Angiotensin Receptor Research Articles

P114 SHORT-TERM EFFECTS OF BLOOD PRESSURE LOWERING DRUGS ON CARDIOVASCULAR EVENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED, PLACEBO-CONTROLLED, DOUBLED-BLIND TRIALS

Background and Objective: There remains uncertainty about the short-term effects of blood pressure (BP) lowering drugs on cardiovascular events. This meta-analysis of double-blind, short-term randomised trials, evaluated the effect of BP-lowering drugs on cardiovascular events compared to placebo. Methods: A systematic search was performed in the following databases: MEDLINE, Cochrane Central Register of Controlled Trials, and Epistemonikos. Trials satisfying the following criteria were included: (i) randomized, double-blind placebo-controlled trials of 2-26 weeks published in English language; (ii) adults (age ≥18 years) with hypertension (BP ≥140/90 mmHg) or taking BP-lowering drugs; (iii) intervention: oral fixed dose of BP-lowering drug(s) as either monotherapy or combination therapy from five major classes (angiotensin converting enzyme, angiotensin-II receptor blockers, calcium channel blockers, beta-blockers, and diuretics); (iv) placebo comparator; (v) reported data on cardiovascular events; (vi). The primary outcome was major adverse cardiovascular events (MACE), defined as stroke, transient ischaemic attack (TIA), myocardial infarction, heart failure, angina or coronary revascularisation. Results: 451 trials (93121 participants [mean age 54yrs, 56% males, mean follow-up 8 weeks] were included. There was no effect of the intervention compared to placebo on MACE (0.19% versus 0.43%; relative risk [RR] 0.89, 95% CI 0.69-1.14, p=0.35). There was a significant reduction in stroke (0.01% versus 0.05%; RR 0.37 [0.19-0.72]; p<0.001) and TIA (0.001% versus 0.01%; RR 0.26 [0.08-0.82]; p=0.02). Subgroup analysis suggested combination therapy provided the most benefit in stroke reduction (RR 0.21 [0.04-1.01], p=0.05), but benefits were observed across all anti-hypertensive groups for TIA outcomes. There were no between group differences in all-cause or cardiovascular mortality, myocardial infarction, heart failure hospitalization, angina or coronary secularization. Conclusions: This meta-analysis of placebo-controlled RCTs demonstrated reduced stroke and TIA events with BP-lowering drugs even at short-term follow up. These findings suggest BP lowering treatment should be initiated as soon as possible in at risk individuals because even 8 weeks of treatment can significantly reduce the risk of stroke/TIA.

Abstract P134: Effects of Antihypertensive Medications on All-cause Dementia: Evidence from Target Trial Emulation of 3 Million US Veterans

Introduction: Hypertension is a modifiable risk factor for all-cause dementia. Mechanistic and observational evidence suggest angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) may differentially affect dementia risk. Objective and Methods: We used longitudinal electronic health records of over 3 million US Veterans to conduct a target trial emulation with a new-user, active comparator design. We compared the intention-to-treat effect of initiating ARBs vs ACEIs (1/1/2000-12/31/2022) on dementia risk. We controlled for >60 baseline covariates using inverse probability (IP) of treatment and overlap weighting. Dementia was ascertained using diagnosis codes and medications. We nonparametrically estimated the cause-specific cumulative incidence for each treatment group under the competing risk of death then computed treatment effects as weighted risk ratios with bootstrapped 95% confidence intervals. We also evaluated all-cause death and a composite outcome of dementia or death (dementia/Death) using Cox regression. Results: Among the 3,190,356 included Veterans (mean age 63, 5% female, 64% White, and 15% Black), 13% initiated ARBs and 87% initiated ACEIs. Overall, 8% developed dementia and 35% died over a median follow-up of 8 years. The risk of dementia was lower among ARB vs ACEI initiators (10-year risk ratio: 0.95 (0.94, 0.96)). The risk of all-cause death and dementia/Death were also lower among ARB vs ACEI initiators with overlap weighting. Conclusions: Among US Veterans with hypertension, ARB vs ACEI initiation was associated with a moderately lower risk of dementia. Future work assessing sustained treatment with ARB vs ACEI is needed to inform their use to reduce dementia risk.

