Effect of pre-transplantation use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in kidney transplant recipients-propensity score-matched analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARBs) can cause acute kidney injury under dehydratation or in hemodynamically unstable conditions. Regarding kidney transplantation (KT), the risk of using ACEi/ARBs before surgery is not well established. Therefore, we evaluated the clinical outcomes to determine the effect of preoperative use of ACEi/ARBs on KT. METHODS: We retrospectively collected 1187 patients who received living-donor KT between January 2017 and December 2021. We conducted a propensity score-matched analysis between the ACEi/ARB(+) and ACEi/ARB(-) groups and evaluated the effects of ACEi/ARBs on delayed graft function, post-KT renal function, hyperkalemia events, rejection, and graft survival. RESULTS: The ACEi/ARB(+) group showed a similar incidence of delayed graft function as the ACEi/ARB(-) group (1.8% vs. 1.0%, P = 0.362). The risk of delayed graft function was not upregulated in the ACEi/ARB(+) group after propensity score-matching (odds ratio: 0.50, 95% confidence interval (CI) 0.13-2.00). Postoperative creatinine levels and the slope of creatinine levels after KT also were not significantly different between the two groups (creatinine slope from POD#0 to POD#7: - 0.73 ± 0.35 vs. - 0.75 ± 0.32 mg/dL/day, P = 0.464). Hyperkalemia did not occur more often in the ACEi/ARB(+) group than in the ACEi/ARB(-) group during perioperative days. Rejection-free survival (P = 0.920) and graft survival (P = 0.621) were not significantly different between the two groups. CONCLUSIONS: In KT, the preoperative use of ACEi/ARBs did not significantly affect clinical outcomes including delayed graft function, postoperative renal function, hyperkalemia events, incidence of rejection, and graft survival rates compared to the patients who did not receive ACEi/ARBs.

Effects of Antihypertensive Agents on the Clinical Outcome of Hospitalized COVID-19 Patients Concomitant with Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Given the ongoing COVID-19 pandemic, it is crucial to prioritize the management of underlying diseases in infected patients, with hypertension being one of the most common conditions. However, there lies a complicated correlation between antihypertensive agents and COVID-19 infection. OBJECTIVES: This study is to systematically evaluate the impact of continuing or discontinuing antihypertensive agents on mortality and infection severity in hospitalized patients with both hypertension and COVID-19. METHODS: A systematic electronic search was conducted on PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov to identify relevant clinical trials published between 1948 and September 2022. Two independent reviewers assessed the quality of the included studies and extracted relevant data. The primary outcome of interest was the relationship between in-hospital mortality and administration of antihypertensive agents. RESULTS: The meta-analysis revealed that continuous administration of antihypertensive agents, compared with discontinuation, significantly reduced in-hospital mortality among hypertension patients with COVID-19 infection [OR=0.49, 95 %CI (0.38, 0.65), p < 0.001, I2=65.3 %]. Specifically, patients receiving ACEI/ARB type agents had even lower mortality rates. Meta-regression analyses were conducted to examine the impact of publication date, sample size, study design, and mean age of the patients, and the results showed that the number of participants in the included studies was the primary source of heterogeneity (p = 0.032). The findings indicated a clear association between the use of antihypertensive agents and reduced mortality in these patients. CONCLUSION: nder the current circumstance of the sustained COVID-19 pandemic, it is recommended to continue the use of antihypertensive agents for patients with hypertension during COVID-19 infection, as it can help reduce the risk of mortality.

Effect of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on In-Hospital Outcomes Based on Renal Function Among Critically Ill Patients: Findings From the Medical Information Mart for Intensive Care IV Database.

