Angiotensin-converting Enzyme Inhibitors In Patients Research Articles

ACE Inhibitors and Angiotensin Receptor Blockers for the Primary and Secondary Prevention of Cardiovascular Outcomes: Recommendations from the 2024 Egyptian Cardiology Expert Consensus in Collaboration with the CVREP Foundation.

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in regulating blood pressure (BP), with dysregulation of RAAS resulting in hypertension and potentially heart failure (HF), myocardial infarction (MI), cardio-renal syndrome, and stroke. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), have advantages beyond BP control. However, differences between these two drug classes need to be considered when choosing a therapy for preventing cardiovascular events. A panel of 36 Egyptian cardiologists developed consensus statements on RAAS inhibitors for primary and secondary prevention of cardiovascular outcomes and stroke, using a modified three-step Delphi process. The consensus statements highlight the importance of effective BP control and the role of RAAS blockade for prevention and management of various cardiovascular diseases. ACEis and ARBs differ in their mode of action and, thus, clinical effects. On the basis of available evidence, the consensus group recommended the following: ACEis should be considered as first choice (in preference to ARBs) to reduce the risk of MI, for primary prevention of HF, and for secondary prevention of stroke. ACEis and ARBs show equivalent efficacy for the primary prevention of stroke. Evidence also favors the preferential use of ACEis in patients with type 2 diabetes, for BP control, for the primary prevention of diabetic kidney disease, and to reduce the risk of major cardiovascular and renal outcomes. Treatment with an ACEi should be started within 24 h of ST segment elevation MI (and continued long term) in patients with HF, left ventricular systolic dysfunction, and/or diabetes. Angiotensin receptor/neprilysin inhibitors (ARNIs) are the first choice for patients with HF and reduced ejection fraction, with ACEis being the second choice in this group. ARBs are indicated as alternatives in patients who cannot tolerate ACEis. ACEis may be associated with cough development, but the incidence tends to be overestimated, and the risk can be reduced by use of a lipophilic ACEi or combining the ACEi with a calcium channel blocker. RAAS blockade is an essential component of hypertension therapy; however, the protective effects provided by ACEis are superior to those of ARBs. Therefore, an ACEi is indicated in almost all cases, unless not tolerated.

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

Angiotensin Receptor Blockers Versus Angiotensin Converting Enzyme Inhibitors in Acute Myocardial Infarction Without Heart Failure

BackgroundWhether angiotensin II receptor blockers (ARBs) can be an alternative to angiotensin-converting enzyme inhibitors (ACEIs) in patients without heart failure (HF) after acute myocardial infarction (MI) remains controversial. The aim of this study was to compare clinical outcomes between initial ARB and ACEI therapy in patients with MI without HF. MethodsBetween 2010 and 2016, a total of 31,013 patients who underwent coronary revascularization for MI with prescription of ARBs or ACEIs at hospital discharge were enrolled from the Korean nationwide medical insurance data. Patients who had HF at index MI were excluded. The primary outcome was all-cause death. The secondary outcomes included recurrent MI, hospitalization for new heart HF, stroke, and a composite of each outcome. ResultsOf 31,013 patients, ARBs were prescribed in 12,685 (40.9%) and ACEIs in 18,328 (59.1%). Patients receiving ARBs had a lower discontinuation rate compared with those receiving ACEIs (28.2% vs 43.5%, adjusted hazard ratio [HR] 0.34; 95% confidence interval [CI] 0.31-0.37; P < .01). During a median follow-up of 2.2 years, 2480 patients died. The incidence rate of all-cause death in patients receiving ARBs and those receiving ACEIs was 27.7 and 22.9 per 1000 person-years, respectively (adjusted HR 1.04; 95% CI 0.95-1.13; P = .40). There were no significant differences in the secondary outcomes between patients receiving ARBs and those receiving ACEIs, except stroke (19.2 vs 13.6 per 1000 person-years; adjusted HR 1.17; 95% CI 1.04-1.32; P = .01). In a subgroup analysis, a higher mortality was observed with ARBs compared with ACEIs in patients with diabetes. ConclusionsIn this nationwide cohort, there was no significant difference in the incidence of all-cause death between ARBs and ACEIs as discharge medications in patients with myocardial infarction without heart failure. Angiotensin II receptor blockers would be an alternative to ACEIs for those intolerant to ACEI therapy.

