Search

Competing Interests: Competing interests: Jordan Weinstein reports consultancy and advisory work for AstraZeneca, Bayer, BI/Lily, Alexion, Merck, Amgen, Janssen, Otsuka and CPD Network. Louis-Philippe Girard reports consultancy and advisory work for Otsuka and Astra Zeneca. Robert McKelvie reports consultancy and advisory work for Otsuka, AstraZeneca, Bayer, Merck and Novartis. Karthik Tennankore reports consultancy and advisory work for Otsuka, Janssen, Astra Zeneca, Baxter and Bayer. Sodium zirconium cyclosilicate is licensed by AstraZeneca Canada. Patiromer is imported and distributed by Otsuka Canada. No other competing interests were declared.

Aims: The role of renin-angiotensin-aldosterone system (RAAS) blockers on the course of coronavirus disease 2019 (COVID-19) is debated. We assessed the association between chronic use of RAAS blockers and mortality among inpatients with COVID-19 and explored reasons for discrepancies in the literature., Methods and Results: We included adult hypertensive patients from a prospective nationwide cohort of 3512 inpatients with COVID-19 up to June 30, 2020. Cox proportional hazard models with various adjustment or propensity weighting methods were used to estimate the hazard ratios (HR) of 30-day mortality for chronic users versus non-users of RAAS blockers. We analyzed data of 1160 hypertensive patients: 719 (62%) were male and 777 (67%) were older than 65 years. The main comorbidities were diabetes (n = 416, 36%), chronic cardiac disease (n = 401, 35%), and obesity (n = 340, 29%); 705 (61%) received oxygen therapy. We recorded 135 (11.6%) deaths within 30 days of diagnosis. We found no association between chronic use of RAAS blockers and mortality (unadjusted HR = 1.13, 95% CI [0.8-1.6]; propensity inverse probability treatment weighted HR = 1.09 [0.86-1.39]; propensity standardized mortality ratio weighted HR = 1.08 [0.79-1.47]). Our comprehensive review of previous studies highlighted that significant associations were mostly found in unrestricted populations with inappropriate adjustment, or with biased in-hospital exposure measurement., Conclusion: Our results do not support previous concerns regarding these drugs, nor a potential protective effect as reported in previous poorly designed studies and meta-analyses. RAAS blockers should not be discontinued during the pandemic, while in-hospital management of these drugs will be clarified by randomized trials. NCT04262921., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

There is limited data on the effect of sacubitril-valsartan on the echocardiographic parameters in acute decompensated heart failure (ADHF). We prospectively enrolled 68 consecutive patients with ADHF who received sacubitril-valsartan (N = 34, S/V group) or angiotensin inhibition-based therapy (N = 34, ACEi/ARB group). Two-dimensional echocardiography with speckle tracking (2D-STE) was performed at baseline and after 3 months of treatment. Changes in 2D-STE parameters, including global longitudinal strain (GLS), were compared between the groups by t test and ANCOVA. Baseline characteristics were similar between the groups. Following 3 months of treatment, LVEF and GLS significantly improved in the S/V group (mean LVEF from 27 to 34.5% and GLS from - 6.6 to - 9.4%) but not in ACEi/ARB group. The improvement in LVEF and GLS was more prominent in patients with non-ischemic cardiomyopathy. In patients with ADHF 3-month treatment with sacubitril-valsartan, compared to guideline directed medical therapy without sacubitril, improves LVEF and GLS. Graphical Abstract A typical change in GLS in a patient with acute decompensated heart failure after 3 months of sacubitril-valsartan.

Among the plethora of debilitating neurological disorders of COVID-19 syndrome in survivors, the scope of SARS-CoV-2-induced dysautonomia (DNS) is yet to be understood, though the implications are enormous. Herein, we present an inclusive mini-review of SARS-CoV-2-induced DNS and its associated complications. Although, the direct link between Covid-19 and DSN is still speculative, the hypothetical links are thought to be either a direct neuronal injury of the autonomic pathway or a para/post-infectious immune-induced mechanism. SARS-CoV-2 infection-induced stress may activate the sympathetic nervous system (SNS) leading to neuro-hormonal stimulation and activation of pro-inflammatory cytokines with further development of sympathetic storm. Sympathetic over-activation in Covid-19 is correlated with increase in capillary pulmonary leakage, alveolar damage, and development of acute respiratory distress syndrome. Furthermore, SARS-CoV-2 can spread through pulmonary mechanoreceptors and chemoreceptors to medullary respiratory center in a retrograde manner resulting in sudden respiratory failure. Taken together, DSN in Covid-19 is developed due to sympathetic storm and inhibition of Parasympathetic nervous system-mediated anti-inflammatory effect with development of cytokine storm. Therefore, sympathetic and cytokine storms together with activation of Renin-Angiotensin-System are the chief final pathway involved in the development of DSN in Covid-19.

Background: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve cognitive function. The authors therefore tested the primary hypothesis that preoperative use of angiotensin inhibitors is associated with less delirium in critical care patients. Post hoc, the association between postoperative use of angiotensin system inhibitors and delirium was assessed., Methods: The authors conducted a single-site cohort study of adults admitted to Cleveland Clinic critical care units after noncardiac procedures between 2013 and 2018 who had at least one Confusion Assessment Method delirium assessment. Patients with preexisting dementia, Alzheimer's disease or other cognitive decline, and patients who had neurosurgical procedures were excluded. For the primary analysis, the confounder-adjusted association between preoperative angiotensin inhibitor use and the incidence of postoperative delirium was assessed. Post hoc, the confounder-adjusted association between postoperative angiotensin system inhibitor use and the incidence of delirium was assessed., Results: The incidence of delirium was 39% (551 of 1,396) among patients who were treated preoperatively with angiotensin system inhibitors and 39% (1,344 of 3,468) in patients who were not. The adjusted odds ratio of experiencing delirium during critical care was 0.98 (95% CI, 0.86 to 1.10; P = 0.700) for preoperative use of angiotensin system inhibitors versus control. Delirium was observed in 23% (100 of 440) of patients who used angiotensin system inhibitors postoperatively before intensive care discharge, and in 41% (1,795 of 4,424) of patients who did not (unadjusted P < 0.001). The confounder-adjusted odds ratio for experiencing delirium in patients who used angiotensin system inhibitors postoperatively was 0.55 (95% CI, 0.43 to 0.72; P < 0.001)., Conclusions: Preoperative use of angiotensin system inhibitors is not associated with reduced postoperative delirium. In contrast, treatment during intensive care was associated with lower odds of delirium. Randomized trials of postoperative angiotensin-converting enzymes inhibitors and angiotensin receptor blockers seem justified.

