Angiotensin II Receptor Blocker Therapy Research Articles

Drug repositioning for Alzheimer’s disease and related dementias: Network meta‐analysis using individual participant data

AbstractBackgroundAlzheimer’s disease and related dementias (AD/ADRD) are chronic neurodegenerative pathology and bring a growing public health concern worldwide; particularly, treatments for AD/ADRD remain limited. Drug repositioning has alternate potential to provide an opportunity to accelerate newly identified treatments for individuals with AD/ADRD. Like, some studies have investigated effects of antihypertensive medications on dementia risk, but inconsistent results are reported. In this study, we aim to determine whether existing or approved drugs, including antihypertensive drugs and hormone replacement therapy, enable to reduce the risk of dementia or cognitive impairment.MethodWe searched PubMed, MEDLINE and EMBASE for published trials up to December 31, 2020. The primary outcome of interest was incident dementia or incident cognitive decline. We examined the following candidate repurposed drugs, including hormone replacement therapy and antihypertensive drug classes: diuretics, beta blockers (BB), angiotensin‐converting enzyme inhibitors (ACE‐I), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), alpha blockers, central agonists, vasodilators, and aldosterone blockers. We conducted a random‐effects network meta‐analysis using individual participant data to identify both direct and indirect evidence from the include trials.ResultFour trials, including 19,632 participants and 10 candidate repurposed drugs, met the eligibility criteria, as shown in Figure 1. The results of network meta‐analysis were presented as a league table in Figure 2. We found that aldosterone blockers (OR = 2.32; 95% CI: 1.41 to 3.81), ARB (OR = 1.31; 95% CI: 1.07 to 1.60) and hormone therapy (OR = 1.36; 95% CI: 1.08 to 1.71) were less effective in reducing dementia risk when compared with ACE‐I. Moreover, all the other drugs reduced dementia risk statistically significantly compared with aldosterone blockers (ORs ranging from 0.46 (95% CI: 0.27 to 0.79) for alpha blockers to 0.59 (95% CI: 0.35 to 0.99) for hormone replacement therapy).ConclusionOur findings showed some classes of antihypertensive drugs may have more potential to prevent the incidence of dementia or cognitive decline than the other classes. However, further research for validation of our results is needed.

A case of tongue swelling after S-1, oxaliplatin, and trastuzumab for HER2-positive gastric cancer

BackgroundWe report a case of a patient with HER2-positive gastric cancer with marked tongue swelling during the second cycle of S-1, oxaliplatin, and trastuzumab.Case presentationThe patient was a 74-year-old male, who was taking an angiotensin II receptor blocker (ARB) for pre-existing hypertension, with no history of allergies, diagnosed with HER2-positive gastric cancer, treated with tegafur, gimeracil, and oteracil potassium (S-1) and oxaliplatin for the first cycle, and trastuzumab was added from the second cycle. Three weeks after initiation, during an outpatient visit, grade 2 oral mucositis and significant enlargement of the patient's tongue were observed. Due to the risk of airway obstruction, the patient was referred to an otolaryngologist. After examination, hereditary angioedema was ruled out, and treatment was discontinued in view of ARB-induced angioedema. However, the tongue swelling did not improve markedly. Considering disease progression due to the discontinuation of chemotherapy, it was decided to change S-1 to capecitabine and continue treatment, and chemotherapy was resumed.ConclusionsAngioedema has been reported to be hereditary and drug-related, and angiotensin-converting enzyme (ACE) inhibitors and ARBs have also been reported to lead to drug-related adverse events. Since the patient had oral mucositis at the time of onset and was taking an ARB, it is thought that oxaliplatin and S-1(SOX), and trastuzumab during ARB therapy induced oral mucositis, leading to the development of angioedema.