Angiotensin Converting Enzyme Inhibitors: Interaction Issues in Patients with Glaucoma and Arterial Hypertension. Review

The purpose of the review is to evaluate the interaction of angiotensin-converting enzyme inhibitors in patients with glaucoma and concomitant arterial hypertension using literature data. Glaucoma is the main cause of blindness and visual impairment, as well as the main cause of irreversible blindness worldwide. Pharmacotherapy, laser or surgical treatments are used to reduce IOP levels, as well as prevent deterioration of visual field defects. However, 40 % of patients develop glaucomatous neuropathy despite ongoing therapy. This prompts the investigation of alternative causes of damage to the optic nerve, and abnormal blood pressure levels, both too low and too high, are considered as a possible risk factor. Arterial hypertension occurs in 48–65 % of patients with glaucoma and is the most common systemic disease in patients with glaucoma. Currently, angiotensin converting enzyme (ACE) inhibitors are considered the “gold standard” in the treatment of arterial hypertension, in the pathogenesis of which activation of the renin-angiotensin system (RAS) plays an important role. The renin-angiotensin system (RAS) is a hormonal system responsible for regulating blood pressure and fluid and electrolyte balance in the body. Local tissue-specific RAS were found, including in the structures of the eyeball: cornea, aqueous humor, iris, ciliary body, vitreous body, retina. These data indicate that the local RAS plays an important role in the regulation of the physiology of the eye and may become a target in the development of new antiglaucoma drugs. Animal studies, as well as studies in various patient groups, show that systemic antihypertensive drugs that inhibit the RAS, such as ACE inhibitors, reduce IOP. These studies support the concept that RAS inhibitory drugs may be potential antiglaucoma drugs in the future, as ACE inhibitors can improve the outflow of intraocular fluid, thereby reducing IOP.

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.

Renin‐angiotensin-aldosterone system inhibitors and mortality risk in elderly patients with atrial fibrillation. Insights from the nationwide START registry

BackgroundArterial hypertension is the most common cardiovascular comorbidity in atrial fibrillation (AF). Few studies investigated management strategies of hypertension in AF. Materials and methodsWe included 5769 AF patients on oral anticoagulants from the nationwide ongoing Italian START registry. We investigated the prescription of antihypertensive drugs and mortality risk. Subgroup analyses according to sex and major cardiovascular comorbidities were performed. ResultsMean age was 80.8 years, 46.1% were women; 80.3% of patients were hypertensive. Furosemide (30.1%) was the most frequent diuretic followed by hydrochlorothiazide (15.4%) and potassium canrenoate (7.9%). 61.1% received β-blockers: 34.2% bisoprolol, 6.2% atenolol. Additionally, 36.9% were on angiotensin converting enzyme inhibitors (ACE-I): ramipril (20.9%), enalapril (5.3%) and perindopril (2.8%); 31.7% were on angiotensin receptors blockers (ARBs): valsartan (7.6%) and irbesartan (6.4%). Amlodipine and lercanidipine were prescribed in 14.0% and 2.3%, respectively. ACE-I (p < 0.001), α-blockers (p = 0.020) and Dihydropyridines calcium channel blockers (p = 0.004) were more common in men, while ARBs (p = 0.008), thiazide diuretics (p < 0.001) and β-blockers (p < 0.001) in women.During 22.61 ± 17.1 months, 512 patients died. Multivariable Cox regression analysis showed that ACE-I (Hazard ratio [HR] 0.758, 95% Confidence Interval [95%CI] 0.612–0.940, p = 0.012) and ARBs (HR 0.623, 95%CI 0.487–0.796, p < 0.001) inversely associated with mortality. ACE-I/ARBs inversely associated with mortality in both sexes and in patients with diabetes. This associastion was evident for ACE-I in patients with previous cardiovascular disease, and for ARBs in HF. ConclusionA lower mortality risk was found in AF patients on ACE-I/ARBs. Different prescription patterns of antihypertensive drugs between men and women do exist.