COVID-19, which is caused by the single-stranded RNA severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has introduced significant therapeutic dilemmas in several areas. One of these is concern regarding the use of renin-angiotensin system (RAS) inhibitors. Dysfunction of the RAS has been observed in COVID-19 patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs), are associated with improved or worse clinical outcomes, remains unclear. RAS inhibitors are currently widely used in the treatment of hypertension. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with co-morbidities such as hypertension, coronary heart disease, and diabetes mellitus, particularly in the elderly. Therefore, several recently published research papers have focused on the management of hypertension during the COVID-19 pandemic, as this co-morbidity was found to be the most common in patients with coronavirus infections. SARS-CoV-2 viral surface protein is known to attach angiotensin converting enzyme-2 (ACE-2) on the cell membrane to facilitate viral entry into the cytoplasm. While the SARS-CoV-2 viral load remains the highest in upper respiratory tract of COVID-19 patients, it has also been reported in multiple sites in COVID-19, and patients not infrequently require the Intensive Care Units (ICU) admission. However, despite the theoretical concerns of possible increased ACE2 expression by RAS blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection, and indeed they have been shown to be beneficial in some animal studies. In this review we summarise the pathophysiology of the interaction between RAS, ACEIs/ARBs inhibitors and COVID-19, and conclude, on the basis of current data, that RAS blockade should be maintained during the current coronavirus pandemic.

Background: Angiotensin receptor neprilysin inhibitor (ARNI, sacubitril/valsartan) reduces sudden death in heart failure with reduced ejection fraction (HFrEF). Corrected QT (QTc), T-wave peak to T-wave end interval (Tp-e) and Tp-e/QTc are electrocardiographic indices of ventricular repolarization heterogeneity. We aimed to assess the effects of switching from ramipril to ARNI on electrocardiographic indices of ventricular repolarization. Methods: A total of 48 patients with HFrEF (mean age: 63.3 ± 11.7 years; 36 males, 77.1% ischaemic etiology) were enrolled. All patients had New York Heart Association functional class II-III, left ventricular ejection fraction ≤35% and previously switched from ramipril to ARNI treatment. The standard 12-lead electrocardiograms on ramipril treatment and 1 month after ARNI treatment were analysed; heart rate, QTc, Tp-e and Tp-e/QTc were calculated. Minnesota Living with Heart Failure Questionnaire (MLWHFQ) scores and N-terminal pro-BNP (NT-proBNP) values were recorded. Results: QTc (415.2 ± 19.7 ms vs. 408.5 ± 20.8 ms, p  = 0.022), Tp-e (100.7 ± 13.8 ms vs. 92.9 ± 12.1 ms, p  < 0.001), Tp-e/QTc (0.242 ± 0.028 vs. 0.227 ± 0.029, p  = 0.003) and heart rate (73.2 ± 4.7 bpm vs. 71.1 ± 4.9 bpm, p  = 0.027) were reduced after ARNI. ARNI switch associated with improvement in MLWHFQ scores (32.4 ± 7.1 ms vs. 22.6 ± 7.0 ms, p  < 0.001) and reduction of NT-proBNP (2457 ± 1879 pg/ml to 1377 ± 874 pg/ml, p  < 0.001). Pearson's correlation analysis revealed moderate correlations of MLWHFQ score with Tp-e ( r  = 0.543, p  = 0.001) and Tp-e/QTc ( r  = 0.556, p  = 0.001). Conclusions: Switching from ramipril to ARNI favourably alters QTc, Tp-e and Tp-e/QTc in HFREF. ARNI reduces symptoms of HFREF assessed by MLWHFQ and lowers NT-proBNP levels. Reduction in Tp-e and Tp-e/QTc correlate with clinical improvement in patients with HFrEF.

Cisplatin (CDDP; cis-diamine dichloroplatinum)-induced nephrotoxicity is the main reason for dose limitations, which can reduce the efficacy of cancer treatment. Lower blood pressure and administration of renin angiotensin system (RAS) inhibitors have been reported as factors that exacerbate CDDP-induced nephrotoxicity; however, the detailed mechanisms remain unknown and the results of previous studies are conflicting. In this study, we examined the influence of various hypotensive drugs, including RAS inhibitors and calcium channel blockers, on CDDP-induced nephrotoxicity in BALB/c mice. The mice were divided into nine groups: (1) CDDP group (15 mg/kg CDDP), (2) AML group (5 mg/kg amlodipine), (3) ENA group (2.5 mg/kg enalapril), (4) telmisartan (TEL) group (10 mg/kg telmisartan), (5) LOS group (10 mg/kg losartan), (6) CDDP + AML group, (7) CDDP + ENA group, (8) CDDP + TEL group, and (9) CDDP + LOS group. Nephrotoxicity was evaluated by measuring serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, the kidney sections were stained with Masson's trichrome and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) to assess the renal fibrosis area and apoptotic area. Serum CRE and BUN levels were increased in the CDDP + ENA, CDDP + LOS, and CDDP + TEL groups compared to those in the CDDP alone group, and the CDDP + AML group showed an increasing trend. However, there was no correlation between ∆CRE or ∆BUN levels and ∆ systolic blood pressure. The CDDP + TEL group showed a significant increase in the renal fibrosis area. These results suggest that exacerbation of CDDP-induced nephrotoxicity is not correlated with systolic blood pressure but is associated with administration of RAS inhibitors, particularly TEL.

Background: US guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF), who tolerate an ACEI (angiotensin-converting enzyme inhibitor) or ARB (angiotensin II receptor blocker), be switched to sacubitril/valsartan to reduce morbidity and mortality. We compared characteristics and healthcare utilization between Veterans with HFrEF who were switched to sacubitril/valsartan versus maintained on an ACEI or ARB., Methods: retrospective cohort study of treated HFrEF (July 2015-June 2017) using Veterans Affairs data. The index date was the first fill for sacubitril/valsartan and if none, for an ACEI or ARB. Treated HFrEF was defined by (1) left ventricular ejection fraction ≤40%, (2) ≥1 in/outpatient HF encounter, and (3) ≥1 ACEI or ARB fill, all within 1-year preindex. Poisson regression models were used to compare baseline characteristics and 1:1 propensity score-matched adjusted 4-month follow-up healthcare utilization between sacubitril/valsartan switchers and ACEI or ARB maintainers., Results: Switchers (1612; 4.2%) were less likely than maintainers (37 065; 95.8%) to have a history of myocardial infarction or hypertension, and more likely to be black, have a lower left ventricular ejection fraction, and higher preindex healthcare utilization. Switchers were less likely to experience follow-up all-cause hospitalizations (11.2% versus 14.0%; risk ratio 0.80 [95% CI, 0.65-0.98], P value 0.035)., Conclusions: Few Veterans with treated HFrEF were switched to sacubitril/valsartan within the first 2 years of Food and Drug Administration approval. Sacubitril/valsartan use was associated with a lower risk for all-cause hospitalizations at 4 months follow-up. Reasons for lack of guideline-recommended sacubitril/valsartan initiation warrant investigation and may reveal opportunities for HFrEF care optimization.

