Angiotensin-converting Enzyme Inhibitor Group Research Articles

Effect of the angiotensin-receptor-neprilysin inhibitor in heart failure patients with left ventricular ejection fraction higher than 40.

The angiotensin-receptor-neprilysin inhibitor (ARNI) reduced cardiovascular deaths and heart failure hospitalization in patients with heart failure of reduced ejection fraction (HFrEF). Its role in non-HFrEF patients was not clear. This study aims to answer this question.In this retrospective study, we enrolled 928 patients diagnosed with non-HFrEF, 492 of them received angiotensin converting enzyme inhibitor (ACEI) and the rest 436 received angiotensin-receptor-neprilysin inhibitor. Outcomes were compared by Kaplan-Meier survival analysis and various clinical parameters were investigated using Cox multivariable analysis, followed by interaction analysis. Minnesota living with heart failure Questionnaire (MLHFQ) was employed as one of the criteria to assess heart failure outcome.The cardiovascular (CV) death or HF hospitalization at 24 months occurred in 49 patients in ACEI group compared with 31 in ARNI group (Hazard Ratio (HR): 1.231, 95% confidence Interval (CI): 1.080-2.460, P = .031). And ARNI showed better prognosis of HF hospitalization (HR: 1.283, 95%CI: 1.065-1.360, P = .038). Cumulative Kaplan-Meier estimates of endpoints, ARNI could reduce the incidence of CV death or HF hospitalization (P = .042) and HF hospitalization (P = .035). The stratified analysis revealed that participants with age less than 70 years old had a lower incidence of CV death or HF hospitalization (HR: 1.194, 95%CI: 1.011-1992, P = .031) after treated with ARNI. Patients received diuretics could benefit from ARNI (HR: 1.383, 95%CI: 1.082-1.471, P = .019). Similar results were also observed in patients with heart rate lower than 90 bpm (HR: 1.556, 95%CI: 1.045-2.386, P = .003) and patients with atrial fibrillation history (HR: 1.873, 95%CI: 1.420-2.809, P = .011). ARNI could improve the quality of life both from the total, emotional and physical aspects.ARNI is an efficacy treatment strategy to improve the outcome and quality of life in patients with non-HFrEF.

A comparison between statin with ACE inhibitor or ARB therapy in STEMI patients who underwent successful PCI with drug-eluting stents

Background and aimsStudies of the comparative clinical outcomes between statin with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) in ST-segment elevation myocardial infarction (STEMI) patients are limited. We compared 2-year clinical outcomes between statin with ACEI or ARB therapy in STEMI patients after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES). MethodsA total of 11,706 STEMI patients were enrolled and separated into two groups: the ACEI group (statin + ACEI, n = 8705) and the ARB group (statin + ARB, n = 3001). The primary endpoint was major adverse cardiac events (MACE) defined as all-cause death, recurrent MI (re-MI), and any coronary revascularization. Secondary endpoints were the individual components of MACE and target vessel failure (TVF). ResultsAfter propensity score-matched (PSM) analysis, two PSM groups (2729 pairs, n = 5458, C-statistic = 0.675) were generated. The cumulative incidences of MACE, re-MI, and any coronary revascularization were similar between the two groups. However, the cumulative incidences of all-cause death (hazard ratio [HR], 1.548; 95% confidence interval [CI], 1.091–2.197; p = 0.014) and cardiac death (HR, 1.850; 95% CI, 1.218–2.811; p = 0.004) were significantly higher in the ARB group compared with the ACEI group after PSM analysis. ConclusionsThe combination of statin with ACEI may be the preferred treatment strategy to reduce mortality rates in STEMI patients after successful PCI with DES rather than statin with ARB in this study during a 2-year follow-up period.

Distinct effects of antihypertensives on depression in the real-world setting: A retrospective cohort study