Abstract P340: Efficacy and safety of a novel single-pill combination (SPC) of allisartan isoproxil and sustained-release indapamide for uncontrolled hypertension by allisartan isoproxil monotherapy: a multicenter, randomized, double-blind, parallel-group phase III study

Introduction: SAL0108 by Shenzhen Salubris Pharmaceuticals Co., Ltd is a novel SPC containing 240mg of allisartan isoproxil (AI) and 1.5 mg of sustained-release (SR) indapamide. AI is a novel angiotensin receptor blocke available in China for over ten years and has the same active compound EXP3174 with losartan, while indapamide SR is a long-standing thiazide-type diuretic. Hypothesis: We assessed the hypothesis that SAL0108 is more effective than AI monotherapy. Methods: Patients with uncontrolled HTN after AI monotherapy for a minimum duration of 4 weeks were enrolled and randomized 2:1 to receive SAL0108 or continue AI treatment for a 12-week duration (double-blinded phase). Subsequently, all participants receive SAL0108 treatment until week 52 (extended period). The primary endpoint was the change in mean seated systolic blood pressure (msSBP) from baseline to week 12, assessed utilizing a treatment policy estimand within the full analysis set. Results: A total of 366 patients were enrolled, with 243 randomized to SAL0108 cohort and 123 to AI cohort. The mean age was 58.7 years, with 50.3% of patients being female. Baseline characteristics were comparable between the two cohorts. After 12 weeks of treatment, the mean change in msSBP from baseline was -15.48±17.96 mmHg in SAL0108 cohort, and -10.19±17.93 mmHg in AI cohort. SAL0108 demonstrated a significantly greater reduction in msSBP compared to AI, showing a mean difference of -5.29 mmHg (95% CI: -9.24 to -1.33; P=0.009). The achievement of msSBP/diastolic blood pressure of < 130/80 mmHg at week 12 was observed in 15.3% and 6.3% of patients in SAL0108 and AI cohorts, respectively (proportion difference 8.9%; P=0.016). Throughout the double-blinded phase, adverse events were observed in 56.8% of patients in SAL0108 cohort (most commonly being hyperuricemia, hyperlipidemia and COVID-19 infection) and 45.5% in AI cohort. Serious adverse events (SAEs) occurred in 1.7% and 4.1% of patients receiving SAL0108 and AI, respectively, and were deemed unrelated to the study drugs. Hypokalemia was infrequent, noted in 4.1% of SAL0108 recipients and 1.6% of AI recipients. During extended period, SAEs were observed in 3.9% of patients and were unrelated to SAL0108. No deaths related to the study drugs were reported. Conclusions: In conclusion, SAL0108 exhibits better efficacy in reducing blood pressure compared to AI monotherapy. The results also highlight the favorable safety profile of SAL0108 for long-term HTN management.

Abstract P105: Comparative Effectiveness between Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors on Mortality: a Nationwide, Population-based, Prospective Cohort Study in China

Background: Contemporary evidence comparing the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin II receptor blockers (ARBs) on long-term outcomes in patients with hypertension is sparse and inconsistent. The aim is to compare the effectiveness of ACEI monotherapy versus ARB monotherapy on all-cause death and cardiovascular death. Methods: Based on a nationwide, population-based prospective cohort project, which covered 318 study sites from 2014 to 2021 in China. Detailed information was collected by questionnaire, physical measurement, and blood test. Participants aged 35-75 years with hypertension and taking ACEI or ARB monotherapy once daily, and with good medication adherence at baseline were included. Information on mortality was followed up until 31 December 2021. Stabilized inverse probability treatment weighting (IPTW) was applied to compare the effectiveness. Results: 68 771 (49326 ARB, 19445 ACEI) participants were finally included, with a mean age of 59.9±8.3 years and 40.2% being female. During a median follow-up time of 44 months, 785 cardiovascular deaths and 1657 deaths were recorded. Compared with ACEI monotherapy, ARB monotherapy was associated with a quarter relative risk reduction of cardiovascular death (IPTW rates: 0.95 % Vs 1.43%, HR =0.73 [ 95%CI , 0.62-0.87]) and one-fifth relative risk reduction of all-cause death (IPTW rates: 2.13% Vs 2.84%, HR =0.80 [ 95%CI , 0.71-0.89]). These differences remained consistent after further adjusting for blood pressure and with differences more pronounced in patients with controlled and newly onset hypertension. Sensitive analysis and subgroup analysis yielded consistent results. Conclusions: Attention should be paid that ARB can be preferred to ACEI in patients with hypertension in terms of long-term health outcomes. Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2021-I2M-1-011), and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4, NCRCSZ-2023-016). Keywords: Hypertension, Angiotensin receptor blocker, Angiotensin-converting enzyme inhibitor, Mortality, Comparative effectiveness