RAAS inhibitors in patients undergoing transcatheter aortic valve implantation: insights from the EffecTAVI registry

Abstract Background Aortic Stenosis (AS) is the most common heart disease in western countries, with a prevalence that is increasing in tandem with life expectancy. Renin-angiotensin-aldosterone system (RAAS) activation participates to myocardial fibrosis and worse clinical consequences. Purpose The association between baseline treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and cardiovascular (CV) mortality was evaluated in hypertensive patients with severe AS undergoing transcatheter aortic valve implantation (TAVI). Methods We retrospectively examined hypertensive patients with AS who had undergone TAVI at 2-year follow-up. Univariable and multivariable Cox regression models were built according to baseline RAAS inhibitors (RAASi) therapy status and a second analysis was undertaken by categorizing patients in ARBs (n= 110), ACEi (n= 112) and other antihypertensive meds (n= 105). As a sensitivity analysis, survival-time data were converted to case-control data in order to conduct a case–control study nested in the observational study. Results The present analysis included 327 hypertensive patients with severe AS undergoing TAVI. During the 2-year follow-up 43 patients died for CV death. In univariable Cox regression, the rate of the 2-year CV mortality was significantly lower in patients taking RAASi at baseline (HR=0.44, 95% CI 0.23-0.81 p=0.009), however after multivariable adjustment for significant confounders baseline treatment with RAASi was no more significant. Patients were then grouped based on ARBs/ACEIs/other antihypertensive therapy (Figure 1). In the univariate regression analysis ARBs therapy was associated with 65% reduction in CV mortality (HR=0.35, 95% CI 0.15-0.78 p=0.011) significantly lower than other anti-hypertensive meds (figure 1). The results were confirmed in multivariate analysis adjusted for significant confounders (HR=0.34, 95% CI 0.14-0.85 p=0.021). To reduce the risk of bias and better evaluate the stability of the results, a case–control study nested in the observational study was performed. Based on preliminary analysis, patients exposed to ARBs were selected as the case group, those not exposed as the control group, matching controls and cases in a 1:1 manner and balancing for sex, chronic kidney disease, atrial fibrillation and type 2 diabetes mellitus. Multivariable logistic regression analyses were conducted to determine the possible risk factors for CV mortality. After adjusting for the effect of significant confounders, the use of ARBs was found to be associated with a significant reduced risk of CV mortality (OR 0.30, 95% CI 0.11 – 0.82, p=0.019) (Figure 2). Conclusion In patients with severe AS undergoing TAVI, baseline treatment with ARBs was associated with reduced risk of CV mortality over 2 years of follow-up compared to the use of other antihypertensive drugs. The results were also confirmed by the nested, balanced, case-control analysis.KM curves grouped for ACEI/ARBs/otherAdjusted odds-ratio in the nested case-c

PROGNOSTIC IMPACT OF RENIN ANGIOTENSIN ALDOSTERONE SYSTEM INHIBITOR IN HYPERTENSIVE PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION

Objective: The purpose of this study was to determine the prognostic impact of baseline treatment with RAAS inhibitors (RAASi) on all-cause mortality in a population of patients with severe AS who underwent transcatheter aortic valve implantation (TAVI). Design and method: The study included 373 patients with AS who had undergone TAVI. Analyses were undertaken on the subgroup of hypertensive individuals (n 327) with 2 years of follow-up. Clinical characteristics were compared using Kruskal-Wallis non-parametric test for independent samples and study-stratified multivariable Cox proportional hazards regression models was built according to baseline RAASi therapy status. A second analysis was undertaken by categorizing patients receiving RAASi medication (n 222) into those receiving angiotensin II receptor blockers (ARBs) (n 110) and those receiving angiotensin-converting enzyme inhibitors (ACEi) (n 112). Results: Taking RAASi at baseline in the hypertensive patients group was significantly related to gender (Women 56,8%), heart failure (25,7%), chronic kidney disease (CKD) (25,7%), atrial fibrillation (AF) (19,4), being on calcium-channel blocker (26,6%) or anti-platelet therapy (68,5%) (all p < 0,05). All-cause mortality occurred in 23 (10,4%) of the patients on RAASi, 9 (8,2%) on ARBs and 14 (12,4%) on ACEi. In univariate COX regression model treatment with a RAASi was related with a reduction in 2-year all-cause mortality (EXP 0.46, p 0.011). After multivariable correction for significant confounders the association was not statistically significant (p = 0.08). Analyzing ACEi ARBs separately baseline ARB therapy was associated with significant reduction in all-cause mortality (EXP 0.44, p 0.028) (Figure) that was confirmed in multivariate analysis (EXP 0.42, p 0.038) with no impact in baseline ACEi use (Table). Heart failure (EXP 2.87, p < 0.001), atrial fibrillation (EXP 2.39, p 0.005) and chronic kidney disease (EXP 2.08, p 0.02) were all related with an increased 2-year all-cause mortality, but after multivariable correction only heart failure remained statistically significant. Conclusions: ARBs, but not ACEi, are independently associated with a decreased risk of 2-year all-cause death in a cohort of hypertensive patients with severe AS who underwent TAVI. While it is true that these results have molecular basis, additional research is required to corroborate these findings.

Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm

AimsIn genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age.MethodsSince 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment.ResultsBoth ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB.ConclusionWe demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period.

Adverse Events After Initiating Angiotensin-Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker Therapy in Individuals with Heart Failure and Multimorbidity

BackgroundCurrent clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. However, evidence is lacking on whether routine follow-up testing reduces therapy-related adverse events in adults with heart failure and if multimorbidity influences the association between laboratory testing and these adverse events. MethodsWe conducted a retrospective cohort study among adults with heart failure from 4 US integrated health care delivery systems. Multimorbidity was defined using counts of chronic conditions. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACEI or ARB therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. ResultsWe identified 3629 matched adults with heart failure initiating ACEI or ARB therapy between January 1, 2005, and December 31, 2012. Follow-up testing was not significantly associated with 30-day all-cause mortality (adjusted hazard ratio [aHR] 0.45, 95% confidence interval [CI] 0.14; 1.39) and hospitalization with hyperkalemia (aHR 0.73, 95% CI, 0.33; 1.61). However, follow-up testing was significantly associated with hospitalization with acute kidney injury (aHR, 1.40, 95% CI, 1.01; 1.94). Interaction between multimorbidity burden and follow-up testing was not statistically significant in any of the outcome models examined. ConclusionsRoutine laboratory monitoring after ACEI or ARB therapy initiation was not associated with risk of 30-day all-cause mortality or hospitalization with hyperkalemia across the spectrum of multimorbidity burden in a cohort of patients with heart failure.

Assessment of the comparative efficiency of treatment with angiotensin-converting enzyme inhibitor and angiotensin II receptor blockers in patients who are old and senile with stage 3, grade 2–3 hypertension

BACKGROUND: The problem of sex differences in the treatment of hypertension is currently relevant because of the different disease course in men and women. Particular attention should be paid to the age aspect of the problem, since the clinical and hemodynamic parameters of arterial hypertension (AH) in patients who are old and senile have their specifics.&#x0D; AIM: This study aimed to assess the sex aspect of the comparative efficiency of the angiotensin-converting enzyme inhibitor (ACEI) perindopril and angiotensin II receptor blockers (ARB) losap, losartan, and lorista patients who are old and senile with stage 3, grade 23 hypertension.&#x0D; MATERIALS AND METHODS: A total of 185 patients with stage 3, grade 23 hypertension were examined. Two randomized groups of patients were formed depending on the therapy received. Group 1 received ACEI (perindopril), and group 2 patients received ARBs (lozap, losartan, and lorista). Patients kept a diary in which the amount and types of pain, dizziness, and heart palpitations were noted. In addition, the Health, Activity, and Mood Questionnaire and daily self-monitoring of blood pressure every 3 h during the hospital stay and for 23 months after discharge were used. The obtained information was processed using variation statistics and the difference method.&#x0D; RESULTS: The analysis of the comparative efficiency of ARBs and ACEIs revealed significant sex differences in hemodynamic parameters. The ARB group of drugs showed a more pronounced decrease in 24-h blood pressure monitoring (24-h BPM) and the number of pain episodes in the heart area in women compared with men. When using ACEI, no sex difference in the decrease in 24-h BPM indicators was observed. However, significant differences in clinical symptoms of both men and women were found. In women, compared with men, ACEIs had a greater positive effect on the subjective state in points (according to the Health, Activity, and Mood Questionnaire).&#x0D; CONCLUSIONS: The results suggest that ARB therapy for women who are old and senile with stage 3, grade 23 hypertension. For men of a similar age with this pathology, therapy with both ACEIs and ARBs may be recommended.

