Use Of Angiotensin-converting Enzyme Inhibitors Research Articles

Comparative efficacy of novel drugs as an addition to guideline-directed medical therapy for heart failure with reduced ejection fraction: a network meta-analysis of randomised controlled trials

Abstract Background Heart failure with reduced ejection fraction (HFrEF) is the global public health burden with a prevalence of 1% of adults. The current guidelines suggest the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i) to reduce mortality. Soluble guanylyl cyclase (sGC) and omecamtiv mecarbil (OMM) have also been studied in HFrEF. However, there has been no head-to-head comparison of the efficacy and cumulative incidence interpretation of the outcome of the novel drugs. Purpose To compare all drugs and possible combinations of guideline-directed medical therapy (GDMT) including ACEI, ARB, BB, and MRA, and novel drugs including ivabradine (IVA), ARNI, SGLT2i, sGC and OMM to find the best additional novel drug to the GDMT. Methods This network meta-analysis (MA) is part of the study registered on PROSPERO (CRD42021262029). A systematic search of MAs and randomised controlled trials (RCT) was performed on biomedical databases from inception to June 2021. All MAs and RCTs were selected against eligibility criteria. A primary composite outcome or a composite of cardiovascular death or heart failure hospitalisation was the outcome of focus. In addition, secondary outcomes, i.e., cardiovascular death and heart failure hospitalisation were analysed. Individual patient data was constructed from Kaplan-Meier-extracted data; then data from all studies were combined. A mixed-effect parametric survival model with accelerated failure time was used, considering individual study as random effects and treatments as a fixed-effect. Median failure time for each regimen and hazard ratios (HR) comparing between regimens with 95% confidence intervals (CI) were then estimated from KM data. Results Cumulative incidence of the primary outcome from each regimen is displayed in Figure 1. Compared to the GDMT or ACEI+BB+MRA, BB+MRA+ARNI (HR 0.80, 95% CI 0.74–0.88), ACEI+BB+MRA+IVA (HR 0.82, 95% CI 0.75–0.90), ACEI+BB+MRA+SGLT2i (HR 0.75, 95% CI 0.68–0.82), ACEI+BB+MRA+sGC (HR 0.91, 95% CI 0.83–0.99), and ACEI+BB+MRA+OMM (HR 0.92, 95% CI 0.86–0.99) showed superior benefits. However, ACEI+BB (HR 0.68, 95% CI 0.59–0.79) and ACEI+BB+ARB (HR 0.81, 95% CI 0.67–0.98) were both statistically significantly inferior to the GDMT. The treatment combination of ACEI+BB+MRA+SGLT2i showed the highest risk reduction of 25%. More details are provided in Figure 2. The analysis of secondary outcomes showed a corresponding trend with ACEI+BB+MRA+SGLT2i combination reducing the risk of cardiovascular death by 25% (HR 0.75, 95% CI 0.68–0.82) and heart failure hospitalisation by 25% (HR 0.75, 95% CI 0.68–0.82) versus the GDMT. Conclusion The network MA showed that the SGT2i is currently the best additional drug to the GDMT in the treatment of HFrEF. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Faculty of Medicine Ramathibodi Hospital, Mahidol University

Factors associated to renin-angiotensin-aldosterone system inhibitors discontinuation or down-titration due to hyperkalaemia in patients with chronic cardiovascular conditions

Abstract Background/Introduction The renin-angiotensin-aldosterone system inhibitors (RAASI) are one of the keystones of the medical treatment in chronic cardiovascular disorders and have shown improvements in clinical outcomes in many clinical trials. Hyperkalaemia is a well-defined non-desirable effect of RAASI that occasionally forces to interrupt these medications. That enforced RAASI discontinuation or down-titration due to hyperkalaemia may have adverse prognostic consequences. Purpose Describe the demographical, clinical and pharmacological variables associated to a higher risk of RAASI discontinuation or down-titration due to hyperkalaemia among individuals with chronic cardiovascular conditions. Methods We used data from more than 375,000 individuals 55 years of age or older, included in the population-based healthcare database of a public Institute of Health between 2015 and 2017. We included participants with at least one relevant condition: chronic heart failure, chronic kidney disease, diabetes mellitus, ischemic heart disease or hypertension. They had to be under RAASI treatment as of January 1st, 2016, and with evidence of at least one episode of hyperkalaemia (serum potassium >5.0 mmol/L) during 2016. Then, were classified in one of the two following profiles: RAASI treatment discontinuation or down-titration versus RAASI treatment unchanged or up-titrated. For the statistical analysis, we used logistic regression to calculate the multivariable-adjusted odds ratios of each study variable, comparing RAASI discontinuation or down-titration group to RAASI treatment unchanged or up-titrated controls (reference group). Results In the multivariable-adjusted model, the risk of RAASI treatment discontinuation or down-titration due to hyperkalaemia was significantly associated with the use of RAASI, very high comorbidity index, potassium derangements (both hypokalaemia and hyperkalaemia), prior hospitalizations and prior emergency visits. Among RAASI treatments, the use of Angiotensin receptor blockers (OR 2.518, 95% CI 2.317–2.735) and Angiotensin-converting enzyme inhibitors (OR 2.341, 95% CI 2.149–2.549) were associated with a higher risk of RAASI discontinuation or down-titration due to hyperkalaemia than Aldosterone inhibitors (1.428, 95% CI 1.285–1.584). Conclusion These results suggest that vulnerable populations such as those with very high comorbidity index, potassium derangements or prior emergency visits or hospitalizations have a higher risk of RAASI treatment discontinuation or down-titration due to hyperkalaemia. A more careful and exhaustive management of RAASI should be advised in those patients. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Josep Comin-Colet has received speaker fees from Vifor Pharma.