BackgroundEvidence is increasing that pathways of antihypertensives may have a role in the pathogenesis of depression. However, how the class of antihypertensives affects depression risk remains unclear. MethodsThe effects of different classes of antihypertensives on depression were explored using an insurance database in Beijing, China. Antihypertensives in our study included calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), and diuretics (DIUs). Those initially treated with only one class of antihypertensives were included. Stratified analysis was conducted for demographic characteristics, comorbidities, and statin prescriptions. ResultsIn total, 181,709 newly detected hypertension patients were included. The median follow-up period was 4.33 years and 19,030 participants were with depression by the end. After adjusting for covariates, the incidence density (95% confidence interval, CI) of depression in the BB, ACEI, DIU, CCB, and ARB groups was 3.16 (2.98–3.33), 3.10 (2.91–3.29), 2.70 (2.45–2.94), 2.67 (2.53–2.81), and 2.30 (2.16–2.43) per 100 person-years, respectively. Compared with ARB group, the hazard ratio (95% CI) of depression for BB, ACEI, DIU, and CCB group was 1.37 (1.32–1.43), 1.35 (1.28–1.42), 1.17 (1.08–1.27), and 1.16 (1.12–1.21), respectively. Stratified analysis suggested the highest depression ID remained within the BB or ACEI group. LimitationsDetailed clinical information was unavailable, which may introduce bias. Patients on monotherapy as initial treatment were included and caution is needed for extrapolation. ConclusionsCompared with ARBs, there may be a class effect of other antihypertensives on the risk of depression.

Reversal of an unfavorable effect of hydrochlorothiazide compared to angiotensin converting enzyme inhibitor on serum uric acid and oxypurine levels by estrogen–progestin therapy in hypertensive postmenopausal women

Background: The aim was to assess the effect of estrogen–progestin therapy (EPT) on serum levels of uric acid (SUA) and its precursors xanthine (X) and hypoxanthine (HX), and on uric acid (UA) renal excretion in hypertensive postmenopausal women treated with an angiotensin-converting enzyme inhibitor (ACEI) or thiazide diuretic (HCTZ) (ClinicalTrials.gov identifier: NCT03921736, registered 19 April 2019).Methods: Postmenopausal women with untreated essential hypertension were recruited to the study. The control group consisted of 40 postmenopausal women with normal blood pressure. Hypertensive women were randomized to two groups: hydrochlorothiazide (n = 50) or perindopril (n = 50) and to a group receiving or not receiving EPT (EPT+/EPT−) due to vasomotor symptoms. The follow-up period was one year. Blood pressure measurements as well as blood tests for SUA and its precursors X and HX were performed at baseline and after 12 months.Results: In hypertensive women, baseline serum X and HX were significantly higher when compared to the group of normotensive women. Treatment with HCTZ led to a statistically significant increase in SUA in the subgroup of EPT- women. In this group concentrations of X and HX increased significantly after 12 months. UA/X significantly decreased after treatment with HCTZ. Lack of EPT resulted in a decrease of renal plasma flow in the HCTZ group. However, in the HCTZ and EPT + group, SUA decreased significantly when compared to baseline. None of these unfavorable effects was observed in the ACEI group regardless of EPT.Conclusions: 1) EPT prevents the development of hyperuricemia during antihypertensive treatment with thiazide diuretics. 2) Arterial hypertension and menopause cause impairment of UA excretion and increase the levels of SUA and its precursors X and HX. 3) EPT reduces the risk of hyperuricemia in postmenopausal women.

Is Chronic Kidney Disease Progression Influenced by the Type of Renin-Angiotensin-System Blocker Used?

Introduction: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce proteinuria and slow renal disease progression more effectively than other therapies in patients with chronic kidney disease (CKD). However, differences regarding efficacy and safety between these therapies remain controversial. Objectives: Aim of this study was to analyze the different treatment effect of ACEI, ARB, and non-ACEI/ARB in CKD progression. The primary outcome was survival to end-stage renal disease (ESRD) and/or death and to ESRD censored by all-cause death, secondary outcomes were proteinuria reduction and hyperkalemia. Methods: We analyzed data from 1,120 patients extracted from the National Renal Healthcare Program cohort, which included 17,238 CKD nondialysis subjects who were successively monitored between ­September 1, 2004 and August 31, 2016. Inclusion criteria were at least a 1-year follow-up, 3 clinical visits, and no previous treatment with ACEI or ARB. From the baseline visit onward, patients continued with 3 different treatment schemes: no ACEI/ARB, started on ACEI or ARB, but while avoiding both treatments in combination. Chi², t test, binary logistic regression, and multivariate regression models (Cox proportional Hazard model and competing risk Fine and Gray model were used for statistical analysis. Results: Mean age and follow-up were 67.9 (± 15) and 3.8 (± 2) years, respectively. Estimated glomerular filtration rate averaged 42.1 ± 23 mL/min/1.73 m² and 300 (27%) patients were diabetics. Progression to ESRD was significantly worse in the no ACEI/ARB group (hazard ratio [HR] 4.23, 95% CI 1.28–13.92) versus ACEI (reference group; p = 0.01). The analysis by competing-risks’ regression showed significantly higher risk of ESRD in the no ACEI/ARB group (HR 3.63, 95% CI 1.34–9.85) versus ACEI (p = 0.01). There were no significant differences between ACEI and ARB groups (HR 1.31, 95% CI 0.37–4.66) regarding the risk of progression to ESRD. Survival was similar in all 3 groups (p = 0.051). Statistically significantly more patients experienced reductions in proteinuria/albuminuria in ACEI and ARB groups (together) versus no ACEI/ARB group (p = 0.016, OR 1.82, 95% CI 1.12–2.94). No difference in hyperkalemia frequency was found between them (p = 0.17). Conclusions: In patients with CKD, treatment with ACEI or ARB had a superior effect than no ACEI or ARB treatment on slowing kidney disease progression and on proteinuria reduction. Efficacy of ACEI and ARB was comparable.