P026 A PRESCRIPTION TREND ANALYSIS OF ANTIHYPERTENSIVE PHARMACOTHERAPY ACROSS DIFFERENT SPECIALTIES IN INDIA

Objective: To evaluate the temporal trends in the prescription patterns of antihypertensive medications among healthcare practitioners in India. Methods: The IQVIA (formerly Quintiles and IMS Health) prescription audit data came from prescriptions of a panel of 6000 private sector primary care clinicians for the different classes of antihypertensive drugs; beta-blockers(BB), calcium channel blockers(CCB), angiotensin receptor blockers(ARB), angiotensin-converting enzyme(ACE) inhibitors, and diuretics were examined. The analysis encompassed the period from 2014 to 2022. Additionally, combinations of these drug classes involving two or three medications were also subject to analysis. Results: Cardiologists’ prescription rates for antihypertensive medications stood at 21% in 2017 and decreased to 19% by 2023. In 2023, the highest rate of prescribing antihypertensive drugs was observed among consultant physicians, with a rate of 30%, followed by general practitioners at 27%. In addition, during COVID-19, the prescription share of general practitioners was highest (31%). Among antihypertensive medications, the prescription rates for BBs were highest (32%), followed by ARBs & CCBs (25% & 24% respectively). Single-drug formulation of anti-hypertensive medications was the most preferred (60%) among Indian clinicians. Prescription shares of fixed-dose combinations (FDC) of two antihypertensive drugs showed a slight decline (36% in 2017 to 34% in 2023) & FDCs of triple-drug exhibited an upward trend (3% in 2017 to 5% in 2023). Among the two drug FDCs, ARB & diuretics were most preferred (25% prescription share) & triple drug FDCs, CCB, ARB & diuretics were most preferred. Conclusions: Cardiovascular medications are prominent in the Indian pharmaceutical market, with antihypertensives standing out as one of the most frequently prescribed treatments. Consultant physicians and general practitioners manage the majority of hypertension cases. Notably, there has been an observed rise in preference for triple-drug combinations of antihypertensive medications, indicating a trend toward a more aggressive approach to hypertension management among Indian clinicians. The insights gleaned from this investigation can further assist healthcare professionals in crafting tailored treatment strategies for individuals grappling with hypertension. Such personalized approaches hold promise in enhancing treatment adherence and ultimately improving the QoL.

O90 EFFICACY AND SAFETY OF DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS AS FIRST-LINE THERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Background: Hypertension remains the primary cause of mortality worldwide, resulting in about 11 million deaths annually. Despite recent hypertension guidelines advocating for dual combination of antihypertensive drugs as the first-line therapy for most patients, many patients do not receive this therapy. Objective: To assess, among adults with hypertension, dual combinations of AHTDs compared to monotherapy as first-line treatment for blood pressure (BP)-lowering efficacy and safety. Methods: We systematically searched multiple electronic databases until December 2022 to identify relevant randomized, double-blind trials. We included trials involving adults with hypertension who were either treatment naive or untreated for at least 2 weeks, compared dual combinations of drugs with monotherapy from 5 major classes of AHTDs (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and diuretics), for a duration of at least 4 weeks and reported data on BP reduction. AHTDs and their combinations were categorized based on standard daily doses. Outcomes were reduction in BP, treatment related adverse events (TRAE) and withdrawals from the treatment due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: We included 98 trials (636 comparisons and 25892 participants). Overall, baseline mean BP was 159/102 mmHg. Overall BP reduction with dual combination compared to monotherapy was 4.4 (CI: 3.8-5.1)/3.5 (CI:3.2-3.9) mmHg. Compared with standard-dose monotherapy, dual combinations of <1 + <1, 1 + <1 and 1 + 1 (i.e. low-to-standard dose), showed a dose-response relationship in reducing BP by 1.4 (CI: 0.01-2.7)/2.3 (CI: 1.4-3.1), 4.4 (CI: 3.6-5.2)/ 3.3 (CI: 2.9-3.8) and 7.8 (CI: 6.2-8.9)/5.2 (CI: 4.4-5.9) mmHg, respectively. TRAEs [4.8% vs 4.9%; RR 0.92 (0.80 to 1.06)] and WDAEs [0.8% vs 0.9%; RR 1.8 (1.5 to 2.1)] were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy. Conclusion: First-line treatment with low-to-standard dose dual combination therapy is more efficacious and equally safe compared to monotherapy to reduce BP.