Renal dysfunction is associated with increased mortality and length of hospital stay in critically ill patients. However, it remains unclear whether the early administration of an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) for intensive care unit patients with renal dysfunction is associated with reduced in-hospital mortality. We conducted a retrospective analysis of critically ill patients who received early administration of an ACEI/ARB within 72 hours after being hospitalized. Patients were selected from the Medical Information Mart for Intensive Care IV database. We included 18,986 critically ill patients in our analysis. After propensity score matching, our final study cohort of 4974 patients consisted of patients who received early administration of an ACEI/ARB (n = 2487) and nonusers (n = 2487). Results of logistic regression showed that early administration of an ACEI/ARB was associated with reduced risk of in-hospital mortality (odds ratio, 0.64; 95% confidence interval, 0.53-0.77; P < .001) and intensive care unit death (odds ratio, 0.56; 95% confidence interval, 0.45-0.70; P < .001) when compared to nonusers. There was no meaningful interaction for early administration of an ACEI/ARB versus nonusers across estimated glomerular filtration rate in outcomes. Sensitivity analysis showed there was no difference in the outcomes between early administration of ACEI and that of ARB. In this study, we found that early administration of an ACEI/ARB was associated with a reduced risk of in-hospital adverse outcomes based on renal function among critically ill patients. There was no interaction between early administration of an ACEI/ARB and in-hospital adverse outcomes across estimated glomerular filtration rate.

ACEI/ARB and beta-blocker therapies for preventing cardiotoxicity of antineoplastic agents in breast cancer: a systematic review and meta-analysis.

Anthracyclines and trastuzumab are widely used to treat breast cancer but increase the risk of cardiomyopathy and heart failure. With the use of trastuzumab and anthracycline-containing medications, this study intends to evaluate the effectiveness and security of current treatments against cardiotoxicity. We conducted a systematic review of randomized controlled trials (RCTs), which used at least one angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or beta-blocker (BB) to prevent cardiotoxicity of antineoplastic agents for breast cancer, in 4 databases (PubMed, Cochrane Library, EMBASE, Web of Science) from inception to 11 May 2022, without language restrictions. The outcome of interest was left ventricular ejection fraction (LVEF) and adverse events. Stata 15 and R software 4.2.1 were used to perform all statistical analyses. The Cochrane version 2 of the risk of bias tool was used to assess the risk of bias, and the grading of recommendations assessment, development, and evaluation (GRADE) assessment was used to appraise the quality of the evidence. Fifteen randomized clinical studies with a total of 1977 patients were included in the analysis. The included studies demonstrated statistically significant LVEF in the ACEI/ARB and BB treatment groups (χ2 = 184.75, I2 = 88.6%, p = 0.000; SMD 0.556, 95% CI 0.299 to 0.813). In an exploratory subgroup analysis, the benefit of experimental agents on LVEF, whether anthracyclines or trastuzumab, was prominent in patients treated with ACEIs, ARBs, and BBs. Compared to placebo, ACEI/ARB and BB treatments in breast cancer patients protect against cardiotoxicity after trastuzumab and anthracycline-containing medication treatment, indicating a benefit for both.

Influence of Renin-Angiotensin System Inhibitors on the Treatment of Metastatic Renal Cancer.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are mainly known as anti-hypertensive drugs. Recent evidence suggests their anti-tumor potential against renal cancer. More than one-fourth of patients present with metastasis on their first visit. OBJECTIVE: The purpose of the current study was to examine the potential clinical impact of ACEI/ARB on metastatic renal cell carcinoma (mRCC). METHODS: We searched through several online databases, including Pubmed, Scopus, Web of Science, and Embase, to find clinical studies that have investigated the association between treatment with ACEI/ARB and the survival of patients with mRCC. The hazard ratio (HR) and 95% confidence interval (95% CI) were utilized to assess the strength of the association. RESULTS: A total of 6 studies with a total number of 2,364 patients were found eligible for the final analysis. The HR for the relationship between ACEI/ARB use and overall survival (OS) showed patients undergoing treatment with ACEI/ARB to have higher OS than non-users (HR: 0.664, 95% CI 0.577-0.764, p=0.000). Furthermore, the HR for the relationship between ACEI/ARB use and progression-free survival (PFS) showed patients undergoing treatment with ACEI/ARB to have higher PFS than non-users (HR: 0.734, 95% CI 0.695-0.794, p=0.000). CONCLUSION: The results of this review offer ACEI/ARB as a potential therapeutic option associated with improved survival outcomes in patients receiving anti-vascular endothelial growth factor therapy.

Renin-angiotensin system inhibition and in-hospital mortality in acute coronary syndrome patients with advanced renal dysfunction: findings from CCC-ACS project and a nationwide electronic health record-based cohort in China.