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma.

BACKGROUNDNeoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs.AIMTo elucidate the role of ARBs and ACE-Is in HCC.METHODSWe performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. s, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.RESULTSThirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs.CONCLUSIONIn humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

Angiotensin-converting enzyme inhibitor prescription is associated with decreased progression-free survival (PFS) and overall survival (OS) in patients with lung cancers treated with PD-1/PD-L1 immune checkpoint blockers.

e20512 Background: Angiotensin converting enzyme (ACE) inhibitors are used to treat hyperblood pressure and congestive heart failure. Preclinical evidence show that ACE has a role in both innate and adaptive responses thus suggesting a capacity of ACE to promote antitumor immunity. Interaction between ACE inhibitors and Immune checkpoint blockers (ICB) has not been investigated in cancer patients (pts). Our study evaluated the effect of ACE inhibitors in Non Small cell lung cancer (NSCLC) pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective multicohort retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for NSCLC at Dijon Cancer Center, and at the University of Montreal Hospital. ACE inhibitors groups were defined as pts treated with ACE inhibitors given during the treatment with ICB. PFS and OS were compared between both groups among all pts. Statistical analyses were performed using the Kaplan-Meier method and Cox univariate analysis. Multivariate Cox regression analyses was used to adjust for classical prognostic factors. Tumor RNA sequencing were performed and CIBERSORT was used to estimate immune cell infiltration in ACE inhibitors group and None ACE inhibitors group. Results: Among 283 pts included (177 pts from Dijon, and 106 pts from Montreal), 27 (10%) received ACE inhibitors. ACE inhibitors group did not differ from None ACE inhibitors group for main clinical prognostic characteristics. However, ACE inhibitors group are more frequently treated with statin, beta blocker and metformin. ACE inhibitors group had shorter median PFS compared to None ACE inhibitors group : 2.5 vs. 3.8 months, p = 0.02 (HR = 1.7 IC95% 1.1-2.5 p = 0.02 Cox Univariate). The negative impact of ACE inhibitors group was maintained after multivariate analyses adjusting for risk factors (HR = 1.9 IC95% 1.1-3.5 p = 0.02 for PFS and HR = 2.3 IC95% 1.2-4.4 p = 0.01 for OS). RNA sequencing and CIBERSORT analysis underlines that ACE inhibitors group has lower M1 macrophage, activated Mast cells, NK cells and memory activated T cells thus suggesting an immunosuppressive state. Conclusions: ACE inhibitors prescription concomitant to the PD-1/PD-L1 inhibitors treatment impairs the outcome in patients with advanced NSCLC pts. This reduction is independent of classical prognostic factors. Biological date underlines an immunosuppressive state in ACE inhibitors group. These data should be validated in larger cohort.

Comparing the Efficacy of Angiotensin Converting Enzyme In-hibitors with Calcium Channel Blockers on the Treatment of Di-abetic Nephropathy: A Meta-Analysis