Abstract P104: Kidney arteriolar responses to liver-targeted small interference RNA (siRNA) targeting angiotensinogen in diabetic rats: comparison with other renin-angiotensin system blockers

Objective: Inhibition of the renin-angiotensin system (RAS) with ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) is associated with concentric thickening of renal arteries and arterioles and parenchymal disease. Here we evaluated to what degree this also occurs during RAS inhibition with siRNA targeting hepatic angiotensinogen (AGT). Methods: Male hypertensive heterozygous transgenic rats overexpressing mouse renin (TGR(mRen2)27 rats), made diabetic with streptozotocin, were treated with the ARB valsartan (4 mg/kg/day), the ACEi captopril (6 mg/kg/day), AGT siRNA (30 mg/kg every 2 weeks), AGT siRNA + valsartan, or captopril + valsartan for 3 weeks, starting at 15 weeks after induction of diabetes. After 3 weeks of treatment, kidneys were removed, and immunocytochemistry was performed on Bouin’s fixed kidney sections using antibodies against renin or α-smooth muscle actin. Juxtaglomerular index and wall thickness were assessed using tiling pictures of both renin and α-smooth muscle actin sections from the slides. Tubular degeneration was scored by summing up scores for tubular atrophy, interstitial fibrosis, and tubulointerstitial inflammation. Concentric vascular hypertrophy was assessed in a blinded manner. Results: All treatments increased juxtaglomerular index, and the largest increases were observed in dual treatment groups, consistent with the highest degree of RAS blockade in these groups. Tubular scores increased after induction of diabetes, and the highest scores were seen in dual treatment groups, significance versus vehicle being reached in the valsartan + captopril group only (P<0.05). Afferent arteriole wall thickness increased in all treatment groups, and the greatest increases were observed during dual treatment. Finally, concentric vascular hypertrophy was observed in 1 of 7 (14%) diabetic Ren2 rats; this percentage increased during RAS blocker treatment of these rats, numerically reaching the highest values during dual treatment. Conclusions: Our data suggest that, in the hypertensive diabetic rat model, high levels of RAS blockade, irrespective of the type of blockade, may result in an increase in afferent arteriole thickness and concentric vascular hypertrophy. AGT siRNA in combination with RAS inhibitors should be further explored in clinical studies.

Abstract P439: An Uncommon and Missed Diagnosis of Hypertension: Fibromuscular Dysplasia

Introduction: Fibromuscular dysplasia is a noninflammatory vascular disease most commonly affecting carotid and renal arteries, especially in young to middle aged women. Renal artery stenosis may cause refractory and severe hypertension in these patients without traditional risk factors. Case: A 58-year-old woman with uncontrolled hypertension on calcium channel and angiotensin receptor blocker and history of left carotid artery stenosis, and carotid endarterectomy at the age of 48 years, was referred cardiac evaluation. Patient’s twin sister had a diagnosis of fibromuscular dysplasia (FMD). Her blood pressure was 190/90 mmHg at presentation. Computed Tomography Angiography (CTA) of the abdomen/pelvis showed a typical nodular stenosis of the mid renal artery consistent with FMD. Patient underwent renal angiogram and successful percutaneous transluminal angioplasty. She still required medical therapy but her BP significantly improved. Discussion: Our patient had severe hypertension, carotid artery stenosis and even surgery but had missed FMD diagnosis for > 10 years. Physicians should have a high level of clinical suspicion for young and middle aged women with refractory hypertension and/or artery stenosis, aneurysm, or dissection in any vascular bed. CTA should be performed for renal and carotid artery imaging looking for typical “string of beads” appearance. Cerebral artery aneurysm should also be evaluated. The inheritance pattern for FMD such as PHACTR1 is most consistent with an autosomal dominant trait with variable penetrance. Renal artery angioplasty may lessen the degree of refractory or severe hypertension.

P148 EFFICACY AND SAFETY OF SACUBITRIL/ALLISARTAN FOR THE TREATMENT OF PRIMARY HYPERTENSION: A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY

Background: This randomized, double-blind, phase 3 study assessed the efficacy and safety of sacubitril/allisartan, an angiotensin receptor neprilysin inhibitor, compared with olmesartan in Chinese patients with mild to moderate hypertension. Methods: Eligible patients aged 18-75 years (n=1197) with mild to moderate hypertension were randomized to receive sacubitril/allisartan 240 mg (n=399), sacubitril/allisartan 480 mg (n=399), or olmesartan 20 mg (n=399) once daily for 12 weeks. Patients who completed the 12-week treatment then received another 12-week extended treatment (n=1084) and 28-week prolonged treatment (n=189). The primary end point was a reduction in clinic mean sitting systolic blood pressure (msSBP) from baseline with various doses of sacubitril/allisartan versus olmesartan at 12 weeks. Secondary efficacy variables included clinic and 24-h ambulatory blood pressure for the comparison between sacubitril/allisartan and olmesartan at week 12, 24, and 52. Results: Sacubitril/allisartan 240 mg/day provided a greater reduction in msSBP than olmesartan at 12 weeks (between-group difference: -1.9 mmHg [95% confidence interval -4.2 to 0.4 mmHg], P=0.0007, for non-inferiority). Sacubitril/allisartan 480 mg/day provided a significantly greater reduction in msSBP than olmesartan at 12 weeks (between-treatment difference: -5.0 mmHg [95% confidence interval -7.3 to -2.8 mmHg], P<0.001, for superiority). Greater reductions in 24-h, daytime and nighttime systolic and diastolic blood pressure were also observed with both doses of sacubitril/allisartan compared with olmesartan (P≤0.001 for 480 mg/day). The blood pressure reductions tended to be dose-dependent for sacubitril/allisartan. Sacubitril/allisartan was well tolerated, and no cases of angioedema or death were reported. Conclusions: Sacubitril/allisartan is effective for the treatment of hypertension and well tolerated in Chinese patients.

