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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.)

Background and Objectives: Autism is a developmental disability characterized by impairment of motor functions and social communication together with the development of repetitive or stereotyped behaviors. Neither the exact etiology or the curative treatment of autism are yet completely explored. The goals of this study were to evaluate the possible effects of perindopril on a rat model of autism and to elucidate the possible molecular mechanisms that may contribute to these effects. Materials and Methods: In a rat model of sodium valproate (VPA)-induced autism, the effect of postnatal administration of different doses of perindopril on growth and motor development, social and repetitive behaviors, sirtuin-1, oxidative stress and inflammatory markers, PI3K/Akt/GSK-3β pathway, JAK2/STAT3 axis, and PPAR-gamma signaling in the hippocampal tissues were investigated. The histopathological and electron microscopic changes elicited by administration of the different treatments were also investigated. Results : Perindopril dose-dependently combatted the effects of prenatal exposure to VPA on growth and maturation, motor development, and social and repetitive behaviors. In addition, the different doses of perindopril ameliorated the effects of prenatal exposure to VPA on sirtuin-1, oxidative stress and inflammatory markers, PI3K/Akt/GSK-3β pathway, JAK2/STAT3 axis, and PPAR-gamma signaling. These effects had a mitigating impact on VPA-induced histopathological and electron microscopic changes in the hippocampal tissues. Conclusions : Perindopril may emerge as a promising agent for amelioration of the pathologic changes of autism spectrum disorders.

Obesity has emerged as a worldwide health concern due to its increasing prevalence. Adipocytes have the ability to express angiotensin-converting enzyme 2 receptors (ACE2) and several adipocytokines. These expressions could lead to the activation of a cytokine storm, which in turn promotes the development of cardiovascular diseases. The aim of this study was to investigate the impact of perindopril and losartan exposure on the ACE2 and interleukin 6 (IL-6) levels in adipocyte cells. This study used an in vivo true experimental design utilizing a post-test-only control group. A total of 24 adult male albino rats were divided into four groups, one group served as the non-obese (negative control), while the other three groups were obese: (1) the positive control (untreated obese rats); (2) perindopril group (2 mg/kg BW/day orally for 4 weeks); and (3) losartan group (20 mg/kg BW/day for 4 weeks). Afterwards, the rats were euthanized, and the visceral fat tissue were obtained during dissection. The levels of ACE2 and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA). Losartan administration in obese rats resulted in a notable elevation in ACE2 levels compared to both the perindopril group (losartan vs perindopril, p =0.011) and the positive control ( p =0.004). In addition, the treatment of perindopril and losartan in obese rats resulted in a significant reduction in IL-6 levels when compared to the positive control (perindopril vs positive control, p= 0.020; losartan vs positive control, p= 0.002, respectively). This study provides insight into the administration of perindopril and losartan, which could suppress the pro-inflammatory (IL-6) but increase the ACE2 levels in adipose tissue., Competing Interests: All the authors declared that there is no conflict of interest., (© 2024 The Author(s).)

Background: Limited data exist on the relationship between declining kidney function and cardiovascular events, dementia, and mortality in patients with a history of stroke.Thus the aims of the study were to investigate functional relationships between dynamic kidney function change and cardiovascular outcomes, and clarify whether adding kidney parameters to conventional cardiovascular risk factors improves model discrimination., Methods: Post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) clinical trial of blood pressure lowering for the secondary prevention of stroke. We examined the association between dynamic kidney function defined as percentage change (declines of >30%, and >0 to ≤30%, and increases of ≥0 to <30%, and ≥30%) in estimated glomerular filtration rate (eGFR) over 2 years and recurrent stroke, major cardiovascular events, dementia and all-cause death over the next 2 years using Cox proportional hazard models controlling for eGFR at registration and potential confounders. Restricted cubic splines were used to assess the functional relationships. C-statistics and Net Reclassification Improvement (NRI) at 2 years were used to assess model discrimination., Results: In 4591 patients followed for a mean of approximately 2 years, 254 (5.5%) developed recurrent stroke, 391 (8.5%) had a major cardiovascular event, 221 (4.8%) developed dementia, and 271 (5.9%) died. Reverse J-like or U-like relationships were observed for percent declines in eGFR and outcomes. Using declines in eGFR of >0 to ≤30% as a reference, increased risks were evident for a greater decline (>30%) in relation to recurrent stroke [adjusted hazard ratio 1.85, 95% confidence interval (CI) 1.20-2.85], major cardiovascular event (2.24, 1.62-3.10) and all-cause death (2.09, 1.39-3.15). A larger increase (≥30%) in eGFR was also associated with a greater risk of all-cause death (1.96, 1.14-3.37). Improvements in the C-statistic were found by adding baseline eGFR and percent change compared with a model with conventional cardiovascular risk factors alone, for major cardiovascular events, dementia, and all-cause mortality., Conclusion: Declining kidney function following an incident cerebrovascular event is associated with additional risk of a major cardiovascular events, dementia, and 2-year mortality. However, a large increase in kidney function was also found to be associated with a higher risk of mortality., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Cadmium (Cd) is one of the most abundant toxic heavy metals, and its exposure is linked to serious kidney intoxication, a major health problem. Evidence reported that inflammatory damage is a key factor in Cd renal intoxication. Perindopril (PER) is an angiotensin-converting enzyme inhibitor approved for treating hypertension and other cardiovascular problems. Significantly, RAS activation results in inflammatory damage. Our study aimed to examine the renoprotective effects of PER in Cd-induced nephrotoxicity, the impact of inflammation, and the underlying molecular mechanisms. PER was given at a dose of 1 mg/kg per day. Cd was injected at a dose of 1.2 mg/kg, as a single dose. Treatment with PER led to a significant decrease in serum levels of urea, creatinine, uric acid, and urine albumin/creatinine ratio. PER effectively mitigated inflammation by decreasing MPO, NO, IL-1β, IL-6, and INF-γ levels mediated by downregulating NF-κB expression and suppressing JAK-1 and STAT3 phosphorylation. PER modulates Ang II/Ang 1-7 axis in Cd-intoxicated rats by decreasing Ang II expression and increasing Ang-(1-7) expression. PER inhibits Cd-induced apoptosis by lowering Bax, cytochrome c, and cleaved caspase 3 expressions while increasing Bcl-2 expression. In conclusion, PER dampens Cd-induced kidney intoxication by modulating Ang II/Ang 1-7 axis, suppressing NF-κB, JAK-1/STAT3, and apoptosis signals., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Mechanical ventilation (MV) is an essential therapy for acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. However, it can also induce mechanical ventilation-induced pulmonary fibrosis (MVPF) and the underlying mechanism remains unknown. Based on a mouse model of MVPF, the present study aimed to explore the role of the angiotensin-converting enzyme/angiotensin II/angiotensin type 1 receptor (ACE/Ang-2/AT1R) axis in the process of MVPF. In addition, recombinant angiotensin-converting enzyme 2(rACE2), AT1R inhibitor valsartan, AGTR1-directed shRNA and ACE inhibitor perindopril were applied to verify the effect of inhibiting ACE/Ang-2/AT1R axis in the treatment of MVPF. Our study found MV induced an inflammatory reaction and collagen deposition in mouse lung tissue accompanied by the activation of ACE in lung tissue, increased concentration of Ang-2 in bronchoalveolar lavage fluid (BALF), and upregulation of AT1R in alveolar epithelial cells. The process of pulmonary fibrosis could be alleviated by the application of the ACE inhibitor perindopril, ATIR inhibitor valsartan and AGTR1-directed shRNA. Meanwhile, rACE2 could also alleviate MVPF through the degradation of Ang-2. Our finding indicated the ACE/Ang-2/AT1R axis played an essential role in the pathogenesis of MVPF. Pharmacological inhibition of the ACE/Ang-2/AT1R axis might be a promising strategy for the treatment of MVPF., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: The present real-world analysis aims to compare the drug utilization, hospitalizations and direct healthcare costs related to the use of single-pill combination (SPC) or free-equivalent combination (FEC) of perindopril and bisoprolol (PER/BIS) in a large Italian population., Methods: This observational retrospective analysis was based on administrative databases covering approximately 7 million subjects across Italy. All adult subjects receiving PER/BIS as SPC or FEC between January 2017-June 2020 were included. Subjects were followed for 1 year after the first prescription of PER/BIS as FEC (± 1 month) or SPC. Before comparing the SPC and FEC cohorts, propensity score matching (PSM) was applied to balance the baseline characteristics. Drug utilization was investigated as adherence (defined by the proportion of days covered, PDC) and persistence (evaluated by Kaplan-Meier curves). Hospitalizations and mean annual direct healthcare costs (due to drug prescriptions, hospitalizations and use of outpatient services) were analyzed during follow-up., Results: The original cohort included 11,440 and 6521 patients taking the SPC and FEC PER/BIS combination, respectively. After PSM, two balanced SPC and FEC cohorts of 4688 patients were obtained (mean age 70 years, approximately 50% male, 24% in secondary prevention). The proportion of adherent patients (PDC ≥ 80%) was higher for those on SPC (45.5%) than those on FEC (38.6%), p < 0.001. The PER/BIS combination was discontinued by 35.8% of patients in the SPC cohort and 41.7% in the FEC cohort (p < 0.001). The SPC cohort had fewer cardiovascular (CV) hospitalizations (5.3%) than the free-combination cohort (7.4%), p < 0.001. Mean annual total healthcare costs were lower in the SPC (1999€) than in the FEC (2359€) cohort (p < 0.001)., Conclusion: In a real-world setting, patients treated with PER/BIS SPC showed higher adherence, lower risk of drug discontinuation, reduced risk of CV hospitalization, and lower healthcare costs than those on FEC of the same drugs., (© 2023. The Author(s).)