Renin-Angiotensin Blockade Reduces Readmission for Acute Chest Syndrome in Sickle Cell Disease.

RationaleAcute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Current treatment is supportive-supplemental oxygen, transfusions, and antibiotics. Prevention of ACS may reduce morbidity and mortality in patients with SCD.Acute chest syndrome appears similar to pulmonary fat embolism (PFE), a complication of severe skeletal trauma or orthopedic procedures from pulmonary micro-vessel blockage by bone marrow fat. Vascular obstruction and bone marrow necrosis occur in PFE and ACS. Pulmonary fat embolism rat models have shown that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) mitigate damage in PFE. These medications could work similarly in ACS. We hypothesize that time to readmission after one hospitalization for ACS will be reduced in patients taking ACEI or ARB compared to patients who are not.MethodsThis is a retrospective cohort study. Inclusion criteria are adults (18 to 100 years) with sickle cell anaemia (HbSS), hemoglobin SC (HbSC) disease, sickle cell thalassemia (HbSβThal), hospitalized with ACS over 16 years (January 1, 2000, to March 31, 2016); patients who take and don’t take ACEI or ARB. Children (<18 years old), elderly adults (>100 years old), pregnant patients, and patients with sickle cell trait were excluded.Data was collected from the Health Facts database, which contains de-identified information from the electronic medical records of hospitals in which Cerner© has a data use agreement.Kaplan-Meier estimates explored a time-to-event model of ACS readmission. Multivariable analysis (age, gender, smoking history) was conducted using Cox proportional hazards regression. Results were reported around a 95% confidence interval.ResultsThere were 6972 patients in total. Of which, 9.6% (n = 667) reported taking ACEI or ARB. Results for the covariates were: average age of 38 years old; 63% female (n = 4366/6969); 16% smokers (n = 1132).Readmission rates were higher for patients not taking ACEI/ARB than those who did: 0.44 (95% CI 0.43, 0.46) versus 0.28 (95% CI 0.24, 0.31) at one year, and 0.56 (95% CI 0.55, 0.58) versus 0.33 (95% CI 0.29, 0.37) at two years. Age had the strongest effect on readmission rates for patients taking ACEI/ARB (adjusted hazards ratio 0.78 [95% CI 0.68, 0.91]).ConclusionPatients with SCD who reported taking ACEI or ARB had lower readmission rates for ACS; age was the strongest covariate. Our results may have a significant impact on the prevention of ACS. Prospective studies comparing ACEI or ARB therapy versus placebo are needed to confirm this preventative effect.

