Combination Of Angiotensin Receptor Blockers Research Articles

Guideline directed medical therapy induced nephrotoxicity in HFrEF patients; an insight to its mechanism

Guideline Directed Medical Therapy (GDMT) has been the standard pharmacotherapy for the treatment of Heart Failure patients with reduced Ejection Fraction (HFrEF) recommended by the European Society of Cardiology (ESC). However, patients on GDMT are likely to possess nephrotoxicity as an adverse effect. We utilized multiple system biology tools like ADVER-Pred, gene enrichment analysis, molecular docking, molecular dynamic simulations, and MMPBSA analysis to predict a possible molecular mechanism of how selected combinations of GDMT may cause nephrotoxicity. As per the ACC/AHA/ESC guidelines, we categorized the drugs as category 1 including β-blockers (BB), angiotensin receptor blockers (ARB), and sodium-glucose cotransporter-2 inhibitors (SGLT2I), category 2 includes BB’s, SGLT2I, and angiotensin receptor-neprilysin inhibitors (ARNI), and category 3 includes BB’s, SGLT2I, and angiotensin-converting enzyme (ACE) inhibitors. Enrichment analysis predicted category 2 drugs to possess the highest number of proteins to be involved in the development of nephrotoxicity i.e. 79.41%. The targets HBA1, CBR1, ATG5, and SLC6A3 were the top hub genes with an edge count of 7 followed by GPX1 with an edge count of 6. Molecular docking studies revealed candesartan-SLC6A3 to possess the highest binding affinity of −10.2 kcal/mol. In addition, simulation studies displayed empagliflozin-CBR1 to possess the highest stability followed by candesartan-ATG5. A combination of β-blockers, ARBs, and SGLT2I are predicted to likely possess nephrotoxicity which may be due to the modulation of HBA1, CBR1, ATG5, and GPX1. In conclusion, candesartan and empagliflozin are most likely to cause nephrotoxicity via the modulation of HBA1, CBR1, ATG5, and GPX1. Communicated by Ramaswamy H. Sarma

Angiotensin receptor blockers reduced the risk of post stroke cognitive impairment among first‐ever ischemic stroke patients

AbstractBackgroundThe effect of antihypertensive drug classes in reducing the risk of post‐stroke cognitive impairment (PSCI) remains elusive. We aimed to investigate the association between antihypertensive drug classes and the risk of PSCI among ischemic stroke patients using data collected from a tertiary hospital in Indonesia.MethodsWe carried out a retrospective analysis of data from a medical database in Sardjito General Hospital Yogyakarta, Indonesia. We identified the first‐ever ischemic stroke patients hospitalized between June 2018 to May 2019 and whose serial measurements of cognitive function were available up to 90 days after stroke. The effect of antihypertensive drug classes on PSCI was measured by using multivariate logistic regression analysis.ResultsWe found 71.11% patients developed PSCI at 90 days after stroke. Forty‐one patients (44.09%) received no antihypertensive drugs, 14 (15.05%) with angiotensin receptor blockers (ARB), 20 (21.50%) with calcium channel blockers (CCB), and 18 (19.35%) with combination of ARB and CCB. After controlling covariates, we found that ARB reduced the risk of PSCI by 64% (aOR 0.364, 95% CI = 0.14‐0.91, p<0.05), with improvement of total MoCA‐INA score by 3.113 points (p<0.05).ConclusionsAmong first‐ever ischemic stroke patients, ARB showed more favorable outcome on reducing the risk of PSCI and improving cognitive performance at 90 days after stroke. These findings may contribute to assist clinicians for selecting antihypertensive drug classes in PSCI prevention.

