Angiotensin-converting Enzyme Inhibitors Users Research Articles

Different Kynurenine Pathway Dysregulation in Systemic Sclerosis in Men and Women.

Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc's inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences in KP activation among SSc patients and assess the impact of angiotensin-converting enzyme (ACE) inhibitors and estimated glomerular filtration rate (eGFR) on KP metabolite concentrations. We enrolled 48 SSc patients and 53 healthy controls, quantifying KP metabolites (tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA)) in serum via high-performance liquid chromatography. Separate multivariate analyses of covariance (MANCOVAs) for women and men were performed to ascertain mean differences between patients and healthy controls while correcting for age. For our secondary objective, we conducted a MANCOVA to explore disparities in ACE inhibitor users and non-users among patients, with BMI correction. Our findings revealed decreased TRP concentrations but increased KYNA/TRP ratio and KYN/TRP ratio in both male and female SSc patients compared to their respective controls. Unlike women, SSc males exhibited higher KYN concentrations and decreased KYNA/KYN ratio relative to their controls. Additionally, SSc patients using ACE inhibitors had higher serum KYNA levels than non-users. Notably, we established a significant correlation between eGFR and KYNA in SSc patients. These results indicate differential KP activation in male and female SSc patients, with males demonstrating heightened KP activation. While ACE inhibitors may influence the KP in SSc patients, further research is necessary to comprehensively understand their impact on symptoms and prognosis in the context of these KP alterations.

Evaluation of antihypertensive medications use and survival in patients with ovarian cancer: a population-based retrospective cohort study

BackgroundDespite declining mortality in most countries and in Lithuania, ovarian cancer burden has remained high. Studies have indicated that antihypertensive medications use may help to improve ovarian cancer survival, however findings remain controversial. The aim of the study was to analyse the association between post-diagnosis antihypertensive medications intake and cancer-specific survival in ovarian cancer patients.MethodsThis retrospective cohort study included 588 ovarian cancer cases diagnosed between 2013 and 2015. Hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) were estimated using multivariable Cox proportional hazards models to assess associations between antihypertensive medications and ovarian cancer-specific mortality.ResultsIn total, 279 (47%) patients died during the follow-up; 242 (87%) of them died due to ovarian cancer. The risk of ovarian cancer death was reduced in angiotensin-converting enzyme inhibitors (ACE inhibitors) users vs. non-users (HR 0.55, 95% CI: 0.36–0.83). Subgroup analysis showed better ovarian cancer survival in higher dose ACE inhibitors users (HR 0.46, 95% CI: 0.28–0.77, p for trend 0.002); the effect was also stronger in age 51–65 years, stage I–III, surgery or chemotherapy treatment, pre-diagnosis ACE inhibitor users’ and pre-diagnosis hypertension subgroups. The risk of cancer-specific death was slightly lower among calcium-channel blocker and angiotensin-receptor blocker users and higher among beta-blocker users as compared to non-users, however chance and confounding could not be ruled out. We found no association between the use of centrally and peripherally acting antiadrenergic agents and diuretics and risk of ovarian cancer-specific mortality.ConclusionsOur findings imply that post-diagnosis use of ACE inhibitors may be associated with reduced ovarian cancer-specific mortality; however, further research is needed for the comprehensive assessment.

The role of angiotensin converting enzyme (insertion)/(deletion) and angiotensin II type 1 receptor (A1166C) gene polymorphisms in antiproteinuric effect of ACE inhibitors in type 2 diabetic Iraqi patients