In diabetes, increased oxidative stress and impaired trace element metabolism play an important role in the pathogenesis of diabetic nephropathy. The objective of this research was to examine the outcomes of blocking the renin-angiotensin system, using either the angiotensin-converting enzyme inhibitor (ACEI), perindopril, or the angiotensin II type 1 (AT1) receptor blocker, irbesartan, on oxidative stress and trace element levels such as Zn, Mg, Cu, and Fe in the kidneys of diabetic rats that had been induced with streptozotocin. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as a control. The second group of rats developed diabetes after receiving a single intraperitoneal dose of STZ. The third and fourth groups of rats had STZ-induced diabetes and received daily dosages of irbesartan (15 mg/kg b.w/day) and perindopril (6 mg/kg b.w/day) treatment, respectively. Biochemical analysis of the kidneys showed a distinct increase in oxidative stress, indicated by heightened levels of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activities, as well as reduced glutathione (GSH) levels in the kidneys of diabetic rats. In the kidneys of diabetic rats, the mean levels of Fe and Cu were found to be significantly higher than those of the control group. Additionally, the mean levels of Zn and Mg were significantly lower in the diabetic rats compared to the control rats. Both perindopril and irbesartan decreased significantly MDA content and increased SOD activities and GSH levels in the kidneys of rats with diabetes. The Zn and Mg concentrations in the kidneys of diabetic rats treated with perindopril and irbesartan were markedly higher than in untreated STZ-diabetic rats, while the Cu and Fe concentrations were significantly lower. The urinary excretion of rats treated with perindopril and irbesartan showed a pronounced increase in Cu levels, along with a significant reduction in Zn and Mg levels. Although diabetic rats demonstrated degenerative morphological alterations in their kidneys, both therapies also improved diabetes-induced histopathological modifications in the kidneys. Finally, the present results suggest that manipulating the levels of Zn, Mg, Cu, and Fe - either through ACE inhibition or by blocking AT1 receptors - could be advantageous in reducing lipid peroxidation and increasing antioxidant concentration in the kidneys of diabetic rats., Competing Interests: Declaration of competing interest No conflicts of interest, financial or otherwise are declared by the author(s). All authors approved the final manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: This analysis compared adherence, cardiovascular (CV) events and all-cause mortality incidence, and healthcare costs among hypertensive patients treated with perindopril (PER)/indapamide (IND)/amlodipine (AML) in single-pill combination (SPC) vs. multiple-pill combination, in a real-world setting in Italy., Methods: In this observational retrospective analysis of Italian administrative databases, adult patients treated with PER/IND/AML between 2010 and 2020 were divided into two cohorts: single-pill vs. multiple-pill. Patient data were available for at least one year before and after index date. Propensity score matching (PSM) was applied to reduce selection bias. Adherence was defined as proportion of days covered: non-adherence, <40%; partial adherence, 40-79%, and adherence ≥80%. Mortality incidence and CV events as single, or composite, endpoints were evaluated after first year of follow-up. Healthcare cost analyses were performed from the perspective of the Italian National Health Service., Results: Following PSM, the single-pill cohort included 12 150 patients, and the multiple-pill cohort, 6105. The SPC cohort had a significantly higher percentage of adherent patients vs. the multiple-pill cohort (59.9% vs. 26.9%, P  < 0.001). Following the first year of follow-up, incidence of all-cause mortality, and combined endpoint of all-cause mortality and CV events were lower in the SPC cohort compared with multiple-pill cohort. Average annual direct healthcare costs were lower in the single-pill cohort (€2970) vs. multiple-pill cohort (€3642); cost of all drugs and all-cause hospitalizations were major contributors., Conclusion: The SPC of PER/IND/AML, compared with multiple-pill combination, is associated with higher adherence to medication, lower incidence of CV events and mortality, and reduced healthcare costs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The 2022 draft Russian guidelines on arterial hypertension recommend initiation of antihypertensive therapy with a combination of drugs in most patients with blood pressure above 150 / 90 mm Hg and / or in the presence of high-risk criteria. In 2021, the results of a 12-year analysis of the Brisighella Heart Study (BHS) were published. The aim of this study was to compare the use of different triple antihypertensive drug combinations in an Italian cohort of patients in real-life clinical practice. Combination antihypertensive therapy with a renin-angiotensin-aldosterone system inhibitor, amlodipine, and thiazide/thiazide-like diuretics provides a better blood pressure control compared to other antihypertensive drug combinations. The use of the triple combination of amlodipine/indapamide/perindopril is associated with a better metabolic profile than any other considered combination of antihypertensive drugs and a more pronounced organ-protective effect.

Introduction: Differences in class or molecule-specific effects between renin-angiotensin-aldosterone system (RAAS) inhibitors have not been conclusively demonstrated. This study used South African data to assess clinical and cost outcomes of antihypertensive therapy with the three most common RAAS inhibitors: perindopril, losartan and enalapril., Methods: Using a large, South African private health insurance claims database, we identified patients with a hypertension diagnosis in January 2015 receiving standard doses of perindopril, enalapril or losartan, alone or in combination with other agents. From claims over the subsequent 5 years, we calculated the risk-adjusted rate of the composite primary outcome of myocardial infarction, ischaemic heart disease, heart failure or stroke; rate of all-cause mortality; and costs per life per month (PLPM), with adjustments based on demographic characteristics, healthcare plan and comorbidity., Results: Overall, 32,857 individuals received perindopril, 16,693 losartan and 13,939 enalapril. Perindopril-based regimens were associated with a significantly lower primary outcome rate (205 per 1000 patients over 5 years) versus losartan (221; P < 0.0001) or enalapril (223; P < 0.0001). The risk-adjusted all-cause mortality rate was lower with perindopril than enalapril (100 vs. 139 deaths per 1000 patients over 5 years; P = 0.007), but not losartan (100 vs. 94; P = 0.650). Mean (95% confidence interval) overall risk-adjusted cost PLPM was Rands (ZAR) 1342 (87-8973) for perindopril, ZAR 1466 (104-9365) for losartan (P = 0.0044) and ZAR 1540 (77-10,546) for enalapril (P = 0.0003)., Conclusion: In South African individuals with private health insurance, a perindopril-based antihypertensive regimen provided better clinical and cost outcomes compared with other regimens., (© 2023. The Author(s).)