Effect of antihypertensive medications on the risk of open-angle glaucoma

The purpose of this study was to identify the effect of antihypertensive medication on risks of open-angle glaucoma (OAG) among patients diagnosed with hypertension (HTN). A total of 5,195 patients, who were diagnosed with HTN between January 1, 2006 and December 31, 2015, and subsequently diagnosed with OAG, were selected for analysis. For each OAG patient, 5 non-glaucomatous, hypertensive controls were matched (n = 25,975) in hypertension diagnosis date, residential area, insurance type and economic status. Antihypertensive medications were stratified into 5 types: angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), β-blockers and diuretics. Relative risks were calculated. After adjusting for age, sex, body mass index, lifestyle, comorbidities, blood pressure (BP), follow-up duration, and use of other types of antihypertensive drugs, ARB and CCB were found to slightly increase OAG risks (RR 1.1087 (95% CI 1.0293–1.1942); 1.0694 (1.0077–1.1349), respectively). Combinations of ARB with diuretics (1.0893 (1.0349–1.1466)) and CCB (1.0548 (1.0122–1.0991)) also increased OAG risks. The risks for OAG were found to increase by antihypertensive medication use, but the effects appeared to be small. Further studies are necessary to identify the associations of increased BP, medication and therapeutic effect with OAG.

A Review on Neuroinflammatory Pathway Mediating Through Ang-II/AT1 Receptors and a Novel Approach for the Treatment of Cerebral Ischemia in Combination with ARB's and Ceftriaxone.

Ischemic stroke is one of the prevalent neurodegenerative disorders; it is generally characterized by sudden abruption of blood flow due to thromboembolism and vascular abnormalities, eventually impairing the supply of oxygen and nutrients to the brain for its metabolic needs. Oxygen-glucose deprived conditions provoke the release of excessive glutamate, which causes excitotoxicity. Recent studies suggest that circulatory angiotensin-II (Ang-II) has an imperative role in initiating detrimental events through binding central angiotensin 1 (AT1) receptors. Insufficient energy metabolites and essential ions often lead to oxidative stress during ischemic reperfusion, which leads to the release of proinflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and cytokines like interleukin-18 (IL-18) and interleukin- 1beta (IL-1β). The transmembrane glutamate transporters, excitatory amino acid transporter-2 (EAAT-2), which express in astroglial cells, have a crucial role in the clearance of glutamate from its releasing site and convert glutamate into glutamine in normal circumstances of brain physiology. During cerebral ischemia, an impairment or dysfunction of EAAT-2 attributes the risk of delayed neuronal cell death. Earlier studies evidencing that angiotensin receptor blockers (ARB) attenuate neuroinflammation by inhibiting the Ang-II/AT1 receptor-mediated inflammatory pathway and that ceftriaxone ameliorates the excitotoxicity-induced neuronal deterioration by enhancing the transcription and expression of EAAT-2 via the nuclear transcriptional factor kappa-B (NF-kB) signaling pathway. The present review will briefly discuss the mechanisms involved in Ang-II/AT1-mediated neuroinflammation, ceftriaxone-induced EAAT-2 expression, and the repurposing hypothesis of the novel combination of ARBs and ceftriaxone for the treatment of cerebral ischemia.

A Real-World Analysis of Post-Marketing Surveillance Data Assessing the Incidence of Hyperkalemia or Acute Kidney Injury in Patients on Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin-Receptor Blockers

Background: The widely used Renin-angiotensin-aldosterone system inhibitor (RASI) may increase the risk of hyperkalemia and acute kidney injury (AKI). We aimed to analyze the RASI-related AKI or hyperkalemia reported in the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database to optimize patients’ treatment and provide a reference for a clinically safe and rational prescription. Methods: We obtained data in FAERS recorded from January 2004 to December 2020. Disproportionality analysis and Bayesian analysis were used in data mining to screen the suspected AKI or hyperkalemia after RASI. The time to onset, hospitalization, and prognosis of RASI-associated AKI or hyperkalemia were also investigated. Results: We identified 11,301 RASI-related adverse events (AEs) of hyperkalemia and AKI in the FAERS database; 4997 were due to Angiotensin-converting enzyme inhibitors (ACEIs), 5658 were due to angiotensin receptor blockers (ARBs), and 646 were due to the combination of ACEI and ARB. AKI was more commonly reported in patients with ARB (78.42%) than ACEI users (57.27%). Hyperkalemia cases were reported more in ACEI users (28.70%) than ARB users (14.14%). The median time to onset of RAS-associated AKI was 135.0 (17.0–620.0) days. RASI-associated hyperkalemia occurred relatively later in ACEI users, with a median onset time of 261.0 (43.0–1097.7) days, compared with that of 200.5 (52.0–636.0) days in ARB users (p < 0.001). Among all AEs, 72.39% of cases received hospitalization. Death occurred in 6.3% of the renal AE cases. The elderly and heart failure were potential risk factors for death in patients who developed RASI-associated renal AEs, with an increased Odds Ratio (OR) compared with younger age (OR = 1.32) and hypertension patients (OR = 2.55). Based on the criteria of the four algorithms, the ACEI and ARB combination further increased the incidence of AKI and hyperkalemia, demonstrating the highest Reporting Odds Ratios (RORs), Proportional Reporting Ratios (PRRs) and Empirical Bayesian Geometric Average (EBGMs). Conclusions: Patients who indicated RASI for heart failure demonstrated a higher death risk when AEs occurred. ACEI combined with ARB can increase the incidence of hyperkalemia and AKI. Careful and individualized management is necessary.