The angiotensin converting enzyme (ACE) I\D gene polymorphism influences the blood ACE enzyme activity. Renoprotective effect of ACE inhibitors (ACEIs) varies among patients due to genetic variation, particularly in Renin-Angiotensin-Aldosterone System genes. This study investigates the genetic variations of ACE I\D and AGT1RA1166C gene polymorphisms in the antiproteinuric effect of ACEI therapy in type 2 diabetes mellitus (T2DM) patients. This is a cross-sectional study that included 76 T2DM patients who are ACEI users, divided into two groups: T2DM without diabetic kidney disease (DKD) included 31 patients, and T2DM with DKD included 45 patients. Urine samples were taken for measurement of urine albumin and creatinine, then calculation of albumin-creatinine ratio (ACR). Blood samples were taken for the measurement of serum parameters and also for the extraction of DNA for genetic evaluation of ACEI/D and AGT1RA1166C gene polymorphisms. The results reveal that T2DM patients carrying the ID genotype have significantly lower ACE1 levels compared to DD and II carriers (p = 0.012). When grouping patients according to the ACR, serum ACE1 and angiotensin-converting enzyme 2 (ACE2) levels were higher in DKD compared to normalbuminuric patients, with the only significant difference for ACE2. After subdividing according to ACE I\D genotypes, the ACE2 differences were only significant in DD genotype carriers (p = 0.049) between DKD and normalbuminuric groups. While for AGT1RA1166C polymorphisms, the AC genotype shows non-significantly lower levels for ACE1 and ACE2. After subdividing according to AGT1RA1166C genotypes, ACE2 levels were significantly higher in DKD patients carrying the AA genotype (p = 0.015). Binary logistic regression analysis revealed that both ACE (I\D) and AGT1RA1166C genes are significant predictors of ACE1 levels after controlling age, gender, and DKD state. This study concluded that both genes are predictors of ACE1 levels; in addition, ID genotype carriers and AC genotype carriers had lower ACE1 and ACE2 levels with lower ACR and higher glomerular filtration rate, identifying better ACEIs responses in ID and AC carriers.

Decreased risk of radiation pneumonitis with concurrent use of renin-angiotensin system inhibitors in thoracic radiation therapy of lung cancer.

Radiation pneumonitis (RP) is the primary dose-limiting toxicity associated with radiotherapy. This study aimed to observe the effects of renin-angiotensin system inhibitors in Chinese patients with lung cancer who received thoracic radiation. Patients with lung cancer who received thoracic radiation at a total dose of ≥45 Gray between October 2017 and December 2022 were enrolled in this study. We retrospectively evaluated the factors influencing grade 2 or higher RP. A total of 320 patients were enrolled in this study; 62 patients were identified as angiotensin receptor blockers or angiotensin-converting enzyme inhibitor users. Additionally, 99 patients (30.9%) had grade 2 or higher RP, and the incidence in the renin-angiotensin system inhibitor group was 17.7% (11 out of 62 patients). Patients in the renin-angiotensin system inhibitors (RASi) group were older and had a higher percentage of males, lower percentage of ECOG score 0, higher percentage of hypertension, and higher percentage of adenocarcinoma than those in the non-RASi group. ECOG score [hazard ratio (HR) = 1.69, p = 0.009], history of smoking (HR = 1.76, p = 0.049), mean dose (HR = 3.63, p = 0.01), and RASi (HR = 0.3, p = 0.003) were independent predictive factors for RP. All subgroups benefited from RASi. This study showed that oral RASi administration has the potential to mitigate the incidence of grade 2 or higher RP in patients with lung cancer undergoing thoracic radiotherapy. To validate and further substantiate these findings, additional prospective research is warranted.

Assessing the reliability of serum macrophage migration inhibitory factor as a marker for diabetic nephropathy prediction in type 2 diabetes patients and the effect of ACE inhibitors on its level

Abstract Diabetic nephropathy (DN) is a prevalent chronic microvascular diabetic complication. As inflammation plays a vital role in the development and progress of DN the macrophages migration inhibitory factor (MIF), a proinflammatory multifunctional cytokine approved to play a critical function in inflammatory responses in various pathologic situations like DN. This study aimed To assess serum levels of MIF in a sample of Iraqi diabetic patients with nephropathy supporting its validity as a marker for predicting nephropathy in T2DM patients. In addition, to evaluate the nephroprotective effect of angiotensin-converting enzyme (ACE) inhibitors in terms of their influence on MIF levels. This is a case-control study involving ninety subjects that have been divided into three groups: twenty apparently healthy control group and seventy patients with type 2 diabetes mellitus divided into two equal groups according to the presence of diabetic nephropathy that has been further divided into two groups according to the use of ACE inhibitors or not. Serum MIF, urea, creatinine, RBS, HbA1c, BMI, eGFR, and urinary albumin to creatinine ratio have been measured for each subject. Serum MIF’s highest levels were observed in the diabetic nephropathy patients (24.9 ng/ml) followed by the diabetics (14. 1 ng/ml) with the lowest level observed in the control group (4.8 ng/ml). There was a significant relation between MIF levels and ACE inhibitors (p-value <0.05) with reduced MIF levels in ACE inhibitors users. The ROC curve showed that MIF has a good performance in disease prediction. These findings support the reliability of MIF as a biomarker for the prediction of diabetic nephropathy and the possible reducing effect of ACE inhibitors on MIF levels.