Background: Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure-lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension., Methods: This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70 years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8 weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24 weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome., Discussion: Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03246555 , registered on July 25, 2017.

Background/aims: Limited comparative data concerning long-term clinical outcomes of combination therapy between beta-blockers (BB) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) therapy in patients with ST-segment elevation myocardial infarction (STEMI) are available. We thought to compare 2-year major clinical outcomes between BB with ACEI and BB with ARB therapy in patients with STEMI after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES)., Methods: 13,873 STEMI patients who underwent successful PCI with DES were enrolled and divided into two groups as the BB with ACEI group (n = 10,393) and the BB with ARB group (n = 3480). The clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death, cardiac death (CD), recurrent myocardial infarction (re-MI), total coronary revascularization (target lesion revascularization [TLR], target vessel revascularization [TVR], non-TVR) during the 2-year follow-up period., Results: After propensity score-matched (PSM) analysis, two PSM groups (3296 pairs, n = 6592, C-statistic = 0.675) were generated. Although the incidences of re-MI, TLR, and TVR were similar, the incidences of MACE (8.3% vs. 6.8%, log-rank p = 0.038, hazard ratio [HR] 1.210, 95% confidence interval [CI] 1.010-1.451, p = 0.039), all-cause death, CD, total revascularization, and non-TVR of the BB with ARB group were significantly higher than the BB with ACEI group after PSM. In addition, diabetes and multivessel disease were significant predictors for non-TVR., Conclusions: The combination BB with ACEI may be beneficial for reducing MACE in STEMI patients after successful PCI with DES than the BB with ARB.

Background: People with chronic kidney disease (CKD) are at an increased risk of developing hyperkalaemia due to their declining kidney function. In addition, these patients are often required to reduce or discontinue guideline-recommended renin-angiotensin-aldosterone system inhibitor (RAASi) therapy due to increased risk of hyperkalaemia. This original research developed a model to quantify the health and economic benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD., Methods: A patient-level simulation model was designed to fully characterise the natural history of CKD over a lifetime horizon, and predict the associations between serum potassium levels, RAASi use and long-term outcomes based on published literature. The clinical and economic benefits of maintaining sustained potassium levels and therefore avoiding RAASi discontinuation in CKD patients were demonstrated using illustrative, sensitivity and scenario analyses., Results: Internal and external validation exercises confirmed the predictive capability of the model. Sustained potassium management and ongoing RAASi therapy were associated with longer life expectancy (+ 2.36 years), delayed onset of end stage renal disease (+ 5.4 years), quality-adjusted life-year gains (+ 1.02 QALYs), cost savings (£3135) and associated net monetary benefit (£23,446 at £20,000 per QALY gained) compared to an absence of RAASi to prevent hyperkalaemia., Conclusion: This model represents a novel approach to predicting the long-term benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD, irrespective of the strategy used to achieve this target, which may support decision making in healthcare.

Background/aims: Olmesartan, a widely used angiotensin II receptor blocker (ARB), has been linked to sprue-like enteropathy. No cases of olmesartan-associated enteropathy have been reported in Northeast Asia. We investigated the associations between olmesartan and other ARBs and the incidence of enteropathy in Korea., Methods: Our retrospective cohort study used data from the Korean National Health Insurance Service to identify 108,559 patients (58,186 females) who were initiated on angiotensin converting enzyme inhibitors (ACEis), olmesartan, or other ARBs between January 2005 and December 2012. The incidences of enteropathy were compared among drug groups. Changes in body weight were compared after propensity score matching of patients in the ACEis and olmesartan groups., Results: Among 108,559 patients, 31 patients were diagnosed with enteropathy. The incidences were 0.73, 0.24, and 0.37 per 1,000 persons, in the ACEis, olmesartan, and other ARBs groups, respectively. Adjusted rate ratios for enteropathy were: olmesartan, 0.33 (95% confidential interval [CI], 0.10 to 1.09; p = 0.070) and other ARBs, 0.34 (95% CI, 0.14 to 0.83; p = 0.017) compared to the ACEis group after adjustment for age, sex, income level, and various comorbidities. The post hoc analysis with matched cohorts revealed that the proportion of patients with significant weight loss did not differ between the ACEis and olmesartan groups., Conclusion: Olmesartan was not associated with intestinal malabsorption or significant body weight loss in the general Korean population. Additional large-scale prospective studies of the relationship between olmesartan and the incidence of enteropathy in the Asian population are needed.

Introduction: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi., Methods: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi., Results: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer., Conclusions: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.

Background: The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity., Methods: This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay., Results: After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.62-1.52; I = 0%) or MACE (OR, 1.12; 95% CI, 0.82-1.52; I = 0%). However, withholding therapy was associated with significantly less intraoperative hypotension (OR, 0.63; 95% CI, 0.47-0.85; I = 71%). No effect estimate could be pooled concerning length of hospital stay and congestive heart failure., Conclusions: This meta-analysis did not demonstrate an association between perioperative administration of ACE-I/ARB and mortality or MACE. It did, however, confirm the current observation that perioperative continuation of ACE-I/ARBs is associated with an increased incidence of intraoperative hypotension. A large randomized control trial is necessary to determine the appropriate perioperative management of ACE-I and ARBs.