Heavy weekly alcohol consumption versus binge drinking after an acute coronary syndrome and risk of major adverse cardiovascular events at one year follow up

Abstract Background The association between heavy weekly alcohol consumption or binge drinking and the risk of major adverse cardiovascular events (MACE) after acute coronary syndromes (ACS) is still unclear. Purpose To determine the risks of MACE at one year follow up according to baseline alcohol consumption, especially in patients with heavy weekly alcohol consumption or binge drinking. Methods We analyzed data of 6053 patients hospitalized in 4 Swiss centres for an ACS and followed over 12 months. Data on alcohol consumption were collected at baseline and at one year follow up after ACS. Binge drinking was defined as the consumption of ≥6 units of alcohol on one occasion, for the 12-months period preceding the one-year follow up. We defined MACE as a composite of cardiac death, myocardial infarction, stroke or clinically indicated target vessel coronary revascularization. We applied Cox regression to assess the risk of MACE associated with heavy alcohol weekly consumption (>14 standard units/week) compared to light consumption (<1 standard unit/week) or abstinence, as well as the risk with binge drinking, compared to no binge drinking, adjusting for baseline differences (age, sex, body-mass index, smoking, diabetes, peripheral artery disease, stroke, hypertension, use of aspirin, anticoagulation, statin, beta-blocker, ACE-inhibitor or ATII receptor blocker). Results At baseline, 817 (13.4%) patients reported heavy weekly alcohol consumption and 717 (11.8%) reported to have at least one episode of binge drinking per month. The risk for MACE at one year follow up was not increased in those with heavy weekly consumption compared to light consumption (8.7% vs. 8.5%, HR 0.96, 95% CI 0.69–1.33, P=0.80) or no consumption (8.7% vs. 10.3%, HR 1.26, 95% CI 0.88–1.80, P=0.21). However, the risk of MACE was higher in those reporting binge drinking with less than one episode a month (9.4% vs. 7.7%, HR 1.67, 95% CI 1.32–2.12, P<0.001), as well as in those with at least one episode of binge drinking per month (13.4% vs. 7.7%, HR 2.07, 95% CI 1.62–2.65, P<0.001), when compared to no binge drinking. Conclusion In contrast to regular heavy alcohol consumption, binge drinking behavior is associated with significant increased risk of MACE 12 months after ACS. Funding Acknowledgement Type of funding sources: None.

Primary care screening and prevention of heart failure coordinated by cardiologist in rural areas

