two-pill users had died. In a multivariate model adjusted for age, gender, duration and intensity of prior hypertension therapy, initial dose of amlodipine and perindopril, diabetes, hyperlipidemia, and complexity of care, the hazard ratio for risk of discontinuation over 42 months in the two-pill versus single-pill amlodipine + perindopril group was 1.94 (95% CI 1.83-2.06). The hazard ratio for discontinuation in two-pill versus single-pill users of any calcium channel-angiotensin inhibition therapy was 1.86 (1.74-1.99). The adjusted hazard ratio for risk of death over 48 months was 1.83 (1.55-2.16), but the mortality outcome may be an overestimate due to residual confounding., Conclusions: Use of a single-pill, fixed-dose combination in hypertension is associated with superior persistence and reduced mortality compared with use of two pills, suggesting a higher priority for the use of fixed-dose combinations.

Background: Initiation of antihypertensive therapy with a two-drug fixed-dose combination (FDC) in a single tablet may be recommended in patients at high risk of cardiovascular events to improve adherence and effectiveness. Preferred combinations include an angiotensin-converting enzyme inhibitor with a dihydropyridine calcium antagonist., Objective: This study assessed adherence to and the safety, tolerance, and effectiveness of the perindopril/amlodipine FDC in Greek patients with hypertension and stable coronary artery disease (CAD) over a 4-month period., Methods: A total of 1907 patients with hypertension and CAD (59.1% males) who had recently (≤2 weeks) commenced treatment with the perindopril/amlodipine FDC (5/5, 5/10, 10/5, or 10/10 mg) were studied at baseline and at 1 and 4 months. Adherence to treatment was assessed with the Morisky Medication-taking Adherence Scale (MMAS)., Results: Seven patients (0.4%) did not attend the scheduled visits. In total, 1607 (84.6%) patients received a constant treatment dose throughout the study. High adherence (MMAS score = 0) was reported by 1592 (83.6%), 1628 (85.7%), and 1477 (77.7%) patients at the second and the third visit and at both visits, respectively. Adverse reactions were reported by only 13 (0.7%) patients, were all minor, and did not result in treatment discontinuation. Office blood pressure (BP) was significantly decreased at the third visit (130.8 ± 8.4/78.2 ± 6.4 mmHg) compared with baseline (156.5 ± 15.0/89.9 ± 9.6 mmHg; p < 0.001), regardless of previous antihypertensive treatment. Patients with grade 1, 2, and 3 hypertension at baseline showed a reduction in BP of 19.3/9.4, 31.5/13.5, and 47.8/22.2 mmHg, respectively (p < 0.001). Uncontrolled hypertension (≥140/90 mmHg) was notably reduced from 90.3% at baseline to 18.5% at the third visit., Conclusions: The perindopril/amlodipine FDC is characterized by high adherence and effectiveness, regardless of previous treatment. Degree of BP reduction was related to baseline BP levels. Clinical trials registration number (Protocol Number): IC4 - 05985 - 011 - GRC.

Introduction: In management of hypertension patient adherence is one of the most important factors. In hypertension the cardiovascular risk reduction can be reached only by prolonged and effective pharmacotherapy., Aim: To evaluate the persistence of one-year treatment of free and fixed-dose combination of perindopril/amlodipine in hypertension., Method: Information from the National Health Insurance of Hungary prescriptions database on pharmacy claims between October 1, 2012 and September 30, 2013 was analysed. Authors identified patients who filled prescriptions for free and fixed-dose combination of perindopril/amlodipine, prescribed for the first time for hypertension. Patients have not received antihypertensive therapy with similar active substances during the one year before. Apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied., Results: 109,248 patients met the inclusion criteria. Combination antihypertensive therapy with perindopril/amlodipine was started with a free or a fixed-dose combination of these agents in 19,365 and 89,883 patients, respectively. One year persistence rate in patients taking perindopril/amlodipine as a free combination was 27.15%, whereas it was 46.89% in those on the fixed-dose combination. Mean duration of persistence was 177.6 days in patients on the perindopril/amlodipine free, whereas 245.7 days on fixed-dose combination. Actual rate of discontinuation was approximately twice higher with the treatment of free, compared with the use of the fixed-dose combination (hazard ratio =1.94 [95% CI: 1.91-1.98], p<0.001). Orv Hetil. 2017; 158(36): 1421-1425.