Background and Aims: Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD., Methods and Results: HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA., Conclusion: Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) on the risk of pneumonia and severe exacerbations in patients with COPD., Patients and Methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1) of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death., Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15-1.29) than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16-1.21) than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring hospitalization (aHR, 1.24; 95% CI, 1.21-1.28) or emergency department visits (aHR, 1.16; 95% CI, 1.13-1.18), pneumonia requiring mechanical ventilation (aHR, 1.35; 95% CI, 1.24-1.47), and mortality (aHR, 1.33; 95% CI, 1.26-1.42)., Conclusion: ARBs were associated with lower rates of pneumonia, severe pneumonia, and mortality than ACEis in patients with COPD., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: The beneficial effect of renin-angiotensin system (RAS) inhibitors has been well-established in patients with cardiovascular disease; however, their effectiveness in patients with chronic limb-threatening ischemia (CLTI), a selected disease-burdened population, is largely unknown. The purpose of this study was to evaluate long-term outcomes of RAS inhibitor use in patients with CLTI undergoing a vascular intervention., Methods: For this study, all patients with CLTI undergoing a first-time revascularization (bypass or endovascular) were analyzed at our institution between 2005 and 2014. Patients discharged on an RAS inhibitor (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) were compared with those not on an RAS inhibitor. The inverse probability of treatment weighting with additional regression analyses were used to determine the long-term risk of mortality and major adverse events. A sensitivity analysis was performed to assess the dose-related therapeutic response of RAS inhibitors (low-dose vs high-dose therapy)., Results: Between 2005 and 2014, 1303 limbs from 1161 patients were identified. Of these patients, 52% were discharged on an RAS inhibitor, with 67% discharged on a high-dose therapy and 33% on a low-dose therapy. Patients discharged on an RAS inhibitor suffered more frequently from diabetes, hypertension, and myocardial infarction, whereas those not on an RAS inhibitor had more chronic kidney disease (all P < .05). There was no difference in the proportion of patients presenting with tissue loss. After adjustment for these and other baseline covariates, RAS inhibitor use was associated with less late mortality (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.65-0.94). Discharge on a high-dose RAS inhibitor was associated with lower mortality (HR, 0.70; 95% CI, 0.57-0.86), whereas a low-dose RAS inhibitor was not associated with less mortality (HR, 0.95; 95% CI, 0.73-1.24) compared with patients not prescribed an RAS inhibitor. This association remained significant when comparing high-dose with low-dose therapy (HR, 0.74; 95% CI, 0.55-0.98). No associations were found between RAS inhibitor use and major adverse limb event (HR, 0.95; 95% CI, 0.73-1.22), major amputation (HR, 0.82; 95% CI, 0.57-1.18), or reintervention (HR, 1.05; 95% CI, 0.85-1.31). These point estimates were not different for those on angiotensin-converting enzyme inhibitors vs angiotensin receptor blockers, nor were they affected by the type of revascularization., Conclusions: Patients with CLTI prescribed an RAS inhibitor at discharge demonstrated significantly less long-term mortality, whereas limb events were unaffected. These data indicate that, in these heavily burdened patients, the benefit is restricted to those on a high dose, which underscores the importance of attaining these doses., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Among patients with proteinuric chronic kidney disease (CKD), current guideline recommendations mandate the use of agents blocking the renin angiotensin aldosterone system (RAAS) as first-line antihypertensive therapy based on randomized trials demonstrating that RAAS inhibitors are superior to other antihypertensive drug classes in slowing nephropathy progression to end-stage renal disease. However, the opportunities for adequate RAAS blockade in CKD are often limited, and an important impediment is the risk of hyperkalemia, especially when RAAS inhibitors are used in maximal doses or are combined. Accordingly, a large proportion of patients with proteinuric CKD may not have the anticipated renoprotective benefits since RAAS blockers are often discontinued due to incident hyperkalemia or are administered at suboptimal doses for fear of the development of hyperkalemia. Two newer potassium binders, patiromer and sodium zirconium cyclosilicate (ZS-9), have been shown to effectively and safely reduce serum potassium levels and maintain long-term normokalemia in CKD patients receiving background therapy with RAAS inhibitors. Whether these novel potassium-lowering therapies can overcome the barrier of hyperkalemia and enhance the tolerability of RAAS inhibitor use in proteinuric CKD awaits randomized trials., (Published by Elsevier Inc.)

Objective: The objective of this study was to summarize the literature regarding the effects of renin-angiotensin system blockade (RASB) using angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on human abdominal aortic aneurysm (AAA) growth, rupture, and perioperative mortality., Methods: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our review protocol was registered at the International Prospective Register of Systematic Reviews (CRD42016054082). We searched the Cochrane Central Register of Controlled Trials database, MEDLINE, and Embase from inception to 2017 for studies examining the effects of ACEi or ARB treatment on AAA growth, rupture, or perioperative mortality. Review, abstraction, and quality assessment were conducted in duplicate, and a third author resolved discrepancies. We assessed study quality using the Cochrane and Newcastle-Ottawa scales. We used random-effects models to calculate pooled mean differences and odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was quantified using the I 2 statistic., Results: Our search yielded 525 articles. One randomized and seven observational studies involving 35,448 patients were included. Inter-rater agreement was excellent (κ = 0.78), and risk of bias was low to moderate. All studies investigated ACEis, three studies investigated ARBs, and two studies included a composite RASB group consisting of ACEi or ARB users. Five studies assessed AAA growth, two assessed rupture rate, and one reported 30-day mortality after elective open repair. There was no difference in AAA growth rate between RASB and control (mean difference, 0.03 mm/y; 95% CI, -0.40 to 0.46; P = .88; I 2  = 60%). No protective effect of RASB (OR, 0.92; 95% CI, 0.72, 1.16; P = .47; I 2  = 90%) was demonstrated for AAA rupture. Finally, RASB increased 30-day mortality in patients undergoing elective open AAA repair (OR, 5; 95% CI, 1.4, 27) according to a single well-adjusted study., Conclusions: RASB does not appear to affect AAA growth and rupture rate but increases elective perioperative mortality. The small number of heterogeneous, retrospective studies and limited long-term follow-up preclude a definitive dismissal of RASB as pharmacotherapy for AAA. Prospective, long-term data are needed to clarify the effect of RASB on AAA growth, rupture, and perioperative mortality., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The association between angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) doses on outcomes in patients with heart failure (HF) with reduced ejection fraction is uncertain. The objective of this study was to investigate the effect of dose of ACEI and ARBs on outcomes and drug discontinuation in patients with HF with reduced ejection fraction., Methods and Results: MEDLINE, Ovid SP, and Embase were searched from the inception of these databases till August 2016. Randomized controlled trials that compared high doses of ACEI or ARB against low doses among patients with HF with reduced ejection fraction were included. Pooled analysis was done using a random-effects model, and quality of the studies was assessed by JADAD scale. The main outcomes were all-cause mortality and drug discontinuation. A total of 6 studies (4841 patients in low-dose and 4330 patients in high-dose groups) were included. Compared with low dose, high-dose ACEI or ARBs decreased all-cause mortality modestly (relative risk, 0.94; 95% confidence interval (CI), 0.89-1.00; P =0.05; I 2 =0%) and composite of HF hospitalizations and all-cause mortality (relative risk, 0.93; 95% CI, 0.87-1.00; P =0.04; I 2 =39.8%). No significant difference was found between the 2 groups in HF hospitalizations (relative risk, 0.94; 95% CI, 0.70-1.26; P =0.68; I 2 =52.8%) and all-cause hospitalizations (relative risk, 0.97; 95% CI, 0.85-1.11; P =0.67; I 2 =31.7%) risk. Discontinuation rates were also not significantly different in both groups (odds ratio, 1.13; 95% CI, 0.92-1.39; P =0.25; I 2 =32.6%)., Conclusions: In patients with HF with reduced ejection fraction, compared with lower doses, higher doses of ACEI and ARB significantly though modestly improved the composite end point of all-cause mortality or HF hospitalization without significantly increasing the chances of discontinuation., (© 2017 American Heart Association, Inc.)