Background: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study., Methods: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables., Results: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo., Conclusion: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rossios et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To uncover the potential effect of Perindopril on cardiac fibrosis caused by pressure overload and the underlying mechanism. Cardiac fibrosis model in mice was established by TAC method. Mice were assigned into sham group, TAC group, 2 mg/kg Perindopril group (Per (2 mg/kg)) and 8 mg/kg Perindopril group (Per (8 mg/kg)). Cardiac structure changes were assessed by measuring HW/BW, HW/TBL, LW/BW and LW/TBL in each group. Echocardiography was performed to assess mouse cardiac function by recording EF, LVIDd, IVSd and LVPWd. Relative levels of fibrosis markers were determined. AngII content was examined by ELISA. Besides, mRNA levels of key genes in the AngII/AT1R pathway were finally detected. TAC induced cardiac insufficiency, left ventricular dilatation, cardiac hypertrophy and myocardial collagen deposition in mice. In addition, fibrosis markers were upregulated in mice of TAC group. Perindopril markedly reversed TAC-induced pathological changes in cardiac structure and function of mice. Meanwhile, Perindopril dose-dependently reversed the upregulated genes in the AngII/AT1R pathway. Perindopril improves cardiac fibrosis induced by pressure overload through activating the AngII/AT1R pathway.

The purpose of this study was to elucidate the therapeutic effect of different antihypertensive drugs (amlodipine and perindopril) on hypertension induced by apatinib and bevacizumab. Sixty patients with hypertension treated with apatinib or bevacizumab were selected and divided into two groups: one group was treated with amlodipine and the other group was treated with perindopril. Before and after treatment, the dynamic blood pressure (BP) measurement (systolic BP [SBP] and diastolic BP [DBP]), echocardiography (left ventricular end-diastolic diameter, interventricular septal thickness [IVST], left ventricular posterior wall thickness [LVPWT], and left atrial diameter [LAD]), and detection of nitric oxide (NO) content in venous blood were performed. In the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, daytime mean SBP (dSBP), daytime mean SSD (dSSD), daytime mean SBP CV, night mean SBP (nSBP), night mean SSD, 24hDBP, 24hDSD, 24 h DBP CV, daytime mean DBP (dDBP), daytime mean DSD (dDSD), daytime mean DBP CV, night mean DBP (nDBP), LAD, and LAD index (LADi) after treatment were all lower than before treatment, while NO was higher than before treatment (all P < 0.05). In the perindopril group, the 24hSBP, dSBP, nSBP, 24hDBP, dDBP, nDBP, LAD, LADi, IVST, LVPWT, and left ventricular mass index (LVMI) after treatment were lower than before treatment, and NO level after treatment was higher than before treatment (all P < 0.05). After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, nSBP, 24hDBP, 24hDSD, dDBP, dDSD, nDBP, night mean DSD, and NO were all lower while the LAD, LADi, IVST, LVPWT, and LVMI were higher in the amlodipine group than those in the perindopril group (all P < 0.05). Our study suggests that the SBP and DBP variability of amlodipine in the treatment of hypertension induced by apatinib and bevacizumab is slightly better than that of perindopril, but the effect of perindopril in improving endothelial function indices NO and echocardiographic data is better than that of amlodipine., Competing Interests: None

The hormone, relaxin (RLX), exerts various organ-protective effects independently of etiology. However, its complex two-chain and three disulphide bonded structure is a limitation to its preparation and affordability. Hence, a single chain-derivative of RLX, B7-33, was developed and shown to retain the anti-fibrotic effects of RLX in vitro and in vivo. Here, we determined whether B7-33 could retain the other cardioprotective effects of RLX, and also compared its therapeutic efficacy to the ACE inhibitor, perindopril. Adult male 129sv mice were subjected to isoprenaline (ISO; 25 mg/kg/day, s.c)-induced cardiomyopathy, then s.c-treated with either RLX (0.5 mg/kg/day), B7-33 (0.25 mg/kg/day; equivalent dose corrected for MW) or perindopril (1 mg/kg/day) from days 7-14 post-injury. Control mice received saline instead of ISO. Changes in animal body weight (BW) and systolic blood pressure (SBP) were measured weekly, whilst cardiomyocyte hypertrophy and measures of vascular dysfunction and rarefaction, left ventricular (LV) inflammation and fibrosis were assessed at day 14 post-injury. ISO-injured mice had significantly increased LV inflammation, cardiomyocyte hypertrophy, fibrosis, vascular rarefaction and aortic contractility in the absence of any changes in BW or SBP at day 14 post-injury. Both B7-33 and RLX equivalently reduced LV fibrosis and normalised the ISO-induced LV inflammation and cardiomyocyte hypertrophy, whilst restoring blood vessel density and aortic contractility. Comparatively, perindopril lowered SBP and the ISO-induced LV inflammation and vascular rarefaction, but not fibrosis or hypertrophy. As B7-33 retained the cardioprotective effects of RLX and provided rapid-occurring anti-fibrotic effects compared to perindopril, it could be considered as a cost-effective cardioprotective therapy., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Single-pill combination therapy for hypertension is recognized to improve adherence to treatment. However, less is known about the benefits of triple single-pill combinations. This retrospective observational analysis aimed to assess changes in adherence when treatment was switched from perindopril (PER)/indapamide (IND) + amlodipine (AML) to PER/IND/AML single-pill combination, in Italian clinical practice., Methods: This analysis used data extracted from administrative databases of Italian healthcare entities. Adult patients receiving PER/IND/AML were selected, and the prescription date was considered as the index date. Among them, those who had a prescription for PER/IND + AML during the 12 months before the index date and a prescription of PER/IND/AML during 6 months of follow-up were included. Adherence was calculated as the proportion of days covered (PDC: PDC < 40%, non-adherent; PDC = 40-79%, partially adherent; PDC ≥ 80%, adherent)., Results: Among the identified patients, 158 were exposed users and were included in the analysis. When patients were compared before and after switch to triple single-pill combination, the proportion of adherent patients was significantly higher with PER/IND/AML single-pill combination (75.3%) than with PER/IND + AML combination (44.3%) (P < 0.05). Conversely, the proportion of non-adherent patients was lower with the PER/IND/AML single-pill combination (14.6%) vs PER/IND + AML (17.7%) (P < 0.001)., Conclusion: This real-world analysis showed that switching to a triple single-pill combination could offer an opportunity to improve adherence to antihypertensive treatment in real-life clinical practice., (© 2023. The Author(s).)