Abstract Purpose Current guidelines do not support community-wide screening for undetected asymptomatic left ventricular systolic dysfunction (LVSD), reduced (HFrEF), mid-range (HFmrEF) or preserved (HFpEF) heart failure (HF), either with natriuretic peptides (NTproBNP) or open access echocardiography (echo). Universal access to NTproBNP testing (with reimbursement in primary care) before referral for tissue doppler and speckle-tracking echo may be needed to facilitate HF diagnosis at earlier, more treatable stage. Methods 4376 consecutive patients (pts) were referred from January 2015 by general practitioners (GP) to echolab with suspected HF symptoms (unexplained breathlessness or ankle swelling). After confirmation elevated NTproBNP (>400 pg/mL) and MESA (Multi-Ethnic Study of Atherosclerosis) 5-year HF risk score ≥10 points and after exclusion significant valvular disease and abnormal electrocardiogram or chest x-ray in subgroup of randomly selected 829 asymptomatic elderly (≥65 years) pts (age 71±4 years, 48% women) with continued usual care by GP was compared with randomly selected 833 asymptomatic elderly pts from 5 GP practices in rural areas with prospective follow-up by regional cardiologist. Results At referral in both groups were similar baseline characteristics, 14% pts were treated with ACE-inhibitor (ACEi), 5% beta-blockers (BB) and 39% loop-diuretics. After cardiologist consultation loop-diuretics withdrawn in 90% pts, ACEi and BB use increased significantly to 98% and 82% in both groups (all p<0.001). Global LVSD (EF≤50%) was detected in 5% at baseline and 23% pts after 5 years in GP group, respectively 5.4% at baseline and 7% after 5 years in cardiologist group (p<0.001). Systolic dysfunction (S'≤6.0 cm/s) occurred in 14% at baseline and 38% pts after 5 years in GP group, respectively 15% at baseline and 21% after 5 years in cardiologist group (all p<0.001). Reduced global longitudinal (GLS<16%) observed in 20% at baseline and 51% pts after 5 years in GP group, respectively 21% at baseline and 29% after 5 years in cardiologist group (all p<0.001). At baseline we found 0.5% pts with new-onset HF in both groups (only HFmrEF). After mean follow-up of 54±4 months in cardiologist group developed new HF in 3% pts (1% HFmrEF, 2% HFpEF) compared with 19% pts (3% HFrEF, 7% HFmrEF, 9% HFpEF) in GP group (p<0.001). Significant (p<0.001) predictors of incident HFmrEF were systolic dysfunction (S'≤6.0 cm/s), hazard ratio (HR) 2.2, 95% CI 1.82–2.9) and reduced GLS (HR 3.5, 95% CI 3.1–3.9), all p<0.01. The strongest (p<0.001) predictors of incident HFpEF were new-onset atrial fibrillation (HR 1.9, 95% CI 0.9–3.9) and echo-detected left ventricular hypertrophy (septal and posterior wall thickness ≥13 mm, HR 1.52, 95% CI 1.22–1.89), all p<0.01. Conclusions For preventing HF progression is required additional research focused on cooperative care between GP and specialised HF outpatient clinic. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by grant from the Slovak Society of Cardiology 2015 Selective screening of heart failure stages in regional settings

S1563 ACE Inhibitor Use Is Associated With Angioectasias on Video Capsule Endoscopy (VCE) in Patients With Iron Deficiency Anemia

