Pharmacological inhibition of the ACE/Ang-2/AT1 axis alleviates mechanical ventilation-induced pulmonary fibrosis.

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.

A Retrospective Observational Real-Word Analysis of the Adherence, Healthcare Resource Consumption and Costs in Patients Treated with Bisoprolol/Perindopril as Single-Pill or Free Combination.

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.

Patients with cardiovascular conditions often need to take many pills. This may result in patients not taking their pills as prescribed (i.e., low adherence) and compromise the potential benefits derived from prescription of cardiovascular protective drugs. Simplifying treatment by combining drugs into a single pill can improve adherence and, consequently, patient outcomes. In this analysis using data from real clinical practice, we explored whether using a single pill of perindopril and bisoprolol is associated with higher levels of adherence, lower proportion of patients with hospitalizations and lower economic costs than using the same drugs prescribed as free-equivalent combination in a large sample of the Italian population of approximately 7 million people. We identified two groups of patients taking single pill or free-equivalent combination of perindopril and bisoprolol (4688 patients in each cohort). Over 1-year follow-up, patients taking single pill were more likely to be adherent and were less likely to stop taking their treatment. They also had fewer cardiovascular hospitalizations with shorter hospital admission and had lower healthcare direct costs. In conclusion, simplifying treatment by combining perindopril and bisoprolol in a single pill instead of two may have a positive effect on adherence, outcomes and healthcare costs already after 1 year.

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker on oxidative stress and metabolism of elements in kidney of STZ-induced diabetic rats.

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.

A real-world analysis of outcomes and healthcare costs of patients on perindopril/indapamide/amlodipine single-pill vs. multiple-pill combination in Italy.

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.

[Efficacy and Organoprotection of Triple Combinations in the Treatment of Arterial Hypertension].

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.

Angioedema postoperatorio de inicio tardío, desencadenado por un inhibidor de la enzima convertidora de angiotensina: previsión de vía aérea de emergencia / Late-onset postoperative angioedema triggered by angiotensin-converting enzyme inhibitor: an emergent airway forethought

El angioedema es una situación potencialmente mortal, debido al riesgo de compromiso de la vía aérea que da lugar a un deterioro de la función respiratoria, hipoxia y, por último, paro cardiopulmonar. Puede ser provocado o desencadenado por agentes farmacéuticos, factores emocionales o fisiológicos, traumatismo de la vía aérea superior, o estrés quirúrgico.Un varón de 46 años de edad, a quien se había prescrito previamente perindopril, desarrolló angioedema de lengua 4h después de recibir el alta de la UCPA (unidad de cuidados postanestésicos). Se convocó a un equipo multidisciplinar, que destacó una estrategia de manejo de la vía aérea en caso de empeoramiento. Dicha estrategia consistió en intubación con fibroscopio por parte del anestesiólogo, o bien traqueostomía quirúrgica practicada por el equipo de cirugía, realizándose ambas técnicas con el paciente despierto y ventilación espontánea.El objetivo de este informe de caso es alertar de que el angioedema es una situación potencialmente mortal. Para un manejo óptimo, es importante preparar de antemano una estrategia detallada de manejo de la vía aérea, a implementar por parte de un equipo multidisciplinar. (AU)

Angioedema is a potentially life-threatening condition due to the risk of airway compromise leading to deterioration of respiratory function, hypoxia, and ultimately, cardiopulmonary arrest. It can be either unprovoked or triggered by pharmaceutical agents, emotional or physiologic factors, upper airway trauma, or surgical stress.A 46-year-old man previously prescribed perindopril developed angioedema of the tongue 4h after being discharged from the Post Anesthesia Care Unit (PACU). A multidisciplinary team was called and they outlined an airway management strategy to use in the event of worsening. The strategy consisted of either fiberoptic intubation by an anesthesiologist or surgical tracheostomy performed by the surgical team, both performed with the patient awake and in spontaneous ventilation.The aim of this case report is to raise awareness that angioedema is a potentially life-threatening condition. For optimal management, it is important to prepare in advance a detailed airway management strategy to be implemented by a multidisciplinary team. (AU)

Perindopril improves cardiac fibrosis through targeting the AngII/AT1R pathway.

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.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

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.

Comparing Cardiovascular Outcomes and Costs of Perindopril-, Enalapril- or Losartan-Based Antihypertensive Regimens in South Africa: Real-World Medical Claims Database Analysis.

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.

Comparison of antihypertensive drugs amlodipine and perindopril on blood pressure variability after long-term treatment of hypertension induced by apatinib and bevacizumab.

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.

The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy.

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.

Adherence to Triple Single-Pill Combination of Perindopril/Indapamide/Amlodipine: Findings from Real-World Analysis in Italy.

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.

Medication adherence is defined by the World Health Organization as the "extent to which a person's behavior (in taking medication) corresponds with agreed recommendations from a healthcare provider". Low levels of medication adherence in hypertension have been linked with increased disease burden and with higher costs for patients. Patients with hypertension whose blood pressure is poorly controlled often need to receive more than one pill. Nevertheless, having to take many pills may result in poor adherence, i.e., patients not taking their treatment as prescribed. Combining multiple drugs into a single pill for the management of hypertension is known to improve adherence; however, limited evidence exists about the benefits of triple single-pill combinations compared with equivalent free combinations in real clinical practice. This analysis evaluated changes in adherence before and after patients switched from a three-drug therapy of perindopril/indapamide single-pill + amlodipine (PER/IND + AML) to perindopril/indapamide/amlodipine (PER/IND/AML) taken as a single pill. In this analysis, real-world data from Italian administrative databases covering around 11% of the Italian population were used. Overall, 158 patients were included. More patients were found to be adherent after switch to PER/IND/AML single pill (75.3% vs 44.3% of PER/IND + AML combination). Partially adherent and poorly adherent patients were fewer with PER/IND/AML single-pill combination (10.1% and 14.6%, respectively) compared to PER/IND + AML combination (38.0% and 17.7%, respectively). These findings indicate that switching to a simplified therapy in which all three drugs are taken in one pill may offer an opportunity for increasing the number of patients that are adherent to their medication.

Benefit of treatment based on indapamide mostly combined with perindopril on mortality and cardiovascular outcomes: a pooled analysis of four trials.

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.

Perindopril prevents development of obesity and hypertension in middle aged diet-induced obese rat models of metabolic syndrome.

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.

Clinical Utility of Short-Term Blood Pressure Measures to Inform Long-Term Blood Pressure Management.

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.

Effect of 3, 2-Drug Combinations of Antihypertensive Therapies on Blood Pressure Variability in Black African Patients: Secondary Analyses of the CREOLE Trial.

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.

The Impact of International Nonproprietary Names Integration on Prescribing Reimbursement Medicines for Arterial Hypertension and Analysis of Medication Errors in Latvia.

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.

Comparing Flaxseed and Perindopril in the Prevention of Doxorubicin and Trastuzumab-Induced Cardiotoxicity in C57Bl/6 Mice.

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.

The cardioprotective effects of perindopril in a model of polymicrobial sepsis: The role of radical oxygen species and the inflammation pathway.

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-1ß), 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.

Effectiveness of indapamide/amlodipine single-pill combination in patients with isolated systolic hypertension: post-hoc analysis of the ARBALET study.

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.