The fixed association of atorvastatin, perindopril and amlodipine was recently launched by the firm SERVIER under the name of Lipertance®. It is the first fixed association of a statin, an ACE inhibitor and a calcium blocker present on the Belgian market to handle the risk factors that are hypertension and dyslipidemia which can be used both in primary and secondary cardiovascular prevention. The interests of such a triple combined therapy are many in terms of morbimortality reduction, as observed in ASCOT trial. Besides these results, the association of these three agents gives probably a synergic effect, which would be more effective to protect both heart and vessels. Moreover, a fixed association will improve treatment compliance and adherence, which are generally quite poor in the management of cardiovascular risk factors. Lipertance® is available with three different doses : 20/5/5 mg, 20/10/5 mg and 40/10/10 mg, respectively for atorvastatin, perindopril and amlodipine. Contraindications and side effects are the same as each component of this association and are well known.

Fixed combinations of two or three drugs are being frequently used in cardiovascular diseases. This approach markedly increases adherence of the patients to prolonged therapy and thus leads to better control of the diseases. Fixed combinations are often used in hypertension and coronary artery disease (CAD). Cosyrel is the first fixed combination of betablocker (bisoprolol fumarat) and ACE inhibitor (perindopril arginin) available in czech market. The advantage is availability in several concentrations (10 mg/10 mg, 10 mg/5 mg a 5 mg/10 mg a 5 mg/5 mg) , when first indicates bisoprolol dose and the second perindopril. This combination is indicated in arterial hypertension and/or in stable CAD (in patients after myocardial infarction or revascularisation) and/or in dosages 5 mg/5 mg and 5 mg/10 mg in patients with chronic heart failure with systolic dysfunction. This article aimed to evaluate briefly clinical characteristics of this fixed combination. Bisoprol and perindopril arginin have a lot of data indication their positive impact on CV risk and prognosis.Key words: bisoprolol - coronary artery disease - heart failure - hypertension - perindopril.

Introduction: In everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking., Methods: In this retrospective pooled analysis of three large perindopril outcome trials (ADVANCE, EUROPA, PROGRESS), clinical outcomes were evaluated in 29,463 patients with vascular disease. Multivariate Cox regression analyses were performed in patients randomized to a perindopril-based regimen or placebo (treatment effect), and data were stratified according to background beta-blocker treatment. The primary endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke., Results: The cumulative incidence of the primary endpoint over mean follow-up of 4.0 years (Sd 1.0) was significantly lower in the beta-blocker/perindopril group (9.6%; 545/5700 patients) as compared to beta-blocker/placebo (11.8%; 676/5718 patients) (p < 0.01). Adding perindopril to existing beta-blocker treatment reduced the relative risk of the primary endpoint by 20% (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.71-0.90), non-fatal myocardial infarction by 23% (HR 0.77; 95% CI 0.65-0.91), and all-cause mortality by 22% (HR 0.78; 95% CI 0.68-0.88) as compared to placebo. Significant treatment benefit was not observed for stroke (HR 0.93; 95% CI 0.75-1.15). Significance was maintained for the primary endpoint and cardiovascular endpoints when data were further stratified by baseline hypertension. However, the mortality benefit was only observed in patients with hypertension with background beta-blocker use., Conclusions: These data suggest that the beneficial cardioprotective effects of perindopril treatment are additive to the background beta-blockers use.