The angiotensin-converting enzyme inhibitors (ACEIs) could improve the symptoms of diabetic nephropathy. Whether the calcium channel blockers (CCBs) could be as effective as ACEIs on treating diabetic nephropathy is controversial. Here, we aimed to compare the efficacy of ACEIs with CCBs on the treatment of diabetic nephropathy by performing a meta-analysis of randomized controlled trials (RCTs). The Pubmed, Medline, Embase and The Cochrane Database were searched up to July 2017 for eligible randomized clinical trials studies. Effect sizes were summarized as mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (P-value<0.05). Seven RCTs involving 430 participants comparing ACEIs with CCBs were included. No benefit was seen in comparative group of ACEIs on systolic blood pressure (SBP) (MD=1.05 mmHg; 95% CI: -0.97 to 3.08, P=0.31), diastolic blood pressure (DBP) (MD= -0.34 mmHg; 95% CI: -1.2 to 0.51, P=0.43), urinary albumin excretion rates (UAER) (MD=1.91μg/min; 95% CI: -10.3 to 14.12, P=0.76), 24-h urine protein (24-UP) (SMD=-0.26; 95%CI: -0.55 to 0.03, P=0.08), glomerular filtration rate (GFR) (SMD=0.01; 95% CI: -0.38 to 0.41, P=0.95). On safety aspect, the risk of adverse reactions between ACEIs group and CCBs group are similar (RR=1.18; 95% CI: 0.61 to 2.28; P=0.61). Both ACEIs and CCBs could improve the BP, UAER, 24h-UP, and GFR of diabetic nephropathy to a similar extent.

Association of Angiotensin Modulators With the Course of Idiopathic Pulmonary Fibrosis

Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF. All patients randomized to placebo (n= 624) in the CAPACITY and ASCEND studies were categorized by antihypertensive treatment at baseline. Outcomes of disease progression (first occurrence of≥ 10%absolute decline in %predicted FVC,≥ 50-m decline in 6-min walk distance, or death) and all-cause mortality were assessed over 52weeks. At baseline, 111 and 121 patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), respectively; 392 were receiving neither. In multivariable analyses adjusted for differences in baseline characteristics compared with the non-ACEi/ARB group, ACEi treatment (hazard ratio [HR], 0.6 [95%CI, 0.4-0.9]; P= .026), but not ARB (HR, 0.9 [95%CI, 0.6-1.2]; P= .413), was associated with slower disease progression. Furthermore, the increase in all-cause mortality associated with cardiovascular disease was not observed in the ACEi group (HR, 1.1 [95%CI, 0.5-2.9]; P= .782), which presented a similar percentage of IPF-related mortality as the non-ACEi/ARB group (3.6%vs3.6%). In contrast, patients in the ARB group had greater risk of all-cause mortality (HR, 2.5 [95%CI, 1.2-5.2]). These observations were validated in a pooled analysis that included patients from the INSPIRE trial. Prospective clinical trials are needed to evaluate whether angiotensin modulators may be beneficial to clinical outcomes in IPF. ClinicalTrials.gov; Nos.: NCT01366209, NCT00287716, NCT00287729, NCT00075998; URL: www.clinicaltrials.gov).

ANALYSIS OF APPROACHES TO THE DEVELOPMENT AND VALIDATION OF THE METHODS OF ANALYSIS OF SOME ACTIVE PHARMACEUTICAL INGREDIENTS FROM THE GROUP OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN DRUGS AND BIOLOGICAL LIQUIDS

The quantity of medication brought into the marketplace is growing each year. Analytical method development is increasingly being introduced into fundamental pharmaceutical research and pharmaceutical analysis practice, taking into account their high sensitivity, accuracy, specificity and expressiveness. Search criteria was analytical method development for medicines from group of ACE inhibitors. Literature survey has been done in range of years 1990-2018 to make the review updated and comprehensive and to show the new approacheches to the development of the methods of analysis ACE inhibitors. The sources were world recognized journals and key words used as filter were angiotensin-converting enzyme inhibitors, captopril, enalapril, method development, spectrophotometry, HPLC, UHPLC. The current review is created with an intended to focus on the advantage of HPLC. Literature survey revealed that a number of methods have been reported for estimation of ACE inhibitors individually or in combination with other drugs. However, there is very few analytical methods reported for the simultaneous analysis of these drugs in a combined dosage formulation by HPLC. In additional, analysis of approaches to the development of the methods of analysis of ACE inhibitors in drugs and biological liquids has been shown that HPLC is the most suitable method for analyses ACE inhibitors in substances, drugs, biological liquids to performe routine analysis of medicines, pharmacokinetic (bioequivalence in vivo), dissolution test for final dosages forms (bioequivalence in vitro, biowaiver procedure).

Long-term clinical outcome between beta-blocker with ACEI or ARB in patients with NSTEMI who underwent PCI with drug-eluting stents.