Comparing clinical outcomes of ARB and ACEi in patients hospitalized for acute COVID-19

Continued receipt of Renin–Angiotensin–Aldosterone inhibitors in patients with COVID-19 has shown potential in producing better clinical outcomes. However, superiority between ACEi (angiotensin-converting enzyme inhibitors) and ARB (angiotensin II receptor blockers) regarding clinical outcomes in this setting remains unknown. We retrospectively collected data on patients hospitalized for acute COVID-19 using the nationwide administrative database (Diagnosis and Procedure Combinations, DPC). The DPC data covered around 25% of all acute care hospitals in Japan. Patient outcomes, with focus on inpatient mortality, were compared between patients previously prescribed ACEi and those prescribed ARB. Comparisons based on crude, multivariate and propensity-score adjusted analysis were conducted. We examined a total of 7613 patients (ARB group, 6903; ACEi group 710). The ARB group showed lower crude in-hospital mortality, compared to the ACEi group (5% vs 8%; odds ratio, 0.65; 95% CI 0.48–0.87), however not in the multivariate-adjusted model (odds ratio, 0.95; 95% CI 0.69–1.3) or propensity-score adjusted models (odds ratio, 0.86; 95% CI 0.63–1.2). ARB shows potential in reducing hospital stay duration over ACEi in patients admitted for COVID-19, but does not significantly reduce in-hospital mortality. Further prospective studies are needed to draw a definitive conclusion, but continuation of either of these medications is warranted to improve clinical outcomes.

Early initiation of angiotensin-converting enzyme inhibitor in patients with scleroderma renal crisis: a nationwide inpatient database study.

To evaluate the effectiveness of early initiation of angiotensin-converting enzyme inhibitor (ACEi) in patients with scleroderma renal crisis (SRC). This was a retrospective cohort study using a nationwide inpatient database in Japan from July 2010 to March 2020. All hospitalized patients with SRC were divided into those who received ACEi within 2 days of admission (early ACEi group) and those who did not (control group). Propensity-score overlap weighting analysis was performed to adjust for confounding factors. The primary outcome was the composite of in-hospital mortality or haemodialysis dependence at discharge. Of the 475 eligible patients, 248 (52.2%) were in the early ACEi group and 227 (47.8%) were in the control group. After overlap weighting, the primary outcome was significantly lower in the early ACEi group than in the control group (40.1% vs 49.0%; odds ratio, 0.69; 95% CI: 0.48, 1.00; P = 0.049). The present study showed that early initiation of ACEi was associated with lower composite outcome of in-hospital mortality or haemodialysis dependence at discharge in patients with SRC. Further prospective studies are warranted to verify the present findings.

Role of angiotensin-converting enzyme inhibitors in patients with aortic stenosis

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-2 receptor blockers (ARBs) are used extensively in the treatment of arterial hypertension. There is a widespread belief that these drugs are contraindicated in patients with underlying aortic stenosis due to their vasodilatory effect, which could result in hypotension and syncope. Nonetheless, these drugs may significantly benefit such patients with their proven cardioprotective benefits and positive effects on left ventricular remodelling. Despite widespread concerns about their safety, the currently available studies do not report any significant side effects. Оn the contrary, they find improved survival rates, a reduction in adverse cardiovascular events, and a reduction in symptoms. Further clinical studies and trials are necessary to assess the safety of ACEIs in patients with hypertension and underlying aortic stenosis and their effects on cardiac function and survival.

Improved cardiac outcomes by early treatment with angiotensin-converting enzyme inhibitors in becker muscular dystrophy

Abstract Background The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when left ventricular ejection fraction (LVEF) falls below 40%. Objective To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy. Methods From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and ≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to &amp;lt;35% in patients who received an ACE-i when LVEF fell below 40% (conventional treatment), versus below 50% (early treatment). Results From the 183 patients entered in our registry, we identified 85 whose LVEF was between 40 and 49%, 51 of whom received early and 34 received conventional ACE-i treatment. Among patients with early versus conventional treatments, 2 (3.9%) versus 4 (11.8%) were hospitalized for management of HF [hazard ratio (HR) 0.151; 95% confidence interval (CI) 0.028 to 0.822; p=0.029], and 9 (17.6%) versus 10 (29.4%) had a decrease in LVEF below 35% (HR 0.290; 95% CI 0.121 to 0.694; p=0.005). Conclusions The long-term cardiac outcome of patients presenting with Becker MD was significantly better when treatment with ACE-i was introduced after a decrease in LVEF below 50%, instead of below 40% as recommended in the current practice guidelines issued by professional societies. Funding Acknowledgement Type of funding sources: None. Study EndpointsCardiovascular events during follow-up

Angiotensin-Converting Enzyme Inhibitors Used Concomitantly with Insulin Secretagogues and the Risk of Serious Hypoglycemia.