Objectives: This 4-month, double-blind, randomized, controlled trial was designed to demonstrate the superiority of perindopril/indapamide/amlodipine single pill over perindopril/indapamide after 1 month and to determine further up-titration efficacy and safety in patients with mild-to-moderate hypertension., Methods: After a 1-month run-in period on perindopril/indapamide 5/1.25 mg, patients with SBP/DBP at least 150/95 mmHg and no diabetes or renal insufficiency received perindopril/indapamide/amlodipine 5/1.25/5 mg single pill or continued on the same treatment. At 1, 2, and 3 months, patients with uncontrolled blood pressure (SBP/DBP ≥ 140/90 mmHg) were gradually up-titrated with a higher dose of the triple therapy up to perindopril/indapamide/amlodipine 10/2.5/10 mg in both groups. Efficacy was assessed on office supine SBP (main criterion) and DBP, blood pressure control, and response rates. Treatment effect on ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) parameters was also assessed in two subpopulations of 276 and 263 patients, respectively., Results: A total of 454 hypertensive patients (diabetes and renal insufficiency excluded) were randomized, 227 to each group (56% were men, mean age was 55 years, blood pressure 162.3/101.1 mmHg). After 1 month, superior SBP (-3.1 mmHg, P = 0.02) and DBP (-2.8 mmHg, P < 0.001) reductions were observed with perindopril/indapamide/amlodipine, which were even more pronounced after excluding white-coat effect in the sustained hypertension population (-5.3/-3.7 mmHg). Similar results were observed in terms of blood pressure response (72 vs. 53%, P < 0.0001) and control rates (32 vs. 25%, P = 0.005). Up-titration was effective at each visit in both treatment arms (P < 0.001). Both ABPM and HBPM results confirmed the superiority of the triple therapy at 1 month on ASBP/ADBP and HSBP/HDBP: -4.5/-2.0 mmHg for ABPM (P < 0.001/P = 0.04), and -4.9/-3.1 mmHg for HBPM (both, P < 0.001). Up-titration steps resulted in further significant decreases in both ABPM and HBPM. Both treatment regimens were well tolerated regarding adverse events or laboratory testing. In particular, peripheral edema known to be amlodipine dose dependent, appeared in only a few cases, none with the highest dose. Hypotension, orthostatic hypotension, and cough whatever the dose were infrequent. There were no treatment-related serious adverse events., Conclusion: Perindopril/indapamide/amlodipine in a single pill produces superior reductions in blood pressure compared with dual therapy. Triple therapy up-titration was well tolerated and effective leading to BP control rates of over 80%. Analysis of 24-h ABPM and HBPM results corroborated these findings.

Objective: To measure the placebo-controlled effects of combination therapy on hypotension, treatment discontinuation, and major renal outcomes, according to baseline blood pressure., Methods: We conducted an analysis of the action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation ADVANCE and perindopril protection against recurrent stroke study PROGRESS trials, including 14 684 participants allocated combination therapy or placebo. The mean age was 65 years, 61% were men, and 64% were receiving background blood pressure lowering (BPL) therapy. Participants were stratified into five subgroups by baseline SBP less than 120, 120-129, 130-139, 140-159, and at least 160 mmHg. Discontinuation of study treatment during the active run-in phase and postrandomization follow-up was assessed for hypotension/dizziness and other causes. Major renal outcomes (sustained doubling in creatinine or renal death) were also assessed., Results: Discontinuation during the 4-6-week active run-in phase due to hypotension/dizziness ranged from 3.6% in those with SBP less than 120 mmHg to 1.3% in those with SBP at least 160 mmHg. Median follow-up in the randomized phase was 5.6 years, and discontinuation for hypotension was higher with combination therapy compared with placebo in the less than 120 mmHg group (4.7 vs. 1.2%). However, for each subgroup with baseline SBP 120-129, 130-139, and 140-159 mmHg, the absolute excess of discontinuation due to hypotension with combination therapy was 0.7%. Total discontinuations were only increased in the less than 120 mmHg group (18.4 vs. 12.5%) and the 120-129-mmHg subgroup (17.6 vs. 14.2%). There were no clear differences across the SBP subgroups for the combined renal outcome (overall, 0.8 vs. 0.6%)., Conclusion: Compared with those with baseline SBP 140-159 mmHg, side effects of dual combination BPL are essentially the same for people with SBP 130-139 mmHg and only modestly increased among patients with SBP 120-129 mmHg. During long-term therapy, side effects sufficient to stop treatment that are treatment related (i.e. occur in excess of rates seen with placebo) occur at less than 0.5%/year in patients with baseline SBP 120-139 mmHg. These results have important implications in assessing the likely balance of benefits and side effects of BPL with combination therapy among those with SBP 120-139 mmHg.