Introduction: Small bowel bleeding poses a clinical challenge in patients with vascular lesions. Bleeding recurrence after endoscopic therapy is high and medical therapies have limited efficacy. In those with left ventricular assist devices (LVADs), the use of angiotensin converting enzyme inhibitors (ACEi) has been associated with a reduced rate of gastrointestinal bleeding. Conversely, the antiplatelet effects of ACEi have been described thought due to their effects in decreasing platelet aggregation. Our aim was to determine whether ACEi or angiotensin receptor blocker (ARB) therapy had an impact on the rate of positive VCE small bowel findings in those with iron deficiency anemia (IDA). Methods: Data was collected from consecutive inpatient and outpatient VCE examinations performed between January 1, 2009 to March 1, 2018 at a single U.S. tertiary medical center performed for IDA. VCE studies were excluded in those with incomplete small bowel examinations (9) or technical failure (1). Patient demographics, laboratory values, medication use and endoscopic findings were recorded. VCE findings were based on the P0-P2 grading system. The primary outcome of interest was a positive (P2) VCE. Data were analyzed using Wilcoxon rank-sum test for continuous variables and Fischer’s exact test for dichotomous variables. Bivariate logistic regression was performed to identify independent factors predictive of positive VCE. Results: Eighty-two VCE were included in the final analysis. Median age was 67.6 (IQR: 57.1-75.5) years and 38 (46.3%) patients were male. Thirty-seven (45.1%) VCE examinations were positive with the most common finding of angiectasia in 21 (55.3%). Risk factors for positive VCE are listed in Table 1. In univariate analysis, ACEi therapy associated with both positive VCE (P=0.014) and the presence of angiectasia (P=0.021), whereas ARB therapy did not associate with positive VCE. ACEi findings remained significant in bivariate analysis after controlling for cardiac and pulmonary comorbidities. Conclusion: In this single center study the presence of ACEi use was associated with small bowel and/or stomach angiectasias on VCE in univariate analysis and when controlled for cardiac and pulmonary risk factors. Further studies are required to determine the mechanistic impact of ACEi on gastrointestinal bleeding risk such as the reduction in von Willebrand factor or factors that affect platelet aggregation. Table 1. - Univariate predictors of positive video capsule endoscopy in iron deficiency anemia Negative VCE (n = 45) Positive VCE (n =37) P-value Age, years, mean (SD) 63.6 (15.8) 68.6 (9.3) 0.303 Male sex, n (%) 21 (46.7) 17 (46) 1 White race, n (%) 22 (48.9) 20 (54.1) 0.223 Active smoking, n (%) 6 (14) 11 (29.7) 0.105 Outpatient location, n (%) 31 (68.9) 21 (56.8) 0.357 Chronic kidney disease, n (%) 10 (22.2) 13 (35.1) 0.224 Chronic liver disease, n (%) 3 (6.7) 4 (10.8) 0.696 Congestive heart failure, n (%) 10 (22.2) 13 (35.1) 0.224 Diabetes mellitus, n (%) 15 (33.3) 15 (40.5) 0.645 Cardiac valvular disease, n (%) 7 (15.6) 6 (16.2) 1 Coronary artery disease, n (%) 14 (31.1) 14 (37.8) 0.641 Cardiac arrhythmia, n (%) 10 (22.2) 18 (48.7) 0.019 Chronic lung disease, n (%) 10 (22.2) 13 (35.1) 0.224 Left ventricular assist device, n (%) 2 (4.4) 2 (5.4) 1 Blood transfusion in the preceding 4 weeks, n (%) 17 (37.8) 16 (43.2) 0.656 Aspirin, n (%) 20 (44.4) 14 (37.8) 0.654 Thienopyridine, n (%) 3 (6.7) 2 (5.4) 1 Coumadin, n (%) 1 (2.2) 5 (13.5) 0.086 SSRI/SNRI, n (%) 7 (15.6) 9 (24.3) 0.404 ACEi 7 (15.6) 15 (40.5) 0.014 ARB 9 (20) 7 (18.9) 1 Hemoglobin, g/dL1 9.9 (1.7) 9.2 (2.3) 0.216 Platelets, 109/L1 225.4 (67.5) 208.6 (84.9) 0.202 BUN, mg/dL1 21.9 (13.1) 26.7 (22) 0.869 Creatinine, mg/dL1 1.3 (0.5) 1.9 (1.5) 0.197 Ferritin, ng/mL,1 128 (259) 39.6 (28.7) 0.966 Percent saturation, %1 14.8 (15.1) 13.7 (15.4) 0.76

Experimental evidence for the topical use of angiotensin-converting enzyme inhibitors in eye drops for eye ischemia treatment

Purpose: to evaluate the topical use effect of angiotensin-converting enzyme (ACE) inhibitor (iACE) Enalaprilat in eye drops on eye blood flow volume, hypoxia degree, ACE activity, and total antioxidant activity (TAA) in aqueous humor of rabbits with experimental ocular ischemia.Material and methods. Transient ocular ischemia in 30 Chinchilla rabbits was induced by subconjunctivally injecting 0.2 ml of 1 % Phenylephrine. Ocular ischemia degree was assessed by the minute volume of blood flow (MBF), determined with the help of ophthalmic plethysmography. 0.125 % Enalaprilat was administered by instillations. A CE activity in aqueous humor was measured using a spectrofluorometric assay with 0.1 mM Z-Phe-His-Leu substrate; the degree of hypoxia was estimated by the level of lactate in aqueous humor, which was determined by the enzymatic amperometric method. TAA was determined by registering chemiluminescence kinetics in the hemoglobin-H2O2-luminol model system.Results. A single instillation of iACE in the intact rabbit eye caused a decline of MBF value and A CE activity in aqueous humor. In ocular ischemia, ACE activity and t he lactate level in aqueous humor are increasing, while TAA is decreasing. Enalaprilat instillation in the eyes with ischemia lead to the normalization of MBF, ACE activity, lactate level and TAA in aqueous humor.Conclusion. Topical iACE in eye drops can penetrate eye tissues. Instillations of iACE during ischemia cause a remarkable increase of eye blood flow and reduce ACE activity, which is increased in ischemia. The anti-ischemic effect of iACE is accompanied by antihypoxant and antioxidant effects. Thus, iACE in eye drops can be used in ophthalmology as an anti-ischemic agent.

Changes in Proximal Tubular Reabsorption Modulate Microvascular Regulation via the TGF System.

This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium–glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium–hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.