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

Aprocitentan (a Dual Endothelin-Receptor Antagonist) for Treatment-Resistant Hypertension.

Treatment-resistant hypertension (TRH) is associated with increased cardiovascular risks and progression of chronic kidney disease. The pathophysiology of TRH is multifactorial, including overactivity of the renin-angiotensin-aldosterone system and sympathetic nervous system, endothelial dysfunction, and volume overload. Endothelin-1 is a vasoconstrictive peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, endothelial dysfunction, vascular hypertrophy and remodeling, and fibrosis. Endothelin-1 acts through 2 receptors, ETA and ETB. Activation of ETA receptors in vascular smooth muscle cells results in vasoconstriction, whereas ETB receptor activation results in vasoconstriction in the vascular smooth muscle cells and vasodilation through nitric oxide release in endothelial cells. Aprocitentan is novel, oral, dual endothelin-receptor antagonist that has demonstrated a more favorable tolerability and safety profile in early clinical trials compared with other endothelin-receptor antagonists studied. Phase 2 trial data support a significant reduction in blood pressure compared to placebo and similar blood pressure reduction compared to a moderately dosed angiotensin-converting enzyme inhibitor in patients with essential hypertension. An ongoing phase 3 randomized clinical trial is evaluating aprocitentan's efficacy and safety in patients with TRH receiving multiple antihypertensives. Additional research is needed to determine aprocitentan's role in therapy, but this agent may be a suitable treatment option for TRH.

Renal protection in chronic heart failure: focus on sacubitril/valsartan.

Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers, and mineralocorticoid receptor antagonists in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for heart failure. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin–angiotensin–aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.

Bleeding associated with co-administration of clopidogrel and ACEi in patients undergoing PCI and DAPT

Background and aimsThe coprescription of an angiotensin-converting enzyme inhibitor (ACEi) with clopidogrel reportedly increases bleeding risk. However, studies have not described such an increase in cases of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). MethodsWe analyzed electronic medical records of patients with discharge records of having undergone DAPT after PCI from a national health insurance claims database for January 1, 2006 to December 31, 2014. The date of PCI was the index date, and the primary outcome was major bleeding. The unit of analysis was one person-quarter. We compared patients who were prescribed with those not prescribed an ACEi in the cohort. A Poisson model with inverse probability of treatment weighting was fitted using generalized estimating equations to measure the risk of outcomes. ResultsIn total, 193,258 patients underwent DAPT after PCI; 46% had a coprescription of an ACEi. After screening, 170,775 patients (479,263 person-quarters) remained for analysis. The mean patient age was 65 ± 13 years, and 73.43% were men. In total, 79,739 prescriptions of an ACEi were written: 57%, 14.21%, 8.88%, 7.17%, and 4.68% were for captopril, ramipril, enalapril, perindopril, and imidapril, respectively. A concomitant prescription of an ACEi with clopidogrel was not associated with increased bleeding risk (adjusted rate ratio: 1.08, 99% confidence interval: 0.99–1.17). ConclusionsThe coadministration of an ACEi with clopidogrel after PCI is common. In this real-world cohort study, such coadministration was not associated with an increased risk of major bleeding in patients undergoing DAPT after PCI.

Angiotensin-converting enzyme inhibitors in patients with Alport syndrome: can all patients benefit?

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are prescribed to slow the progression of kidney disease in patients with Alport syndrome. In a recent publication by Yamamura etal. the authors showed an association of ACEi or ARB treatment with delay in ESKD, even for those patients with severe, truncating mutations. Despite these encouraging findings, there remain a number of clinical questions about the use of ACEi and ARBs in Alport syndrome.