AIMS: In acute coronary syndrome (ACS) patients without advanced renal dysfunction [estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2], early (within 24 h of admission) angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) is the guideline-directed medical therapy. The clinical efficacy of early ACEI/ARB therapy among ACS patients with advanced renal dysfunction remains unclear. METHODS AND RESULTS: Among 184 850 ACS patients hospitalized from July 2014 to December 2018 in the Chinese National Electronic Disease Surveillance System Platform (CNEDSSP) cohort and 113 650 ACS patients enrolled from November 2014 to December 2019 in the Improving Care for Cardiovascular Disease in China-ACS Project (CCC-ACS) cohort, we identified 3288 and 3916 ACS patients with admission eGFR < 30 mL/min/1.73 m2 [2647 patients treated with ACEI/ARB (36.7%)], respectively. After 1:1 propensity score matching (PSM) in each cohort, Kaplan-Meier analysis showed that early ACEI/ARB use was associated with a 39% [hazard ratio (HR): 0.61, 95% confidence interval (95% CI): 0.45-0.82] and a 34% (HR: 0.66, 95% CI: 0.46-0.95) reduction in in-hospital mortality in CNEDSSP and CCC-ACS cohorts, respectively, which was consistent in multiple sensitivity analyses. A random effect meta-analysis of the two cohorts after PSM revealed a 32% reduction (risk ratio: 0.68, 95% CI: 0.55-0.84) in in-hospital mortality among ACEI/ARB users. CONCLUSIONS: Based on two nationwide cohorts in China in contemporary practice, we demonstrated that ACEI/ARB therapy initiated within 24 h of admission is associated with a reduction in in-hospital mortality in ACS patients with advanced renal dysfunction. CLINICAL TRIAL REGISTRATION: CCC-ACS project was registered at URL: https://www.clinicaltrials.gov. (Unique identifier: NCT02306616).

Association of ACEI/ARB and statin prescribing patterns with mortality after Transcatheter Aortic Valve Replacement (TAVR): Findings from real-world claims data.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become the standard of care for most patients with severe aortic stenosis (AS), but the impact of medical therapy prescribing patterns on post-TAVR patients has not been thoroughly investigated. METHODS: We analyzed Optum claims data from 9,012 adults who received TAVR for AS (January 2014-December 2018). Pharmacy claims data were used to identify patients who filled ACEI/ARB and/or statin prescriptions during the study's 90-day landmark period post-TAVR. Kaplan-Meier and adjusted Cox Proportional Hazards models were used to evaluate the association of prescribing patterns with mortality during the 3-year follow-up period. Subgroup analyses were performed to examine the impact of 11 potential confounders on the observed associations. RESULTS: A significantly lower adjusted 3-year mortality was observed for patients with post-TAVR prescription for ACEI/ARBs (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.74-0.91, P = .0003) and statins (HR = 0.85, 95% CI 0.77-0.94, P = .0018) compared to patients who did not fill prescriptions for these medications post-TAVR. Subgroup analyses revealed that the survival benefit associated with ACEI/ARB prescription was not affected by any of the potential confounding variables, except preoperative ACEI/ARB prescription was associated with significantly lower risk of mortality vs postoperative prescription only. No other subgroup variables had significant interactions associated with survival benefits, including preoperative use of statins. CONCLUSIONS: In this large-scale, real-world analysis of patients undergoing TAVR, the prescription of ACEI/ARB and statins was associated with a significantly lower risk of mortality at 3-years, especially in those where the medications were initiated preoperatively.

Unfavourable outcomes in patients with heart failure with higher preserved left ventricular ejection fraction.