Objective: The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic indapamide monotherapy or in combination with perindopril as a blood pressure lowering drug in randomized controlled trials (RCTs)., Method: Aggregate data from four published RCTs conducted versus matching placebo were pooled: PATS, a 2-year study (indapamide), and PROGRESS, a 4-year study (indapamide and perindopril), both in patients with a history of stroke or transient ischemic attack; ADVANCE, a 4-year study in patients with type 2 diabetes and cardiovascular risk factor (single-pill combination perindopril/indapamide) and HYVET, a 2-year study in very elderly hypertensive individuals (indapamide and an option of perindopril). The pooled effect (fixed and random) estimate (hazard ratio) was reported with corresponding 95% confidence intervals and P values. Treatment discontinuations were also analysed to assess the net benefit of the treatment., Results: The population involved 24 194 patients (active: 12 113, placebo: 12 081). The fixed-effects meta-analysis of the three mortality endpoints found low statistical heterogeneity ( I2  = 0). Statistically significant risk reductions in the indapamide with or without perindopril-treated patients as compared to placebo were observed for all-cause death (-15%), cardiovascular death (-21%), fatal stroke (-36%) and all strokes (-27%). Other cardiovascular outcomes were improved (risk reduction, 22 to 36%). As expected, discontinuation rates for safety (two studies) were higher in the active group (6.4 vs. 3.9%), while they were similar when discontinuation for any reason is concerned (18.4 vs. 18.0%)., Conclusion: Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Decisions about hypertension management are substantially influenced by blood pressure (BP) levels measured before and soon after starting BP lowering drugs. We aimed to assess the utility of short-term BP changes in individuals in terms of long-term treatment response., Methods: Post hoc analyses of 2 randomized trials with 4-to-6 weeks active run-in for all participants, followed by randomization to active BP lowering treatment (combination perindopril±indapamide) or placebo. We categorized individuals by degree of systolic BP (SBP) change during active run-in treatment and assessed associations with subsequent postrandomization placebo-corrected BP reduction, cardiovascular events, and tolerability. We included individuals with baseline BP ≥140/90 mm Hg from the PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study; 4275 individuals with cerebrovascular disease) and ADVANCE trial (The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; 6610 individuals with diabetes)., Results: During the active run-in period, the proportion of participants with initial SBP changes in 4 categories (SBP increase, 0-9.9 mm Hg decrease, 10-19.9 mm Hg decrease, and ≥20 mm Hg decrease) were 17%, 27%, 28%, and 28% in PROGRESS and 21%, 22%, 24%, and 33% in ADVANCE. Randomization to active therapy achieved similar placebo-corrected long-term BP reductions across the 4 initial SBP change groups in both trials ( P -values for heterogeneity >0.1). There was no significant difference in achieving BP <140/90 mm Hg at follow-up, major cardiovascular events, nor treatment tolerability according to the SBP change during active run-in period (all P -values >0.1)., Conclusions: An individual's apparent BP change immediately after commencing therapy has limited clinical utility. Therefore, more emphasis should be given to use of evidence-based regimens and measures over the long-term to ensure sustained BP control., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00145925.

Aims: The therapeutic properties of anti-hypertensive medications that extend beyond blood pressure lowering have started to become important clinical targets in recent years. This study aimed to assess the cardioprotective effects of perindopril in attenuating complications associated with metabolic syndrome in diet induced obese rats., Main Methods: Male Wistar-Kyoto (WKY) rats aged 16 weeks were fed either standard rat chow (SC) or given a high-fat-high-carbohydrate (HFHC) diet for 20 weeks. Perindopril treatment (1 mg/kg/day) was administered to a subset of WKY rats commencing at week 8 of the 20 week HFHC feeding period. Body weights, food, water and energy intakes, blood pressure, heart rate and glucose tolerance were measured throughout the treatment period. Oxidative stress and inflammatory markers, lipid levels, cardiac collagen deposition, vascular function, aortic and cardiac electrical function were examined after the treatment., Key Findings: WKY rats developed metabolic syndrome after 20 weeks of HFHC feeding, evidenced by the presence of abdominal obesity, dyslipidaemia, glucose intolerance and hypertension. Perindopril treatment prevented the development of obesity and hypertension in WKY-HFHC. Perindopril improved blood lipid profiles in HFHC rats with decreases in LDL cholesterol, triglycerides and total cholesterol. Type I collagen levels were decreased in WKY-HFHC rats along with decreases in left ventricle mass. Perindopril treated rats also showed improved cardiac electrical function indicated by decreases in action potential at 90 % of repolarisation in WKY-HFHC rats., Significance: These results show that perindopril has a profound effect on preventing the development of metabolic syndrome in animals fed a HFHC diet., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The objective of this non-interventional post-marketing clinical trial was to analyze the antihypertensive effect and safety of a fixed combination of perindopril and indapamide in the treatment of unregulated essential hypertension., Patients and Methods: The prospective clinical trial included patients aged 20 to 75 years with essential hypertension and blood pressure values ≥ 140/90 mmHg at baseline. On the basis of the investigator's decision, patients received 2 mg perindopril + 0.625 mg indapamide (group 2+0.625) or 4 mg perindopril + 1.25 mg indapamide (group 4+1.25)., Results: The study included 1173 patients (426 patients in group 2+0.625 and 747 patients in group 4+1.25) at 27 investigational centers in Bosnia and Herzegovina. Mean blood pressure values at baseline and visits after nine months were significantly higher in the 4+1.25 group compared to the 2+0.625 group. There was a significant drop in systolic and diastolic blood pressure in both groups. The target values of systolic and diastolic blood pressure, according to the European Society of Cardiology (2018), were reached after nine months of therapy by more than 80% of patients in the 2+0.625 group, and this number was significantly higher compared to the 4+1.25 group where more than 60% of patients reached target values. Newly diagnosed patients had a better response to therapy. The percentage of patients receiving additional antihypertensive therapy decreased by the end of the study. Age, gender and the existence of diabetes mellitus were identified as negative predictors of target blood pressure achievement. The therapy showed a good safety profile., Conclusion: A fixed combination of perindopril and indapamide was effective and safe in the treatment of unregulated essential hypertension., (Copyright © 2022 by Academy of Sciences and Arts of Bosnia and Herzegovina.)

Background: The effect of 3 commonly recommended combinations of anti-hypertensive agents-amlodipine plus hydrochlorothiazide (calcium channel blocker [CCB]+thiazide), amlodipine plus perindopril (CCB+ACE [angiotensin-converting enzyme]-inhibitor), and perindopril plus hydrochlorothiazide (ACE-inhibitor+thiazide) on blood pressure variability (V) are unknown., Methods: We calculated the blood pressure variability (BPV) in 405 patients (130, 146, and 129 randomized to ACE-inhibitor+thiazide, CCB+thiazide, and CCB+ACE-inhibitor, respectively) who underwent ambulatory blood pressure monitoring after 6 months of treatment in the Comparisons of Three Combinations Therapies in Lowering Blood Pressure in Black Africans trial (CREOLE) of Black African patients. BPV was calculated using the SD of 30-minute interval values for 24-hour ambulatory BPs and for confirmation using the coefficient of variation. Linear mixed model regression was used to calculate mean differences in BPV between treatment arms. Within-clinic BPV was also calculated from the mean SD and coefficient of variation of 3 readings at clinic visits., Results: Baseline distributions of age, sex, and blood pressure parameters were similar across treatment groups. Participants were predominately male (62.2%) with mean age 50.4 years. Those taking CCB+thiazide had significantly reduced ambulatory systolic and diastolic BPV compared with those taking ACE-inhibitor+thiazide. The CCB+thiazide and CCB+ACE-inhibitor groups showed similar BPV. Similar patterns of BPV were apparent among groups using within-clinic blood pressures and when assessed by coefficient of variation., Conclusions: Compared with CCB-containing combinations, ACE-inhibitor plus thiazide was associated with higher levels, generally significant, of ambulatory and within-clinic systolic and diastolic BPV. These results supplement the differential ambulatory blood pressure-lowering effects of these therapies in the CREOLE trial.

