Angiotensin Receptor Blockers Group Research Articles

Abstract 4136604: Efficacy of angiotensin receptor blockers in thoracic aortic aneurysm: meta-analysis of randomized controlled trials

Background: Thoracic aortic aneurysm (TAA) poses a significant risk of aortic dissection and mortality. Angiotensin receptor blockers (ARBs) have been proposed as a potential therapeutic intervention to mitigate these risks but their effects are uncertain. Aim: To evaluate the efficacy of ARBs in patients with TAA. Methods: A comprehensive search of Cochrane CENTRAL, Ovid Medline R, Pubmed, and Web of Science yielded 2563 records, from which 8 unique randomized controlled trials (RCTs) (including 7 Marfan and 1 bicuspid aortic valve+TAA populations) comprising 1575 patients were included in the analysis. The primary outcome measures were aortic dissection and all-cause mortality. Pooled risk ratios (RR) or mean differences (MD) in an inverse variance random-effects model were generated and analyses were performed with “meta” package in R (version 4.3.2). Results: Our analysis reveals no significant beneficial effect of ARBs on aortic dissection (RR 0,62 [95%CI, 0,20; 1,92], I 2 :0%) and all-cause mortality (RR 0,61 [95%CI, 0,18; 2,05], I 2 :0%), irrespective of specific ARB agents (including losartan, irbesartan, and telmisartan), comparators (beta blocker, placebo, or no treatment), disease condition (Marfan syndrome or bicuspid aortic valve), and patient demographics (children or adults). Additionally, there were no significant differences observed between ARB and control groups in changes in ascending aorta and aortic annulus diameter, as well as aortic Z-score at the 3-year mark, including the annual change in ascending aorta (MD 0.04 mm/year [95% CI, -0.07 to 0.15], I 2 :0%) and aortic root diameter (MD -0.06 mm/year [95% CI, -0.22 to 0.10], I 2 :81%) by echocardiography. However, there was a significant reduction in aortic root diameter as assessed by MRI (MD -0.48 mm/year [95%CI, -0.89 to -0.08]) and echocardiography (MD -0.51 mm/3year [95%CI, -0.85 to -0.17]), with low heterogeneity when compared with control. Risk of aortic surgery and severe adverse events were also comparable. Conclusion: We found no significant beneficial effect of ARBs in reducing the risk of aortic dissection or all-cause mortality in patients with TAA. Despite observing a significant reduction in the aortic root diameter by MRI and echocardiography with ARB therapy, other imaging outcomes were comparable between ARB and control groups.

Effectiveness and risk of ARB and ACEi among different ethnic groups in England: A reference trial (ONTARGET) emulation analysis using UK Clinical Practice Research Datalink Aurum-linked data.