AIMS: Newly introduced drugs for heart failure (HF) have been reported to improve the prognosis of HF with preserved ejection fraction (HFpEF) in the lower range of left ventricular ejection fraction (LVEF). We hypothesized that a higher LVEF is related to an unfavourable prognosis in patients with HFpEF. METHODS AND RESULTS: We tested this hypothesis by analysing the data from a prospective multicentre cohort study in 255 patients admitted to the hospital due to decompensated HF (LVEF > 40% at discharge). The primary endpoint of this study was a composite outcome of all-cause death and readmission due to HF, and the secondary endpoint was readmission due to HF. LVEF and the mitral E/e' ratio were measured using echocardiography. In multicovariate parametric survival time analysis, LVEF [hazard ratio (HR) = 1.046 per 1% increase, P = 0.001], concurrent atrial fibrillation (AF) (HR = 3.203, P < 0.001), and E/e' (HR = 1.083 per 1.0 increase, P < 0.001) were significantly correlated with the primary endpoint. In addition to these covariates, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use was significantly correlated with the secondary endpoint (HR = 0.451, P = 0.008). Diagnostic performance plot analysis demonstrated that the discrimination threshold value for LVEF that could identify patients prone to reaching the primary endpoint was ≥57.2%. The prevalence of AF or E/e' ratio did not differ significantly between patients with LVEF ≥ 58% and with 40% < LVEF < 58%. CONCLUSION: A higher LVEF is independently related to poor prognosis in patients with HFpEF, in addition to concurrent AF and an elevated E/e' ratio. ACEI/ARB use, in contrast, was associated with improved prognosis, especially with regard to readmission due to HF. CLINICAL TRIAL REGISTRATION: https://www.umin.ac.jp/ctr/index.htm. UNIQUE IDENTIFIER: UMIN000017725.

Estimated Lifetime Benefit of Combined RAAS and SGLT2 Inhibitor Therapy in Patients with Albuminuric CKD without Diabetes.

BACKGROUND AND OBJECTIVES: Despite high rates of complications in patients with CKD without diabetes, the implementation of proven therapies in this group remains low. Expressing the clinical benefit of a therapy in terms of extra years free from the disease or death may facilitate implementation. We estimated lifetime survival free of kidney failure for patients with albuminuric CKD without diabetes treated with the combination therapy of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter-2 (SGLT2) inhibitors relative to patients not treated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used trial-level estimates of the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ramipril/benazepril; n=690) and SGLT2 inhibitors (dapagliflozin; n=1398) compared with placebo to derive the effect of combination therapy versus no treatment. Using this effect, we estimated treatment effect of combination therapy to the active treatment group of patients with albuminuric CKD without diabetes participating in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (n=697) and projected eventfree and overall survival for those treated and not treated with combination therapy. We also performed our calculations anticipating lower adherence and less pronounced benefits than were observed in the clinical trials. The primary outcome was a composite of doubling of serum creatinine, kidney failure, or death. RESULTS: The aggregate estimated hazard ratio comparing combination therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor versus no treatment for the primary end point was 0.35 (95% confidence interval, 0.30 to 0.41). For a 50-year-old patient until the age of 75 years, the estimated survival free from the primary composite end point was 17.0 (95% confidence interval, 12.4 to 19.6) years with the combination therapy and 9.6 years (95% confidence interval, 8.4 to 10.7) with no treatment with any of these agents, corresponding to a gain in eventfree survival of 7.4 (95% confidence interval, 6.4 to 8.7) years. When assuming lower adherence and less pronounced efficacy of combination therapy, the gain in eventfree survival ranged from 5.3 years (95% confidence interval, 4.4 to 6.1) to 5.8 years (95% confidence interval, 4.8 to 6.8). CONCLUSIONS: Treatment with the combination of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor in patients with albuminuric CKD without diabetes is expected to substantially increase kidney failure-free survival. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Benazepril for Advanced Chronic Renal Insufficiency, NCT00270426, and a Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (Dapa-CKD), NCT03036150.

Early ACEI/ARB use and in-hospital outcomes of acute myocardial infarction patients with systolic blood pressure <100 mmHg and undergoing percutaneous coronary intervention: Findings from the CCC-ACS project.