Aims: Sub-analysis of a retrospective nation-wide observational analysis of heart failure (HF) epidemiology reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018 aimed at angiotensin-converting enzyme inhibitors (ACEI), angiotensin-II-receptor antagonists (ARB) and angiotensin receptor blocker/neprilysin inhibitor (ARNI) use., Methods and Results: ACEi and ARBs were generally used in 87.6% of all HF patients in 2012 (n=154 627); 84.5% in 2013 (n=170 861); 83.5% in 2014 (n=186 963); 81.6% in 2015 (n=198 844); 80.1% in 2016 (n=205 793); 78.0% in 2017 (n=212 152) and in 76.7% in 2018 (n=219 235). In a sub-analysis of patients with a medical procedure and/or examination using an I50.x ICD code accounted for in the given year, ACEi and ARBs were generally used in 99.3% in 2012 (n=63 250); 96% in 2013 (n=62 241); 95.2% in 2014 (n=64 414); 93.3% in 2015 (n=65 217); 91.8% in 2016 (n=65 236); 90.1% in 2017 (n=65 761) and in 88.6% in 2018 (n=66 332). In 2018, the majority of patients with HF were prescribed ramipril (n=49 909; 17.5%) and perindopril (n=44 332; 15.5%). The mostly prescribed ARBs in 2018 were telmisartan (n=18 669; 6.5%); losartan (n=13 935; 4.9%) and valsartan (n=4 849; 1.7%). In 24.5% of cases, ACEIs and ARBs were prescribed in a fixed combination with another drug. ARNI became gradually more prescribed from 2018 (n=9 659 in November 2020)., Conclusion: In an analysis of ACEIs, ARBs and ARNIs utilization in all patients treated for heart failure in the given year in the whole country, we found a comparable rate of drug prescription in comparison with specific heart failure registries. This indicates a good translation of current standard of care into common clinical practice. Ramipril and perindopril remained the mostly prescribed ACEIs and telmisartan became the mostly prescribed ARB. Since 2018, ARNIs began to be widely prescribed., Competing Interests: The authors report no conflicts of interest in this work.

The use of international nonproprietary names (INNs) has been mandatory for prescriptions of state-reimbursed drugs in Latvia since 1 April 2020. In a retrospective analysis, we aimed to examine the impact of the new regulation on changes in the prescribing and dispensing practice of antihypertensive agents with an example of bisoprolol or/and perindopril and their combinations. All state-reimbursed bisoprolol and/or perindopril prescriptions for arterial hypertension were evaluated in two time periods: 1 April 2018 to 31 March 2019 and 1 April 2020 to 31 March 2021. The proportion of INN prescriptions increased from 2.1% to 92.3% (p < 0.001, φ = 0.903). The rate of fixed-dose combinations (FDCs) increased from 60.8% to 66.5% (p < 0.001, φ = 0.059). The rate of medication errors was 0.6%. The most common (80.6%) error was that the dispensed medicine dose was larger or smaller than indicated on the prescription. In addition, prescribing an FDC medicine increased the chance of making an error by 2.5 times on average. Regulatory changes dramatically affected the medicine-prescribing habits of INNs. The increase in FDC prescription rates may align with the recommendations of the 2018 ESC/ESH guidelines. The proportion of total errors is estimated as low, but control mechanisms are needed to prevent them.

Mortality rates associated with myocardial dysfunction due to sepsis and septic shock are generally high across the world. The present study focused on the antioxidant and anti-inflammatory effects of perindopril (PER) for the purpose of preventing the adverse effects of sepsis on the myocardium and developing new alternatives in treatment. The control group received only saline solution via the oral route for 4 days. The second group underwent cecal ligation puncture (CLP), and the third underwent CLP and received PER (2 mg/kg). Rats in the third group received 2 mg/kg PER per oral (p.o.) from 4 days before induction of sepsis. Thiobarbituric acid reactive species (TBARS), total thiol (-SH), interleukin-1 beta (IL-1β), IL-6, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κB/p65) levels increased in the CLP groups. In contrast, PER (2 mg/kg) decreased the levels of biochemical parameters other than total-SH and decreased 8-OHdG, NF-κB/p65 immunopositivity in rat heart tissues. The data from this study show that impairment of the oxidant/antioxidant balance and inflammatory cytokine levels in favor of inflammation in heart tissue under septic conditions results in severe tissue damage. PER administration before sepsis was shown to exhibit antioxidant and anti-inflammatory properties by reducing these effects. This in turn increased the importance of PER as new evidence of its protective effects in heart tissue., (© 2022 Wiley Periodicals LLC.)

Background: We sought to address the paucity of data to support the evidence-based management of hypertension to achieve optimal blood pressure (BP) control on a sex-specific basis in Africa., Methods: We undertook a post hoc analysis of the multicenter, randomized CREOLE (Comparison of Three Combination Therapies in Lowering Blood Pressure in Black Africans) Trial to test the hypothesis that there would be clinically important differences in office BP control between African men and women. We compared the BP levels of 397 and 238 hypertensive women (63%, 50.9 ± 10.5 years) and men (51.2 ± 11.3 years) from 10 sites across sub-Saharan Africa who completed baseline and 6-month profiling according to their randomly allocated antihypertensive treatment., Results: Overall, 442/635 (69.6%) participants achieved an office BP target of <140/90 mm Hg at 6 months; comprising more women (286/72.0%) than men (156/65.5%) (adjusted odds ratio [OR] 1.59, 95% confidence interval [CI] 1.07-2.39; P = 0.023). Women randomized to amlodipine-hydrochlorothiazide (HCTZ) (adjusted OR 3.03, 95% CI 1.71-5.35; P < 0.001) or amlodipine-perindopril (adjusted OR 2.62, 95% CI 1.49-4.58; P = 0.01) were more likely to achieve this target compared with perindopril-HCTZ. Among men, there were no equivalent treatment differences-amlodipine-HCTZ (OR 1.54, 95% CI 0.76-3.12; P = 0.23) or amlodipine-perindopril (OR 1.32, 95% CI 0.65-2.67; P = 0.44) vs. perindopril-HCTZ. Among the 613 participants (97%) with 24-hour ambulatory BP monitoring, women had significantly lower systolic (124.1 ± 18.1 vs. 127.3 ± 16.9; P = 0.028) and diastolic (72.7 ± 10.4 vs. 75.1 ± 10.5; P = 0.007) BP levels at 6 months compared with men., Conclusions: These data suggest clinically important differences in the therapeutic response to antihypertensive combination therapy among African women compared with African men., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity., Methods: Over a six-week period, 81 wild-type C57Bl/6 female mice (8-12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study., Results: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration., Conclusion: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.

Background: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia., Methods: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy., Results: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]., Conclusions: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: This study evaluated the effectiveness of treatment with an indapamide/amlodipine single-pill combination (SPC) in outpatients with uncontrolled isolated systolic hypertension (ISH) aged over 55 years in real-life clinical practice., Methods: This was a post-hoc analysis of the subgroup of patients with ISH from ARBALET, a 3-month, multicenter, observational, open-label study conducted in Russia among patients with grade I or II hypertension who were either uncontrolled on previous antihypertensive treatment or treatment-naïve. The effectiveness of indapamide/amlodipine SPC was assessed by the change in office systolic blood pressure (SBP) and the rate of target SBP (< 140 mmHg) achievement at 2 weeks, 1 month and 3 months, in four age groups: 55-59 years, 60-69 years, 70-79 years, and 80 years or older., Results: The ARBALET study recruited 2217 patients, of whom 626 had ISH and were included in this post-hoc analysis (mean age 66.1 ± 7.8 years; 165 men [26.4%] and 461 women [73.6%]). Target SBP < 140 mmHg was achieved in 43%, 75% and 93% of patients at 2 weeks, 1 and 3 months, respectively. SBP decreased from baseline by 18.8 ± 10.5 mmHg, 27.2 ± 10.6 mmHg and 31.8 ± 9.9 mmHg at 2 weeks, 1 month and 3 months, respectively. In the groups of patients aged 55-59, 60-69, 70-79, and ≥ 80 years, SBP reductions at 3 months compared with baseline were - 30.3 ± 9.4, - 32.4 ± 9.7, - 32.5 ± 10.7, and - 28.9 ± 9.6 mmHg, respectively., Conclusion: This post-hoc analysis of the observational ARBALET study showed that indapamide/amlodipine SPC was associated with significant reductions in BP and high rates of target BP achievement in a broad age range of patients with ISH treated in routine clinical practice., Study Registration Number: ISRCTN40812831., (© 2022. The Author(s).)

Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline (ANT)-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent ANT-induced cardiac damage and provide long-lasting cardioprotection. The present study aimed to examine the cardioprotective effects of perindopril on chronic ANT cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane (DEX) with focus on post-treatment follow-up (FU). Chronic cardiotoxicity was induced by daunorubicin (DAU; 3 mg/kg/week for 10 weeks). Perindopril (0.05 mg/kg/day) was administered before and throughout chronic DAU treatment. After the completion of treatment, significant benefits were observed in perindopril co-treated animals, particularly full prevention of DAU-induced mortality and prevention or significant reductions in cardiac dysfunction, plasma cardiac troponin T (cTnT) levels, morphological damage, and most of the myocardial molecular alterations. However, these benefits significantly waned during 3 weeks of drug-free FU, which was not salvageable by administering a higher perindopril dose. In the longer (10-week) FU period, further worsening of left ventricular function and morphological damage occurred together with heart failure (HF)-related mortality. Continued perindopril treatment in the FU period did not reverse this trend but prevented HF-related mortality and reduced the severity of the progression of cardiac damage. These findings contrasted with the robust long-lasting protection observed previously for DEX in the same model. Hence, in the present study, perindopril provided only temporary control of ANT cardiotoxicity development, which may be associated with the lack of effects on ANT-induced and topoisomerase II β (TOP2B)-dependent DNA damage responses in the heart., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Aims: The use of methotrexate (MTX), a classical immunosuppressant and anti-cancer agent, is associated with multiple organ toxicities, including the intestinal injury. Components of the renin-angiotensin system are expressed in the intestinal epithelium and mucosal immune cells where they provoke pro-inflammatory and pro-oxidant action. The present study was conducted to investigate the potential ability of perindopril (PER), an angiotensin-converting enzyme inhibitor (ACEI), to attenuate MTX-induced intestinal injury with emphasis on the role of the pro-inflammatory TLR4/NF-κB and c-Fos/c-Jun pathways alongside PPAR-γ and SIRT1 cytoprotective signals., Materials and Methods: The intestinal injury was induced by a single-dose injection of 20 mg/kg of MTX i.p at the end of the 5th day. PER was administrated once daily in a dose of 1 mg/kg, i.p, for five days before MTX and five days later., Results: Herein, perindopril attenuated the intestinal injury as seen by lowering the histopathological aberrations and preserving the goblet cells in villi/crypts. These beneficial actions were associated with downregulating the expression of the pro-inflammatory angiotensin II, TNF-α, IL-1β, and IL-6 cytokines, alongside upregulating the anti-inflammatory angiotensin (1-7) and IL-10. At the molecular level, perindopril downregulated the TLR4/NF-κB and c-Fos/c-Jun pathways in inflamed intestine of rats. Moreover, it attenuated the pro-oxidant events by lowering intestinal MDA and boosting GSH, SOD, and GST antioxidants together with PPAR-γ and SIRT1 cytoprotective signals. The aforementioned findings were also highlighted using molecular docking and network pharmacology analysis., Conclusions: Perindopril demonstrated notable mitigation of MTX-induced intestinal injury through suppression of TLR4/NF-κB and c-Fos/c-Jun pathways alongside the augmentation of PPAR-γ/SIRT1 cytoprotective signals., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rationale: Neurofibromatosis type 1 (NF-1) is an autosomal-dominant neurocutaneous disorder that affects the skin, bones, and nervous system. The most common manifestation of kidney involvement is renal artery stenosis; glomerulonephritis is extremely rare. In this case report, we present a patient with NF-1 and immunoglobulin A nephropathy (IgAN)., Patient Concerns: A 51-year-old Korean man previously diagnosed with NF-1 presented with persistent proteinuria and hematuria identified during a routine medical check-up. He had no history of hypertension or diabetes, and denied a history of alcohol use or smoking., Diagnosis: The contrast-enhanced computed tomography scan revealed normal-sized kidneys and no evidence of renal artery stenosis. On the day of the kidney biopsy, laboratory tests showed a serum creatinine level of 1.1 mg/dL, urine protein/creatinine ratio of 1.3 g/g, and urine red blood cell count of >10 to 15/HPF. The kidney biopsy sample revealed IgAN grade III, according to Lee glomerular grading system., Intervention: The patient was advised to take 4 mg of perindopril., Outcome: Three months after the treatment, the urine protein/creatinine ratio decreased to 0.6 g/g, with no change in the serum creatinine level (1.03 mg/dL)., Lessons: A genetic link between NF-1 and IgAN or other glomerular diseases is not established. However, activation of the mTOR pathway may explain this association., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: The PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study) conducted in the early 1990s showed that blood pressure (BP) lowering therapy reduced the risks of recurrent stroke by about 50% after spontaneous intracerebral hemorrhage (ICH). However, the ICH subgroup was a minority, and trial cohorts are invariably selective. Therefore, it is unclear whether the impact of BP control on risk of recurrent stroke in ICH observed in PROGRESS would be as great in real-world practice., Methods: We compared BP control (mean BP during study follow-up) and risks of recurrent stroke after first-ever primary ICH in 2 colocated population-based studies before and after the PROGRESS trial (1995–2001) in Oxfordshire: Oxfordshire Community Stroke Project (OCSP; 1981–1986) and OXVASC (Oxford Vascular Study; 2002–2018)., Results: Two hundred seventy-seven patients (753 patient-years of follow-up) with first-ever primary ICH were ascertained in OXVASC and OCSP. Baseline systolic BP was comparable between the 2 studies (mean/SD=183.8/36.5 in OXVASC versus 178.1/38.2 in OCSP, P=0.30) but among one hundred thirty-seven 90-day survivors, mean BP during follow-up was substantially lower in OXVASC versus OCSP (135.2/16.4 versus 157.3/17.8, P<0.0001). Risks of recurrent stroke (per 100 patient-years) decreased from 10.3 (95% CI, 4.7–19.5) in OCSP to 3.1 (1.8–4.8) in OXVASC (P=0.006), predominantly driven by a reduction at younger ages (5-year risk at age <75 years: 35.4% versus 6.9%, P=0.001; hazard ratio, 0.14 [0.04–0.54])., Conclusions: Risks of recurrent stroke after primary ICH have fallen significantly in Oxfordshire over the past 4 decades, coinciding with substantial improvements in BP control during follow-up.

Introduction: To assess real-life effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in patients with hypertension (HT) and type 2 diabetes mellitus (T2DM), obesity and/or metabolic syndrome (MetS)., Methods: This post hoc analysis pooled raw data from four large observational studies (FORTISSIMO, FORSAGE, ACES, PICASSO). Patients, most with uncontrolled blood pressure (BP) on previous treatments were switched to Per/Ind (10 mg/2.5 mg) SPC at study entry. Office systolic and diastolic blood pressures (SBP and DBP) were measured at baseline, 1 month and 3 months., Results: In the overall pooled population (N = 16,763), mean age was 61 ± 12 years, HT duration 11 ± 8 years, and baseline SBP/DBP 162/94 mmHg. T2DM, obesity and MetS were present in 21%, 49% and 27% of patients, respectively. Subgroups had similar mean age and HT duration to the overall population; patients with T2DM were slightly older (64 ± 10 years) with a longer HT duration (13 ± 8 years). Mean BP was approximately 160/95 mmHg in each subgroup. At 1 month, mean SBP decreased by approximately 20 mmHg in the overall population, and by a further 10 mmHg at 3 months. Similar results were observed in the three subgroups, with mean changes from baseline at 3 months of - 28 ± 15/- 13 ± 10 in T2DM; - 30 ± 15/- 14 ± 10 in obesity; and - 31 ± 15/- 15 ± 9 mmHg in MetS. BP decreases were greatest in patients with grade II or grade III HT. BP control rates (< 140/90 mmHg or 140/85 mmHg for T2DM) at 3 months were 59% in T2DM, 67% in obese, and 66% in MetS. No specific safety concerns were raised, particularly concerning ionic (Na, K) or metabolic profiles., Conclusions: Switching to Per/Ind SPC led to rapid and effective BP decreases in patients with T2DM, obesity, or MetS. BP control was achieved in 6-7 out of 10 previously treated but uncontrolled patients. Treatment was well tolerated. The results confirm the beneficial effects of a Per/Ind SPC for difficult-to-control patient populations.