Clinical outcomes of renin angiotensin system inhibitor-based dual antihypertensive regimens in chronic kidney disease: a network meta-analysis

This study comprehensively investigated clinical outcomes associated with renin angiotensin system inhibitor-based dual antihypertensive regimens in non-dialysis chronic kidney disease (CKD) patients. Keyword searches of databases were performed per PRISMA-NMA guidelines. Frequentist network meta-analysis were conducted with 16 head-to-head randomized controlled trials. The effect sizes of dichotomous and continuous variables were estimated with odds ratio (OR) and standard mean differences (SMD), respectively. The protocol is registered in PROSPERO (CRD42022365927). Dual antihypertensive regimens with combination of angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) demonstrated substantially reduced odd of major cardiovascular disease (CVD) events over other regimens including angiotensin converting enzyme inhibitor (ACEI) monotherapy (OR 3.19) and ARB monotherapy (OR 2.64). Most significant reductions in systolic (SBP) and diastolic blood pressure (DBP) were observed with ARB-based CCB dual regimen over ACEI monotherapy (SMD 17.60 SBP and 9.40 for DBP), ACEI-based CCB regimen (SMD 12.90 for SBP and 9.90 for DBP), and ARB monotherapy (SMD 13.20 for SBP and 5.00 for DBP). However, insignificant differences were noticed for the odds of hyperkalemia, end stage renal disease progression, and all-cause mortality. ARB-based CCB regimen has the greatest benefits on BP reduction as well as major CVD risks in non-dialysis CKD patients.

Relationship between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prescribing and delirium in the ICU-A secondary analysis.

Studies suggest Angiotensin-Converting Enzyme inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) may slow the decline of memory function in individuals with mild to moderate Alzheimer's disease by regulating migroglial activation and oxidative stress within the brain's reticular activating system. Therefore, we evaluated the relationship between delirium prevalence and being prescribed ACEI and ARB in participants admitted to the intensive care units (ICU). A secondary analysis of data from two parallel pragmatic randomized controlled trials was performed. ACEI and ARB exposure was defined as being prescribed an ACEI or an ARB within six months prior to the ICU admission. The primary endpoint was the first positive delirium assessment based on Confusion Assessment Method for the ICU (CAM-ICU) for up to thirty days. A total of 4791 patients admitted to the medical, surgical, and progressive ICU and screened for eligibility for the parent studies between February 2009 and January 2015 from two level 1 trauma and one safety net hospital in a large urban academic health system were included. Delirium rates in the ICU were not significantly different among participants with no exposure to ACEI/ARB (12.6%), or exposure to ACEI (14.4%), ARB (11.8%), or ACEI and ARB in combination (15.4%) in six months prior to the ICU admission. Exposure to ACEI (OR=0.97[0.77, 1.22]), ARB (OR=0.70 [0.47, 1.05]), or both (OR=0.97 [0.33, 2.89]) in six months prior to ICU admission was not significantly associated with odds of delirium during the ICU admission after adjusting for age, gender, race, co-morbidities, and insurance status. While the impact of ACEI and ARB exposure prior to the ICU admission was not associated with the prevalence of delirium in this study, further research is needed to fully understand the impact of antihypertensive medications on delirium.

Effects of voluntary exercise and administration of renin angiotensin inhibitor on cardiac function in inherited dilated cardiomyopathy model.