O22 MATERNAL AND FETAL OUTCOMES OF VARIOUS ANTIHYPERTENSIVE TREATMENT REGIMENS DURING PREGNANCY: INSIGHTS FROM THE CZECH NATIONAL REGISTRY 2012-2022

Introduction: Arterial hypertension affects about 5-10% of pregnancies and has detrimental effects on pregnancy outcomes in both the mother and fetus. This study aimed to analyze the outcomes of pregnancy in women treated with different antihypertensive drugs. Methodology: Nationwide data on all births and abortions in the period 2012-2022 in the Czech Republic were obtained from the National Registry of Reproductive Health (NRRZ) and the National Registry of Reimbursable Health Services (NRHZS). Women who had the diagnosis I10 within one year before pregnancy and were prescribed any antihypertensive drug from selected ATC groups (C02, C03, C07, C08, C09) were classified as pre-existing hypertension. Women diagnosed with O13 or I10 during pregnancy were classified as pregnancy-induced hypertension. Hypoxia in the newborn was defined as pH <7.1 or Apgar score <8 present after delivery. For all factors, univariate logistic regression was used to calculate the odds ratios (OR) of adverse outcomes. Results: There were a total of 1,154,648 deliveries in the 11-year period. 95,215 women (8.2%) had hypertension in pregnancy, out of these 21,094 (22.2%) were treated with antihypertensive drugs. Odds ratios for caesarean section, pre-term delivery, low birth weight, newborn hypoxia, and pre-eclampsia in women using different antihypertensive classes and drugs are shown in the Figure. The risk of maternal and fetal complications was higher with calcium channel blockers (mainly amlodipine) compared to methyldopa and beta-blockers. Among beta-blockers, bisoprolol had the most favorable safety profile. Although used in limited numbers, diuretics, verapamil, ACE-inhibitors and angiotensin receptor blockers (ARBs) appeared to be comparably safe to methyldopa. A combination of multiple antihypertensive drugs was associated with a higher risk of adverse outcomes. Conclusion: Bisoprolol, verapamil, and diuretics seem to have a risk of adverse maternal and fetal outcomes comparable to methyldopa. Amlodipine and multiple antihypertensive drug combinations are associated with increased risk.

Renin-angiotensin system-mediated nitric oxide signaling in podocytes.

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1-7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes.NEW & NOTEWORTHY The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers are Associated with Improved Amputation Free Survival in Chronic Limb-Threatening Ischemia

BackgroundIn the Heart Outcomes Prevention Evaluation (HOPE) study, investigators found that ramipril was associated with improved survival as well as decreased MI and stroke rates in patients with peripheral arterial disease. Nonetheless, their effect on chronic limb-threatening ischemia (CLTI)-specific outcomes is unclear. We aim to assess the effect of ACEIs/ARBs on amputation-free survival in CLTI patients undergoing peripheral vascular intervention (PVI) in a Medicare-linked database. MethodsPatients undergoing PVI in the VQI-VISION database were included. Primary outcome included amputation-free survival. Kaplan Meier survival and multivariable Cox regression analyses were used to assess one-year outcomes. ResultsA total of 34,284 patients were included, and 46.3% of whom were discharged on ACEIs/ARBs. Patients discharged on ACEIs/ARBs were more likely to be smokers, diabetics, and hypertensive. They were also more likely to present with rest pain. The overall one-year survival for patients on ACEIs/ARBs vs those who are not was (79.1% vs 69.4%, P<0.001). Freedom from amputation was 87.8% for patients on ACEIs/ARBs vs 84.2% for those who were not (P<0.001). Amputation-free survival was 70.5% vs 59.5% for ACEIs/ARBs vs no ACEIs/ARBs (P<0.001). After adjusting for potential confounders, ACEIs/ARBs use was associated with lower one-year mortality (HR: 0.77, 95%CI (0.7-0.8), P<0.001), amputation (HR: 0.89, 95%CI (0.8-0.9), P<0.001), and amputation or death (HR: 0.79, 95%CI (0.76-0.8), P<0.001). ConclusionsACEIs/ARBs were independently associated with lower amputation, improved survival, and amputation-free survival at one year in CLTI patients undergoing PVI. The fact that more than half the patients were not discharged on these medications presents an area for potential quality improvement.