New Users of Angiotensin II Receptor Blocker-Versus Angiotensin-Converting Enzyme Inhibitor-Based Antihypertensive Medication Regimens and Cardiovascular Disease Events: A Secondary Analysis of ACCORD-BP and SPRINT.

BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) block distinct components of the renin-angiotensin system. Whether this translates into differential effects on cardiovascular disease events remains unclear. METHODS AND RESULTS We used the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial and the SPRINT (Systolic Blood Pressure Intervention Trial) to emulate target trials of new users of ARBs versus ACEIs on cardiovascular disease events (primary outcome) and death (secondary outcome). We estimated marginal cause-specific hazard ratios (HRs) and treatment-specific cumulative incidence functions with inverse probability of treatment weights. We identified 3298 new users of ARBs or ACEIs (ACCORD-BP: 374 ARB versus 884 ACEI; SPRINT: 727 ARB versus 1313 ACEI). For participants initiating ARBs versus ACEIs, the inverse probability of treatment weight rate of the primary outcome was 3.2 versus 3.5 per 100 person-years in ACCORD-BP (HR, 0.91 [95% CI, 0.63-1.31]) and 1.8 versus 2.2 per 100 person-years in SPRINT (HR, 0.81 [95% CI, 0.56-1.18]). There were no appreciable differences in pooled analyses, except that ARBs versus ACEIs were associated with a lower death rate (HR, 0.56 [95% CI, 0.37-0.85]). ARBs were associated with a lower rate of the primary outcome among subgroups of male versus female participants, non-Hispanic Black versus non-Hispanic White participants, and those randomly assigned to standard versus intensive blood pressure (Pinteraction: <0.01, 0.05, and <0.01, respectively). CONCLUSIONS In this secondary analysis of ACCORD-BP and SPRINT, new users of ARB- versus ACEI-based antihypertensive medication regimens experienced similar cardiovascular disease events rates, with important subgroup differences and lower rates of death overall. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01206062, NCT00000620.

Factors associated with non-adherence to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in older patients with peripheral arterial disease.

Introduction: As in other chronic conditions, medication adherence is important in the treatment of peripheral arterial disease (PAD). Our study aimed at a) analysing non-adherence to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in groups of older ACEI and ARB users with PAD, and b) identifying characteristics associated with non-adherence. Methods: We focused on the implementation phase of adherence (i.e., after treatment initiation and before possible discontinuation of treatment). The study cohort included ACEI/ARB users aged ≥65years in whom PAD was newly diagnosed during 2012. Non-adherence was defined as Proportion of Days Covered (PDC) < 80%. Results: Among 7,080 ACEI/ARB users (6,578 ACEI and 502 ARB users), there was no significant difference in the overall proportion of non-adherent patients between ACEI and ARB users (13.9% and 15.3%, respectively). There were differences in factors associated with non-adherence between the groups of persistent and non-persistent (i.e., discontinued treatment at some point during follow-up) ACEI and ARB users. Increasing age, dementia and bronchial asthma were associated with non-adherence in persistent ACEI users. General practitioner as index prescriber was associated with adherence in the groups of non-persistent ACEI users and persistent ARB users. Conclusion: Identified factors associated with non-adherence may help in determining the groups of patients who require increased attention.

Skin Cancer and Hydrochlorothiazide: Novel Population-Based Analyses Considering Personal Risk Factors Including Race/Ethnicity.

Hydrochlorothiazide, a common antihypertensive, has photosensitive properties, potentially increasing skin cancer risk. We evaluated melanoma and nonmelanoma skin cancer among hydrochlorothiazide users with 3 different cohorts as each allows assessment of different potential cofounders/effect modifiers, including race/ethnicity. We built 3 cohorts using IBM MarketScan Research Databases: Commercial and Encounters (>3.5 million individuals, 2010-2018), a subcohort with health risk assessment respondents (415, 330), and Medicaid (509, 767, 2011-2017). Adults (aged 18+ years) entered the respective cohort with a first-filled prescription (cohort entry) for hydrochlorothiazide (the exposure of interest) or angiotensin-converting enzyme (ACE) inhibitors (the active comparator), with ≥12 months of continuous enrollment with medical/pharmacy coverage at baseline. We excluded those who used hydrochlorothiazide/ACE inhibitor (including fixed-dose combination products) 12 months before cohort entry and those with prior skin cancer, HIV, or organ transplant. We compared the risk for hydrochlorothiazide versus ACE inhibitor using multivariate proportional hazards regression. Baseline characteristics were similar, aside from more Black individuals among hydrochlorothiazide users (43.3% [95% CI, 43.0%-43.6%]) than ACE inhibitor users (28.1% [95% CI, 27.9%-28.3%]). The hazard ratio (95% CI) for nonmelanoma skin cancer related to hydrochlorothiazide (versus ACE inhibitor) was 0.96 (0.91-1.00) in the Commercial cohort, 1.01 (0.77-1.32) for the health risk assessment subcohort, and 1.33 (0.77-2.29) for Medicaid. For melanoma, the respective hazard ratios were 1.07 (0.95-1.20), 0.85 (0.43-1.67), and 0.93 (0.51-1.67), respectively. Our evaluation using 3 different approaches, including adjustment for race/ethnicity, did not establish a clear difference between hydrochlorothiazide and ACE inhibitor in terms of skin cancer risk.

Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and hemorrhoids: A nationwide, population-based study.

The authors investigated whether there is an association between angiotensin-converting-enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) users with hemorrhoids. A total of 21,670 ACEI users and 21,670 ARB users during 2000 - 2012 from a national health insurance database were included. Hemorrhoid incidences were monitored to the end of 2013. To examine the risk of hemorrhoids, the Cox proportional hazard model and the Kaplan-Meier method were used. The incidence rate of hemorrhoids in ARB users was 6.64 per 1000 person-years, which was higher than that of the ACEI users (5.48 per 1000 person-years). The adjusted hazard ratio of hemorrhoids in patients who received ACEI relative to those who received ARB was 0.83 (95% confidence intervals [CI] = 0.75, 0.92). Compared to ARB users, patients who used ACEI more than 740 days per year (adjusted hazard ratios = 0.44; 95% CI = 0.36, 0.54) and more than 7800 mg (adjusted hazard ratios = 0.54; 95% CI = 0.46, 0.65) had a lower risk of hemorrhoids. ACEI users who took a relatively long period or high cumulative dosage were found to less prone to develop hemorrhoids.

A Real-World Analysis of Post-Marketing Surveillance Data Assessing the Incidence of Hyperkalemia or Acute Kidney Injury in Patients on Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin-Receptor Blockers

Background: The widely used Renin-angiotensin-aldosterone system inhibitor (RASI) may increase the risk of hyperkalemia and acute kidney injury (AKI). We aimed to analyze the RASI-related AKI or hyperkalemia reported in the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database to optimize patients’ treatment and provide a reference for a clinically safe and rational prescription. Methods: We obtained data in FAERS recorded from January 2004 to December 2020. Disproportionality analysis and Bayesian analysis were used in data mining to screen the suspected AKI or hyperkalemia after RASI. The time to onset, hospitalization, and prognosis of RASI-associated AKI or hyperkalemia were also investigated. Results: We identified 11,301 RASI-related adverse events (AEs) of hyperkalemia and AKI in the FAERS database; 4997 were due to Angiotensin-converting enzyme inhibitors (ACEIs), 5658 were due to angiotensin receptor blockers (ARBs), and 646 were due to the combination of ACEI and ARB. AKI was more commonly reported in patients with ARB (78.42%) than ACEI users (57.27%). Hyperkalemia cases were reported more in ACEI users (28.70%) than ARB users (14.14%). The median time to onset of RAS-associated AKI was 135.0 (17.0–620.0) days. RASI-associated hyperkalemia occurred relatively later in ACEI users, with a median onset time of 261.0 (43.0–1097.7) days, compared with that of 200.5 (52.0–636.0) days in ARB users (p &lt; 0.001). Among all AEs, 72.39% of cases received hospitalization. Death occurred in 6.3% of the renal AE cases. The elderly and heart failure were potential risk factors for death in patients who developed RASI-associated renal AEs, with an increased Odds Ratio (OR) compared with younger age (OR = 1.32) and hypertension patients (OR = 2.55). Based on the criteria of the four algorithms, the ACEI and ARB combination further increased the incidence of AKI and hyperkalemia, demonstrating the highest Reporting Odds Ratios (RORs), Proportional Reporting Ratios (PRRs) and Empirical Bayesian Geometric Average (EBGMs). Conclusions: Patients who indicated RASI for heart failure demonstrated a higher death risk when AEs occurred. ACEI combined with ARB can increase the incidence of hyperkalemia and AKI. Careful and individualized management is necessary.

Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study.