BackgroundBecause limited comparative data are available, we decided to compare 2-year major clinical outcomes between beta-blockers (BB) with angiotensin converting enzyme inhibitors (ACEI) and BB with angiotensin receptor blockers (ARB) therapy in patients with non-ST-segment elevation myocardial infarction (NSTEMI) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES).MethodsA total 11,288 NSTEMI patients who underwent PCI with DES were enrolled and they were divided into two groups, the BB with ACEI group (n = 7600) and the BB with ARB group (n = 3688). The major clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death, recurrent myocardial infarction (re-MI), total revascularization [target lesion revascularization (TLR), target vessel revascularization (TVR), non-TVR] rate during the 2-year follow-up period.ResultsAfter propensity score-matched (PSM) analysis, two PSM groups (3317 pairs, n = 6634, C-statistic = 0.695) were generated. Although the cumulative incidences of all-cause death, cardiac death, TLR, and non-TVR were similar between the two groups, MACE (HR = 0.832, 95% CI: 0.704–0.982, P = 0.030), total revascularization rate (HR = 0.767, 95% CI: 0.598–0.984, P = 0.037), and TVR rate (HR = 0.646, 95% CI: 0.470–0.888, P = 0.007) were significantly lower in the BB with ACEI group after PSM.ConclusionsIn this study, we suggest that the combination of BB with ACEI may be beneficial for reducing the cumulative incidences of MACE, total revascularization rate, and TVR rather than the BB with ARB after PCI with DES in NSTEMI patients.

Clinical Outcomes at 2 Years Between Beta-Blockade with ACE Inhibitors or ARBs in Patients with AMI Who Underwent Successful PCI with DES: A Retrospective Analysis of 23,978 Patients in the Korea AMI Registry.

Data concerning the clinical impact of combination therapy with β-blockers (BBs) + angiotensin-converting enzyme inhibitors (ACEIs) compared with BBs + angiotensin-receptor blockers (ARBs) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) are limited. We compared the clinical outcomes at 2years between these two combination therapies. We enrolled 23,978 patients with AMI who underwent successful PCI with DES between January 2005 and June 2015 from the Korea AMI Registry (KAMIR) and divided them into the two groups: BB + ACEI (n = 17,310) and BB + ARB (n = 6668). The primary endpoint was major adverse cardiac events (MACE), defined as all-cause death, recurrent myocardial infarction (re-MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR. The secondary endpoints were the cumulative incidences of individual components of MACE and target vessel failure (TVF), a composite of death related to the target vessel, re-MI, or clinically driven TVR. The relative risk of MACE was higher in the BB + ARB group than in the BB + ACEI group after propensity score-matched (PSM) analysis (hazard ratio [HR] 1.204; 95% confidence interval [CI] 1.057-1.370; p = 0.005). The relative risks of all-cause death (HR 1.435 [95% CI 1.117-1.845]; p = 0.005), cardiac death (HR 1.733 [95% CI 1.253-2.396]; p = 0.001), TVR (HR 1.437 [95% CI 1.157-1.784]; p = 0.001), and TVF (HR 1.231 [95% CI 1.065-1.424]; p = 0.005) were also higher in the BB + ARB group after PSM. The BB + ACEI group demonstrated reduced cumulative incidences of MACE, all-cause death, cardiac death, TVR, and TVF compared with the BB + ARB group in patients with AMI who underwent successful PCI with DES during a 2-year follow-up period.

A randomised controlled trial of potential for pharmacologic prevention of new-onset albuminuria, hypertension and diabetes in a remote Aboriginal Australian community, 2008-2013.

IntroductionWe conducted a double-blind randomised controlled trial in a remote-living Australian Aboriginal group at high risk for chronic disease to assess whether pharmacological treatment with angiotensin converting enzyme inhibitor (ACEi) could delay the onset of albuminuria, hypertension or diabetes in people currently free of those conditions.MethodsEligibility criteria in 2008 were age ≥18yr, blood pressure ≤140/90 mm/Hg, urinary albumin creatinine ratio (ACR) < 3.4 mg/mmol, normal levels of glycosylated haemoglobin, and, in females, infertility. A 2011 amendment allowed enrolment of fertile females using long-term contraception. “Treatment” was the ACEi perindopril arginine, or placebo, and participant events were ACR ≥3.4 mg/mmol and/or blood pressure >140/90 mm Hg and/or haemoglobin A1c >6.5%, and/or cardiovascular events. Results were analysed in 125 randomised participants who commenced treatment.ResultsRecruitment was low, especially of women, and dropout rates high: there were finally 60 and 65 people in the ACEi and placebo groups respectively. In females, there were no events among 10 in the ACEi group, versus 5 events among 17 in the placebo group, and longitudinal ACR, HbA1c and blood pressure levels supported probable benefit of ACEi. There was no benefit of ACEi in males, but a probable benefit on diabetes/hypertension events. With the genders combined, there was probable reduction of diabetes (zero vs 4 events, p = 0.068), and of diabetes or hypertension (zero vs 5 events, p = 0.037).DiscussionIn this high-risk population, ACEi probably delays development of albuminuria, diabetes and hypertension in females, and of non-ACR events overall. Repeat investigation with a larger sample size is warranted.