Acute kidney injury (AKI) resulting from septic shock caused by sepsis is an important health problem encountered at rates of 55-73%. Increasing oxidative stress and inflammation following sepsis is a widely observed condition with rising mortality rates. The purpose of this study was to determine whether perindopril (PER) can prevent sepsis-associated AKI with its antioxidant, anti-inflammatory, and anti-apoptotic effects. The control group received an oral saline solution only for 4 days. Cecal ligation and puncture (CLP)-induced sepsis only was applied to the CLP group, while the CLP + PER (2 mg/kg) received CLP-induced sepsis together with 2 mg/kg PER via the oral route for 4 days before induction of sepsis. Finally, all rats were euthanized by anesthesia and sacrificed. TBARS, total SH levels and NF-κβ, TNF-α, and Caspase-3 expression were then calculated for statistical analysis. TBARS, total SH, NF-kβ/p65, TNF-a, and Caspase-3 levels increased in the CLP group. In contrast, oral administration of PER (2 mg/kg) to septic rats reduced TBARS levels and NF-kβ/p65, TNF-α, and Caspase-3 immunopositivity at biochemical analysis. PER treatment appears to be a promising method for preventing sepsis-induced acute kidney injury through its antioxidant anti-inflammation and anti-apoptotic activities.

Introduction: Our objective was to determine the effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in a broad range of patient profiles, including subgroups with varying hypertension severity, age and cardiovascular risk profiles., Methods: Patient data from four large prospective observational studies (FORTISSIMO, FORSAGE, PICASSO, ACES) were pooled. In each study, patients already treated for hypertension were switched to Per/Ind 10/2.5 mg SPC and systolic and diastolic blood pressure (SBP/DBP) measured at the 1-month (M1) and 3-month (M3) visits. Study endpoints included change in SBP and DBP from baseline to M1 and M3 and the percentage of patients achieving BP control (SBP/DBP < 140/90 mmHg for patients without diabetes or < 140/85 mmHg for patients with diabetes)., Results: A total of 16,763 patients were enrolled and received Per/Ind (94% received the full dose of 10/2.5). Mean patient age was 61.4 years (36% were ≥ 65 years old), 57% were women, and 16% had isolated systolic hypertension (ISH). Mean baseline office SBP/DBP was 162/94 mmHg, and mean duration of hypertension was 11 years. Cardiovascular risk factors and comorbid conditions were common in this population. Significant mean reductions in SBP (- 23 mmHg) and DBP (- 11 mmHg) were observed at M1 compared with baseline (P < 0.001), which were maintained at M3 (- 30 mmHg and - 14 mmHg, respectively). At M3, BP control was achieved by 70% of patients (78% for ISH). In patients with SBP ≥ 180 mmHg at baseline (grade III hypertension), the mean SBP/DBP decrease was - 51/- 20 mmHg and 53% achieved BP control. Per/Ind was well tolerated with an overall rate of adverse events of 1.3%, most frequently cough and dizziness at rates of 0.3% and 0.2%, respectively., Conclusion: In this hypertensive population including difficult-to-control patient subgroups, switching to Per/Ind 10/2.5 mg SPC led to rapid and important reductions in BP. BP control was achieved in 70% of patients overall in an everyday practice context.

Background: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes., Methods: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β 2 -microglobulin (B2M), eGFR Cr-Cys , and the average of three estimates (eGFR Cr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors., Results: Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFR Cys , eGFR Cr-Cys , and eGFR Cr-Cys-B2M were associated with a >2-fold higher risk of all clinical outcomes., Conclusions: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFR Cys , eGFR Cr-Cys , and eGFR Cr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted., (© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Introduction: The relationship between blood pressure (BP) and cerebral blood flow (CBF) is not fully understood. This study evaluated the impact of a perindopril arginine/indapamide (Pa/I) single-pill combination (SPC) on CBF in middle-aged patients., Methods: A total of 22 treatment-naïve patients with essential hypertension and at least one hypertension-mediated organ damage and 41 healthy controls were enrolled. At baseline, all participants underwent brain magnetic resonance imaging (MRI); patients with hypertension underwent an additional MRI at end of follow-up. Arterial spin labeling (ASL) was used to calculate CBF in the frontal lobe cortical plate. Patients with hypertension received once-daily Pa/I 5 mg/1.25 mg SPC, which could be increased to Pa/I 10 mg/2.5 mg at 2 weeks if necessary. Patients with hypertension underwent 24-h ambulatory BP monitoring (ABPM) at baseline and end of follow-up., Results: Mean baseline BP values were 146.2/93.1 and 119.1/76.1 mmHg in the hypertension and control groups, respectively. Patients with hypertension had significantly (p < 0.001) lower CBF in the cortical plate of both left (36.2 ± 8.3 vs. 45.3 ± 3.5 ml/100 g/min) and right (37.9 ± 7.9 vs. 45.8 ± 3.2 ml/100 g/min) frontal lobes compared to normotensive controls. At the end of follow-up, there was a statistically significant (p < 0.001) increase in CBF in the cortical plate of both left (from 36.2 ± 8.3 to 47.5 ± 9.8 ml/100 g/min) and right frontal lobes (from 37.9 ± 7.9 to 47.4 ± 10.1 ml/100 g/min) compared to baseline. No significant difference was found between end of follow-up CBF levels in frontal lobes of patients with hypertension and those of healthy controls at baseline. Office BP decreased by 24.2/15.5 mmHg and 24-h ABPM from 145.5/95.3 to 120.8/79.3 mmHg., Conclusion: In middle-aged, treatment-naïve patients with hypertension, Pa/I SPC was associated with increased CBF in the cortical plate of the frontal lobes, which achieved levels of normotensive controls. The increase in CBF had no clear association with observed BP changes., Registration Number: ISRCTN67799751.

Introduction: Abnormal adipokine levels affect blood pressure (BP) regulation. Hypo-adiponectinaemia and hyperleptinaemia were reported in hypertension, little is known about how antihypertensive therapy affects these alterations. This study aimed to evaluate the effects of perindopril versus enalapril on plasma adiponectin, tumour necrosis alpha (TNF-α) and leptin levels in hypertensive individuals. Methods: In the present study, we analysed the samples obtained from 93 treatment-naıve, adult hypertensive patients, randomised to treatement with enalapril (10 mg/d, n  = 31), perindopril (5 mg/d, n  = 31), or maintained on life style modification ( n  = 31). Plasma levels of leptin, adiponectin, TNF-α and lipid profile were determined at baseline, and after 3 months. Results: Compared to subjects maintained on lifestyle modification ( n  = 31), enalapril or perindopril treatment was associated with a significant decrease in BP. Administration of perindopril or enalapril resulted in an increase in plasma adiponectin and a reduction in plasma leptin. No significant changes in lipid profile were observed after treatment. Conclusions: Our results indicate that perindopril is superior to enalapril when it comes to its effect on the human adipose-tissue-derived hormones. This suggests that angiotensin-converting enzyme inhibitors improves the adipokine profile, possibly allowing beneficial effects to hypertensive individuals.