Background: Few studies have evaluated whether acute myocardial infarction (AMI) patients with relatively low blood pressure benefit from early ACEI/ARB use in the era of percutaneous coronary intervention (PCI). Objectives: This study evaluated the associations of ACEI/ARB use within 24 h of admission with in-hospital outcomes among AMI patients with SBP < 100 mmHg and undergoing PCI. Methods: This study was based on the Improving Care for Cardiovascular Disease in China-ACS project, a collaborative registry and quality improvement project of the American Heart Association and the Chinese Society of Cardiology. Between November 2014 and December 2019, a total of 94,623 patients with AMI were enrolled. Of them, 4,478 AMI patients with SBP < 100 mmHg and undergoing PCI but without clinically diagnosed cardiogenic shock at admission were included. Multivariable logistic regression and propensity score-matching analysis were used to evaluate the association between early ACEI/ARB use and in-hospital major adverse cardiac events (MACEs), a combination of all-cause death, cardiogenic shock, and cardiac arrest. Results: Of AMI patients, 24.41% (n = 1,093) were prescribed ACEIs/ARBs within 24 h of admission. Patients with early ACEI/ARB use had a significantly lower rate of MACEs than those without ACEI/ARB use (1.67% vs. 3.66%, p = 0.001). In the logistic regression analysis, early ACEI/ARB use was associated with a 45% lower risk of MACEs (odds ratio: 0.55, 95% CI: 0.33-0.93; p = 0.027). Further propensity score-matching analysis still showed that patients with early ACEI/ARB use had a lower rate of MACEs (1.96% vs. 3.93%, p = 0.009). Conclusion: This study found that among AMI patients with an admission SBP < 100 mmHg undergoing PCI, early ACEI/ARB use was associated with better in-hospital outcomes. Additional studies of the early use of ACEIs/ARBs in AMI patients with relatively low blood pressure are warranted.

Adherence with cardiovascular medications and the outcomes in patients with coronary arterial disease: "Real-world" evidence.

BACKGROUND: Cardiovascular medications are vital for the secondary prevention of coronary arterial disease (CAD). However, the effect of cardiovascular medication may depend on the optimal adherence of the patients. This meta-analysis aims to determine the magnitude of adherence to vascular medications that influences the absolute and relative risks (RRs) of mortality in patients with CAD in real-world settings. METHODS: The Cochrane Library, PubMed, and EMBASE databases were searched through March 1, 2022. Prospective studies reporting association as RR and 95% confidence interval between cardiovascular medication adherence and any cardiovascular events and/or all-cause mortality in patients with CAD were included. A one-stage robust error meta-regression method was used to summarize the dose-specific relationships. RESULTS: A total of 18 studies were included. There is a significant inverse linear association between cardiovascular medication adherence and cardiovascular events (pnonlinearity = .68) or mortality (pnonlinearity = .82). The exposure-effect analysis showed that an improvement of 20% cardiovascular medication adherence was associated with 8% or 12% lower risk of any cardiovascular events or mortality, respectively. In subgroup analysis, the benefit was observed in adherence of stain (RR: 0.90, for cardiovascular events, RR: 0.85, for mortality), angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB)(RR: 0.90, for mortality), and antiplatelet agent (RR: 0.89 for mortality) but not in beta-blocker (RR: 0.90, p = .14, for cardiovascular events, RR: 0.97, p = .32 for mortality). Estimated absolute differences per 1 million individuals per year for mortality associated with 20% improvement were 175 cases for statin, 129 cases for antiplatelet, and 117 cases for ACEI/ARB. CONCLUSION: Evidence from the real word showed poor adherence to vascular medications contributes to a considerable proportion of all cardiovascular disease events and mortality in patients with CAD.

Application of Angiotensin Receptor-Neprilysin Inhibitor in Chronic Kidney Disease Patients: Chinese Expert Consensus.

Chronic kidney disease (CKD) is a global public health problem, and cardiovascular disease is the most common cause of death in patients with CKD. The incidence and prevalence of cardiovascular events during the early stages of CKD increases significantly with a decline in renal function. More than 50% of dialysis patients die from cardiovascular disease, including coronary heart disease, heart failure, arrhythmia, and sudden cardiac death. Therefore, developing effective methods to control risk factors and improve prognosis is the primary focus during the diagnosis and treatment of CKD. For example, the SPRINT study demonstrated that CKD drugs are effective in reducing cardiovascular and cerebrovascular events by controlling blood pressure. Uncontrolled blood pressure not only increases the risk of these events but also accelerates the progression of CKD. A co-crystal complex of sacubitril, which is a neprilysin inhibitor, and valsartan, which is an angiotensin receptor blockade, has the potential to be widely used against CKD. Sacubitril inhibits neprilysin, which further reduces the degradation of natriuretic peptides and enhances the beneficial effects of the natriuretic peptide system. In contrast, valsartan alone can block the angiotensin II-1 (AT1) receptor and therefore inhibit the renin-angiotensin-aldosterone system. These two components can act synergistically to relax blood vessels, prevent and reverse cardiovascular remodeling, and promote natriuresis. Recent studies have repeatedly confirmed that the first and so far the only angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan can reduce blood pressure more effectively than renin-angiotensin system inhibitors and improve the prognosis of heart failure in patients with CKD. Here, we propose clinical recommendations based on an expert consensus to guide ARNI-based therapeutics and reduce the occurrence of cardiovascular events in patients with CKD.