Aim: To assess the persistence of diabetic patients to oral medications., Methods: The study included all type 2 diabetic patients over 40 years, members of one District of Clalit Health Services Israel, who were diagnosed with diabetes mellitus before 2008 and who filled at least one prescription per year during 2008-2010, for the following medications: metformin, glibenclamide, acarbose, statins, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARBs). Purchase of at least 9 monthly prescriptions during 2009 was considered "good medication persistence". We compared HbA1c and LDL levels, according to medication persistence, for each medication; and cross persistence rates between medications., Results: 21,357 patients were included. Average age was 67.0±11.0years, 48.9% were men, and 35.8% were from low SES. Good medication persistence rates for ARBs were 78.8%, ACEI 69.0%, statins 66.6%, acarbose 67.8%, metformin 58.6%, and glibenclamide 55.3%. Good persistence to any of the medications tested was associated with a higher rate of good persistence to other medications. Patients who took more medications had better persistence rates., Conclusions: Different oral medications used by diabetic patients have different persistence rates. Good persistence for any one medication is an indicator of good persistence to other medications. Investment in enhancing medication persistence in persons with diabetes may improve persistence to other medications, as well as improve glycemic control., (Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score., Methods and Results: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new β-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m 2 were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration., Conclusions: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m 2 , but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Drugs interfering with the renin-angiotensin-aldosterone system (RAAS) improved the prognosis in patients with hypertension, heart failure, diabetes and chronic kidney disease. However, combining different drugs brought no further benefit while increasing the risk of hyperkalemia, hypotension and acute renal failure. This was so with combining angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptors type 1 antagonists (ARB). Dissimilarly, in animal disease models this dual therapy proved clearly superior to single drug treatment and became the optimal standard regime for comparison with other treatments. This review analyzes the causes of the discrepancy of effects of the dual therapy between animal experiments versus clinical studies, and is focused on the outcomes in chronic kidney disease. Discussed is the role of species differences in RAAS, of the variability of the disease features in humans versus relative stability in animals, of the genetic uniformity in the animals but not in humans, and of the biased publication habits of experimental versus clinical studies. We attempt to understand the causes and reconcile the discordant findings and suggest to what extent dual RAAS inhibition should be continued in animal experiments and why its application in the clinics should be limited to strictly selected groups of patients.

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The reduction in overall mortality, cardiovascular mortality and the occurrence of myocardial infarction in patients treated with AT1 blockers is comparable with the use of ACE inhibitors. In addition, there is a lower proportion of AT1 blockers withdrawal of treatment due to adverse reactions.Key words: ACE inhibitors - AT1 blockers - cardioprotection - hypertension - renin-angiotensin-aldosteron system.

Aim: To evaluate the effects of canrenone as add-on therapy in patients already treated with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARBs) and hydrochlorothiazide at the maximum dosage (25 mg/d)., Method: In this randomized, open-label, controlled trial, we enrolled 175 Caucasian patients with essential hypertension not well controlled by concomitant ACE-I or ARBs and hydrochlorothiazide. At baseline, 87 patients (57 males and 30 females) were randomized to add canrenone 50 mg, and 88 (56 males and 32 females) patients to canrenone 100 mg, once a day, for 3 months. At baseline and after 3 months, we evaluated blood pressure (BP), pulse pressure (PP), heart rate (HR), fasting plasma glucose (FPG), homeostasis model assessment insulin (HOMA Index), lipid profile, electrolytes, uric acid, estimated glomerular filtration rate (eGFR), plasma urea, aldosterone, B-type natriuretic peptide (BNP), and galectin-3., Results: Blood pressure decreased with both dosages of canrenone, with a better effect with canrenone 100 mg (-20.26 vs -23.68 mm Hg for SBP, and -10.58 vs -12.38 mm Hg for DBP), without a clinically relevant increase in potassium levels. We did not observe any differences regarding FPG or HOMA Index, nor of lipid profile, with the exception of triglycerides, which increased compared to baseline with canrenone 50 mg (+0.25 vs +0.34 mEq/L). Creatinine slightly increased with canrenone 100 mg (+0.02 vs +0.05 mg/dL), although no variations of eGFR were observed in neither groups. There was an increase in aldosterone levels with canrenone 50 mg. No changes in BNP or galectin-3 were recorded., Conclusion: Both canrenone dosages gave a decrease in blood pressure, with a better effect with the higher dose, with only a slight increase in potassium and creatinine levels, which were not clinically relevant. Clinical Trials Registration Eudract number: 2010-023606-13; ClinicalTrials.gov NCT02687178., (© 2016 The Authors. Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.)