The chronic receipt of renin-angiotensin-aldosterone system (RAAS) inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been assumed to be associated with a significant decrease in overall gynecologic cancer risks. This study aimed to investigate the associations of long-term RAAS inhibitors use with gynecologic cancer risks. A large population-based case-control study was conducted from claim databases of Taiwan's Health and Welfare Data Science Center (2000-2016) and linked with Taiwan Cancer Registry (1979-2016). Each eligible case was matched with four controls using propensity matching score method for age, sex, month, and year of diagnosis. We applied conditional logistic regression with 95% confidence intervals to identify the associations of RAAS inhibitors use with gynecologic cancer risks. The statistical significance threshold was p < 0.05. A total of 97,736 gynecologic cancer cases were identified and matched with 390,944 controls. The adjusted odds ratio for RAAS inhibitors use and overall gynecologic cancer was 0.87 (95% CI: 0.85-0.89). Cervical cancer risk was found to be significantly decreased in the groups aged 20-39 years (aOR: 0.70, 95% CI: 0.58-0.85), 40-64 years (aOR: 0.77, 95% CI: 0.74-0.81), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.91), and overall (aOR: 0.81, 95% CI: 0.79-0.84). Ovarian cancer risk was significantly lower in the groups aged 40-64 years (aOR: 0.76, 95% CI: 0.69-0.82), ≥65 years (aOR: 0.83, 95% CI: 0.75-092), and overall (aOR: 0.79, 95% CI: 0.74-0.84). However, a significantly increased endometrial cancer risk was observed in users aged 20-39 years (aOR: 2.54, 95% CI: 1.79-3.61), 40-64 years (aOR: 1.08, 95% CI: 1.02-1.14), and overall (aOR: 1.06, 95% CI: 1.01-1.11). There were significantly reduced risks of gynecologic cancers with ACEIs users in the groups aged 40-64 years (aOR: 0.88, 95% CI: 0.84-0.91), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.90), and overall (aOR: 0.88, 95% CI: 0.85-0.80), and ARBs users aged 40-64 years (aOR: 0.91, 95% CI: 0.86-0.95). Our case-control study demonstrated that RAAS inhibitors use was associated with a significant decrease in overall gynecologic cancer risks. RAAS inhibitors exposure had lower associations with cervical and ovarian cancer risks, and increased endometrial cancer risk. ACEIs/ARBs use was found to have a preventive effect against gynecologic cancers. Future clinical research is needed to establish causality.

An updated meta-analysis: The effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the mortality of hypertensive patients with confirmed COVID-19 infection

Abstract Funding Acknowledgements Type of funding sources: None. Background One of the most common co-morbidities identified among COVID-19 patients was hypertension. Debates on use of Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin-Receptor blockers (ARB) emerged due to an interaction of the said drugs with Angiotensin-converting enzyme 2 (ACE2), an enzyme which is a point of entry of coronavirus. This study aims to give an update on the work of Zhang et al13 in exploring the association of ACEI/ARB use on mortality and disease severity. Methods This meta-analysis involves review of observational studies among hypertensive COVID-19 patients with composite data on ACEI and ARB use. The literature search included studies published from December 2019 until June 30, 2020. Analyses were performed determining the odds ratio of each event using the raw data obtained from each study. Random effects model and Cochran-Mantel-Haenszel Method were utilized at 95% confidence interval. To check for heterogeneity, X2 test and I2 statistic were calculated. Subgroup analyses on ACEI users and ARB users were also done. Cochrane Review Manager (REVMAN 5.3) was used and Forest plots were generated. In this update, the total population of patients with confirmed COVID-19 infection was more than 50,000 with hypertensive patients comprising more than half of the sample population. The analyses done manifested decreased frequency of both outcomes with ACEI/ARB use. Results The calculated odds ratio for mortality and disease severity were 0.63 and 0.56, respectively. However, a statistically significant heterogeneity existed for both outcomes. Subgroup analyses among ACEI users versus ACEI/ARB non-users (odds ratio for mortality = 0.95, I2 = 0%; and odds ratio for disease severity = 0.30, I2 = 0%), and ARB users versus ACEI/ARB non-users (odds ratio for mortality = 0.70, I2 =f 68%; and odds ratio for disease severity = 0.48, I2 = 77%) also manifested decreased frequency of both outcomes. However, significant heterogeneity exists among the ARB users, which is in contrary among the ACEI users. Conclusion The use of ACEI contributes to a statistically significant reduction of mortality and disease severity among hypertensive patients with confirmed COVID-19 infection. We recommend continuing analysis of association of ACEI and ARB use and clinical outcomes since recent analysis suggests a beneficial effect especially in the ACEI group. At present, our findings are still in line with the current recommendation to not discontinue the use of ACEI and ARB among our hypertensive patients.