Background: Obstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with essential hypertension have suggested that nocturnal administration of antihypertensives improves nocturnal blood pressure (BP) without elevating daytime BP. We evaluated the efficacy of this technique in patients with OSA with stage I/II hypertension, both before and after the addition of CPAP., Methods: In this double-blind randomised placebo-controlled crossover trial, patients with moderate-to-severe OSA and hypertension received 6 weeks each of evening or morning perindopril with opposing time-matched placebo. CPAP therapy was subsequently added for 8 weeks in addition to either morning or evening perindopril. The primary outcome was sleep systolic BP (SBP) using 24-hour BP monitoring, analysed using linear mixed models., Results: Between March 2011 and January 2015, 85 patients were randomised, 79 completed both dosing times, 78 completed the CPAP phase. Sleep SBP reduced significantly from baseline with both evening (-6.9 mm Hg) and morning (-8.0 mm Hg) dosing, but there was no difference between dosing times (difference: 1.1 mm Hg, 95% CI -0.3 to 2.5). However, wake SBP reduced more with morning (-9.8 mm Hg) than evening (-8.0 mm Hg) dosing (difference: 1.8 mm Hg, 95% CI 1.1 to 2.5). Addition of CPAP to either evening or morning dosing further reduced sleep SBP, but by a similar amount (evening: -3.2 mm Hg, 95% CI -5.1 to -1.3; morning: -3.3 mm Hg, 95% CI -5.2 to 1.5)., Conclusions: Our findings support combining OSA treatment with morning administration of antihypertensives. Unlike in essential hypertension, our results do not support evening administration of antihypertensives, at least with perindopril. Further research is required before this strategy can be widely adopted into hypertension guidelines and clinical practice., Trial Registration Number: ACTRN12611000216910, Results., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: Blood pressure (BP) control is the main clinical goal in the management of hypertensive patients; however, BP in most of these patients remains uncontrolled, despite the widespread availability of antihypertensive drugs as free-combination therapy. This study compared the efficacy of a fixed-dose triple combination (FDTC) of antihypertensive drugs with that of a free combination of three antihypertensives in patients with uncontrolled hypertension., Methods: Ninety-two patients (mean age 60.8 ± 12.1, 58.0% male) with uncontrolled essential hypertension (office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) previously treated with a renin-angiotensin-aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDTC therapy with perindopril/indapamide/amlodipine (5-10/1.25-2.5/5-10 mg). Patients were age- and sex-matched with a control group of hypertensive patients receiving free-combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-h ambulatory BP monitoring (ABPM) were evaluated at baseline and after 1 and 4 months., Results: Significant reductions in ambulatory 24-h, daytime, and nighttime systolic BP, and pulse pressure (PP) were found in the FDTC group relative to reductions seen with free-combination therapy, after the first month only of follow-up. Target BP values (mean 24-h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of FDTC than free-combination therapy (64.8% vs. 46.9%, p < 0.05) at month 4 of follow-up, despite reductions in 24-h ABPM values from baseline being similar in both groups at this time point., Conclusion: FDTC of perindopril/indapamide/amlodipine was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the free-combination of a RAAS inhibitor, a diuretic, and a calcium antagonist.

Aim: To evaluate the efficiency of triple antihypertensive therapy in patients with uncontrolled hypertension and depressive disorders (DD)., Material and Methods: 153 patients with uncontrolled hypertension were examined, of whom 82 patients were diagnosed with mild and moderate DD. A combination of perindopril 10 mg/day, indapamide SR 1.5 mg/day, and amlodipine at an initial dose of 5 mg/day was given to patients with hypertension and DD. After 4 weeks of treatment, if target blood pressure (BP) levels could not be achieved, the dose of amlodipine was increased up to 10 mg/day. General clinical examination and 24-hour BP monitoring (BPM) were performed in all the patients at baseline and in the patients with DD also after 24 weeks of therapy. The traditional measures of the diurnal BP profile, as well as the parameters characterizing arterial stiffness and central aortic pressure (CAP) were estimated., Results: After 8 weeks of therapy, target BP levels were recorded in 63 (76.8%) patients. After 24 weeks of treatment, the hypertensive patients with DD showed significant positive changes in all the investigated 24-hour BPM parameters and normalization of the diurnal BP profile in 65.1% of cases. During the treatment, there were significant decreases in pulse wave velocity, brachial arterial and aortic augmentation indices, aortic systolic and diastolic pressures, and mean aortic BP and an increase in the velocity of the reflected wave., Conclusion: Triple therapy, including perindopril, indapamide SR, and amlodipine, contributed to the achievement of target BP levels in the majority of hypertensive patients with DD, with significant positive changes in all 24-hour BPM parameters, optimization of the diurnal BP profile in most patients, clinically significant improvement of the parameters that characterize arterial stiffness and CAP.