Background: Renin-angiotensin aldosterone system (RAAS) inhibitors significantly improve outcome in heart failure (HF) patients with reduced ejection fraction (HFREF), irrespective of the occurrence of worsening renal function (WRF). However, in HF patients with preserved ejection fraction (HFPEF), RAAS inhibitors have not been shown to improve outcome but are still frequently prescribed., Methods and Results: Random effect meta-analysis was performed to investigate the relationship between RAAS inhibitor therapy, WRF in both HF phenotypes, and mortality. Studies were selected based on literature search in MEDLNE and included randomized, placebo controlled trials of RAAS inhibitors in chronic HF. The primary outcome consisted of the interaction analysis for the association between RAAS inhibition-induced WRF, HF phenotype and outcome. A total of 8 studies (6 HFREF and 2 HFPEF, including 28 961 patients) were included in our analysis. WRF was more frequent in the RAAS inhibitor group, compared with the placebo group, in both HFREF and HFPEF. In HFREF, WRF induced by RAAS inhibitor therapy was associated with a less increased relative risk of mortality (relative risk, 1.19 (1.08-1.31); P <0.001), compared with WRF induced by placebo (relative risk, 1.48 (1.35-1.62); P <0.001; P for interaction 0.005). In contrast, WRF induced by RAAS inhibitor therapy was strongly associated with worse outcomes in HFPEF (relative risk, 1.78 (1.43-2.21); P <0.001), whereas placebo-induced WRF was not (relative risk, 1.25 (0.88-1.77); P =0.21; P for interaction 0.002)., Conclusions: RAAS inhibitors induce renal dysfunction in both HFREF and HFPEF. However, in contrast to patients with HFREF where mortality increase with WRF is small, HFPEF patients with RAAS inhibitor-induced WRF have an increased mortality risk, without experiencing improved outcome with RAAS inhibition., (© 2017 American Heart Association, Inc.)

Background: The chronic use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker has been associated with hyperkalemia in patients with reduced renal function even after the initiation of hemodialysis. Whether such medications may cause a similar effect in peritoneal dialysis patients is not well established. So, the aim of our study was to analyze the impact of renin-angiotensin-aldosterone inhibitors on the serum levels of potassium in a national cohort of peritoneal dialysis patients., Method: A prospective, observational, nationwide cohort study was conducted. We identified all incident patients on peritoneal dialysis that had angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) prescribed for at least 3 months and a similar period of time without these medications. Patients were divided into 4 groups: Groups I and III correspond to patients using, respectively, an ACEi or ARB and then got the drug suspended; Groups II and IV started peritoneal dialysis without the use of any renin-angiotensin aldosterone system inhibitor and then got, respectively, an ACEi or ARB introduced. Changes in potassium serum levels were compared using 2 statistical approaches: (1) the non-parametric Wilcoxon test for repeated measures and (2) a crossover analysis., Results: Mean potassium serum levels at the first phase of the study for Groups I, II, III, and IV were, respectively, 4.46 ± 0.79, 4.33 ± 0.78, 4.41 ± 0.63, and 4.44 ± 0.56. Changes in mean potassium serum levels for Groups I, II, III, and IV were -0.10 ± 0.60, 0.02 ± 0.56, -0.06 ± 0.46, and 0.03 ± 0.50, respectively., Conclusion: The use of ACEi and ARB was not associated with a greater risk for hyperkalemia in stable peritoneal dialysis patients independently of residual renal function., (© 2017 S. Karger AG, Basel.)

Increased systemic vascular resistance and coronary microvascular dysfunction are well-documented in essential hypertension (EH). We investigated the effect of additional vasodilating treatment on coronary and peripheral resistance circulation in EH patients with high systemic vascular resistance index (SVRI) despite well-treated blood pressure (BP). We enroled patients on stable antihypertensive treatment that were given intensified vasodilating therapy (ACE inhibitor, angiotensin II receptor blocker or calcium channel blocker). Before and following 6 months of intensified therapy, coronary resting and maximal artery flow were measured by transthoracic Doppler echocardiography to calculate coronary flow reserve (CFR) and minimum vascular resistance (C-R min ). Cardiac output was estimated by inert gas rebreathing to calculate SVRI. Maximal forearm blood flow was determined by venous occlusion plethysmography to calculate minimum vascular resistance (F-R min ). Patients were assigned into two groups: high-SVRI and low-SVRI subgroups, based on a median split at baseline. Following additional treatment SVRI decreased more in the high-SVRI group than in the low-SVRI group (14.4 vs -2.2%: P=0.003), despite similar baseline ambulatory BP (132/81 mm Hg) and BP reduction (6.5 and 4.6%: P=0.19). F-R min remained unchanged (6.5 vs -2.0%: P=0.30), while C-R min decreased by 22 and 24% (P=0.80) and CFR increased by 23 and 17% (P=0.16). Thus, intensified vasodilating therapy improved SVRI more in patients with high SVRI than in those with low SVRI. Regardless of SVRI status, the treatment improved cardiac but not forearm dilatation capacity. The substantial improvement of the hypertensive cardiac microvascular dysfunction was not related to the reduction in SVRI.

Objective: To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers., Approach and Results: This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively., Conclusions: Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion., (© 2016 American Heart Association, Inc.)

Background: Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening in the Prospective Comparison of ARNI (angiotensin-receptor-neprilysin inhibitor) with ACEI (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF)., Methods and Results: Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worsening: outpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9-5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0-6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2-6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73-0.86) and was consistent across the components of the latter., Conclusions: Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255., (© 2016 American Heart Association, Inc.)

Background: Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE-inhibitors in a real life clinical setting., Methods: The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M., Results: A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73)., Conclusions: These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control.

Background/aims: Angiotensin II type 1 receptor blockers (ARBs) have not been adequately evaluated in patients without left ventricular (LV) dysfunction or heart failure after acute myocardial infarction (AMI)., Methods: Between November 2005 and January 2008, 6,781 patients who were not receiving angiotensin-converting enzyme inhibitors (ACEIs) or ARBs were selected from the Korean AMI Registry. The primary endpoints were 12-month major adverse cardiac events (MACEs) including death and recurrent AMI., Results: Seventy percent of the patients were Killip class 1 and had a LV ejection fraction ≥ 40%. The prescription rate of ARBs was 12.2%. For each patient, a propensity score, indicating the likelihood of using ARBs during hospitalization or at discharge, was calculated using a non-parsimonious multivariable logistic regression model, and was used to match the patients 1:4, yielding 715 ARB users versus 2,860 ACEI users. The effect of ARBs on in-hospital mortality and 12-month MACE occurrence was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality(1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to0.756; p = 0.006) and 12-month MACE occurrence (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051)., Conclusions: Our results suggest that ARBs are not inferior to, and may actually be better than ACEIs in Korean patients with AMI.