Role of renin–angiotensin system antagonists on long-term mortality post-percutaneous coronary intervention in reduced and preserved ejection fraction

AimsThe use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II-receptor blockers (ARBs) post-myocardial infarction (MI) is supported by evidence based on trials performed in the thrombolysis era. This was prior to primary percutaneous coronary intervention (PCI) being routine practice, and with little direct evidence for the use of these medications in patients with preserved left ventricular (LV) function. This study sought to determine whether there is an association between ACEi/ARB use after PCI for acute coronary syndrome (ACS) and long-term all-cause mortality, with a particular focus on patients with preserved LV function.MethodsThis multicentre, observational study evaluated prospectively collected data of 21,388 patients (> 18 years old) that underwent PCI for NSTEMI and STEMI between 2005 and 2018, and were alive at 30 day follow-up.ResultsIn total, 83.8% of patients were using ACEi/ARBs. Kaplan–Meier analysis demonstrated ACEi/ARB use was associated with a significantly lower mortality in the entire cohort (15.0 vs. 22.7%; p < 0.001) with a mean follow-up of 5.58 years; and independently associated with 24% lower mortality by Cox proportional hazards modelling (HR 0.76, CI 0.67–0.85, p < 0.001). ACEi/ARB therapy was also associated with significantly lower mortality in patients with reduced or preserved LV function, with greater survival benefit with worse LV dysfunction.ConclusionACEi/ARB therapy post-PCI is associated with significantly lower long-term mortality in patients with reduced and preserved LV function. These findings provide contemporary evidence for using these agents in the current era of routine primary PCI, including those with preserved EF.Graphical abstract

Angiotensin II receptor blockers in modulation of transforming growth factor-beta effects on mitral valve myxomatous degeneration

Abstract Growing evidence supports role transforming growth factor-β (TGF-β) as a mediator of the myxomatous changes in the mitral valve prolapse. Recently, angiotensin II receptor blockers (ARB) emerged as a potentially effective inhibitor of TGF-β signaling. Treatment of valvular interstitial cells (VICs) with ARB resulted in effective inhibition of TGF-β-induced ECM expression. Our aim was to evaluate the effect of preoperative ARB therapy in modulation of transforming growth factor-β effects on mitral valve myxomatous degeneration. Methods A total of 233 asymptomatic patients (mean age: 53.8±12.9) undergoing mitral valve surgery for severe mitral regurgitation due to mitral valve prolapse were enrolled in our retrospective, non-randomized, single-center study. Resected abnormal segments of the mitral leaflets (segment of the posterior leaflet or the entire valve) were obtained during mitral valve repair/replacement surgery and examined by experienced pathologists. Immunohistochemical characterization of mitral valve sections was performed with the primary antibodies. Quantification was performed by counting TGF-β1 and TGF-β2 positive cells within 10 random high-power fields divided by the total number of cells in specimens. Quantification of immunohistochemical staining for collagen III was performed by measurement of staining area divided by the total area of the specimens. Results Two hundred thirty-three consecutive patients (66% males, mean age 53.8±12.9 years, range 19–80) with severe MR were enrolled in the study. According to the case reports, 43 patients (18.5%) received losartan or telmisartan before surgery and were included in study group. 190 patients (81.5%) did not receive any ARB and were enrolled in the control group. Histological examination showed disorganized collagen and elastin fibers, expansion of the spongiosa layer in both groups. However, MV specimens' immunohistochemistry revealed a lower expression of type III collagen in ARB group as compared to controls (31.3% ± 10.8% vs. 43.8% ± 15.3%; p&amp;lt;0.001). MV leaflets in control group showed the increased VICs density (95.3±39.9 vs. 70.0±21.7/high-power field, p=0.0001). TGF-β1 and TGF-β2 positive cells were significantly rare in the ARB than in control MV specimens (18% vs. 33%, p=0.012 and 16% vs. 38%, p&amp;lt;0.ehab724.15541, respectively). Expression of type III collagen and TGF-β2 positive cells count showed a weak, but significant correlation (r=0.28; p=0.ehab724.155414). The multivariate Cox analysis showed a decrease in the relative risk of valvular thickening (myxomatous degeneration) with ARB therapy (0.85; 95% CI: 0.61 – 1.17; p=0.01). Conclusions We indicate a beneficial effect of ARB treatment through the inhibition of TGF-β pathway on valvular myxomatous degeneration in patients with MVP. Modulation of the progression of MVP with such therapeutic agents may have great clinical significance. Funding Acknowledgement Type of funding sources: None.