Mortality and use of angiotensin-converting enzyme inhibitors in COVID 19 disease: a systematic review.

Interest exists concerning the use of angiotensin-converting enzyme inhibitors (ACEis) in patients with COVID-19 disease. The aim of the study was to perform a systematic review on mortality associated to the use of ACEi in patients with COVID-19 disease. Search in Medline (PubMed), in ISI Web of Knowledge and in medRxiv database; use of other sources. A total of 33 articles were evaluated. Concerning the papers used to produce the meta-analyses, 7 studies were selected, 5 of which were used. These 5 studies involved a total number of 944 patients treated with ACEi and 5173 not treated with ACEi. Increased mortality was seen in association to the use of ACEi in the context of COVID-19 disease (ACEi users vs nonusers; odds ratio, 1.48; 95% confidence interval, 1.02-2.15; P = .04). When compared to mortality in patients treated with angiotensin receptor blockers, mortality of patients treated with ACEi was not significantly different (odds ratio, 0.96; 95% confidence interval, 0.76-1.21; P = .74). Concerning the remaining reports, different types of data adjustments were used by several authors, after which increased mortality was not seen in association to the use of ACEi in this context. ACEi use could act as a marker of increased mortality risk in some but not all COVID-19 disease settings. The data now presented do not prove a causal relation but argue in favor of carrying out clinical trials studying ACEi in COVID-19 patients, to establish the safety of ACEi use in this context.

Controversy of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) prescription for hypertension patients in coronavirus disease 2019 (COVID-19) pandemic

Coronavirus disease 2019 (COVID-19) pandemic has made all the world in a mess. Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 infects human cells through angiotensin-converting enzyme 2 receptors (ACE receptors). Angiotensin-converting enzyme 2 (ACE) is upregulated in diabetes and cardiovascular diseases including hypertension. Hypertension patients commonly consume angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme inhibitors (ACEIs) which could increase ACE receptors. It was suspected that the ARBs or ACEIs administration may worsen the clinical outcome for the hypertension patients with COVID-19. However, no clinical trial had significantly revealed how appropriate management and prescription of ARBs and ACEIs for the hypertension patients with COVID-19. The use of ARBs and ACEIs for these patients is still controversy. Studies concerning the side effect of single or combination use of ARBs and ACEIs in the hypertension patients with COVID-19 as well as specific morbidity and mortality are needed. This review was aimed to provide understanding concerning the appropriate management and prescription of ARBs and ACEIs for hypertension patients with COVID-19.

Improvement in Angiotensin 1-7 precedes and correlates with improvement in Arterial stiffness and endothelial function following Renin-Angiotensin system inhibition in type 2 diabetes with newly diagnosed hypertension

Background and aimStudies in cell cultures and animal models have revealed the possible pathophysiological factors associated with vascular endothelial dysfunction. However, the same in human subjects has not been clearly established. The current study uses a novel approach to identify the factors associated with endothelial function and arterial function by altering these vascular parameters using Angiotensin-Converting-Enzyme (ACE) inhibition. MethodsDiabetic patients with newly diagnosed hypertension (n = 60) were recruited for the study. Flow-mediated-dilation (FMD), carotid-femoral (cf), carotid-radial (cr) Pulse-wave-velocity (PWV), Augmentation-Index, Carotid-Intima-Media-Thickness (CIMT), serum levels of Renin, Angiotensin II (AngII), Angiotensin-Converting-Enzyme2 (ACE2), Angiotensin1-7 (Ang1-7), E-selectin, Vascular-Cell-Adhesion-Molecule-1 (VCAM-1), Highly-sensitive-C-Reactive-Protein (hsCRP) and Interleukin-10 were measured at baseline (V1), after 1 week (V2) and 3 months (V3) of ACE inhibition in patients of diabetes with newly diagnosed hypertension. The amplitude of change after 1 week (V2–V1) and 3 months (V3–V1) for the clinical and various parameters were correlated with the change in endothelial function and arterial stiffness. ResultsCarotid radial-PWVV2-V1 (p = 0.001) and Ang1-7V2–V1 (p = 0.01) emerged as independent predictors of FMDV2-V1. ReninV2-V1 and VCAM-1V2–V1 independently predicted E-selectinV2-V1 [(p = 0.01) and (p = 0.001), respectively]. ACE 2V2–V1 was the only independent predictor of cf-PWVV2-V1. The same parameters remained as independent predictors of the respective vascular factors after 3 months of ACE inhibition. ConclusionThe study highlights the role of AngII/Ang1-7 balance in alteration of endothelial function and central arterial stiffness in humans in addition to identifying the interrelationship between the renin-angiotensin-aldosterone-system components and clinically ascertainable parameters.