Association of Empagliflozin Treatment With Albuminuria Levels in Patients With Heart Failure

Albuminuria, routinely assessed as spot urine albumin-to-creatinine ratio (UACR), indicates structural damage of the glomerular filtration barrier and is associated with poor kidney and cardiovascular outcomes. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to reduce UACR in patients with type 2 diabetes, but its use in patients with heart failure (HF) is less well studied. To analyze the association of empagliflozin with study outcomes across baseline levels of albuminuria and change in albuminuria in patients with HF across a wide range of ejection fraction levels. This post hoc analysis included all patients with HF from the EMPEROR-Pooled analysis using combined individual patient data from the international multicenter randomized double-blind parallel-group, placebo-controlled EMPEROR-Reduced and EMPEROR-Preserved trials. Participants in the original trials were excluded from this analysis if they were missing baseline UACR data. EMPEROR-Preserved was conducted from March 27, 2017, to April 26, 2021, and EMPEROR-Reduced was conducted from April 6, 2017, to May 28, 2020. Data were analyzed from January to June 2022. Randomization to empagliflozin or placebo. New-onset macroalbuminuria and regression to normoalbuminuria and microalbuminuria. A total of 9673 patients were included (mean [SD] age, 69.9 [10.4] years; 3551 [36.7%] female and 6122 [63.3%] male). Of these, 5552 patients had normoalbuminuria (UACR <30 mg/g) and 1025 had macroalbuminuria (UACR >300 mg/g). Compared with normoalbuminuria, macroalbuminuria was associated with younger age, races other than White, obesity, male sex, site region other than Europe, higher levels of N-terminal pro-hormone brain natriuretic peptide and high-sensitivity troponin T, higher blood pressure, higher New York Heart Association class, greater HF duration, more frequent previous HF hospitalizations, diabetes, hypertension, lower eGFR, and less frequent use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and mineralocorticoid receptor antagonists. An increase in events was observed in individuals with higher UACR levels. The association of empagliflozin with cardiovascular mortality or HF hospitalization was consistent across UACR categories (hazard ratio [HR], 0.80; 95% CI, 0.69-0.92 for normoalbuminuria; HR, 0.74; 95% CI, 0.63-0.86 for microalbuminuria; HR, 0.78; 95% CI, 0.63-0.98 for macroalbuminuria; interaction P trend = .71). Treatment with empagliflozin was associated with lower incidence of new macroalbuminuria (HR, 0.81; 95% CI, 0.70-0.94; P = .005) and an increase in rate of remission to sustained normoalbuminuria or microalbuminuria (HR, 1.31; 95% CI, 1.07-1.59; P = .009) but not with a reduction in UACR in the overall population; however, UACR was reduced in patients with diabetes, who had higher UACR levels than patients without diabetes (geometric mean for diabetes at baseline, 0.91; 95% CI, 0.85-0.98 and for no diabetes at baseline, 1.08; 95% CI, 1.01-1.16; interaction P = .008). In this post hoc analysis of a randomized clinical trial, compared with placebo, empagliflozin was associated with reduced HF hospitalizations or cardiovascular death irrespective of albuminuria levels at baseline, reduced progression to macroalbuminuria, and reversion of macroalbuminuria. ClinicalTrials.gov Identifiers: NCT03057977 and NCT03057951.

Optimal Pharmacologic Treatment of Heart Failure With Preserved and Mildly Reduced Ejection Fraction

In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF. A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021. Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), β-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF. Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model. The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model. In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes. The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and β-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.

Abstract P117: MECHANISMS OF SIGNALING PATHWAYS TRIGGERED BY ANGIOTENSIN I CONVERTING ENZYME IN CHO ECA CELLS TREATED WITH CAPTOPRIL

Renin-Angiotensin System (RAS) is a hormonal system associated with hydroelectrolytic homeostasis and blood pressure control. Angiotensin II (Ang II) is the main and most potent biologically active product in the system, which is produced by the action of Angiotensin Converting Enzyme (ACE) on Ang I. Dysregulation of RAS is an important factor in the development and progression of cardiovascular/renal diseases and diabetes. Experiments and clinical practice have shown that the use of an ACE inhibitor (ACEi) is an effective treatment to attenuate hypertension and diabetic renal damage. In addition, recently the use of ACEi has also been associated with the activation of signaling pathways thus suggesting that ACE can act as a signal transductional molecule. The purpose of this study is to demonstrate the proteins that are differentially regulated when CHO-ECA cells are treated with the ACE inhibitor, captopril. The CHO-ACE cells were cultured in DMEM-SILAC medium in different media: Medium with light chain lysine (LV), medium with heavy chain lysine (P), and control (CT), with DMEM-High Glucose medium. At the 75% confluency, the cells were deprived of serum and then stimulated with captopril (1μM) or vehicle for 2 and 5 minutes (min). CHO-ACE cells were also cultured for the assay analysis of the Kinase Array. ACE activity was determined spectrofluorimetrically using ZPhe-His-Leu as substrate. With the SILAC medium, it was not possible to detect the differently modulated proteins by captopril. The kinase array demonstrated that some signaling pathways were not modulated after Captopril (eg, MSK1/2 and CREB). Other kinases were positively modulated after 2 min stimulation (eg, AMPKa1, HSP27, Akt 1/2/3 T308) and 5 min stimulation (STATa/b, HSP60, b-Catenin) with Captopril. Our screening also has shown that some kinases were negatively modulated following Captopril (eg, p53, PLC-γ1, Pyk2, eNOS). ACE activity in cell lysate group was inexpressive when treated with captopril. Our results expanded the repertoire of kinases modulated by the binding of Captopril to ACE, as well as, the role of ACE as a receptor and the modulation of signaling pathways triggered by this binding, which may imply in the treatment of hypertension.