Angiotensin II Receptor Blockers (ARBs Antihypertensive Agents) Increase Replication of SARS-CoV-2 in Vero E6 Cells.

Several comorbidities, including hypertension, have been associated with an increased risk of developing severe disease during SARS-CoV-2 infection. Angiotensin II receptor blockers (ARBs) are currently some of the most widely-used drugs to control blood pressure by acting on the angiotensin II type 1 receptor (AT1R). ARBs have been reported to trigger the modulation of the angiotensin I converting enzyme 2 (ACE2), the receptor used by the virus to penetrate susceptible cells, raising concern that such treatments may promote virus capture and increase their viral load in patients receiving ARBs therapy. In this in vitro study, we reviewed the effect of ARBs on ACE2 and AT1R expression and investigated whether treatment of permissive ACE2+/AT1R+ Vero E6 cells with ARBs alters SARS-CoV-2 replication in vitro in an angiotensin II-free system. After treating the cells with the ARBs, we observed an approximate 50% relative increase in SARS-CoV-2 production in infected Vero E6 cells that correlates with the ARBs-induced up-regulation of ACE2 expression. From this data, we believe that the use of ARBs in hypertensive patients infected by SARS-CoV-2 should be carefully evaluated.

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia.

IntroductionDespite considerable scientific debate, there have been no prospective clinical studies on the effects of angiotensin II receptor blockers (ARBs) on the course of COVID-19 infection. Losartan is the ARB that was chosen to be tested in this study.MethodsPatients with COVID-19 and mild hypoxia (receipt of ≤ 3 L/min O2 by nasal cannula) admitted to three hospitals were randomized in a 1:1 ratio within 72 h of SARS-CoV-2 nucleic acid testing confirmation to prospectively receive standard of care (SOC) alone or SOC plus losartan 12.5 mg orally every 12 h for 10 days or until hospital discharge, with the option to titrate upward dependent on blood pressure tolerability. Primary composite endpoint was receipt of mechanical ventilation or death before receiving ventilation. Subjects were followed until discharge to home or until an endpoint was met in the hospital.ResultsSixteen subjects received an ARB plus SOC and 15 subjects received SOC alone. The median age was 53 years for both groups. Median time from hospital admission to study enrollment was 2 days (range 1–6) for the ARB group and 2 days (range 1–4) for the SOC group. Mean Charlson comorbidity index was 2 for both groups. One subject in each group achieved the composite endpoint.ConclusionThis small prospective randomized open-label study showed no clinically significant impacts of ARB therapy in mildly hypoxemic patients hospitalized with COVID-19 early in the pandemic. A larger prospective randomized placebo-controlled trial would be needed to confirm these findings or capture less pronounced effects and probably should focus on outpatients earlier in disease course.Trial Registrationclinicaltrials.gov; March 27, 2020; NCT04340557.

Ace in the Hole Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in the First Year after Heart Transplant