Guidelines by the National Institute for Health and Care Excellence recommend an angiotensin receptor blocker (ARB) rather than an angiotensin-converting enzyme inhibitor (ACEi) for the treatment of hypertension for people of African and Caribbean descent, due to an increased risk of angioedema associated with ACEi use observed in US trials. However, the effectiveness and risk of these drugs in Black populations in UK routine care is unknown. We applied a reference trial emulation approach to UK Clinical Practice Research Datalink Aurum data (linked with data from Hospital Episode Statistics and Office for National Statistics) to study the comparative effectiveness of ARB and ACEi in ethnic minority groups in England, after benchmarking results against the ONTARGET trial. Approximately 17,593 Black, 30,805 South Asian, and 524,623 White patients receiving a prescription for ARB/ACEi between 1 January 2001 and 31 July 2019 were included with a median follow-up of 5.2 years. The primary composite outcome was cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using an inverse-probability-weighted Cox proportional hazards model for ARB versus ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale. For the primary outcome, 27,327 (18.0%) events were recorded in the ARB group (event rate: 25% per 5.5 person-years) and 80,624 (19.1%) events (event rate: 26% per 5.5 person-years) in the ACEi group. We benchmarked results against ONTARGET and observed hazard ratio (HR) 0.96 (95% CI: 0.95, 0.98) for the primary outcome, with an absolute incidence rate difference (IRD)% of -1.01 (95% CI: -1.42, -0.60) per 5.5 person-years. We found no evidence of treatment effect heterogeneity by ethnicity for the primary outcome on the multiplicative (Pint = 0.422) or additive scale (Pint = 0.287). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, which occurred in 37,554 (6.6%) people, there was strong evidence of heterogeneity on the multiplicative (Pint = 0.002) and additive scale (Pint < 0.001). Compared to ACEi, ARB were associated with more events in Black individuals (HR 1.20 (95% CI: 1.02, 1.40); IRD% 1.07 (95% CI: 0.10, 2.04); number-needed-to-harm (NNH): 93) and associated with fewer events in White individuals (HR 0.91 (95% CI: 0.88, 0.93); IRD% -0.87 (95% CI: -1.10, -0.63); number-needed-to-treat (NNT): 115), and no differences in South Asian individuals (HR 0.97 (95% CI: 0.86, 1.09); IRD% -0.17 (95% CI: -0.87, 0.53)). For angioedema, HR 0.56 (95% CI: 0.46, 0.67) with no heterogeneity for ARB versus ACEi on the multiplicative scale (Pint = 0.306). However, there was heterogeneity on the additive scale (Pint = 0.023). Absolute risks were higher in Black individuals (IRD% -0.49 (95% CI: -0.79, -0.18); NNT: 204) compared with White individuals (IRD% -0.06 (95% CI: -0.09, -0.03); NNT: 1667) and no difference among South Asian individuals (IRD% -0.05 (95% CI: -0.15, 0.05) for ARB versus ACEi. These results demonstrate variation in drug effects of ACEi and ARB for some outcomes by ethnicity and suggest the potential for adverse consequences from current UK guideline recommendations for ARB in preference to ACEi for Black individuals.

Comparative estimation of the effects of antihypertensive medications on schizophrenia occurrence: a multinational observational cohort study

BackgroundThe association between antihypertensive medication and schizophrenia has received increasing attention; however, evidence of the impact of antihypertensive medication on subsequent schizophrenia based on large-scale observational studies is limited. We aimed to compare the schizophrenia risk in large claims-based US and Korea cohort of patients with hypertension using angiotensin-converting enzyme (ACE) inhibitors versus those using angiotensin receptor blockers (ARBs) or thiazide diuretics.MethodsAdults aged 18 years who were newly diagnosed with hypertension and received ACE inhibitors, ARBs, or thiazide diuretics as first-line antihypertensive medications were included. The study population was sub-grouped based on age (> 45 years). The comparison groups were matched using a large-scale propensity score (PS)-matching algorithm. The primary endpoint was incidence of schizophrenia.Results5,907,522; 2,923,423; and 1,971,549 patients used ACE inhibitors, ARBs, and thiazide diuretics, respectively. After PS matching, the risk of schizophrenia was not significantly different among the groups (ACE inhibitor vs. ARB: summary hazard ratio [HR] 1.15 [95% confidence interval, CI, 0.99–1.33]; ACE inhibitor vs. thiazide diuretics: summary HR 0.91 [95% CI, 0.78–1.07]). In the older subgroup, there was no significant difference between ACE inhibitors and thiazide diuretics (summary HR, 0.91 [95% CI, 0.71–1.16]). The risk for schizophrenia was significantly higher in the ACE inhibitor group than in the ARB group (summary HR, 1.23 [95% CI, 1.05–1.43]).ConclusionsThe risk of schizophrenia was not significantly different between the ACE inhibitor vs. ARB and ACE inhibitor vs. thiazide diuretic groups. Further investigations are needed to determine the risk of schizophrenia associated with antihypertensive drugs, especially in people aged > 45 years.

The Effect of Angiotensin Receptor Blockers on In-Stent Restenosis After Stent Implantation: A Meta-Analysis

Angiotensin receptor blockers (ARBs) have been shown to inhibit restenosis invitro and invivo, but the evidence found in humans is inconsistent. This study aimed to evaluate the effectiveness of ARBs in preventing in-stent restenosis after percutaneous coronary intervention (PCI). Databases including the Cochrane Library, MEDLINE, Web of Science, EMBASE, and CNKI were searched to collect randomised controlled trials on ARBs inhibiting restenosis that were published before October 2022. A total of 1,056 patients enrolled in eight trials were included in the study. The ARBs group showed lower target lesion revascularisation than the control group (RR 0.54; 95% CI 0.34-0.86; p=0.01), but the restenosis incidence between these two groups was not statistically significant (RR 0.85; 95% CI 0.65-1.11; p>0.05). This study found that ARBs might have a potential effect on reducing target lesion revascularisation after PCI in coronary heart disease patients but has no impact on angiographic restenosis.