Prognostic factors, disease course, and treatment efficacy in Duchenne muscular dystrophy: A systematic review and meta-analysis.

Prognostic factors in Duchenne muscular dystrophy (DMD) predict the disease course and may help individualize patient care. The aim was to summarize the evidence on prognostic factors that may support treatment decisions. We searched six databases for prospective studies that each included ≥50 DMD patients with a minimum follow-up of 1 y. Primary outcomes were age at loss of ambulation (LoA), pulmonary function (forced vital capacity percent of predicted, FVC%p), and heart failure. Out of 5074 references, 59 studies were analyzed. Corticosteroid use was associated with a delayed LoA (pooled effect hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.23-0.75, I2 94%), better pulmonary function tests (higher peak FVC%, prolonged time with FVC%p > 50%, and reduced need for assisted ventilation) and delayed cardiomyopathy. Longer corticosteroid treatment was associated with later LoA (>1 y compared to <1 y; pooled HR: 0.50, 95% CI 0.27-0.90) and early treatment start (aged <5 y) may be associated with early cardiomyopathy and higher fracture risk. Genotype appeared to be an independent driver of LoA in some studies. Higher baseline physical function tests (e.g., 6-minute walk test) were associated with delayed LoA. Left ventricular dysfunction and FVC <1 L increased and the use of angiotensin-converting enzyme (ACE) inhibitors reduced the risk of heart failure and death. Fusion surgery in scoliosis may potentially preserve pulmonary function. Prognostic factors that may inform clinical decisions include age at corticosteroid treatment initiation and treatment duration, ACE-inhibitor use, baseline physical function tests, pulmonary function, and cardiac dysfunction.

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

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

The effect of ACE inhibitors and ARBs on outcomes in hospitalized patients with COVID-19.

Background Contradictory opinions exist regarding the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with hypertension, which is the most common comorbidity associated with COVID-19. Herein, the effects of ACEIs and ARBs on outcomes of COVID-19 patients were evaluated.MethodsIn this cross-sectional study, the outcomes of COVID-19 patients were compared between patients who received pretreatment ACEIs or ARBs and those who did not.ResultsThe incidence of moderate and severe forms of COVID-19 was significantly higher in patients taking ACEI/ARB drugs (P-value = 0.012). Also, patients taking ACEI/ARB drugs (P-value = 0.034), patients with hypertension (P-value = 0.011), and patients with dyslipidemia (P-value = 0.011) experienced more severe forms of COVID-19. There was an association between increased length of hospital stay and dyslipidemia (P-value = 0.033) and the use of ACEI/ARB drugs (P-value = 0.041), while no correlation was found between other parameters in univariate linear regression analysis as well as multivariate linear regression. There was an association between increased mortality of patients with increasing age (P-value < 0.001), BMI greater than 30 kg/m2 (P-value = 0.02), asthma (P-value = 0.003), and dyslipidemia (P-value = 0.045).ConclusionsACEI/ARB drugs put COVID-19 patients at high risk for moderate to severe forms of COVID-19 and higher length of hospital stay. Although, it is notable that these drugs did not significantly affect specific adverse outcomes of COVID-19, such as the need for admission to the intensive care unit (ICU), length of ICU stay, ventilation, and mortality.