Risk of Sepsis and Mortality Among Patients With Chronic Obstructive Pulmonary Disease Treated With Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers.

This study aimed to compare the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk and outcomes of sepsis in patients with chronic obstructive pulmonary disease. A retrospective study. Taiwan's National Health Insurance Research Database. All patients with chronic obstructive pulmonary disease who received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for more than 90 days between 2000 and 2005 were recruited for this study. Pairwise matching (1:1) of the angiotensin-converting enzyme inhibitor and angiotensin receptor blocker groups resulted in two similar subgroups with 5,959 patients in each. None. The primary outcome was sepsis, and the secondary outcome was death. The occurrence rate of sepsis was 3.67 per 100 person-years for the patients receiving angiotensin-converting enzyme inhibitors and 2.87 per 100 person-years for those receiving angiotensin receptor blockers. In addition, the patients receiving angiotensin-converting enzyme inhibitors had a higher risk of septic shock (adjusted hazard ratio, 1.45; 95% CI, 1.26-1.67) and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.22-1.40) than those receiving angiotensin receptor blockers. No matter whether the patients had prior severe exacerbation before the index date, those receiving angiotensin-converting enzyme inhibitors had a higher risk of sepsis, septic shock, and mortality than those receiving angiotensin receptor blockers (all p < 0.001). Angiotensin receptor blockers were associated with lower rates of sepsis and mortality than angiotensin-converting enzyme inhibitors in the patients with chronic obstructive pulmonary disease. The similar findings were also noted in subgroup analysis.

Effects of sympathectomy on cardiac remodeling in a doxorrubicin-induced dilated cardiomyopathy model

Introduction: The main cause of cardiac transplantation is dilated cardiomyopathy (DCM), in which there are ventricular dilation and systolic dysfunction, leading to congestive heart failure. Ventricular remodeling involves activation of the sympathetic nervous and renin-angiotensin- aldosterone systems. As such, classic treatments include angiotensin-converting enzyme inhibitors (ACEI), beta-blockers and mineralocorticoid receptor antagonists. Once such treatments only delay the development of the disease, it is important to look for better therapeutic options. Experimental models demonstrated the benefits of sympathetic blockade on preserving ventricular function and preventing left ventricle remodeling after myocardial infarction. Objective: We evaluated the influence of bilateral thoracic sympathectomy on left ventricle remodeling and function in a rat model of doxorubicin induced DCM. Methodology: Animals were randomly divided into 4 groups of 7 rats each. DCM only, bilateral sympathectomy (BS) with DCM, ACEI with DCM and also a negative control group (SHAM). DCM was inducted in the experimental groups through weekly intraperitoneal injection of doxorubicin. Fifteen days after the beginning of DCM induction, bilateral sympathectomy was performed by chemical sclerosis of stellate ganglion with ethanol in the BS group. From this same time point until the end of experimental protocol, animals of the ACEI group received daily, through water ingestion, a enalapril maleate dilution. Ten weeks later, left ventricular function was evaluated with the use of a microtip pressureconductance catheter. Also, extracellular fibrosis were evaluated and BCL-2 expression on myocardial tissue were quantified. Partial Results: DCM group showed an increased left ventricular (LV) end-diastolic volume in relation to Sham group(p=0.034). Also, a significant decrease was observed in LV ejection fraction in DCM group, while bilateral sympathectomy were able to preserve this parameter (p=0,001). Furthermore, both treated groups showed an increased LV stroke work compared to DCM group (p=0,002). Myocardial extracellular fibrosis were more present in control group, whereas both BS and ACE inhibitor treatments reduced the areas of fibrotic tissue (p&lt;0,0001), which can be associated with increased expression of anti-apoptotic BCL-2 in treated groups (p=0,0004). Discussion and Conclusion: Sympathetic blockade was able to suppress myocardial tissue fibrosis, most likely due to increasing anti-apoptotic BCL-2 expression. Moreover, LV function was maintained as observed through LV ejection fraction,stroke work and cardiac efficiency levels. Although ACE inhibitor was also able to inhibit extracellular fibrosis and increase BCL- 2 expression, cardiac function has not been preserved as in BS group. Therefore, we conclude that BS was able to decrease myocardial tissue deterioration and also to preserve LV in a doxorubicin model of DCM in rats. Keywords: Sympathectomy; Cardiomyopathy; Cardiac transplantation; Doxorubicin.