Objective: Discontinuation of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) medications before surgery has been suggested because of the potentially deleterious effects of hypotension. We investigated the effect of preoperative ACEI and/or ARB use on early outcomes after carotid endarterectomy (CEA)., Methods: We examined 3752 consecutive CEA patients within the Vascular Study Group of New England from September 2012 to September 2014 and compared outcomes for patients treated (n = 1772) or not treated (n = 1980) with ACEI and/or ARB preoperatively. Outcomes included perioperative need for intravenous vasoactive medication (IVBPmed) for hypotension or hypertension (HTN), major adverse cardiac events (MACEs), and the combined outcome of stroke or death. Adjusted analysis was performed using multivariable logistic regression of the crude cohort and by constructing a propensity score matched cohort (n = 1441)., Results: ACEI and/or ARB users were more likely to be male (64% vs 59%; P = .001), with a higher prevalence of diabetes (41% vs 28%; P < .0001), HTN (97% vs 82%; P < .0001), coronary artery disease (31% vs 25%; P = .0001), congestive heart failure (10% vs 8%; P = .02), and asymptomatic carotid disease (59% vs 54%; P = .004). Patients who received ACEI and/or ARB preoperatively were more likely to be treated with aspirin (92% vs 88%; P = .0002) and statins (89% vs 85%; P = .001) preoperatively. In the unadjusted analysis, no significant differences were identified in hypotension that required IVBPmed (12% vs 11%; odds ratio [OR], 1.1; 95% confidence interval [CI], 0.9-1.4; P = .22), MACE (3% vs 2%; OR, 1.3; 95% CI, 0.8-1.9; P = .32), or stroke or death (3% vs 3%; OR, 1.0; 95% CI, 0.7-1.6; P = .89) for preoperative ACEI and/or ARB treated and nontreated patients, respectively. Preoperative ACEI and/or ARB usage was, however, associated with HTN that required IVBPmed (13% vs 10%; OR, 1.3; 95% CI, 1.1-1.6; P = .01). Analysis of the propensity score matched cohort revealed no significant differences in hypotension that required IVBPmed (12% vs 12%; OR, 1.0; 95% CI, 0.8-1.3; P = .86), MACE (3% vs 2%; OR, 1.1; 95% CI, 0.7-1.8; P = .62; ), or stroke or death (3% vs 3%; OR, 1.0; 95% CI, 0.7-1.6; P = .91) for patients treated or not treated with preoperative ACEI and/or ARB, respectively. ACEI and/or ARB remained associated with HTN that required IVBPmed (13% vs 10%; OR, 1.3; 95% CI, 1.0-1.7; P = .02). Results were similar after adjustment using logistic regression. The incidence of hospital length of stay >1 day was similar between ACEI and/or ARB treated and not treated patients (29% vs 32%; OR, 0.9; 95% CI, 0.8-1.1; P = .21)., Conclusions: Preoperative ACEI and/or ARB use was associated with marginally increased use of IVBPmed for HTN but not for hypotension and was not associated with increased MACE, stroke, or death. On the basis of these metrics, the use of preoperative ACEI and/or ARB appears safe before CEA., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The management of ischemic nephropathy due to atherosclerotic renal artery stenosis has become increasingly conservative in the modern era, with current guidelines recommending optimized medical therapy as the initial step. The doubts raised by the recently published trials of revascularization strategies have led to a renewed focus on pharmacological strategies promoting blood pressure control and renal protection. It is essential to further elucidate the pathophysiological mechanisms underlying hypoperfusion induced renal microvascular dysfunction with subsequent tissue injury and fibrogenesis. The role of renin angiotensin aldosterone system as a mediator of the main pathophysiological consequences of ischemic nephropathy is well known. However, more recent experimental evidence on the adrenergic system and intrarenal tubular feedback mechanisms has stimulated new interest towards a multi-target therapeutic approach., Methods: This review focuses on the pharmacology of the principle therapeutic drug classes currently used in the treatment of atherosclerotic renal artery stenosis with an analysis of their metabolic aspects and use in clinical practice based on evidence from clinical trials., Results and Conclusions: An optimal pharmacologic approach is crucial for a successful prevention of renal injury and cardiovascular events in this high-risk population. Antihypertensive treatment should include renin angiotensin aldosterone system blockade medication not only for their antihypertensive properties, but especially for those cardio and renoprotective.

Objective: We evaluated the safety and efficacy of hypertension management with Coveram (perindopril/amlodipine combination) in patients with uncontrolled blood pressure (BP). All patients were on previous angiotensin receptor blocker (ARB) treatment., Methods: This was a 3 country, multi-centre (7 cities), open-label, observational study in the Arabian Gulf. Patients (≥18 years) were recruited between October 2012 and November 2013 and followed-up for 3 months after enrolment. Outcomes included changes in BP from baseline and BP goal attainment rates as per Joint National Committee- 8 (<140/90 mmHg for diabetics and those <60 years of age and <150/90 mmHg for those ≥60 years of age without diabetes). Medication tolerance was also assessed from both patient and physician perspectives., Results: Hypertensive patients (n=760; mean age: 51±10 years; 67% were males) were included. A total of 178 patients (23%) were lost to follow-up. The perindopril/amlodipine combination was associated with an overall reduction in systolic BP (SBP) (31 mmHg; p<0.001) and diastolic BP (DBP) (18 mmHg; p<0.001) from baseline. An overall BP control rate was achieved in 87% (n=507) of the participants. There were significant incremental BP reductions with dose up-titration, especially SBP (p<0.001). Those with high SBP (>180 mmHg) at baseline were associated with a mean reduction of 59 mmHg (p<0.001). The perindopril/amlodipine combination had excellent tolerance levels over the study period from both patient and physician perspectives (at 99% and 98%, respectively; p<0.001)., Conclusions: The perindopril/amlodipine combination is an effective and well tolerated anti-hypertensive option in patients on previous ARB treatment.

Background: The aim of this study was to analyze the long-term efficacy and safety of angiotensin-converting enzyme inhibitor (ACEi) and ACEi + angiotensin receptor blocker (ARB) treatments in a cohort of children with Alport syndrome (AS)., Methods: This was a respective review of 79 Chinese children with AS who received ACEi alone or combined ACEi + ARB therapy., Results: The mean age of the pediatric patients with AS at onset of treatment was 8.6 ± 4.1 (range 1.5-16.3) years. The mean duration of follow-up was 2.5 ± 1.8 (range 0.5-7.8) years. For analysis, we separated the children into three groups according to proteinuria level before treatment, namely, <25, 25-50, and ≥50 mg/kg/day, respectively; after 1 year of treatment the proteinuria had decreased from 11.0 to 9.7 mg/kg/day, from 34.6 to 15.2 mg/kg/day, and from 73.0 to 50.0 mg/kg/day in each group, respectively. Proteinuria decreased significantly during the first 2 years of treatment and was stable from the third to fifth years of treatment. There was no statistically significant difference in the antiproteinuric effect of the ACEi and ACEi + ARB treatments in patients with severe or less severe mutations after 1 year of therapy. Five children stopped the ACEi + ARB treatment due to a decline in creatinine clearance., Conclusion: Our findings demonstrate that early and long-term ACEi and ARB treatments in children with AS is efficient and well tolerated. The antiproteinuric effect of ACEi and ARB is of equal value in children with severe and less severe mutations in the COL4An gene.