Dilated cardiomyopathy (DCM) is one of major causes of heart failure (HF) especially in Asia. Although exercise is regarded as one of therapies for HF, the effects of exercise on patients with DCM have not been established. A knock-in mouse model of human inherited DCM, TNNT2 ΔK210, shows similar characteristics to DCM patients. We have showed that one of angiotensin receptor blockers (ARB) is effective on cardiac function and electrical remodeling. We also have found that voluntary exercise improves cardiac function in homozygote model mice (DCM mice). In this study, we examined combination therapy of ARB and exersise in DCM mice. The DCM mice showed enlarged heart and frequent sudden death with t1/2 of ∼70 days. Male DCM mice were divided into 4 groups based on the administration of ARB and voluntary exercise: without drug or exercise (CON), oral administration of ARB (ARB), daily exercise (EXE), and combined ARB and exercise (COMB). The EXE and COMB groups started wheel running at 1 month of age. Cardiac function was measured with echocardiography and electrocardiogram at 2.5 months of age. After sacrifice, weights of body, heart, lung, and lower extremity muscles were measured. Gene expressions of HF- and arrhythmia-related genes in myocardium were quantified by qPCR analysis. There was no significant difference in driving performance between EXE and COMB (EXE: 7.0 ± 1.6 km/day (n = 8), COMB: 6.3 ± 2.2 km/day (n = 7)). On echocardiography, the ejection fraction was significantly improved in only COMB (CON: 21.7 ± 6.1% (n = 6), ARB: 26.9 ± 5.1% (n = 6), EXE: 27.2 ± 4.5% (n = 5), COMB: 31.9 ± 3.6% (n = 6)). On the other hand, the heart weight/body weight ratio decreased in the ARB and the COMB groups. Our results suggest that the combination of ARBs and exercise may have a greater effect on cardiac function in DCM mice.

The Comparative Effectiveness of Monotherapy and Combination Therapies: Impact of Angiotensin Receptor Blockers on the Onset of Alzheimer's Disease.

The criteria for use of Alzheimer's disease (AD) drug Leqembi recommended by the Department of Veterans Affairs (VA) include patients aged 65 years or older with mild cognitive impairment (MCI) or mild AD. Comorbidities that include hypertension, hyperlipidemia, and diabetes are common among these patients. Our objective is to investigate the comparative effectiveness of the administration of one, two, or three medications belonging to the categories of angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), Beta Blockers, Statins, and Metformin, for their potential to delay the clinical onset of AD and provide a window of opportunity for therapeutic intervention. Retrospective matched case-control study. Data from the Department of Veterans Affairs national corporate data warehouse. We conducted an analysis of 122,351 participants (13,611 with AD and 108,740 without AD), aged 65-89, who began at least one of the prescribed medication classes under investigation between October 1998 and April 2018. We utilized Cox proportional hazard regressions, both with and without propensity score weighting, to estimate hazard ratios (HR) associated with the use of different medication combinations for the pre-symptomatic survival time of AD onset. Additionally, we employed a supervised machine learning algorithm (random forest) to assess the relative importance of various therapies in predicting the occurrence of AD. Adding Metformin to the combination of ACEI+Beta Blocker (HR = 0.56, 95% CI (0.41, 0.77)) reduced the risk of AD onset compared to ACEI monotherapy alone (HR = 0.91, (0.85, 0.98)), Beta Blocker monotherapy (HR = 0.86, 95% CI (0.80, 0.92)), or combined ACEI+Beta Blocker (HR=0.85, 95%CI (0.77, 0.94)), when statin prescribers were used as a reference. Prescriptions of ARB alone or the combination of ARB with Beta Blocker showed an association with a lower risk of AD onset. Selected medications for the treatment of multiple chronic conditions among elderly individuals with hypertension, hyperlipidemia, and diabetes as monotherapy or combination therapies lengthen the pre-symptomatic period before the onset of AD.

The impact of the Choosing Wisely Canada campaign on the simultaneous use of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers: interrupted time-series analysis.