SEX-DIFFERENCES IN EFFICACY OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS IN PATIENTS WITH PRIOR MYOCARDIAL INFARCTION

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly prescribed for patients with coronary artery disease. However, evidence supporting the use of ARBs in this population is limited and controversial. Moreover, the effect of sex-differences between ACEIs and ARBs have not been sufficiently evaluated. Our objective was to compare the clinical effectiveness and identify sex-differences of ACEIs and ARBs in patients with a history of myocardial infarction (MI). We conducted a population-based cohort study using linked administrative databases in Ontario, Canada. We included all residents older than 65 years, alive on April 1, 2012, and had a prior hospitalization of MI. Inverse probability of treatment weighting propensity method was used to balance the potential effect of confounding in the treatment groups. The primary outcome was a composite of cardiovascular death, hospitalization for MI and unstable angina. We included 59,353 patients with prior MI. The average age was 77 and 40% were women. In the propensity weighted cohort, the primary outcome occurred in 6.5% of the ACEI group and 5.7% in the ARB group at one year, conferring an increased hazard ratio (HR) for those taking ACEIs (HR 1.14, 95% CI 1.05-1.23, p<0.001). This trend continued at three years, with the primary outcome occurring in 16.0% of those taking ACEI and 15.1% of those taking ARB (HR 1.07; 95% CI 1.02-1.12; p=0.008). Significant interaction by sex was observed such that women prescribed ACEIs had higher HR (1.17; 95% CI 1.10-1.26) compared with ARBs; while no significant difference was seen among men (HR 1.00; 95% CI 0.93-1.06; p<0.001 for interaction). In our study of older patients with a history of MI we found that treatment with ARBs were associated with a lower hazard of clinical outcomes compared to ACEIs. This difference may be related to sex-differences in effectiveness of ACEIs and ARBs. Our findings support the use of ARBs in patients who have had a prior hospitalization for MI.

Efficacy of zofenopril in combination with thiazide diuretics in patients with acute myocardial infarction: a pooled individual data analysis of four randomized, double-blind, controlled, prospective studies.

BackgroundIn the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) studies, early administration of zofenopril after acute myocardial infarction (AMI) was prognostically beneficial as compared to placebo and other angiotensin-converting enzyme inhibitors (ACEIs), such as lisinopril and ramipril. Here, we investigated whether zofenopril efficacy could be affected by a concomitant use of thiazide diuretics (TDs).MethodsThis was a post hoc analysis of pooled individual patient data from the SMILE studies. Patients treated with other diuretics than TDs were excluded. The primary study endpoint was the 1-year combined occurrence of death or hospitalization for CV causes, with or without TD.ResultsAmong 2,995 patients, 263 (8.8%) were treated with a combination including a TD (TD+), whereas 2,732 (91.2%) were not treated with any diuretic (TD−). Proportions of subjects who were treated with TD were equally distributed (p=0.774) within the placebo, zofenopril, and other ACEIs groups. The 1-year risk of major cardiovascular events was similar in TD+ (18.3%) and TD− (16.8%) patients (hazard ratio [HR] 1.04; 95% CI 0.74–1.45; p=0.838). After stratifying per concomitant treatment and TD, the 1-year risk of CV events was significantly lower with zofenopril than with placebo (HR 0.70; 95% CI 0.55–0.88; p=0.002) and other ACEIs (HR 0.58; 95% CI 0.46–0.74; p=0.0001). Treatment with ACEIs and TD as concomitant therapy was associated with a larger blood pressure (BP) reduction (p=0.0001 for systolic BP and p=0.045 for diastolic BP).ConclusionIn post AMI patients, zofenopril maintained its positive impact on prognosis compared to placebo or other ACEIs, regardless concomitant TD administration. In this setting, TD shows advantages in managing the most difficult hypertensive patients.

A Stability-Indicating LC-MS Method for Determination of Perindopril and its Process Related Impurities

Perindopril erbumine belongs to the member of angiotensin-converting enzyme inhibitors group used in the treatment of heart failure and hypertension. Asimple and highly sensitive LC-MS method has been developed for the simultaneous determination of three process-related impurities (L-norvaline, L-norvaline ethyl ester HCl, and (S)-indoline-2-carboxylic acid) in perindopril. Samples were separated using 5 mM ammonium formate (A) and acetonitrile/methanol (B) as the mobile phase on a Symmetry C18 column (75 mm × 4.6 mm, 3.5 μm) using gradient elution mode at a flow rate of 0.6 mL/min. The proposed method was validated as per ICH guidelines and can be used for quality testing of perindopril and determining its process-related impurities in pharmaceuticals.