P1839GLOMERULAR HYPERFILTRATION: THEORY AND APPLICATIONS

Abstract Background and Aims The role of glomerular hyperfiltration in the development and progression of diabetic and non-diabetic chronic kidney disease (CKD) was established during the 80’s of the last century and represented a paradigm shift in current nephrology practice. Method A web-based review of relevant bibliography: articles and textbooks, reporting the development of hyperfiltration theory and its clinical applications was conducted. Results In 1982, after a series of animal studies, Brenner and colleagues proposed that glomerular hyperfiltration, in diabetic and other glomerulopathies, contributes to intrarenal hypertension and predispose to progressive glomerular sclerosis and deterioration of renal function. Clinical trials during late 80’s and early 90’s then focused on inhibition of Renin Angiotensin Aldosteron system (RAAS) to reverse glomerular hyperfiltration, and suggested that ACE inhibitors can be anti-proteinuric independent of their blood pressure-lowering effect in non-diabetic and diabetic nephropathies. In 1993, a randomized controlled trial (RCT) by Lewis and colleagues proved a beneficial effect of captopril in patients with nephropathy caused by type 1 diabetes. Few years later, the results of Ramipril Efficacy in Nephropathy (REIN) study proved the renoprotective role of ACE inhibition in patients with non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria in 2 Lancet articles in 1997 and 1999 respectively. The renoprotective role of RAAS inhibition with ARBs in patients with type 2 diabetes was proven in 3 RCTs published in the New England Journal of Medicine in 2001: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) Study, Irbesartan Diabetic Nephropathy Trial (IDNT), and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Dual blockade with an ACE inhibitor and an ARB was then attempted to further ameliorate glomerular hyperfiltration. Yet this approach was faced by an increased risk of hyperkalemia and acute kidney injury in 2 RCTs: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in 2008 and The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study in 2013. It was until 2014 when evidence appeared for a potential role of SGLT2 inhibition in attenuating glomerular hyperfiltration. The 1st clinical evidence of renoprotective effect of SGLT2i appeared in 2016 when the results of the EMPA-REG OUTCOME study found that empagliflozin was associated with lower rates of renal events. Subsequently, the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program trials and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial found similar reductions in composite renal endpoints. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial published in 2019 was the first study designed to assess the effects of a SGLT2i, canagliflozin, on renal outcomes in patients with type 2 diabetes and albuminuric CKD, and proved significant reduction in the composite renal outcome with canagliflozin. The potentiality for renoprotective role of SGLT2i in patients with non-diabetic CKD has stimulated a number of ongoing clinical trials: DIAMOND and Dapa-CKD using Dapagliflozin and EMPATHY and EMPA-KIDNEY using Empagliflozin. Conclusion The hyperfiltration theory represents the basis for current therapeutic interventions in diabetic and non-diabetic CKD. Current guidelines recommend using RAAS blockers in diabetic and non-diabetic proteinuric CKD and SGLT2i in patients with type 2 diabetes and CKD. Whether SGLT2i could be considered in patients with CKD independent of the diabetic state awaits the results of ongoing studies which might change the management practice of CKD.

Higher doses of loop diuretics limit uptitration of angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction

BackgroundLoop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin–angiotensin system.MethodsLoop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score.ResultsBaseline median loop diuretic dose was 40 [40–100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P < 0.01). After propensity adjustment, higher doses of loop diuretics remained significantly associated with poorer uptitration of ACEi (Beta per log doubling of loop diuretic dose: − 1.66, P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01–1.12), P = 0.021].ConclusionsHigher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk.Graphic abstractThis figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0