Aim: To study the effect of a fixed-dose combination of perindopril arginine/amlodipine (prestans) on the goal levels and variability of blood pressure (BP) according to its office visit-to-visit measurements and self-measurement (OVVM and SM) in a subgroup of 483 people from the population of the Russian observational SUPERIORITY program, most cases of whom are given the combination replacing the previously ineffective mono- and combination antihypertensive therapy (AHT)., Subjects and Methods: The subanalysis included data on 483 patients (34% men) aged 57.9±10.8 years with uncontrolled hypertension, who were both untreated and treated with antihypertensive mono- or combination therapy using a free or fixed-dose combination of 2-3 antihypertensive drugs and in whom the physicians decided to use prestans to correct AHT. The follow-up period was 24 weeks., Results: At the end of the investigation, the patients received prestans in the following doses: 5/5 mg (34% of the patients), 10/5 mg (39.5%), 5/10 mg (3.9%), and 10/10 mg (22%). In the analyzed patient group, the baseline BP was 160.8±8.8/92.6±7.4 mm Hg and dropped to 125.9±7.9/77.8±5.0 mm Hg at 24 weeks (p<0.001). According to SM, the morning BP significantly decreased from 147.0±13.3/85.6±7.2 to 127.5±8.3/78,9±5.6 mm Hg at 24 weeks (p<0.001). The evening BP readings showed the similar trends. Target BP was achieved in 93 and 78% of the patients, as shown by OVVM and SM, respectively. According to SCM, the day-to-day variability of BP significantly decreased from 5.1±3.2/3.4±2.3 Hg mm at Visit 2 to 2.7±2/0/2,3±1/5 mm Hg at Visit 5 (p<0.001)., Conclusion: The use of the fixed-dose combination of perindopril arginine/amlodipine in hypertensive patients just at the beginning of treatment, by switching from insufficiently effective mono- or combination AHT to the fixed-dose combination of perindopril arginine/amlodipine, is an effective way to optimize AHT in clinical practice, which lowers the BP level and variability, as evidenced by both OVVM and SM.

Objective: The burden of vascular diseases remains substantial in patients with type 2 diabetes, requiring identification of further risk markers. We tested the absence of dorsalis pedis and posterior tibial pulses as predictors of major macrovascular and microvascular events, death, and cognitive decline in this population., Research Design and Methods: Data were derived from 11,120 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study. Absent peripheral pulses at baseline were defined as absence of at least one dorsalis pedis or posterior tibial pulse., Results: Absent compared with present peripheral pulses (n = 2,218) were associated with increased 5-year risks for major macrovascular events (hazard ratio 1.47 [95% CI 1.28-1.69], P < 0.0001), myocardial infarction (1.45 [1.13-1.87], P = 0.003), stroke (1.57 [1.23-2.00], P = 0.0003), cardiovascular death (1.61 [1.33-1.95], P < 0.0001), heart failure (1.49 [1.21-1.84], P = 0.0002), all-cause mortality (1.48 [1.29-1.71], P < 0.0001), major microvascular events (1.17 [1.00-1.36], P = 0.04), nephropathy (1.24 [1.00-1.54], P = 0.04), end-stage renal disease or renal death (2.04 [1.12-3.70], P = 0.02), and peripheral neuropathy (1.13 [1.05-1.21], P = 0.0008) after multiple adjustment. Participants with absent dorsalis pedis or posterior tibial pulses had comparable hazard ratios. Risks increased proportionally with the number of absent peripheral pulses, with the highest risks observed in patients with three or four absent pulses. Every additional absent pulse increases the risk of all outcomes., Conclusions: Absent dorsalis pedis and/or posterior tibial pulses are independent predictors of major vascular outcomes in patients with type 2 diabetes. These simple clinical indicators should be used to improve risk stratification and treatment of these patients., (© 2016 by the American Diabetes Association.)