Choosing Wisely is a high-profile campaign seeking to reduce the use of low-value care. We investigated the impact of a Choosing Wisely Canada recommendation against using a combination of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for the management of hypertension, heart failure or diabetic nephropathy on population-level use of these medications in British Columbia, Canada. We identified all people (any age) who were continuously registered with BC's Medical Service Plan between 2010 and 2017 with the targeted conditions. Using prescription claims data and an interrupted time-series analysis, we estimated the number of people on combination therapy per month, the proportion of days covered (PDC) by combination therapy per month and proportion of all combination prescriptions started per month in the 2 years before and after the introduction of the recommendation on Oct. 29, 2014. Of 1 104 593 people (mean age 65 yr, standard deviation 16 yr) in our study cohort, 4.6% were exposed to combination therapy, largely prescribed by family physicians (84%). The number of people on combination therapy and the PDC were declining before the recommendation, but the proportion of combination prescriptions started in the 2 years before the recommendation was increasing. After the recommendation, we observed no statistically significant changes in any outcome. The pre-existing downward trend of the monthly number of people decelerated (16.8, 95% confidence interval [CI] 14.0 to 19.5) and the proportion of prescriptions started increased (0.13%, 95% CI 0.08% to 0.18%). The Choosing Wisely Canada recommendation against using a combination of ACE inhibitors and ARBs was not associated with reduced combination therapy use in the targeted conditions. The observed pre-existing declines in this practice questions the process of selecting recommendations, and the optimal implementation and value of Choosing Wisely campaigns without other reinforcing interventions.

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.

Léčba hypertenze a dyslipidemie po cévní mozkové příhodě

Stroke is the second most common cause of mortality worldwide and the third most common cause of disability. Arterial hypertension is the most prevalent risk factor for stroke. A precise management of arterial hypertension prevents the first episode of stroke and the recurrence. Blood pressure must be decreased carefully and not very vigorously in the acute phase of the stroke. Recommended blood pressure goals in chronic tratment are at least 140 / 90 mm Hg and lower if tolerated. ACE inhibitors or angiotensin receptor blockers in combination with calcium channel blockers or indapamide are favorable antihypertensive drugs. Dyslipidemia is also a strong risk factor for ischaemic stroke and has no relatioship to the other etiologies of stroke. The cardiovascular risk in patients after a stroke is very high. An intensive hypolipidemic treatment by statins, ezetimibe and PCSK9i to LDL-cholesterol goals < 1,4 mmol/l and a 50% decrease was proved to decrease the incidence of recurrent stroke.

Angiotensin Receptor Blockers Evaluated by Office and Home Blood Pressure Measurements. TeleHBPM Study.

ResumoFundamento O tratamento adequado e a obtenção das metas na hipertensão arterial são importantes na redução dos desfechos cardiovasculares.Objetivos Descrever os bloqueadores do receptor de angiotensina (BRA) em monoterapia ou combinação dupla e a taxa de controle da hipertensão arterial.Métodos Estudo transversal que avaliou pacientes em uso de BRA entre 2017 e 2020. Foram excluídos aqueles em uso de três ou mais anti-hipertensivos. As variáveis analisadas foram: sexo, idade, índice de massa corporal, medidas válidas da medida residencial da pressão arterial (MRPA); pressão arterial sistólica (PAS) e diastólica (PAD) obtidas pela MRPA e de forma casual; variabilidade pressórica; classe dos anti-hipertensivos e dos BRAs. Foram utilizados testes de t pareado, qui-quadrado e Fisher, além de sobreposição dos intervalos de confiança de 95% com nível de significância de 5% (p < 0,05).Resultados Foram selecionados 17.013 pacientes; destes, 12.813 preencheram os critérios, dos quais 62,1% eram do sexo feminino. O número médio de medidas válidas foi de 23,3 (±2,0), com médias para a PAS de 126,8±15,8 mmHg e 133,5±20,1 mmHg (p < 0,001) e para a PAD de 79,1±9,7 mmHg e 83,6±11,9 mmHg (p < 0,001) pela MRPA e medida casual, respectivamente. Losartana foi o BRA mais utilizado e o que apresentou comportamentos mais elevados da pressão arterial. As combinações de BRA com diuréticos ou com antagonistas de canal de cálcio tiveram menores valores de pressão arterial.Conclusões Losartana foi utilizada em mais da metade dos pacientes, apesar de ser a menos eficiente na redução e no controle da pressão arterial.