Clinical and preclinical evidence that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent diabetic peripheral neuropathy

Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni’s test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and β-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM.

Beyond β-Blockade: ACE Inhibitors Reduce Non-Cardiac Mortality in High Killip Grade AMI Patients.

This study evaluates the 3-year clinical outcomes of high Killip grade (III/IV) acute myocardial infarction (AMI) patients treated with either β-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI) or BB and angiotensin receptor blockers (ARB). A total of 13,105 patients were registered at the Korea Acute Myocardial Infarction Registry at the National Institute of Health (KAMIR-NIH). Among them, 871 patients with high Killip classification AMI were divided into the BB + ACEI group (n = 489) and the BB + ARB group (n = 381). Following propensity score matching, 343 patients were selected in each group. All patients completed a 3-year follow-up period. The results indicate no significant differences between the BB + ACEI group and BB + ARB group in terms of cardiac death, recurrent myocardial infarction, and the rate of repeat percutaneous coronary intervention. However, the BB + ACEI group exhibited significantly lower risks in major adverse cardiac events (HR = 0.574, 95% CI: 0.421-0.783, p < .001), all-cause mortality (HR = 0.561, 95% CI: 0.404-0.778, p = .001), and non-cardiac death (HR = 0.365, 95% CI: 0.208-0.639, p < .001) compared to the BB + ARB group. Our results suggest that BB + ACEI treatment is more beneficial than BB + ARB for high Killip grade AMI patients. Additionally, the BB + ACEI group has a superior preventative effect on mortality compared to the BB + ARB group.

Angiotensin Receptor Blockers as an Alternative Strategy for Addressing Neurodegeneration in a LPS Mice Model

AbstractBackgroundTo identify new therapeutic strategies that impair the development of Alzheimer’s disease (AD), angiotensin receptor blockers (ARB) were investigated as promising candidates to reduce the risk of developing AD in hypertensive patients. However, the mechanism by which they are able to induce this effect remains unclear. On the other hand, it has been described that neuroinflammation plays an important role in neurodegenerative diseases, including AD, being key in the cognitive decline process. Therefore, the aim of this study is to evaluate the neuroprotective effect of ARB in in vivo and in vitro models of neuroinflammation induced by Lipopolysaccharide (LPS) and to disclose their mechanism of action.MethodBV‐2 microglia cell line was exposed to LPS and treated with the ARB. Meanwhile, 7–8‐week‐old C57/BL6 male exposed to LPS were used as a neuroinflammation model. Animals were treated with saline or intranasal ARB (40 mg/kg/day) for 10 days and LPS (1 mg/kg) was injected in last day, 24h before sacrifice. Before euthanizing, long‐term memory was evaluated by Novel Object Recognition test (NORT). Afterwards, analysis of the dendritic spines, neuroinflammation and molecules related to neurodegeneration and cognitive decline was performed.ResultOur results show a beneficial effect of ARB in neuroinflammation by reverting the memory loss observed in mice that received a LPS injection. This beneficial effect is also correlated to an amelioration of the synapsis dysfunction by the activation of pathways involved in neuroprotection, namely the PI3K/AKT pathway and by differences in spine density. Moreover, molecular studies show that previous treatment with ARB is able to stimulate the anti‐oxidant defense system by increasing SOD2 and Gpx‐1. Also, LPS increased neuroinflammatory markers that were significantly reduced in the ARB group as well as apoptotic factors that were decreased with the treatment. Therefore, contributing to the maintenance of cognitive function avoiding the development of neurodegenerative processes.ConclusionIn conclusion, results demonstrate that intranasal administration of ARB prevents LPS‐induced cognitive decline, through the reduction of neuroinflammation and the activation of neuroprotective pathways, highlighting the potential of ARB in the prevention of AD and other neurodegenerative diseases.

Comparison of clinical outcomes of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors in patients with acute myocardial infarction.