Effects of Renin-Angiotensin System Inhibitors on Mortality and Disease Severity of COVID-19 Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: There is controversy over the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on the prognosis in patients with coronavirus disease 2019 (COVID-19), therefore, we aim to further explore the effect of renin-angiotensin-aldosterone system inhibitors on COVID-19-associated disease severity and mortality. METHODS: We systematically searched PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv from inception to 6 September 2021. The primary outcome was all-cause mortality. Secondary outcome was severe disease which was defined as admission to the intensive care unit, the use of noninvasive or invasive mechanical ventilation, or death. RESULTS: A total of 7 randomized controlled trials involving 1,321 COVID-19 patients were included. Fixed-effects meta-analysis demonstrated that the use of ACEI/ARB was not associated with higher risk of mortality (risk ratio [RR] = 0.84, 95% confidence interval [CI] 0.57-1.22, P = 0.10, I2 = 43%) and disease severity (RR = 0.86, 95% CI 0.71-1.05, P = 0.11, I2 = 47%). However, the subgroup analysis showed that compared with no ACEI/ARB use, the use of ARB was associated with a significant reduction of mortality (RR = 0.23, CI 0.09-0.60, P = 0.55, I2 = 0%) and disease severity (RR = 0.38, CI 0.19-0.77, P = 0.007). CONCLUSIONS: In conclusion, based on the available data, ACEI/ARB is not associated with the risk of mortality and disease severity in COVID-19 patients. And ACEI/ARB medications, especially ARB, should not be discontinued for patients with COVID-19.

Antihypertensive Therapy by ACEI/ARB Is Associated With Intestinal Flora Alterations and Metabolomic Profiles in Hypertensive Patients.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB) are the first-line drugs for the treatment of essential hypertension (HTN), one of the most important risk factors for cardiovascular and cerebrovascular diseases. Intestinal flora and microbial metabolites have been demonstrated to play important roles in blood pressure (BP) regulation and HTN development. However, it remains elusive that intestinal bacteria and metabolites are associated with the protective effects of ACEI/ARB anti-hypertensive drugs against HTN. In this study, we evaluated the effect of ACEI/ARB on gut microbiome and metabolites in patients suffering from HTN. We performed 16S rRNA sequencing and fecal metabolomic analysis of 36 HTN patients placed on ACEI/ARB therapy and 19 newly diagnosed HTN patients with no history of anti-hypertensive treatment. Patients under medication treatment were further classified into well-controlled (n = 24) and poor-controlled (n = 12) groups according to their BP levels. The ACEI/ARB improved the intestinal microbiome of the HTN patients by reducing potentially pathogenic bacteria such as Enterobacter and Klebsiella and increasing beneficial bacteria such as Odoribacter. Moreover, ACEI/ARB therapy was correlated with significant metabolomic changes in the HTN patients, including progressively enhanced inositol from poor-controlled to well-controlled groups. The profiles of gut bacteria were linked to the production of metabolites, and inositol was negatively correlated with Klebsiella, Enterobacter, and Proteobacteria. Our study suggests that ACEI/ARB modulates gut microbial composition and functions and alters microbial metabolites in HTN patients.