Prevalence of Chronic Kidney Disease and Associated Factors among the Diabetic and Prediabetic Population in the Bandare-Kong Cohort Study; A Population-Based Study.

This investigation aims to examine the relationship between diabetes and prediabetes with chronic kidney disease (CKD) while taking into account key risk factors such as gender, age, lifestyle, smoking habits, and blood pressure. Between November 17, 2016, and November 22, 2018, 4063 subjects aged 35 to 70 years were enrolled in the first phase of the Bandare-Kong Non-Communicable Disease (BKNCD) Cohort Study, which is part of the PERSIAN (Prospective Epidemiological Research Studies in IrAN) cohort and was conducted in a coastal region of the Hormozgan province in southern Iran. CKD was calculated using the Modification of Diet in Renal Disease (MDRD) formula based on glomerular filtration rate (GFR)<60 mL/min per 1.73 m2 , or albumin/Cr>30 mg/g in random urine, self-reported kidney failure, or dialysis. Urine albumin and creatinine were determined by standard kits (Pars Azmoon, Tehran, Iran) and the BT1500 automatic chemistry analyzer (Biotecnica Instruments, Rome, Italy). The prevalence of CKD was found to be 15.3%, with 29.6% identified in diabetic individuals and 16.5% in prediabetic patients. So, the prevalence of CKD in diabetics was higher than prediabetics and normal people. Increased age, dysglycemia (diabetes or prediabetes), hypertension, and use of angiotensin receptor blockers were markedly associated with an elevated risk of CKD in adults. The study emphasizes the importance of early detection and management of CKD risk factors, particularly among high-risk individuals, to mitigate CKD progression and associated complications. By addressing modifiable risk factors, proactive screening, and enhanced awareness, significant strides can be made in reducing CKD burden and improving patient outcomes.

Mortality and Health Outcomes Among Patients With Sarcoidosis Treated With Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Sarcoidosis is a multisystem inflammatory disease where management and outcomes can vary widely. The renin-angiotensin-aldosterone system (RAAS) has been implicated in its pathogenesis, yet the impact of RAAS modulators on health outcomes in sarcoidosis remains poorly understood. How do pharmacological modulators of RAAS affect health outcomes in patients diagnosed with sarcoidosis? We conducted a large multicenter investigation using the TriNetX Research Network database. Patients included in our study were individuals diagnosed with sarcoidosis and prescribed either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). All cohorts were matched for important covariates, and outcomes measured included mortality, cardiac and respiratory outcomes, and sepsis rates following sarcoidosis diagnosis. We observed an increased mortality risk among sarcoidosis patients prescribed ACE inhibitors compared to patients prescribed ARB therapies. Furthermore, sarcoidosis patients prescribed ACE inhibitors had worse cardiac and respiratory outcomes, and increased sepsis rates compared to the ARB cohort. Our findings suggest that ACE inhibitors and ARB's have divergent effects on outcomes in sarcoidosis patients. These findings highlight the potential pathogenic role of RAAS signaling in this disease and underscore the importance of carefully selecting RAAS modulators for individuals with sarcoidosis.

Evaluation of Anxiolytic Activity of Angiotensin Receptor Blockers Using Actophotometer Test in Wistar Rats.

Introduction Anxiety disorders are common mental illnesses impacting quality of life, with current treatments like benzodiazepines andselective serotonin reuptake inhibitors (SSRIs)facing limitations due to side effects. Angiotensin receptor blockers (ARBs), used primarily for hypertension, have shown potential neuropsychiatric benefits, including anxiolytic effects. This study explores the anxiolytic effects of two ARBs, telmisartan and losartan, by evaluating locomotor activity in Wistar rats, aiming to identify new treatment options for anxiety through modulation of the renin-angiotensin system. Aim To evaluate the anxiolytic activity of telmisartan and losartan in experimental Wistar rats. Materials and methods The study was carried out afterconsent was obtained from the Institutional Animal Ethics Committee (IAEC). The rats were divided into four groups: group 1 (control group) received distilled water (2 ml/kg), group 2 (diazepam 2 mg/kg group) received diazepam (2 mg/kg), group 3 (telmisartan 5 mg/kg group) received telmisartan (5 mg/kg), and group 4 (losartan 5 mg/kg group) received losartan (5 mg/kg). The actophotometer test, which measures the locomotor activity levels of rats, was utilized to evaluate their anxiolytic activity. The percent decrease in locomotor activity was calculated for statistical evaluation. Results Our investigation found that the telmisartan 5 mg/kg and losartan 5 mg/kg groups had considerable anxiolytic activity (p<0.05) compared to the control group, and it was comparableto the diazepam 2 mg/kg (p>0.05) group. Conclusion The findings of our study indicate that ARBs, specifically telmisartan 5 mg/kg and losartan 5 mg/kg, exhibit potential anxiolytic effects, evidenced by a significant reduction in locomotor activity in the actophotometer test. These results imply that ARBs could be considered as possible therapeutic agents for anxiety, providing a new perspective on their use beyond traditional cardiovascular applications.