FIVE-YEAR DYNAMICS OF SECONDARY PREVENTION IN PATIENTS WITH STABLE ANGINA AT SPECIALIZED OUT-PATIENT LEVEL IN MOSCOW (PHARMACOEPIDEMIOLOGY STUDY)

Aim. To assess five-year trend in terms of specialists’ adherence to guidelines on secondary prevention of cardiovascular diseases in patients with stable angina on the level of out-patient specialized healthcare institution in Moscow. Material and methods. Two-stage retrospective pharmacoepidemiological study was conducted. The object of the study – patient medical records. At the first stage of the study medical records of 2915 patients with stable angina visited the healthcare institution for the first time in 2006 were included, at the second stage – medical records of 1633 patients with stable angina with primary visit in 2011. Results. Over the five-year period prescription rates of drugs improving prognosis in patients with stable angina significantly increased: antiplatelets – up to 82.7%, beta-blockers – up to 74.3%, statins – up to 45.6%. Despite of no changes registered in prescription rate of the ACE inhibitors, marked increase up to 14.7% in prescription rate of angiotensin receptor blockers was revealed. In the prescription structure of pharmacological groups changes were detected concerning the preferred choice of a specific drug. Due to implementation of dual antiplatelet therapy into clinical practice a reduced number of recommendations of acetylsalicylic acid as monotherapy (down to 93.0%) and increased – in combination with clopidogrel (up to 5.4%) was registered at the second stage of the study. Over a five-year period bisoprolol (55.0%) occupied the leading position in the group of beta-blockers. Metoprolol’s prescription rate decreased to 27.4%. Prescription rate of atenolol decreased down to 3.1%, while that of nebivolol increased up to 8.3%. When choosing among statins specialists recommended significantly more often atorvastatin (up to 52.9%). In the group of ACE inhibitors three drugs preserved their leading positions. Meanwhile the number of recommendations of enalapril increased up to 50.8%, perindopril – up to 24.1%. Analysis of prescribed doses revealed significant increase in recommendations of specific drugs in higher daily doses: acetylsalicylic acid 100 mg – up to 71.1%, simvastatin and atorvastatin 20 mg – up to 60.5% and 41.9%, respectively. When prescribing beta-blockers and ACE inhibitors specialists continued to use minimal and medium therapeutic doses, possibly due to dose titration in patients with comorbidities. Conclusion. Study results demonstrated positive trend in terms of specialists’ adherence to guidelines on secondary prevention of cardiovascular diseases in patients with stable angina. However, a number of problem aspects were identified that require further optimization of medical and preventive measures in healthcare institutions.

Effects of angiotensin receptor blocker at discharge in patients with heart failure with reduced ejection fraction: Korean Acute Heart Failure (KorAHF) registry

BackgroundAfter introduction of up-titration strategy, there are limited data on comparison between the effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) in patients with heart failure with reduced ejection fraction (HFrEF). The study sought to investigate the association between treatment with ARB at discharge and clinical outcomes in patients with HFrEF compared with treatment with ACEI or no renin angiotensin system blocker (RASB). MethodsThe KorAHF registry is a prospective multicenter cohort and included patients who were hospitalized for acute heart failure (AHF). We studied 3005 patients with HFrEF (<40%), and divided into ARB (n=1190), ACEI (n=1090), and no RASB (n=725) groups. Propensity score matching was performed. ResultsAll-cause death occurred in 346 patients (29.1%) in the ARB group, 315 patients (28.9%) in the ACEI group, and 305 (42.1%) in the no RASB group. After propensity score matching (ARB vs. ACEI, 827 pairs), there was no significant difference between the two groups in the rate of death (HR 0.91, 95% CI 0.76–1.09, p=0.32). All-cause death was significantly lower in the ARB group than in the no RASB group (ARB vs. no RASB, 538 pairs, HR 0.69, 95% CI 0.56–0.83, p<0.001). The ARB group had a significantly lower discontinuation rate than the ACEI group (20.8% vs. 33.6%, p<0.001). ConclusionsFor treatment of AHF with reduced EF after hospitalization, ARB at discharge shows a mortality benefit comparable to that of ACEI. In addition, tolerability of medication was greater for ARB than for ACEI.