Hepatic ischemia reperfusion (IR) is an inevitable clinical problem for surgical procedures such as liver transplantation and liver resection. This study was designed to evaluate the protective effect of perindopril (PER) against hepatic IR injury. Thirty-two rats were used and randomly allocated into four groups. Sham control group was subjected to sham operation and received saline only, IR group was subjected to IR and received vehicle, PER group was pretreated with PER (one milligram per kilogram per day i.p. for 10 consecutive days), and IR+PER group was pretreated with PER then subjected to IR. Liver function biomarkers (aspartate aminotransferase and alanine aminotransferase), oxidative stress (glutathione, malondialdehyde, myeloperoxidase, and superoxide dismutase) and inflammation markers (tumor necrosis factor-alpha, interferon-gamma, and inteleukin-10 [IL-10]), mRNA expression of NF-κB-p65 and TLR-4, as well as protein expression of JAK1, STAT-3, PI3K, mTOR, Akt, and Nrf-2 were investigated concomitantly with histopathological examination. The results indicated that, hepatic IR induced a significant alteration in liver function biomarkers and structure, oxidative stress, and inflammation. At the molecular level, up-regulation of NF-κB-p65, TLR-4, JAK1, and STAT-3 concomitantly with down-regulation of Nrf-2, IL-10, PI3K, Akt, and mTOR were observed. These disturbances were alleviated by pretreatment of IR rats with PER in concomitant with hepatic structural improvement. Conclusively, the protective effect of PER presumably may be relevant to its ability to reduce oxidative stress, ameliorate the inflammatory processes, and modify the related signaling pathways. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1935-1949, 2020. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)

Objective: To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A 1c (HbA 1c ) at baseline., Research Design and Methods: We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models., Results: During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA 1c level ( P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk ( P = 0.15) or HbA 1c levels ( P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA 1c at baseline ( P = 0.09 and 0.18, respectively)., Conclusions: The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA 1c ., (© 2020 by the American Diabetes Association.)

This experiment aimed to study the effect of trimetazidine combined with perindopril on NT-proBNP levels in rats with dilated cardiomyopathy (DCM). 40 SD rats were selected and 10 rats were randomly selected to continue to be fed as the blank group. The other 30 rats were injected with adriamycin to establish the DCM rat model. Then they were divided into 3 groups, namely control group (without any drug intervention), trimetazidine group (with trimetazidine single-agent intervention) and combination drug group (with trimetazidine combined with perindopril intervention), with 10 DCM rats in each group. After 4 weeks of intervention, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic diameter (LVESD) of rats were measured by echocardiography. The changes of plasma brain natriuretic peptide (BNP) level and n-terminal pro-brain natriuretic peptide (NT-proBNP) were detected by ELISA. RT-PCR was used to detect the regulation of angiotensin II type 1 receptor (AT1Rs) and lamin A mRNA expression in rat myocardium. After the intervention, the LVEF%, LVEDD and LVESD measured values of the rats in the combination drug group were significantly better than those in the trimetazidine group and the control group (P&lt; 0.05). The BNP, NT-proBNP and AT1Rs levels of the rats in the combination drug group were significantly lower than those in the trimetazidine group and the control group. The difference was statistically significant (p&lt; 0.05). The lamin A expression of the rats in the combination drug group was significantly higher than that in the trimetazidine group and the control group. The difference was statistically significant (P&lt; 0.05). Compared with trimetazidine single-agent, trimetazidine combined with perindopril can significantly improve the cardiac function of rats with dilated cardiomyopathy, reduce the serum NT-proBNP level and improve the expression of AT1Rs and lamin A in rats.

Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I 2  = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two-by-two factorial design. In the blood pressure-lowering arm, patients were treated using a fixed combination of the ACE-inhibitor, perindopril, and the thiazide-like diuretic, indapamide, or placebo, whereas in the glucose-lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose-lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end-points were major macro- and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow-up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment., (© 2020 John Wiley & Sons Ltd.)

Over the last 30 years, the number of cardiovascular causes of death has decreased, but Cardi-ovascular Disease has been the leading cause of mortality and morbidity in the Czech Republic. In spite of a clear decline, this still persisting primacy is due to the failure to achieve the target recommended values and the late initiation of pharmacotherapy. We know that lifetime LDL cholesterol exposure reduced by 1 mmol/l is associated with a 54% reduction in the incidence of coronary events. A lifetime lower systolic BP of 10 mmHg is associated with a 45% reduction in the incidence of coronary events. Lifetime exposure to a combination of LDL cholesterol lower by 1 mmol/l and systolic BP lower by 10 mm Hg was associated with a 78% reduction in the lifetime risk of coronary events and a 68% reduction in the lifetime risk of a cardiovascular death. The benefits of this intervention increase over time - long-term exposure to even a small difference in LDL cholesterol and systolic pressure can significantly reduce the lifetime risk of cardiovascular disease, if it persists over the time. In this respect, the recently presented new common ESC/ EAS recommendations from 2019, that is to focus treatment on dyslipidemia on a lifelong approach of reducing CV risk and therapeutic lifelong intervention with aim to achieve lower LDL cholesterol levels at all risk levels. Perindorpil antihypertezive and atorvasatin hypolipidemic drugs, ideally in a fixed combination, are able to reduce the patient&#39;s CV risk early. The ideal motivation for adherence of patients is the introduced concept of the vascular age, respectively the aging.

Context: Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes., Objective: To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes., Design and Setting: The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit., Results: Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication., Conclusions: In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Most antihypertensive drugs used in monotherapy or in combination therapy reduce the left ventricular mass index (LVMI). However, little is known about the effects on LVMI of a triple fixed-dose combination (TFC) therapy, containing in a single pill an angiotensin-converting enzyme inhibitor (ACEI), a diuretic and a calcium channel blocker (CCB)., Methods: In this prospective open-label study, 92 patients with essential hypertension were randomized to treatment with a TFC of perindopril/indapamide/amlodipine at different doses or a triple free combination therapy (FCT) including ACEI/diuretic/CCB. Office blood pressure (BP) measurement, 24 h-ambulatory BP monitoring and echocardiography were performed at baseline and during a 14-month follow-up. The BP variability (BPV) over 24 h was calculated as ± standard deviation of the daytime systolic BP. Differences between office and monitored BP and LVMI were evaluated by ANOVA for repeated measures., Results: A significant BP-lowering effect was observed for both treatments. At follow-up, BPV was reduced in both the treatment groups vs. the baseline (14.0±1.5 vs. 17.0±1.8 and 16.2±2.1 vs. 17.6±2.3, respectively), but it was lower in the TFC vs. the FCT group (14.0±1.5 vs. 16.1±2.2, P < 0.05). LVMI was lower in both the treatment groups, but the change was greater for TFC vs. FCT (-8.3±4.9% vs. -2.0 ±2.1%, P < 0.0001). Left ventricular hypertrophy (LVH) regression was greater in the TFC vs. the FCT group (43.5% vs. 30.4%, P < 0.05)., Conclusions: Independently of BP values achieved, the antihypertensive TFC therapy was more effective than FCT in LVMI reduction and LVH regression, possibly related to drugs' intrinsic properties and to BPV modulation., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: Brachial blood pressure (BP) is a predictor of cardiovascular events. Evidence suggests that central BP (CBP) provides additional information for cardiovascular risk assessment. Methods to assess 24-h CBP are now available. Our objective was to assess the feasibility of 24-h CBP monitoring in clinical trials and its ability for drug evaluation., Methods: Data are issued from an international phase 3 randomized clinical trial comparing the efficacy of perindopril/indapamide/amlodipine vs. perindopril/indapamide (Per/Ind), in uncontrolled hypertensive patients treated with Per/Ind. 24-h ambulatory BP monitoring (ABPM) was performed at baseline and after 1-month treatment using the Mobil-O-Graph device which provide brachial BP and CBP and arterial parameters., Results: From the 345 patients included in the ABPM substudy, 276 had two valid ABPM (M0 and M1) for brachial BP assessment (80%). After applying device/software built-in and expert quality control criteria on these recordings, 210 (76%) had valid data at M0 and M1 for the assessment of CBP. After 1 month, superior ambulatory central SBP reductions were observed in the perindopril/indapamide/amlodipine (n = 101) vs. Per/Ind group (n = 109) for 24-h/daytime/night-time periods (-4.5 mmHg, P = 0.002/-5.0, P < 0001/-4.1 mmHg, P = 0.016, respectively). Similar trends were observed for pulse wave velocity and other central parameters., Conclusion: Recording 24-h central ABPM and its derived arterial parameters needs a strict expert quality control and must consider a loss of up to 39% of the population included in the ABPM substudy. This method can be used to assess drug effect.