Abstract 18: Persistent beneficial effects of angiotensinogen small interfering RNA (siRNA) and valsartan in spontaneously hypertensive rats after drug removal

Objective: Dual blockade of the renin-angiotensin system (RAS) with siRNA targeting hepatic angiotensinogen (AGT) plus the angiotensin receptor blocker valsartan synergistically lowers blood pressure and diminishes cardiac hypertrophy in spontaneously hypertensive rats (SHR). Since the effects of one siRNA injection may last for up to six months, here we evaluated whether the REVERSIR (reverse siRNA silencing, RVR) technology and/or stopping valsartan might acutely reverse the effects of dual RAS blockade in SHR. Methods: Ten-week old SHR were subjected to a 3-week treatment with vehicle or AGT-siRNA (10 mg/kg) + valsartan (4 mg/kg per day), followed by administration of vehicle or AGT-RVR at doses of 1, 10 and 20 mg/kg, both with and without continuation of valsartan, for 1 week. Mean arterial blood pressure (MAP) was monitored using radiotelemetry, and circulating AGT and renin were measured by enzyme-kinetic assay. Results: Baseline MAP was 143±2 mm Hg. Dual treatment lowered MAP by ≈70 mm Hg, cardiac hypertrophy (heart weight/tibia length) by ≈30%, and circulating AGT by &gt;99%, while renin increased &gt;100-fold versus vehicle. Discontinuing valsartan or applying AGT-RVR (1, 10 or 20 mg/kg) increased MAP similarly (by ≈20 mm Hg), while discontinuing valsartan + AGT-RVR (10 mg/kg) increased MAP by ≈40 mm Hg. Changes in cardiac hypertrophy mimicked those in MAP. Only valsartan discontinuation + AGT-RVR fully restored circulating AGT and renin to normal. When discontinuing valsartan only, AGT remained suppressed by &gt;95%, and renin was up 10-fold, while with AGT-RVR 1, 10 and 20 mg/kg only, AGT suppression was 25, 50 and 50%, while renin was up 25-, 15- and 15-fold, respectively. Conclusions: Discontinuing valsartan or applying AGT-RVR in SHR treated with valsartan + AGT siRNA partially restored MAP, AGT, and renin, likely reflecting the fact that this approach replaces dual RAS blockade by single RAS blockade. However, although discontinuing valsartan plus AGT-RVR fully restored RAS activity, MAP and cardiac hypertrophy remained suppressed under this condition. This agrees with observations that early RAS inhibition resets genetic pathways and networks, allowing persistent blood pressure normalization even when treatment has stopped.

Abstract P304: A Prescription Trend Analysis of Antihypertensive Pharmacotherapy across Different Specialties in India

Objective: To evaluate the temporal trends in the prescription patterns of antihypertensive medications among healthcare practitioners in India. Methods: The prescription audit data utilized in this study, sourced from IQVIA, originated from a panel comprising 6000 clinicians practicing within the private sector. These prescriptions encompassed various classes of antihypertensive drugs, namely beta-blockers (BB), calcium channel blockers (CCB), angiotensin receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors, and diuretics. The analysis spanned the period from 2014 to 2022. The study also included an examination of combinations involving two or three medications from these drug classes. Results: Cardiologists' prescription rates for antihypertensive medications stood at 21% in 2017 and decreased to 19% by 2023. In 2023, the highest rate of prescribing antihypertensive drugs was observed among consultant physicians, with a rate of 30%, followed by general practitioners at 27%. Among anti-hypertensive medications, the prescription rates for BBs were highest (32%), followed by ARBs &amp; CCBs (25% &amp; 24% respectively); which remained almost constant throughout the study period. Single-drug formulation of antihypertensive medications was the most preferred (60%) among Indian clinicians. Prescription shares of fixed-dose combinations (FDC) of two antihypertensive drugs showed a slight decline (36% in 2017 to 34% in 2023) &amp; FDCs of triple-drug exhibited an upward trend (3% in 2017 to 5% in 2023). Among the two drug FDCs, ARB &amp; diuretics were most preferred (25% prescription share) &amp; triple drug FDCs, CCB, ARB &amp; diuretics were most preferred (76% prescription share). Conclusions: Antihypertensive drugs are the most commonly prescribed medication in the cardiology segment. Consultant physicians and general practitioners manage the majority of hypertension cases. Notably, there has been an observed rise in the preference for triple-drug combinations of antihypertensive medications, indicating a trend toward a more aggressive approach to hypertension management among Indian clinicians. The insights gleaned from this investigation can further assist healthcare professionals in crafting tailored treatment strategies for individuals grappling with hypertension. Such personalized approaches hold promise in enhancing treatment adherence and ultimately improving the quality of life for patients.