Angiotensin receptor blockers (ARBs) are considered an alternative to angiotensin-converting enzyme inhibitors (ACEIs) in patients with acute myocardial infarction (AMI), but in the era of extensive use of preventive therapies and percutaneous coronary intervention, this has not been adequately evaluated in Asians. This retrospective cohort study used data from the Taiwan National Health Insurance Research Database. In total, 52,620 patients initially hospitalized due to AMI between 2002 and 2015 were assessed. After propensity score matching, 14,993 patients each were assigned to ACEI and ARB groups. Patients who received ARBs had significantly lower all-cause mortality (adjusted hazard ratio [aHR]: 0.82; 95% confidence interval [CI]: 0.75-0.90) and hospitalization for heart failure (aHR: 0.92; 95% CI: 0.85-0.99) compared with those who received ACEIs at 18 month follow-up. No significant difference was observed between the two groups in terms of major adverse cardiovascular events (aHR: 098; 95% CI: 0.90-1.07), cardiovascular death (aHR: 0.82; 95% CI: 0.68-1.00), ischemia stroke (aHR: 0.93; 95% CI: 0.77-1.11), and nonfatal myocardial infarction (aHR: 1.04; 95% CI: 0.93-1.17). ARBs showed benefits in many subgroups in terms of all-cause mortality and cardiovascular death. Real-world data demonstrate that ARBs might be associated with lower all-cause mortality and hospitalization for heart failure compared with ACEIs among patients with AMI.

COMPARISON OF CLINICAL BENEFITS BETWEEN TELMISARTAN AND OTHER ANGIOTENSIN RECEPTOR BLOCKERS IN HYPERTENSION PATIENTS WITH COMBINATION THERAPY: MULTICENTER REAL-WORLD STUDY

Objective: Background Telmisartan have potent blood pressure lowering effect as well as the other pleiotrophic effects including PPAR-??/?? dual activation. In large clinical studies, telmisartan demonstrated the comparable clinical benefits with angiotensin converting enzyme inhibitor. However, there were few studies of direct comparison between telmisartan and the other angiotensin receptor blockers (ARBs). This study aimed to compare the cardiovascular and renal protective effect between telmisartan and the other ARBs in patients with the advanced hypertension who required two or more anti-hypertensive drugs. Design and method: This study used the Observation Medical Outcomes Partnership-Common Data Model database of three tertiary hospitals in Korea. 19,247 Patients were prescribed at least two antihypertensive drugs including ARBs, were selected from January 1, 2017 to December 31, 2019. 3,437 patients in the telmisartan group and 15,810 patients in the other ARB group were matched 1:1 through propensity score matching. Major adverse cardiovascular event (MACE), heart failure (HF) hospitalization and new-onset dialysis were compared for 3,386 patients in each group. Result: Before the matching, there was a higher proportion of patients with a history of myocardial infarction (MI) in the telmisartan group compared to the other ARB group. After the matching, average on-treatment blood pressure was similar between two groups. Over a three-year period, the incidence of MACE and HF hospitalization did not differ significantly between the two groups. Compared to the other ARB group, the telmisartan group had a lower incidence of new-onset dialysis (1.3% vs 1.9%, p-value = 0.04). However, this difference was not statistically significant in the multivariable Cox regression model. Conclusions: Telmisartan has similar cardiovascular and renal protective effects to other ARBs in patients with advanced hypertension who are taking at least two anti-hypertensive medications. Figure. Kaplan-Meier curves showing the incidence of MACE and dialysis in the telmisartan group and the other ARB group.

Renin-Angiotensin-Aldosterone System Inhibitions and Cardiovascular Outcomes in Acute Myocardial Infarction With Renal Impairment