<h3>Purpose</h3> Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are first line agents for treatment of hypertension in the general population, particularly in the setting of diabetes. However, safety data for their use after heart transplant (HT) is limited due to concerns regarding renal insufficiency and hyperkalemia. <h3>Methods</h3> Retrospective single-center study of HT recipients from January 2017 to December 2019 who received ACEi or ARB therapy within the first-year post-transplant. Patients were evaluated for development of acute kidney injury (AKI), hyperkalemia or other complications after initiation of ACEi/ARB therapy. <h3>Results</h3> A total of 42 patients were included. The cohort was primarily male (81%), with a median (IQR) age of 55.3 (37.7-61.3) years at initiation of therapy. SMX-TMP was used in 39 (83%) while on ACEi/ARB therapy. Median (IQR) estimated glomerular filtration rate (eGFR) at initiation of therapy was 70.2 (56-102.2) mL/min/1.73 m². The lowest eGFR within the first two weeks after initiation of ACEi/ARB was 57.7 (54.4-96.2) mL/min/1.73 m² (Fig 1A). Only one (2.2%) patient had a >50% decline in eGFR within the first 2 weeks of therapy. Hyperkalemia (potassium >5.4 mmol/L) within in the first month after initiation of therapy was observed in 3 (6.5%) patients (Fig 1B). Within the first year post-transplant, therapy was discontinued in 12 (32.4%) patients receiving ACEi, mostly due to AKI or hyperkalemia, and therapy was discontinued in 1 (11.1%) patient receiving ARB (Fig 1B). Of the 9 ARB patients, 4 (44.4%) were previously on ACEi therapy. <h3>Conclusion</h3> ACEi and ARB therapies can be safely initiated in patients with preserved renal function within the first-year post-transplant; however, a third of patients eventually discontinued therapy, mainly due to worsening renal function and hyperkalemia. Close monitoring is required when initiating a patient on ACEi/ARB to ensure safety while using these medications.

Clinical pharmacogenetics of angiotensin II receptor blockers

This scientific review presents a current data on the effect of genetic polymorphism of CYP2C9 genes and genes encoding components of the renin-angiotensin-aldosterone system (RAAS) on the angiotensin II receptor blockers (ARBs) pharmacokinetics and pharmacodynamics. The data shows that genetic polymorphisms of these genes determine the large interindividual variability of the pharmacological response to ARBs. In this article, we carried out a comprehensive review of recent findings on interpatient variability in antihypertensive therapy response due to genetic factors and individualized treatment approach in ARBs therapy.

Adverse impact of renin\u2013angiotensin system blockade on the clinical course in hospitalized patients with severe COVID-19: a retrospective cohort study

The association between angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) and the risk of mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19) was investigated. This retrospective cohort study was performed in all hospitalized patients with COVID-19 in tertiary hospitals in Daegu, Korea. Patients were classified based on whether they received ACE-I or ARB before COVID-19 diagnosis. The analysis of the primary outcome, in-hospital mortality, was performed using the Cox proportional hazards regression model. Of 130 patients with COVID-19, 30 (23.1%) who received ACE-I or ARB exhibited an increased risk of in-hospital mortality (adjusted hazard ratio, 2.20; 95% confidence interval [CI], 1.10–4.38; P = 0.025). ACE-I or ARB was also associated with severe complications, such as acute respiratory distress syndrome (ARDS) (adjusted odds ratio [aOR], 2.58; 95% CI, 1.02–6.51; P = 0.045) and acute kidney injury (AKI) (aOR, 3.06; 95% CI, 1.15–8.15; P = 0.026). Among the patients with ACE-I or ARB therapy, 8 patients (26.7%) used high equivalent doses of ACE-I or ARB and they had higher in-hospital mortality and an increased risk of ARDS and AKI (all, P < 0.05). ACE-I or ARB therapy in patients with severe COVID-19 was associated with the occurrence of severe complications and increased in-hospital mortality. The potentially harmful effect of ACE-I or ARB therapy may be higher in patients who received high doses.

The role of renin-angiotensin system and angiotensin-converting enzyme 2 (ACE2) in the development and course of viral infection COVID-19 in patients with diabetes mellitus

The role of renin-angiotensin system (RAS) in general and angiotensin-converting enzyme 2 (ACE2) in particular in the pathogenesis and course of viral infection caused by SARS-CoV-2 (COVID-19) is of particular interest. This is due not only to the fact that ACE2 is a receptor for the virus the target cells. RAS hyperactivation in patients with arterial hypertension, cardiovascular disease and diabetes mellitus, is considered one of the most important factors for a more severe infection in persons with concomitant pathology. In addition, the effects of PAS blockage with angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) remains one of the most discussed topics in the literature on COVID-19. Thisreview presents the data on the interaction between the virus and the main components of RAS and the factors influencing their expression level, the impact of ACE inhibitors and ARBs therapy on the disease outcome, and presents theperspectives of the treatment with recombinant ACE 2.