Background: Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not., Methods: Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-)., Results: Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5%) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1%; P<0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1%) than in the RCT+ AZL-M group (64.1%), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1%). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (≤0.5%) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility., Conclusions: These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities.

Hypertension is one of the major risk factor able to promote development and progression of several cardiovascular diseases, including left ventricular hypertrophy and dysfunction, myocardial infarction, stroke, and congestive heart failure. Also, it is one of the major driven of high cardiovascular risk profile in patients with metabolic complications, including obesity, metabolic syndrome and diabetes, as well as in those with renal disease. Thus, effective control of hypertension is a key factor for any preventing strategy aimed at reducing the burden of hypertension-related cardiovascular diseases in the clinical practice. Among various regulatory and contra-regulatory systems involved in the pathogenesis of cardiovascular and renal diseases, renin-angiotensin system (RAS) plays a major role. However, despite the identification of renin and the availability of various assays for measuring its plasma activity, the specific pathophysiological role of RAS has not yet fully characterized. In the last years, however, several notions on the RAS have been improved by the results of large, randomized clinical trials, performed in different clinical settings and in different populations treated with RAS inhibiting drugs, including angiotensin converting enzyme (ACE) inhibitors and antagonists of the AT1 receptor for angiotensin II (ARBs). These findings suggest that the RAS should be considered to have a central role in the pathogenesis of different cardiovascular diseases, for both therapeutic and preventive purposes, without having to measure its level of activation in each patient. The present document will discuss the most critical issues of the pathogenesis of different cardiovascular diseases with a specific focus on RAS blocking agents, including ACE inhibitors and ARBs, in the light of the most recent evidence supporting the use of these drugs in the clinical management of hypertension and hypertension-related cardiovascular diseases.

Background: Renin-angiotensin system (RAS) inhibitor use after acute myocardial infarction (AMI) is a quality indicator, but there may also be reasons not to use this therapy. We sought to determine how chronic kidney disease (CKD) and acute kidney injury (AKI) affected RAS inhibitor prescription after AMI in patients with and without decreased ejection fraction (EF)., Methods: Participants from the TRIUMPH registry were categorized by admission estimated glomerular filtration rate (eGFR in mL/min per 1.73 m(2); severe [<30], moderate [30-59], mild [60-89], and no [≥90] CKD) and occurrence of AKI (an increase in creatinine ≥0.3 mg/dL or ≥50%). Renin-angiotensin system inhibitor prescriptions at discharge were compared across categories of CKD, AKI, and decreased EF (<40% vs ≥40%) using a hierarchical modified Poisson model., Results: Among 4,223 AMI patients (mean age 59.0 years, 67.0% male, 67.3% white), RAS inhibitor use decreased significantly with lower eGFR (P < .001), but there was no effect of decreased EF on this relationship (interaction P = .40). Without AKI, severe and moderate CKD were associated with significantly less RAS inhibitor use: relative risks (RRs) 0.67 (95% CIs, 0.58-0.78) and 0.94 (0.90-0.99), respectively. When AKI occurred, CKD was associated with less RAS inhibitor use: RRs 0.84 (0.76-0.93) for mild CKD, 0.78 (0.68-0.88) for moderate CKD, and 0.50 (0.42-0.61) for severe CKD. Ejection fraction <40% was associated with use (RR 1.11, 1.03-1.18), independent of renal function., Conclusions: Chronic kidney disease and AKI are associated with fewer RAS inhibitor prescriptions at discharge, but in both AKI and non-AKI patients, eGFR was more strongly associated with use than EF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Few studies evaluated the effects of pentoxifylline on hard endpoints in patients with predialysis stage 5 chronic kidney disease (CKD). Thus, we tried to explore the effects of pentoxifylline and its interaction with renin-angiotensin-aldosterone system (RAAS) blockade on the development of endstage renal disease (ESRD) and mortality. This nationwide cohort study retrospectively included patients who had a serum creatinine level of >6 mg/dL and received erythropoiesis-stimulating agents (ESAs) between 2000 and 2010. We analyzed 7,366 pentoxifylline users and 7,366 propensity score-matched nonusers. Using Cox proportional hazard models, pentoxifylline reduced the risks of ESRD and the composite renal outcome but not that of mortality. In terms of the risks of developing ESRD, pentoxifylline alone exerted a comparable beneficial effect to combined therapy with an RAAS inhibitor and greater renoprotection than RAAS inhibitor monotherapy. This study suggests pentoxifylline is efficacious in slowing progression to ESRD in patients with predialysis stage 5 CKD., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

Background: Renin-angiotensin-aldosterone system (RAS) blockers are commonly used for cardiovascular diseases. Currently, little information exists for the Asian population on angioedema, a rare yet serious adverse event., Objective: This study aimed to describe characteristics of RAS blockers-associated angioedema (RASBA) in Thai patients., Methods: A retrospective study using the national pharmacovigilance database of Thailand was undertaken. Cases indicating the presence of angioedema with RAS blockers uses from 1984-2011 were identified. Patient demographics, co-morbidities, concomitant drugs, information for the RAS blockers and angioedema were obtained as well as causality assessment and quality of reports., Results: A total of 895 cases were identified. Mean age was 59.9+12.8 years and 66.5% being female. Most angioedema events (48.6%) occurred during the first week of treatment. Angiotensin converting enzyme inhibitors (87.7%) were the most commonly implicated agents followed by angiotensin receptor blockers (10.5%), aldosterone antagonist (2.1%) and direct renin inhibitor (0.2%). Out of the 895 cases incorporated in this study, 165 (18.4%) were classified as serious events and resulted in hospitalization. The overall case fatality rate was 0.4%. Respiratory disturbance occurred in 46 cases (5.1%). Patients with respiratory complications tended to be younger (53.4+13.9 vs 60.3+12.7 years old; p=0.002) and with higher frequency of allergy history (26.1% vs 14.7%; p=0.032) compared to those without respiratory complications. Based on multivariate logistic regression, the adjusted OR for history of allergy was 2.23 (95%CI: 1.04 - 4.78, p = 0.041)., Conclusions: RASBA in Thai population occurred mostly in elderly female patients and often led to hospitalization. Since large number of patients is regularly exposed to RAS-blockers, a nationwide attempt to raise awareness of clinicians when prescribing RAS-blockers is prudent.