ObjectiveTo compare the clinical outcomes of patients with acute myocardial infarction with renal impairment (AMI-RI) treated with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in real-world clinical settings. Patients and MethodsA total of 4790 consecutive patients with AMI-RI between November 1, 2011, and December 31, 2015, were subdivided into ACEI (n=2845) and ARB (n=1945) treatment groups. The primary end points were major adverse cardiac and cerebrovascular events, including all-cause mortality, nonfatal myocardial infarction, any revascularization, cerebrovascular accident, rehospitalization, and stent thrombosis. Propensity score matching (PSM) was used to adjust for group differences. ResultsThe ARB group had a significantly higher incidence of major adverse cardiac and cerebrovascular events (at 3-year follow-up) than the ACEI group according to the unadjusted analysis (3-year hazard ratio [HR], 1.60; 95% CI, 1.43 to 1.78) and the PSM-adjusted analysis (3-year HR, 1.34; 95% CI, 1.15 to 1.56). However, any revascularization (3-year HR, 1.21; 95% CI, 0.95 to 1.54) and rehospitalization (3-year HR, 1.21; 95% CI, 0.88 to 1.67) were not significantly different between groups in the PSM-adjusted analysis. Compared with the ARB group, the ACEI group had lower rates of all-cause mortality at estimated glomerular filtration rates of at least 15 or less than 90 mL/min/1.73 m2 in the unadjusted data and at least 60 or less than 90 mL/min/1.73 m2 in the PSM-adjusted analysis. ConclusionTreatment with ACEIs seemed to be more beneficial than treatment with ARBs for patients with AMI-RI; further prospective studies are required to confirm these results.

Effect of renin angiotensin blockers on angiotensin converting enzyme 2 level in cardiovascular patients

BackgroundRenin–angiotensin–aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors.MethodsA total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA.ResultsAssessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes.ConclusionACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level.Trial registrationRetrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).Graphical abstract

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support–Free Days in Patients Hospitalized With COVID-19

Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. ClinicalTrials.gov Identifier: NCT02735707.

Angiotensin receptor-neprilysin inhibitor delays progression from paroxysmal to persistent atrial fibrillation

Progression from paroxysmal to persistent atrial fibrillation (AF) is linked to adverse clinical outcomes. The present study sought to clarify whether angiotensin receptor-neprilysin inhibitor (ARNI) can delay AF progression. A retrospective cohort study was conducted on consecutive patients with paroxysmal AF admitted at the Second Affiliated Hospital of Nanchang University between January 2017 and January 2022. The risk of AF progression from paroxysmal to persistent was compared between paroxysmal patients treated with ARNI and those who received an angiotensin receptor blocker (ARB). Seven-day Holter monitoring was performed to identify persistent AF. Propensity-score matched analysis was performed to compare the two groups. Cox-regression was used to estimate the hazard ratio (HR) for AF progression events. A total of 1083 patients were screened, and 113 patients in the ARB group and 57 patients in the ARNI group were eligible for analysis. Before propensity-score matching, the ARNI therapy was associated with a lower risk of AF progression than the ARB therapy (HR 0.34; 95% confidence interval [CI] 0.14–0.81; P = 0.015) after a median follow-up of 705 (interquartile range [IQR] 512 to 895) days. Among 170 patients, 47 ARNI-treated patients were successfully matched to 47 ARB-treated patients. After a median follow-up of 724 (541–929) days, compared to ARB, ARNI significantly reduced the risk of AF progression (HR 0.32; 95% CI 0.12–0.88; P = 0.016). ARNI may be superior to ARB in reducing the risk of progression from paroxysmal to persistent AF.

Enhancing the Anti-angiogenic Effect of Bevacizumab with ACE Inhibition on mCRC.

Angiotensin 2 has been shown to promote angiogenesis through multiple pathways. Reduction of angiotensin 2 production by angiotensin-converting enzyme inhibitors (ACEi) could enhance the antiangiogenic effect of bevacizumab and lead to improved survival. Data from metastatic colorectal cancer (mCRC) patients treated with bevacizumab in our hospital were retrospectively collected. Patients were divided into groups taking ACEi or angiotensin receptor blockers (ARB) or neither. We performed survival analysis and COX proportional hazard modelling and calculated the hazard ratio (HR). Multivariate analyses were performed to measure the impact of factors affecting survival, and subgroup analyses were performed for patients younger than 65years. We enrolled 133 patients who received bevacizumab therapy. Eighty patients were male, and 53 were female. Twenty-three patients received ACEi treatment, and 34 patients received ARB. The median age was 58years. Progression-free survival was higher in the ACEi group than in the ARB group or in the group receiving neither (7.66 vs. 5.98 vs. 5.0months; p < 0.01), corresponding to a HR of 0.44 for the ACEi group (95% CI 0.26-0.74). Overall survival was not significantly longer in the ACEi group than in the ARB group or in the group receiving neither (22.0 vs. 23.5 vs. 19.7months; p = 0.30), HR 0.66 (95% CI 0.38-1.2). In a subgroup analysis, overall survival was higher in patients younger than 65years in the ACEi group (45.0 vs. 16.2months; p = 0.02). In the final analysis, ACEi use in patients treated with bevacizumab resulted in prolonged progression-free survival, but this did not affect overall survival. Because our study is the first to look at the enhancement of the effect of bevacizumab by ACEi treatment and ACEi receiving patients are older, it would be useful to confirm our results by randomized trials.