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

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

Study of the reliability of serum vascular endothelial growth factor and its soluble receptor as markers of diabetic nephropathy in type 2 diabetes patients

The levels of circulating angiogenic and anti-angiogenic factors, namely vascular endothelial growth factor–A (VEGF-A) and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), have been linked to the development of renal dysfunction due to the proliferation of microvasculature within the kidneys of type 2 diabetic (T2DM) patients. The study aims to scrutinize serum levels of VEGF and sVEGFR-1 in a sample of Iraqi diabetic nephropathy patients to support their reliability as markers for the prediction of nephropathy in type 2 diabetes mellitus patients as well as to assess the ACE inhibitor’s effect on the levels of these two markers. Method: The ninety participants of this case-control study were split into three groups: thirty-five patients with T2DM and an equal number of patients with DN and the third group involve twenty apparently healthy individuals as the control group. The two diabetic groups have been further divided into four groups according to the ACE inhibitors use. Laboratory measurements involve the glycemic indices, renal function test with serum VEGF-A and sVEGFR-1. Results: the median serum levels of VEGF-A show valuable discrepancies between the three groups (p-value&lt;0.05) but for sVEGFR-1 it doesn’t show a notable difference between the DM and the DN groups only(p-value&gt; 0.05).

Síndrome nefrótico secundario a preeclampsia: presentación, manejo y evolución clínica observados en 5 años de experiencia

IntroductionNephrotic syndrome (NS) is rare during pregnancy. The main cause is severe pre-eclampsia (PR). Our aim was to describe the clinical presentation, analytical features, medical management, and progress of women with NS due to PE. Materials and methodsA descriptive, retrospective study, conducted from 01/01/2017 to 01/01/2022 (5years). Women with a gestational age (GA) ≥20weeks were included in the study, hospitalised due to hypertensive disorders in pregnancy (HDP), with no evidence of kidney damage prior to gestation. ResultsOf the 652 HDP, 452 PE and 21 NS were identified. Maternal age was 25±5.7 years, GA at diagnosis was 33.1±5.1 weeks. All the women had facial and peripheral oedema: 5 pleural effusion, 3 pericardial effusion, and 2 anasarca. Their p24 was 6.17±2.34grams (3.10-10.8), serum albumin 2.5±0.27g/dL (2.10-2.90), and serum cholesterol 281.4±21.7mg/dL (251-316). Thirteen developed maternal complications: acute kidney damage, pulmonary oedema, dilated cardiomyopathy, eclampsia, and HELLP syndrome. They all remained hypertensive postpartum, and required a combination of two to three antihypertensive drugs. They all received statins postpartum, and angiotensin converting enzyme (ACE) inhibitors to manage proteinuria. None developed hyperkalaemia or creatinine elevation. Hospital stay was 10.4±3.7days. All nephrotic range proteinuria parameters reversed prior to discharge. No deaths were recorded. ConclusionPresentation ranged from peripheral oedema to serous involvement. Severity of proteinuria varied. Use of ACE inhibitors did not precipitate hyperkalaemia or kidney failure. Maternal complications were frequent, but no deaths were recorded.

Potential for repurposing oral hypertension/diabetes drugs to decrease asthma risk in obesity

Objective Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma. Methods Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years. Exposure was defined by the prescription pickup of ACE-I, TZD, and/or ARB for at least 4 weeks. The outcome, time until new-onset of clinician-diagnosed asthma, was studied using survival analysis. The propensity scoring method controlled for treatment selection bias. Results 2.83 million eligible veterans, including 77,278 with incident asthma, were studied. As compared to those unexposed, the use of ACE-I alone, TZD alone, or their combinations were each associated with decreased risk for incident asthma (hazard ratios of 0.88, 0.74, and 0.20, respectively; p < 0.001 for all analyses in the fully adjusted statistical models). TZD lowered the risk among racial/ethnic minority subjects more than among White participants (p < 0.001). On the other hand, ARB use alone or in combination with TZD was associated with a higher risk for incident asthma. Conclusions Use of ACE-I and/or TZD was associated with a lower risk for incident asthma in overweight/obese patients with diabetes mellitus and/or hypertension.

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on the Rupture Risk Among Hypertensive Patients With Intracranial Aneurysms.