Background: Recurrence of atrial fibrillation (AF) after ablation is still high. Perindopril plays an essential role in AF induction and maintenance., Objective: We aimed to prove that perindopril (8 mg) could prevent recurrence after pulmonary vein isolation., Methods: Patients with paroxysmal AF who received radiofrequency ablation were randomized to a 3-month course of perindopril 8 mg once daily (perindopril group) or placebo (placebo group). Angiotensin-II (Ang-II) therapy and standard transthoracic echocardiography were performed. All 256 patients with paroxysmal AF who received radiofrequency ablation were randomized. And we followed them for complete 1 year. The 3-month recurrence and the 1-year recurrence were compared between the 2 groups., Results: The 3-month recurrence of AF was observed in 33 (26.19%) of 126 patients in the placebo group vs 19 (14.62%) of 130 patients who received perindopril 8 mg once daily (χ2, P = .021). One-year recurrence of AF was observed in 36 (28.5%) of 126 patients in the placebo group as compared with 21 (16.2%) of 130 patients who received perindopril after 1 year (P = .017). The κ value was 0.94 in the control group (P < .001) and 0.96 in the perindopril group (P < .001) between 3-month and 1-year recurrence. The Ang-II level was related to the left atrial distance with the reduction in AF recurrence (r = 0.17, P = .005 at 3 months; r = 0.25, P < .001 at 1 year)., Conclusion: Perindopril is an effective and safe treatment for the prevention of AF recurrence after radiofrequency catheter ablation. This effect seems to be strongly associated with a significant decrease in Ang-II level and left atrial distance., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Long-term therapy with a combination of perindopril and amlodipine has shown a beneficial effect on the morbidity and mortality of patients with stable coronary artery disease (SCAD) and hypertension. On the basis of the antiproliferative, antithrombotic, and antiatherogenic effects of the active substances, we initiated data collection to examine the short-term cardioprotective effect of perindopril/amlodipine fixed-dose combination therapy in this patient group. The aim of this study was to evaluate the effect of perindopril/amlodipine fixed-dose combination on the Canadian Cardiovascular Society (CCS) class and exercise capacity of patients with SCAD in everyday medical practice., Methods: This was a multicenter, prospective, observational, non-interventional, open-label, 6-month clinical study. Patients attended four visits (inclusion, and at months 1, 3, and 6), and clinical information was collected [risk factors, comorbidities, blood pressure (BP), and heart rate measured at the physician's office, drug treatment, CCS class, adverse events, optional laboratory blood tests, and exercise electrocardiography (ECG)]., Results: This study included 3472 patients. The mean office systolic BP/diastolic BP decreased from 157.5 ± 12.9/92.9 ± 8.6 to 130.3 ± 8.3/79.8 ± 6.1 mmHg (P < 0.0001). During the 6-month study period, a favorable change in CCS grading was observed following treatment with fixed-dose combination perindopril/amlodipine: CCS I, from 42.6% to 71.4%; CCS II, from 46.4% to 26.5%; CCS III, from 10.2% to 2.0%; and CCS IV, from 0.8% to 0.1% (all P < 0.0001). In those patients who had exercise ECG at inclusion and the end of month 6 (n = 197) the mean performance, measured in watts, increased from 88.9 ± 37.9 to 110.5 ± 38.4 W (+24.4%; P < 0.001) and from 7.86 ± 2.95 to 8.78 ± 2.92 metabolic equivalent of task (MET) (+11.7%; P < 0.001). No serious adverse events were reported and the treatment was found to have a positive impact on patients' metabolic profiles., Conclusion: The fixed-dose combination of perindopril and amlodipine improved the CCS class and exercise capacity in patients with SCAD after 6 months of treatment. The fixed-dose combination of perindopril and amlodipine can have favorable effects on the cardiovascular system, not only by its BP-lowering effect and its effect on vascular resistance but also through its direct cardiovascular protective effects., Funding: Egis Pharmaceuticals., Trial Registration: 21938-1/2011-EKU (698/PI/11.).