Angiotensin receptor blockade is associated with increased risk of giant cell arteritis.

Angiotensin II is implicated in GCA pathology. We examined whether the use of angiotensin receptor blockers (ARBs) is associated with GCA risk compared with angiotensin-converting enzyme inhibitors (ACEis) or other antihypertensives. We performed a matched cohort study including adults who were initiators of antihypertensives in UK primary care data between 1995 and 2019. Treatment-naïve individuals without prior GCA or PMR were categorized into three groups-ARB initiators, ACEi initiators, or other antihypertensive initiators (beta-blockers, calcium channel blockers, diuretics or alpha-adrenoceptor blockers)-and followed for up to 5 years. Incident GCA was defined using validated Read codes, with age of onset ≥50 years and two or more glucocorticoid prescriptions. Inverse probability-weighted Cox models were used to model outcome risk, adjusting for lifestyle parameters, comorbidities and comedications. Among >1 million new starters of antihypertensives (81 780 ARBs, 422 940 ACEis and 873 066 other antihypertensives), the incidence rate of GCA per 10 000 patient-years was 2.73 (95% CI 2.12, 3.50) in the ARB group, 1.76 (95% CI 1.25, 2.39) in the ACEi group and 1.90 (95% CI 1.37, 2.56) in the other antihypertensives group. The hazard of GCA was higher in ARB initiators [hazard ratio (HR) 1.55; 95% CI 1.16, 2.06] than initiators of ACEis, but similar between initiators of other antihypertensives and ACEis (HR 1.08; 95% CI 0.87, 1.35). Initiation of ARBs is associated with a higher risk of GCA compared with ACEis or other antihypertensives. Mechanistic studies of angiotensin receptor biology will provide further clarity for our findings.

Comparison Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with Unstable Angina with Preserved Left Ventricular Systolic Function.

The present study evaluated the clinical results of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) treatment in patients with unstable angina (UA) with preserved left ventricular systolic function who underwent percutaneous coronary intervention (PCI) due to uncertainty regarding the long-term prognosis using ACEI or ARB. A total of 1627 UA patients with preserved left ventricular systolic function after PCI were enrolled. After propensity score matching, there were no differences in major adverse cardiovascular and cerebrovascular events (MACCEs) (hazard ratio (HR) = .860, 95% confidence interval (CI): .465-1.590, P = .630), all-cause death (HR = .334, 95% CI: .090-1.238, P = .101), nonfatal myocardial infarction (HR = 4.929, 95% CI: .576-42.195, P = .145), stroke (HR = 1.049, 95% CI: .208-5.290, P = .954) and target vessel revascularization (TVR) (HR = 1.276, 95% CI: .537-3.031, P = .581) between the ACEI and ARB groups. In conclusion, prognoses were comparable between ACEI or ARB treatment in UA patients who had preserved left ventricular systolic function after PCI.

Activation of TRPC6 by AngⅡ Induces Podocyte Injury and Participates in Proteinuria of Nephrotic Syndrome.