Mounting experimental evidence supports the concept that the RAAS (renin-angiotensin-aldosterone system) is involved in the pathogenesis of intracranial aneurysm rupture. However, whether RAAS inhibitors could reduce the rupture risk of intracranial aneurysms remains unclear. We performed a chart review of a multicenter, prospectively maintained database of 3044 hypertensive patients with intracranial aneurysms from 20 medical centers in China. The patients were separated into ruptured and unruptured groups. Univariable and multivariable logistical regression analyses were performed to determine the association between the use of RAAS inhibitors and the rupture risk. Sensitivity analyses and subgroup analyses were performed to verify the robustness of the results. In multivariable analyses, female sex, passive smoking, uncontrolled, or unmonitored hypertension, use of over 2 antihypertensive medications, RAAS inhibitors use, antihyperglycemic agents use, hyperlipidemia, ischemic stroke, and aneurysmal location were independently associated with the rupture risk. The use of RAAS inhibitors was significantly associated with a reduced rupture risk compared with the use of non-RAAS inhibitors (odds ratio, 0.490 [95% CI, 0.402-0.597]; P=0.000). Compared with the use of non-RAAS inhibitors, the use of ACE (angiotensin-converting enzyme) inhibitors (odds ratio, 0.559 [95% CI, 0.442-0.709]; P=0.000) and use of ARBs (angiotensin receptor blockers; odds ratio, 0.414 [95% CI, 0.315-0.542]; P=0.000) were both significantly associated with a reduced rupture risk. The negative association of the rupture risk with RAAS inhibitors was consistent across 3 analyzed data and the predefined subgroups (including controlled hypertension). The use of RAAS inhibitors was significantly associated with a decreased rupture risk independent of blood pressure control among hypertensive patients with intracranial aneurysms.

Albuminuria in Patients with Type 2 Diabetes Mellitus: a Single Center Cross-Sectional Study

Introduction: Diabetes mellitus is one of the commonest non-communicable diseases in Nepal and is associated with long term microvascular and macro vascular complications. Detection of albumin in urine is the earliest recognizable feature in the development of proteinuric diabetic nephropathy. This study aims to study the prevalence as well the determinants of albuminuria in patient with Type 2 diabetes mellitus visiting the medical OPD of College of Medical Sciences-Teaching hospital. Methods: This was a cross-sectional study done from January to June 2022 among Type 2 diabetes patients presenting to medical OPD for the comprehensive diabetes management. Relevant epidemiological, clinical and laboratory data were obtained. Urine dipstick test was done to screen for albuminuria. The prevalence and determinants of albuminuria were studied. Results: Study among 360 patients with mean age of 58.5 + 10.9 years and the mean duration since the diagnosis of diabetes of 6.8 + 5.5 years, showed that the prevalence of albuminuria was 33.3%. Albuminuria in these patients was found to have significant association with age (P&lt;0.001), duration since diagnosis of diabetes (&lt;0.001) and HbA1c (P&lt;0.001). No significant association of albuminuria was found with gender (P=0.087), hypertension (P=0.063) and previous use of Angiotensin-converting enzyme inhibitors/ Angiotensin II receptor blockers. (P=0.217) Conclusions: Albuminuria is highly prevalent among our cohort of diabetic patients. Increasing age, longer duration since diagnosis of diabetes and higher HbA1c are the factors significantly associated with it.

Impact of the withdrawal of renin-angiotensin-aldosterone inhibitors on mortality in COVID-19 patients

BackgroundChronic use of Angiotensin-converting enzyme (ACE) inhibitors (ACEi) and aldosterone-receptor blockers (ARB) is not associated with worse outcomes in patients with COVID-19. However, evidence on the impact of their discontinuation during hospital admission is scarce. Our aim was to determine whether withdrawal of ACEi, ARB and mineralocorticoid receptor antagonists (MRA) is associated with all-cause mortality in a real-life large cohort of patients with SARS-CoV-2 infection. MethodsObservational cohort study from a large referral center from 1 March 2020 to 20 April 2020. Withdrawal of renin-angiotensin-aldosterone system inhibitors was defined as the absence of any received dose during hospital admission in patients receiving chronic treatment. Prescriptions during admission were confirmed by data from the central pharmacy computerized system. ResultsA total of 2042 patients (mean age 68.4±17.6, 57.1% male) with confirmed COVID-19 were included. During a median follow-up of 57 (21-55) days, 583 (28.6%) died. Prior to hospital admission 468 (22.9%), 343 (16.8%) and 83 (4.1%) patients were receiving ACEi, ARB and MRA respectively. During the study period, 216 (46.2%), 193 (56.3%) and 41 (49.4%) were withdrawn from the corresponding drug. After adjusting for age, cardiovascular risk factors, baseline comorbidities and in-hospital COVID-19 dedicated treatment, withdrawal of ACE inhibitors (hazard ration [HR] 1.48 [95% confidence interval –CI– 1.16-1.89]) and MRA (HR 2.01 [95% CI 1.30-3.10]) were shown to be independent predictors of all-cause mortality. No independent relationship between ARB withdrawal and mortality was observed. ConclusionACEi and MRA withdrawal were associated with higher mortality. Strong consideration should be given to not discontinuing these medications during hospital admission.