Objective: Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in type 2 diabetes, but the relationship between other vascular diseases and PAD has been poorly investigated. We examined the impact of previous microvascular and macrovascular disease on the risk of major PAD in patients with type 2 diabetes., Research Design and Methods: We analyzed 10,624 patients with type 2 diabetes free from baseline major PAD in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) clinical trial. The primary composite outcome was major PAD defined as PAD-induced death, peripheral revascularization, lower-limb amputation, or chronic ulceration. The secondary end points were the PAD components considered separately., Results: Major PAD occurred in 620 (5.8%) participants during 5 years of follow-up. Baseline microvascular and macrovascular disease were both associated with subsequent risk of major PAD after adjustment for age, sex, region of origin, and randomized treatments. However, only microvascular disease remained significantly associated with PAD after further adjustment for established risk factors. The highest risk was observed in participants with a history of macroalbuminuria (hazard ratio 1.91 [95% CI 1.38-2.64], P < 0.0001) and retinal photocoagulation therapy (1.60 [1.11-2.32], P = 0.01). Baseline microvascular disease was also associated with a higher risk of chronic lower-limb ulceration (2.07 [1.56-2.75], P < 0.0001) and amputation (1.59 [1.15-2.22], P = 0.006), whereas baseline macrovascular disease was associated with a higher rate of angioplasty procedures (1.75 [1.13-2.73], P = 0.01)., Conclusions: Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not., (© 2016 by the American Diabetes Association.)

Background: Central aortic blood pressure (CBP) and CBP-derived parameters are independent predictors of cardiovascular risk. Angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors plus calcium channel blockers are the recommended first-line treatments in hypertensive diabetic patients; however, the effect in reducing CBP when a dose is skipped has not been established yet. The aim was to determine whether the fixed-dose combination of olmesartan/amlodipine (OLM/AML) provides equal efficacy and safety as the perindopril/AML (PER/AML) combination in reducing CBP, augmentation index (AIx), and pulse wave velocity (PWV) when a drug dose is missed., Methods: In this noninferiority, randomized, double-blind, double-dummy parallel group, controlled design trial, 88 patients received either OLM 20-40mg/AML 5-10mg (41 patients) or PER 4-8mg/AML 5-10mg (47 patients) for 24 weeks. The main endpoint was the aortic systolic BP (SBP) after 24 weeks of treatment at 48 hours from the last administration., Results: The OLM/AML combination reached the noninferiority criteria in reducing central systolic BP after 24 weeks of treatment and after the missed dose, compared to the PER/AML combination (-17 and -8mm Hg, respectively). Peripheral BP, AIx, and PWV were significantly lower in both groups after 24 weeks of treatment and 48 hours after the missed dose, observing a trend to a greater reduction in CBP-derived parameters in the OLM/AML group., Conclusions: The OLM/AML combination is safe, well tolerated, and not inferior to the combination of PER/AML in lowering CBP and CBP-derived parameters in diabetic patients. OLM/AML provides longer-lasting efficacy in terms of CBP reduction compared to PER/AML., (© American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Objectives: Although single-pill, fixed-dose combinations (FDCs) are widely endorsed for the reduction of blood pressure and cardiovascular risk, studies to date have not evaluated the differences between FDCs and free associations using matched drugs and doses. The objective of this study was to determine whether switching from a free association of perindopril/amlodipine to the FDC formulation led to significant improvements in efficacy and tolerability., Methods: In this subanalysis of the previously published SYMBIO study, we looked at the effect of switching patients from a free association of perindopril/amlodipine to an equivalent dose of FDC (N = 335). In the SYMBIO study, concomitant antihypertensive medications were allowed; however, they remained unchanged till the end of the study. Blood pressure was measured at baseline, 1, and 3 months. Targets were defined as blood pressure <140/90 mmHg or <130/80 mmHg for patients with type 2 diabetes mellitus or at high cardiovascular risk., Results: Compared to baseline, mean blood pressure decreased significantly after 1 and 3 months of treatment with FDC perindopril/amlodipine. Mean changes from baseline were -15.6 ± 14.3/-7.7 ± 9.1 mmHg at 1 month (p < 0.0001) and -23.3 ± 16.4/-11.3 ± 9.8 mmHg at 3 months (p < 0.0001). The percentage of patients who reached their blood pressure target increased from 16.0 % at baseline to 50.6 % at 1 month, to 75.9 % at 3 months. The incidence of ankle edema decreased from 14.9 % at baseline, to 9.9 % at 1 month, to 5.4 % at 3 months. The relative risk reduction for ankle edema was -37.5 % at 1 month (vs. baseline; p < 0.001) and -57.2 % at 3 months (vs. baseline; p < 0.001)., Conclusions: These data suggest that switching from a free association of perindopril/amlodipine to the same dose of the FDC formulation led to significant improvements in efficacy and tolerability.