O52 KIDNEY ARTERIOLAR RESPONSES TO LIVER-TARGETED SMALL INTERFERENCE RNA (SIRNA) TARGETING ANGIOTENSINOGEN IN DIABETIC RATS: COMPARISON WITH OTHER RENIN-ANGIOTENSIN SYSTEM BLOCKERS

Objective: Inhibition of the renin-angiotensin system (RAS) with ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) is associated with concentric thickening of renal arteries and arterioles and parenchymal disease. Here we evaluated to what degree this also occurs during RAS inhibition with siRNA targeting hepatic angiotensinogen (AGT). Methods: Male hypertensive heterozygous transgenic rats overexpressing mouse renin (TGR(mRen2)27 rats), made diabetic with streptozotocin, were treated with the ARB valsartan (4 mg/kg/day), the ACEi captopril (6 mg/kg/day), AGT siRNA (30 mg/kg every 2 weeks), AGT siRNA + valsartan, or captopril+valsartan for 3 weeks, starting at 15 weeks after induction of diabetes. After 3 weeks of treatment, kidneys were removed, and immunocytochemistry was performed on Bouin's fixed kidney sections using antibodies against renin or α-smooth muscle actin. Juxtaglomerular index and wall thickness were assessed using tiling pictures of both renin and α-smooth muscle actin sections from the slides. Tubular degeneration was scored by summing up scores for tubular atrophy, interstitial fibrosis, and tubulointerstitial inflammation. Concentric vascular hypertrophy was assessed in a blinded manner. Results: All treatments increased juxtaglomerular index, and the largest increases were observed in dual treatment groups, consistent with the highest degree of RAS blockade in these groups. Tubular scores increased after induction of diabetes, and the highest scores were seen in dual treatment groups, significance versus vehicle being reached in the valsartan+captopril group only (P&lt;0.05). Afferent arteriole wall thickness increased in all treatment groups, and the greatest increases were observed during dual treatment. Finally, concentric vascular hypertrophy was observed in 1 of 7 diabetic Ren2 rats; this percentage increased during RAS blocker treatment of these rats, numerically reaching the highest values during dual treatment. Conclusions: Our data suggest that, in the hypertensive diabetic rat model, high levels of RAS blockade, irrespective of the type of blockade, may result in an increase in afferent arteriole thickness and concentric vascular hypertrophy. AGT siRNA in combination with RAS inhibitors should be further explored in clinical studies.

In-hospital initiation of angiotensin receptor-neprilysin inhibition in acute heart failure: the PREMIER trial.

The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients. This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels. A total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were -35%/-45% (Sac/Val group) and -18%/-32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68-0.94; P = .008) at Week 4 and 0.81 (95% confidence interval 0.68-0.95; P = .012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction < 40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident. In-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America. ClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046).

Use of antihypertensive agents and its present perspective: an observational retrospective study

Objectives: To evaluate the utilization of antihypertensive agents for the patients of Hypertension and subsequently their health outcome at a Tertiary Care Level Hospital and to observe the relationship among demographic profile of the patients. Materials and Methods: An observational retrospective study was undertaken collecting total 680 patients’ data from patient admission ticket of a Tertiary Care Level Hospital. Mainly drugs used and outcome of the patients were recorded. Of all patients 306 were found to be treated with calcium channel blockers (CCBs), 77 with angiotensin receptor blockers (ARBs), 229 with CCBs plus ARBs, 46 with CCBs plus ARBs and beta blockers and only 22 patients got CCBs, ARBs and diuretics. Data were statistically analysed in respect of demographic profile, drugs used and clinical features of the patients. Results: Best outcome was observed in patients treated with solely CCBs where in 289 out of 306 patients, hypertension was controlled. 194 out of 229 patients with CCBs and ARBs showed desired outcomes. 41 out of 77 with only ARBs, 29 out of 46 with CCBs, ARBs and beta blockers and 16 out of 22 with CCBs, ARBs and diuretics ended with positive results. Conclusion: Calcium channel blockers alone and in few cases in combination with angiotensin receptor blocking agents are very effective in controlling hypertension. Keywords: Hypertension, calcium channel blockers and angiotensin receptor blockers