Impact of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use, and statin use on presentation and outcomes in patients with giant cell arteritis.

Few, separate, small retrospective studies in giant cell arteritis (GCA) reported that patients: (a) with diabetes mellitus had less positive temporal artery biopsies (TAB); (b) on angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) experienced fewer relapses; and (c) on statins experienced the same frequency of clinical complications and relapses as non-exposed patients. This retrospective chart review study simultaneously investigated the impact of these 3 factors on a cohort of patients followed in 2 large Canadian centers (Hamilton and Toronto, ON). One hundred and thirty-seven patients diagnosed with GCA between 1993 and 2015 were included in the study. Presenting symptoms, TAB results, disease complications and outcomes (relapses, duration of glucocorticoid use) were compared between exposed (diabetes/ACE/ARB/statin) and non-exposed patients, with adjustment for main potential confounding variables. Temporal artery biopsies was less often positive in patients with pre-existing diabetes (relative risk 0.24; 95% CI: 0.069-0.81). Patients who developed diabetes after diagnosis had a lower relapse-free survival (adjusted hazards ratio [HR] 0.28; 95% CI: 0.095-0.84). Patients taking ARBs prior to diagnosis were more likely to successfully discontinue glucocorticoids without a flare in the following 3months (adjusted HR 2.46; 95% CI: 1.2-5.3). Clinical complications and relapse rates did not differ between patients on statin therapy or not. Diabetic patients with GCA were less likely to have a positive TAB, and more likely to relapse. ARB therapy prior to diagnosis showed an association with success at discontinuing glucocorticoids. Statin therapy did not alter the clinical presentation or course of GCA.

Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)

The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. History of taking ACEIs or ARBs at the time of COVID-19 testing. Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate

It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Bioanalytical Assessment of Plasma Concentrations of Angiotensin-Converting Enzyme II Inhibitors and Angiotensin Receptor Blockers: A Pilot Study Among Patients Hospitalized With Acute Heart Failure.

Although angiotensin-converting enzyme II inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve chronic heart failure (HF) outcomes, their potential harms and benefits in acute HF (AHF) is less clear. We explored the relationship between ACEI or ARB plasma concentrations among patients with AHF with in-hospital change in estimated glomerular filtration rate (eGFR). From August 2016-June 2017, patients with AHF prescribed an outpatient ACEI or ARB were enrolled before AHF treatment. All patients were given twice their home dose of diuretic intravenously and received clinical care at the discretion of the medical team. Of 61 patients in the parent study, saved plasma from 34 who were prescribed an outpatient ACEI or ARB was included in this substudy. Liquid chromatography-tandem mass spectrometry was performed to assess ACEI or ARB plasma concentrations before AHF treatment. Change in eGFR was computed using the Chronic Kidney Disease Epidemiology Collaboration equation, which adjusts for age, sex, and race; diuretic dose and enrollment eGFR were used to adjust for HF severity. Multiple linear regression adjusting for enrollment eGFR and diuretic dose was performed to examine the relationship between drug concentration (undetectable/low vs. in/above-range) and in-hospital change in eGFR. Of 34 patients with AHF, median age was 63 years (interquartile range, 58-78 years), 19 (55.9%) were women, median eGFR at enrollment was 55.6 mL/min (interquartile range, 35.2-75.3 mL/min), and for 11 (32.4%), no ACEI or ARB was detectable in plasma. Medication concentrations in- or above-reference range were associated with in-hospital decrease in eGFR of 8.3 mL/min (95% confidence interval, 15.3-1.3 mL/min decrease), after adjusting for enrollment eGFR and diuretic treatment. Bioanalytical assessment of medication levels may be useful to guide in-hospital ACEI and ARB therapy for patients with AHF.