Efficacy and safety of combination therapy with sodium-glucose cotransporter 2 inhibitors and renin-angiotensin system blockers in patients with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: This study was designed to evaluate the efficiency and safety of combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors and renin-angiotensin system blockers such as angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) in patients with type 2 diabetes mellitus (T2DM). METHODS: We searched the PubMed, Embase, Web of Science and Cochrane Library databases from their inception to May 2020. Two authors independently performed study selection, risk-of-bias assessment and data extraction. The quality and risk of bias were assessed by the Cochrane Risk of Bias Tool. Statistical heterogeneity was determined by the I2 statistics. RESULTS: Seven studies including 1757 patients were analysed. Compared with ACEI/ARB alone, combination therapy with SGLT2 inhibitors and ACEIs/ARBs produced a reduction in systolic blood pressure (SBP) [weighted mean difference (WMD) -3.84 mmHg], diastolic blood pressure (DBP; WMD -1.06 mmHg), 24 h ambulatory SBP (WMD -4.59 mmHg), 24-h ambulatory DBP (WMD -2.08 mmHg), urine albumin:creatinine ratio (WMD -29.70%), evaluated glomerular filtration rate (WMD -3.46 mL/min/1.73 m2), haemoglobin A1c [standardized mean difference (SMD) -0.48], fasting plasma glucose (SMD -0.28), uric acid (SMD -0.35) and body weight (SMD -0.29). The risk of hypoglycaemia with combination therapy was higher than in the control group (risk ratio 1.37). As for the risks of total adverse events, genital infection and urinary tract infection, no significant difference was revealed. CONCLUSION: Compared with ACEI/ARB alone, the combination therapy with SGLT2 inhibitors and ACEIs/ARBs in T2DM was effective and well-tolerated and could achieve additional effects including better control of blood pressure, improvement of renal outcomes, alleviation of long-term renal function and a decrease in blood glucose and body weight. The combination therapy showed an increased risk of hypoglycaemia.

The Effect of Cardiovascular Medications on Disease-Related Outcomes in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Background: Multiple studies have revealed that idiopathic pulmonary fibrosis (IPF) patients are more at risk for cardiovascular diseases and that many IPF patients receive cardiovascular medications like statins, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and anticoagulants. Existing studies have reported divergent findings on the link between cardiovascular medications and fibrotic disease processes. The aim of this study is to synthesize the evidence on the efficacy of cardiovascular medications in IPF. Methods: We searched studies reporting the effect of cardiovascular medications on IPF in the PubMed, Embase, Web of Science, Cochrane Library, and two Chinese databases (China National Knowledge Infrastructure database and China Wanfang database). We calculated survival data, forced vital capacity (FVC) decline, and IPF-related mortality to assess the efficacy of cardiovascular medications in IPF. We also estimated statistical heterogeneity by using I2 and Cochran Q tests, and publication bias was evaluated by risk of bias tools ROBINS-I. Results: A total of 12 studies were included in the analysis. The included studies had moderate-to-serious risk of bias. Statin use was associated with a reduction in mortality (hazard ratio (HR), 0.89; 95% CI 0.83-0.97). Meta-analysis did not demonstrate any significant relationship between statin use and the FVC decline (HR, 0.86; 95% CI 0.73-1.02), ACEI/ARB use, and survival data (HR, 0.92; 95% CI 0.73-1.15) as well as anticoagulant use and survival data (HR, 1.16; 95% CI 0.62-2.19). Conclusion: Our study suggested that there is a consistent relationship between statin therapy and survival data in IPF population. However, there is currently insufficient evidence to conclude the effect of ACEI, ARB, and anticoagulant therapy on IPF population especially to the disease-related outcomes in IPF.

Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies.

Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-LRx versus placebo up to 2 months. IONIS-AGT-LRx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-LRx significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878).

Comparative efficacy of different renin angiotensin system blockade therapies in patients with IgA nephropathy: a Bayesian network meta-analysis of 17 RCTs.

BACKGROUND: IgA nephropathy (IgAN) is still one of the most prevalent forms of primary glomerulonephritis globally. However, no guidelines have clearly indicated which kinds of renin angiotensin system blockade therapies (ACEIs or ARBs or their combination) in patients with IgAN result in a greater reduction in proteinuria and a better preservation of kidney function. Thus, we conducted a Bayesian network analysis to evaluate the relative effects of these three therapy regimens in patients with IgAN. METHODS: The protocol was registered in PROSPERO with ID CRD42017073726. We comprehensively searched the PubMed, the Cochrane Library, Embase, China Biology Medicine disc, WanFang and CNKI databases for studies published since 1993 as well as some grey literature according to PICOS strategies. Pairwise meta-analysis and Bayesian network analysis were conducted to evaluate the effect of different regimens. RESULTS: Seventeen randomized controlled trials (RCTs) involving 1,006 patients were analyzed. Co-administration of ACEIs and ARBs had the highest probability (92%) of being the most effective therapy for reducing proteinuria and blood pressure, but ACEIs would be the most appropriate choice for protecting kidney function in IgAN. CONCLUSION: The combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy in IgAN. ACEIs appear to be a more renoprotective therapy regimen among three therapies.