Comparative Risk of Angioedema With Sacubitril-Valsartan vs Renin-Angiotensin-Aldosterone Inhibitors

BackgroundData on angioedema risk among sacubitril-valsartan (SV) users in real-world settings are limited. ObjectivesWe sought to evaluate the risk of angioedema among SV new users compared with angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor-blocker (ARB) new users separately. MethodsWe conducted a propensity score–matched cohort study, comparing SV new users (no use of SV, ACE inhibitor, ARB 6 months before) and SV new users with prior use (within 183 or 14 days) of ACE inhibitor or ARB (ACE inhibitor–SV and ARB-SV users; recent ACE inhibitor–SV and recent ARB-SV users, respectively) vs ACE inhibitor and ARB new users separately. ResultsCompared with ACE inhibitor, SV new (HR: 0.18; 95% CI: 0.11-0.29) and ACE inhibitor–SV users (HR: 0.31; 95% CI: 0.23-0.43) showed lower risk of angioedema. On the other hand, there was no difference in angioedema risk when SV new users (HR: 0.59; 95% CI: 0.35-1.01) or ARB-SV users (HR: 0.85; 95% CI: 0.58-1.26) were compared with ARB new users. Compared with SV new users, ACE inhibitor–SV users (HR: 1.62; 95% CI: 0.91-2.89) trended toward higher angioedema risk, which intensified when the ACE inhibitor to SV switch occurred within 14 days (recent ACE inhibitor–SV) (HR: 1.98; 95% CI: 1.11-3.53). Similarly, ARB-SV users (HR: 2.03; 95% CI: 1.16-3.54) experienced an increased risk compared with SV new users, which intensified for the more recent switchers (recent ARB-SV) (HR: 2.45; 95% CI: 1.36-4.43). ConclusionsWe did not observe an increased risk of angioedema among SV new users compared with ACE inhibitor or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACE inhibitor or ARB compared with SV new users.

Angiotensin-converting enzyme inhibitors reduce community-acquired pneumonia hospitalization and mortality.

Pneumonia is a global disorder and a common reason for prolonged hospitalization. Angiotensin-converting enzyme inhibitors (ACEi) have pleiotropic effects that support a role in modulating pneumonia, but results have been controversial. The present study was conducted to elucidate an ACEi-induced pneumonia benefit in at-risk neurologically impaired population and to determine whether a mortality benefit exists. A cohort study using a large health-system of 29,011 unique ACEi users and 1635 case patients 65 years of age or older without neurological disorders affecting swallowing who were admitted with community-acquired pneumonia hospitalization and followed up from January 1, 2015 to December 31, 2019 (5 years). The association between ACEi use and pneumonia hospitalization and mortality were determined after propensity score matching using Cox and logistic regression. The experimental cohort was 74.9± 7.3 years and 51% were male. ACEi users had lower odds of acquiring pneumonia versus ACEi non-users (odds ratio) 0.72 [95% Confidence Interval (CI) 0.51 to 0.99]; p=0.048. The risk of short-term mortality (<30 days) (HR) 0.42, p < 0.001 and long-term mortality (≥30day) (HR) 0.83, p < 0.002 was significantly lower for ACEi users compared with the ACEi non-users. ACEi use in patients at risk of pneumonia without neurological swallowing disorders is associated with reduction in hospitalization and lowering of short- and long-term mortality. Given the high incidence of morbidity and mortality associated with pneumonia, and the susceptibility in older populations with underlying cardiovascular or renal disease or social dependencies, our data support the prescribing of ACEi in these populations to reduce pneumonia hospitalization risk as well as short- and long-term mortality.

Pharmacovigilance study of the association between dipeptidyl peptidase–4 inhibitors and angioedema using the FDA Adverse Event Reporting System (FAERS)

Dipeptidyl peptidase-4 (DPP-4) plays a minor role in degrading vasoactive peptides that cause angioedema when angiotensin-converting enzyme (ACE) is present and fully functional. This study investigated the association between DPP-4 inhibitors (DPP-4Is) and angioedema, including cases where the concomitant use of ACE inhibitors (ACEIs) was absent. We obtained data from the US Food and Drug Administration Adverse Event Reporting System and performed a disproportionality analysis, using the reporting odds ratio (ROR) and information component (IC) for signal detection in patients aged ≥ 40 years, stratified by age group and sex. No signal was detected for DPP-4Is when the entire dataset was analyzed. However, a signal was detected for the entire female subset group, the three stratified female groups aged ≥ 60 years, and males in their 40 s. After excluding the data of concomitant ACEI users, most ROR and IC values were lower and significant only for females in their 60 s and males aged ≥ 80 years. Regarding individual DPP-4Is signals, those detected for saxagliptin and sitagliptin in some age groups disappeared after excluding the data of ACEI users. Notably, linagliptin was the only DPP-4I where signals were detected in most female groups, regardless of age and without concomitant ACEI use. Our findings suggest that some DPP-4Is were associated with a higher reporting of angioedema as per age and sex, even in the absence of concomitant ACEI use.