Background: Nephrotic syndrome (NS) is a common glomerular disease, and podocyte injury is the character of primary NS, usually caused by minimal change disease and membranous nephropathy. Podocytopathy is primarily associated with glomerular proteinuria. Losartan, an angiotensin receptor blocker (ARB), is commonly used in the treatment of NS, and the AngiotensinⅡ (AngⅡ)–transient receptor potential ion channel 6 (TRPC6) axis has been reported to act on podocytes to regulate proteinuria in NS. Therefore, the purpose of this study was to explore the relationship in between AngⅡ–TRPC6, podocyte injury, and proteinuria based on the adriamycin (ADR) NS rat model. Method: All male rats were divided into three groups: control group, model group, and ARB group. The rats in the model group were induced by ADR, and the rats in the ARB group received losartan after induction of renal injury for 4 weeks. The changes in parameters related to renal dysfunction, and glomerular and podocyte structural damage, such as AngⅡ, AngⅡ type I receptor (AT1R), TRPC6, CaN, Caspase-3, Nephrin, and Podocin, were analyzed. Furthermore, the kidneys were isolated for study via transmission electron microscopy (TEM), immunohistochemistry, and western blot (WB) after the rats were sacrificed. In vitro, immortalized mouse MPC5 podocytes were used to investigate the regulatory effect of flufenamic acid (Flu) and SAR7334 (SAR) on the AngⅡ-TRPC6 signaling axis. Flow cytometry and WB were conducted to determine the relationship between podocyte injury and AngⅡ-TRPC6. Results: In vivo results showed that NS rats developed massive albuminuria and abnormal renal function, accompanied by abnormally increased levels of AngⅡ, TRPC6, AT1R, and CaN and a decreased expression of actin molecules in podocytes, extensive fusion of foot processes (FP), loss of glomerular structural integrity, collapse of podocyte structure, and skeletal reorganization. In vitro experiments indicated that both AngⅡ and Flu (the specific agonist of TRPC6) stimulated the expressions of TRPC6, AT1R, and Caspase-3 in podocytes. The AngⅡ receptor–blocker losartan and TRPC6-specific inhibitor SAR blocked the overexpression of the aforementioned proteins. In addition, SAR also attenuated the degradation of podocyte structural proteins and inhibited the fluorescence intensity of intracellular calcium (Ca2+) and cell apoptosis. Conclusion: The involvement of AngⅡ in the occurrence of NS proteinuria may be related to podocyte injury induced by activated TRPC6.

Retrospective Analysis of Use of Angiotensin Receptor Blockers and Patellar Cartilage Volume Among Patients with Knee Osteoarthritis

PurposeWe reported Losartan reduces loss of patellar cartilage in patients with knee osteoarthritis (Kale &amp; Jackson FASBEBJ, 35(S1) and using animal model (Osteoarthritis and Cartilage, 2019, 27; 676‐686). This retrospective study explores whether the patellar cartilage volume loss reduction in patients with knee osteoarthritis is class effect of Angiotensin Receptor Blockers (ARBs) or it is confined to losartan.MethodsData for this study was used from Osteoarthritis Initiative (OAI) publicly available database. A total of 4796 men and women aged 45‐79 years were into the study primarily consisting of those with knee OA and those at high risk for developing knee OA. Our study focused on the progression sub cohort, which consisted of 1390 subjects with knee OA. This study used three measurement periods; baseline, 12 months and 24 months. Patients with missing data for entire series or part missing data were excluded from analysis. Patients’ data then divided into losartan group, control group (patients without losartan, and without other ARBs) and patients with other ARBs (excluding losartan). Specific data sets for the analysis included of demographics such age, sex, race (Clinical_FNOH, Enrollees), patient drug usage (MIF00), Magnetic Resonance Imaging (MRI) data sets on cartilage volume were used from KMRI_FNIH_Qcart_Biomediq00 (baseline), KMRI_FNIH_Qcart_Biomediq01 (12 months), and KMRI_FNIH_Qcart_Biomediq03 (24 months). The patellar cartilage volume variables were V00PatellarCartilage (baseline), V01PatellarCartilage (12 months) and V03PatellarCartilage (24 months). Additional protocol details are published and available on the internet (https://oai.epi‐ucsf.org/datarelease/docs/StudyDesignProtocol.pdf).ResultsOur analysis of the progression sub cohort included a total of 582 patients with symptomatic knee OA. For identifying effects of losartan as reported previously, our analysis of the progression sub cohort included a total of 85 (44 %) were men and 108 (56 %) women with symptomatic knee OA. Average age of the participants for this group was 59.6 years (SD, 8.7 years; range, 45–78 years). Most of the participants in this group were Caucasian (n=142; 73.6 %) and African American (n=42; 21.8 %). Of the 193 patients included in analysis for effect of losartan, 30 patients were taking losartan and remaining 163 patients were placed into control group. Average age of the participants was 59.6 years (SD, 8.7 years; range, 45–78 years).Our analysis show that there was no significant loss of cartilage volume with patients on losartan over baseline at 12 months (5 %) and 24 months (8 %) post enrollment. Patients without losartan showed significantly higher cartilage loss at 24 months post enrollment over baseline (~15 %, p≤ 0.05, Student’s t‐test assuming unequal variances).For the ARBs group, preliminary analysis showed that there are 478 patients taking ARBs excluding losartan. Among the 478 patients, 77 patients have complete patellar cartilage volume data for three time points which we will use for our analysis.ConclusionThis study suggests that losartan reduces loss of patellar cartilage in patients with knee osteoarthritis. Analysis of other ARBs and their effects on cartilage volume is in progress.