Clinical features of hypertensive patients with COVID-19 compared with a normotensive group: Single-center experience in China.

BACKGROUND: SARS-CoV-2 has spread worldwide and poses a great threat to human health. Among COVID-19 patients, those with hypertension have been reported to have higher morbidity and mortality. This study was conducted to provide the international community with a deeper understanding of COVID-19 with hypertension. METHODS: A total of 623 COVID-19 patients enrolled in Wuhan's hospital were studied from January to March 2020. The epidemiology, clinical features, and laboratory data of hypertensive patients with COVID-19 were collected, retrospectively analyzed, and compared with a normotensive group. The use of antihypertensive drugs, general treatment, and clinical outcomes of hypertensive patients were also analyzed. RESULTS: The median ages in hypertensive patients with mild and severe COVID-19 were both significantly greater than the median age in the normotensive group. But there was no significant gender difference between the hypertensive and normotensive groups. All patients had lived in Wuhan area. Common symptoms of all patients included fever, cough, and fatigue. Chest computed tomography (CT) scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. All (315 (100%)) of the hypertensive patients received antiviral therapy (Umifenovir was used alone or in combination with Ribavirin), antibiotic therapy (215 (68.3%)), and corticosteroids (118 (37.5%)). The results suggest that the combination of Umifenovir and Ribavirin as initial therapy for hypertensive patients with COVID-19 is effective and safe. There were no significant differences in laboratory data between the mild cases in the hypertensive and the normotensive groups. In the severe cases, the hypertensive patients had higher plasma levels of D-dimer, C-reactive protein (CRP), and Interleukin-6 (IL-6) (P < 0.05). Furthermore, the hypertensive patients who were treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) were not represented in a statistically significant manner between the mild and severe groups (p > 0.05). CONCLUSION: In this study, we demonstrated that the hypertensive patients who were treated with ACEI/ARB did not have an increased risk of developing severe COVID-19. Umifenovir and Ribavirin played an important role in the treatment of viral pneumonia. Hypertensive patients with severe viral pneumonia had stronger inflammatory responses than nonhypertensive patients.

Hypertension in Patients Hospitalized with COVID-19 in Wuhan, China.

It is unclear whether patients with hypertension are more likely to be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population and whether there is a difference in the severity of coronavirus disease (COVID-19) pneumonia in patients who have taken ACEI/ARB drugs compared with those who have not.This observational study included data from all patients with clinically confirmed COVID-19 admitted to Hankou Hospital, Wuhan, China, between January 5 and March 8, 2020. Data were extracted from clinical and laboratory records. Follow-up was cut off on March 8, 2020.A total of 274 patients, 75 with hypertension and 199 without hypertension, were included in the analysis. Compared with patients without hypertension, patients with hypertension were older and were more likely to have preexisting comorbidities, including chronic renal insufficiency, cardiovascular disease, diabetes mellitus, and cerebrovascular disease. Moreover, patients with hypertension tended to have higher positive rate for SARS-CoV-2 PCR detection. Multivariate logistic regression analysis showed that age (P = 0.005) and gender (P = 0.019) were independent risk factors associated with the severity of pneumonia in patients on admission, whereas ACEI/ARB treatment (P = 0.184) was not.Patients with COVID-19 with hypertension were significantly older and were more likely to have underlying comorbidities, including chronic renal insufficiency, cardiovascular disease, diabetes mellitus, and cerebrovascular disease. ACEI/ARB drugs did not influence the severity of pneumonia in patients with SARS-CoV-2. In future studies, a larger sample size and multi-center clinical data would be needed to support these conclusions.