Impact of renin-angiotensin system inhibitors on the survival of patients with rectal cancer

BackgroundRenin-angiotensin system inhibitors (RASIs) are widely used in the treatment of hypertension. However, their impact on the outcome of the combined treatment of rectal cancer is poorly understood. The aim of this study was to assess the effect of RASIs on the survival of rectal cancer patients with associated hypertension after neoadjuvant treatment and radical resection.MethodsBetween 2008 and 2016, 242 radical (R0) rectal resections for cancer were performed after neoadjuvant treatment in patients with associated hypertension. At the time of treatment, 158 patients were on RASIs, including 35 angiotensin-receptor antagonists (ARB) users and 123 angiotensin-converting enzyme inhibitors (ACEI) users. Eighty-four patients were on drugs other than RASIs (non-RASI users). The survival analysis was performed using the Kaplan–Meier estimator with the log-rank test and the Cox proportional hazards model.ResultsThe log-rank test showed a significantly worse overall survival (OS) in the group of ACEI users compared to ARB users (p = 0.009) and non-RASI users (p = 0.013). Disease-free survival (DFS) was better in the group of ARB users compared to ACEI users. However, the difference was not statistically significant (p = 0.064). The Multivariate Cox analysis showed a significant beneficial effect of ARBs on OS (HR: 0.326, 95% CI: 0.147–0.724, p = 0.006) and ARBs on DFS (HR: 0.339, 95% CI: 0.135–0.850, p = 0.021) compared to ACEIs. Other factors affecting OS included age (HR: 1.044, 95% CI: 1.016–1.073, p = 0.002), regional lymph node metastasis (ypN +) (HR: 2.157, 95% CI: 1.395–3.334, p = 0.001) and perineural invasion (PNI) (HR: 3.864, 95% CI: 1.799–8.301, p = 0.001). Additional factors affecting DFS included ypN + (HR: 2.310, 95% CI: 1.374–3.883, p = 0.002) and PNI (HR: 4.351, 95% CI: 1.584–11.954, p = 0.004).ConclusionsThe use of ARBs instead of ACEIs may improve the outcome of the combined therapy for rectal cancer patients with associated hypertension.

Fracture Risk and Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9–79.1), range 50.0–96.6 yr; 574 women, median age 65.5 yr (58.1–75.4), range 50.1–94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2–13.2) and 10.9(6.3–11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00–2.37; 1.90, 1.18–3.05; 2.15, 1.26–3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34–5.29) and adjusted (2.03, 1.01–4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07–2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74–2.22). No other differences were observed. In men, lower dose (0 < DDD ≤ 1) ARB use was associated with an increased risk of fracture. ACEI or ARB use was not associated with increased risk of incident fracture in women. These findings may be important for antihypertensive treatment decisions in individuals with a high risk of fracture.

Angiotensin Receptor Blocker is Associated with a Lower Fracture Risk: An Updated Systematic Review and Meta-Analysis.

Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in the treatment of hypertension. Hypertension is often accompanied by osteoporosis. However, the relationship between ACEI/ARB and fractures remains controversial. The purpose of this meta-analysis was to update the potential relationship between ACEI/ARB and fractures. Methods This meta-analysis was identified through PubMed, EMBASE, Cochrane Library, and Web of Science. Related studies about ACEI/ARB with the risk of fracture were published from inception to June 2022. Results Nine qualified prospective designed studies, involving 3,649,785 subjects, were included in this analysis. Overall, the RRs of ACEI compared with the nonusers were 0.98 (95% CI: 0.88, 1.10; P < 0.001) for composite fractures and 0.96 (95% CI: 0.87, 1.05; P=0.048) for hip fractures; the RRs of ARB compared to the nonusers were 0.82 (95% CI: 0.73, 0.91; P < 0.001) for composite fractures and 0.85 (95% CI: 0.74, 0.97; P=0.028) for hip fractures. Furthermore, in the subgroup analysis, male may benefit from ARB (RR = 0.65, 95% CI: 0.49, 0.89, P=0.028), and the European may also benefit from ARB (RR = 0.86, 95% CI: 0.80, 0.93, P=0.015). Conclusions ACEI usage will not decrease the risk of osteoporosis fracture. On the contrary, ARB usage can decrease the risk of total fracture and hip fracture, especially for males and Europeans. Compared with ACEI, for patients at higher risk of fracture in cardiovascular diseases such as hypertension, the protective effect of ARB should be considered.