The Effect of Angiotensin II Receptor Blockers in Patients with Hypertrophic Cardiomyopathy: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials.

Angiotensin receptor blocker (ARB) therapy has been evaluated to slow down the disease progression in patients with hypertrophic cardiomyopathy (HCM), but there is scarce evidence available to date. Therefore, our meta-analysis aimed to explore the efficacy of ARB therapy as a potential disease-modifying treatment in patients with HCM. A literature search was performed using PubMed, Scopus, Web of Science, Embase, Cochrane library, and Clinicaltrials.gov databases from inception to December 13th, 2021. We included only randomized controlled trials (RCTs). The quality of included studies was assessed by the Cochrane Collaboration's tool. Primary outcomes included the reduction in left ventricular mass and improvement in other echocardiographic features of myocardial dysfunction. The secondary outcome was a net reduction in systolic blood pressure. Meta-analysis was performed using pooled standardized mean difference (SMD) and corresponding 95% confidence interval (CI). A total of 1286 articles were screened. Seven RCTs met the inclusion criteria representing a total of 397 patients with HCM (195 patients were in the ARB group). ARB treatment was associated with significant reduction in left ventricular mass (SMD: -0.77; 95% CI: -1.40, -0.03; p = 0.04). ARB therapy was also associated with a significant reduction in systolic blood pressure (SMD: -0.33; 95% CI: -0.61, -0.05: p = 0.02). ARB therapy is associated with a marked reduction in left ventricular mass and systolic blood pressure in patients with hypertrophic cardiomyopathy. We recommend further studies with a larger patient population size to confirm the findings of our meta-analysis. OSF Registries, DOI: 10.17605/OSF.IO/DAS7C.

Pharmacometabolomic study of drug response to antihypertensive medications for hypertension marker identification in Han Chinese individuals in Taiwan

Various groups of antihypertensive drugs targeting different pathways have been developed; however, the pharmacometabolic responses to these drugs have rarely been compared to elucidate the common pathway of blood pressure regulation. Here, we performed a comparative multi-dimensional pharmacometabolic study on the four major lines of antihypertensive drugs, namely angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics (DIURs), through ultra-performance liquid chromatography coupled to quantum time-of-flight mass spectrometry. Two hundred fifty patients with young-onset hypertension, who were equally divided among five study groups: non-medicated, ACEi, ARB, CCB, and DIUR groups, were recruited. In a metabolome-wide association study conducted through analysis of covariance, 37 molecular features significantly associated with pharmacometabolic responses to antihypertensive drugs were identified. One-third of these features were shared by multiple medications. ACEis, ARBs, and DIURs shared more features than CCB, partially reflecting that ACEis, ARBs, and DIURs affect the renin-angiotensin-aldosterone system. Thirteen molecular features were consistently identified by all four models of the analysis of covariance. A tandem mass spectrometry (or MS/MS) experiment was performed to decipher the chemical structure of these 13 molecular features, including ARB-associated lysophosphatidylcholine (P4135), CCB-associated diacylglycerol(15:0/18:2) (P1175), and DIUR-associated oleamide (P1516). In addition, diacylglycerol(15:0/14:2) (P408) was significantly associated with the pharmacometabolic response to all four antihypertensive drugs. The identified metabolites provide insights into the mechanisms of blood pressure regulation and potential predictive markers of pharmacometabolic responses to antihypertensive drugs.