This post hoc analysis from the Sevikar Compared to the Combination of Perindopril Plus Amlodipine on Central Arterial Blood Pressure in Patients With Moderate-to-Severe Hypertension (SEVITENSION) study assessed the efficacy and tolerability of olmesartan (OLM) and amlodipine (AML) in reducing central systolic blood pressure (CSBP) compared with perindopril (PER) plus AML in hypertensive patients with type 2 diabetes. Patients were randomized to OLM/AML 40/10 mg or PER/AML 8/10 mg for 24 weeks. The primary efficacy endpoint was the absolute change in CSBP from baseline to week 24, which was greater with OLM/AML (-13.72±1.14 mm Hg) compared with PER/AML (-10.21±1.11 mm Hg). The between-group difference was -3.51±1.60 mm Hg (95% confidence interval, -6.66 to -0.36 mm Hg) and was within the noninferiority margin (2 mm Hg) as well as the superiority margin (0 mm Hg). In addition, OLM/AML was associated with a higher proportion of patients achieving blood pressure normalization. In hypertensive patients with diabetes, the fixed-dose combination of OLM/AML was superior to PER/AML in reducing CSBP, as well as other secondary endpoints., (© 2015 Wiley Periodicals, Inc.)

Background: Inadequate blood pressure (BP) control remains a serious concern worldwide. Recent evidence suggests that the combination of a calcium channel blocker (CCB) with an angiotensin-converting enzyme inhibitor (ACEi) in patients with essential hypertension provides effective BP control with decreased adverse cardiac and renal events., Objectives: This study was designed to quantitatively evaluate the efficacy and tolerability of a fixed dose combination of perindopril and amlodipine in the Kingdom of Saudi Arabia on a population of patients with essential hypertension, as well as to identify the predictors of BP control in this population., Methods: This was an observational, multicenter, open-label cohort study of patients with essential hypertension with or without diabetes mellitus, treated with a fixed dose combination of perindopril and amlodipine. Patients were followed up in four-week intervals for a total of 12 weeks. They were initially started on the lowest dose of the ACEi/CCB combination and up-titrated at each follow-up according to their response to treatment. The primary end-point of the study was the percentage of patients with controlled BP at study termination (week 12)., Results: A total of 1996 patients completed the study. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) control was observed in 93.3% of patients at week 12. As for the predictors of BP control, it was found that female gender was associated with more BP control [odds ratio (OR) = 1.76, 95% CI: 1.14-2.70, p value = 0.01], whereas older age was associated with less BP control (OR = 0.98, 95% CI: 0.96-1.00, p value = 0.02). Similarly, having type I and type II diabetes mellitus was also associated with less BP control (OR = 0.19, 95% CI: 0.08-0.45, p < 0.0001 and OR = 0.33, 95% CI: 0.22-0.48, p < 0.0001, respectively). In a qualitative assessment, both investigators and patients perceived efficacy and tolerability of perindopril/amlodipine to be excellent., Conclusion: We found that a fixed combination of perindopril/amlodipine is effective in controlling BP in patients with essential hypertension, with older age, male gender, and diabetes mellitus being independent risk factors for less BP control.