Angiotensin II Receptor Blocker Associated With Less Outcome Risk in Patients With Acute Kidney Disease.

Objective: The aim of this study was to explore the respective use of angiotensin-converting-enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on the outcomes of patients who could be weaned from dialysis-requiring acute kidney injury (AKI-D). Methods: This case–control study enrolled 41,731 patients who were weaned from AKI-D for at least 7 days from Taiwan’s National Health Insurance Administration. We further grouped AKI-D patients according to ACEi and ARB use to evaluate subsequent risks of all-cause mortality and re-dialysis. The outcomes included the all-cause mortality and new-onset of end-stage kidney disease (ESKD; re-dialysis) following withdraw from AKI-D. Results: A total of 17,141 (41.1%) patients surviving AKI-D could be weaned from dialysis for at least 7 days. The overall events of mortality were 366 (48.9%) in ACEi users, 659 (52.1%) in ARB users, and 6,261 (41.3%) in ACEi/ARB nonusers, during a mean follow-up period of 1.01 years after weaning from AKI-D. In regard to all-cause of mortality, pre-dialysis ARB users had lower incidence than ACEi users [hazard ratio (HR 0.82), p = 0.017]. Compared with ACEi/ARB nonusers, continuing ARB users had a significantly low risk of long-term all-cause mortality (adjusted hazard ratio 0.51, p = 0.013) after propensity score matching. However, new users of ACEi at the acute kidney disease (AKD) period had a higher risk of re-dialysis after weaning than ACEi/ARB nonusers (aHR 1.82, p < 0.001), whereas neither ACEi nor ARB users confronted significantly increased risks of hyperkalemia after weaning. Conclusions: Compared with patients without ACEi/ARB, those continuing to use ARB before the event and after weaning had low all-cause mortality, while new users of ACEi at AKD had increased risk of re-dialysis. AKI-D patients continuing to use ACEi or ARB did not have higher risk of hyperkalemia. Future prospective randomized trials are expected to confirm these findings.

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients.

Maintenance drugs are used to treat chronic conditions. Several classes of maintenance drugs have attracted attention because of their potential to affect susceptibility to and severity of COVID-19. Using claims data on 20% random sample of Part D Medicare enrollees from April to December 2020, we identified patients diagnosed with COVID-19. Using a nested case-control design, non-COVID-19 controls were identified by 1:5 matching on age, race, sex, dual-eligibility status, and geographical region. We identified usage of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), statins, warfarin, direct factor Xa inhibitors, P2Y12 inhibitors, famotidine and hydroxychloroquine based on Medicare prescription claims data. Using extended Cox regression models with time-varying propensity score adjustment we examined the independent effect of each study drug on contracting COVID-19. For severity of COVID-19, we performed extended Cox regressions on all COVID-19 patients, using COVID-19-related hospitalization and all-cause mortality as outcomes. Covariates included gender, age, race, geographic region, low-income indicator, and co-morbidities. To compensate for indication bias related to the use of hydroxychloroquine for the prophylaxis or treatment of COVID-19, we censored patients who only started on hydroxychloroquine in 2020. Up to December 2020, our sample contained 374,229 Medicare patients over 65 who were diagnosed with COVID-19. Among the COVID-19 patients, 278,912 (74.6%) were on at least one study drug. The three most common study drugs among COVID-19 patients were statins 187,374 (50.1%), ACEI 97,843 (26.2%) and ARB 83,290 (22.3%). For all three outcomes (diagnosis, hospitalization and death), current users of ACEI, ARB, statins, warfarin, direct factor Xa inhibitors and P2Y12 inhibitors were associated with reduced risks, compared to never users. Famotidine did not show consistent significant effects. Hydroxychloroquine did not show significant effects after censoring of recent starters. Maintenance use of ACEI, ARB, warfarin, statins, direct factor Xa inhibitors and P2Y12 inhibitors was associated with reduction in risk of acquiring COVID-19 and dying from it.