[Clinical comprehensive evaluation of Huangkui Capsules in treatment of chronic kidney diseases].

Based on Guidelines for the Management of Clinical Comprehensive Evaluation of Drugs(trial version 2021), this study aims to sort out the clinical evidence of Huangkui Capsules(HC) in the treatment of chronic kidney diseases in aspects of safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine( &quot;6+1&quot; dimensions) from real-world data, secondary literature evaluations, questionnaires, and public data, with the methods in evidence-based medicine, epidemiology, pharmacoeconomics, and health technology. Furthermore, with multi-criteria decision analysis(MCDA) model and CSC v2.0, the clinical value of the medicine is comprehensively assessed. All the above are to highlight the advantages and characteristics of HC and lay a basis for scientific decision-making by the medical management department. The dimensions are graded A, B, C, or D. According to the conclusions from phase Ⅳ clinical trial, spontaneous reporting system(SRS), systematic review and Meta-analysis, acute toxicity and long-term toxicity tests, it mainly results in the adverse reactions of nausea, abdominal distension, vomiting, pruritus, rash, and good prognosis in patients. According to the available research, the safety evidence is sufficient and the risk is controllable, so the safety of this medicine is grade B. According to Meta-analysis, HC in combination with conventional drugs in the treatment of chronic kidney disease is superior to conventional drugs alone in reducing urinary protein, serum creatinine concentration, and blood urea nitrogen. In addition, HC combined angiotensin receptor blocker(ARB) or angiotensin converting enzyme inhibitor(ACEI) is outstanding in improving total clinical effective rate, reducing 24 h urinary protein quantity, urinary albumin excretion rate, serum creatinine concentration, triglyceride, and total cholesterol in the treatment of diabetic nephropathy as compared with ARB or ACEI alone. As for chronic nephritis, the application together with ARB or ACEI can raise the total effective rate, reduce 24 h urinary protein content, serum creatinine concentration, and blood urea nitrogen, and delay the progress of the disease. HC boasts high-quality evidence in treating chronic kidney disease, diabetic nephropathy, and chronic nephritis. It has obvious clinical significance in treating chronic kidney disease and thus its efficacy in this aspect is grade B. It has outstanding clinical significance for diabetic nephropathy and chronic nephritis and corresponding and the effectiveness is grade A. As for the pharmacoeconomic value, HC combined with ARB or ACEI is more economical in the treatment of chronic kidney disease than Bailing Capsules combined with ARB or ACEI, with high-quality evidence, and thus the economy of the formula is grade B. HC is a key solution to the high urinary protein in patients with hypotension and chronic kidney disease. The innovation is evidenced by the methods to ensuring drug supply, community-level supply, drug safety, effectiveness, and reasonable price, as wells as the aspects of enterprise philosophy, equipment management, research and development in process and technology, enterprise management and marketing. Thus, the prescription is grade A in innovation. The suitability, as evidenced in drug administration, technical management, drug storage, information service, and medication, is grade B. The course of the medicine is affordable, and it is accessible in a wide range of areas and hospitals. Thus, the accessibility is grade A. HC was developed from an in-hospital preparation, with application in numerous patients and thus large-scale real-world data. As a result, HC is grade B in terms of characteristics of traditional Chinese medicine. After comprehensive evaluation, the clinical value of HC in treating chronic kidney disease is class B, and that for diabetic nephropathy and chronic nephritis is class A. The result is of great reference value for the basic clinical medication management.

Ефективність і безпечність фіксованих комбінацій блокаторів повільних кальцієвих каналів, блокаторів рецепторів ангіотензину та тіазидних діуретиків у лікуванні артеріальної гіпертензії

Наведено аналіз результатів дослідження ефективності й безпечності фіксованих комбінацій блокатора повільних кальцієвих каналів (БКК) амлодипіну й блокатора рецепторів ангіотензину (БРА) валсартану (Комбісарт) та амлодипіну, валсартану й тіазидного діуретика гідрохлортіазиду (Комбісарт Н) компанії ПАТ «Київський вітамінний завод» порівняно з препаратами Ексфорж й Ексфорж Н (Novartis Pharma, Швейцарія) у лікуванні хворих на артеріальну гіпертензію ІІ–ІІІ стадії. Установлена терапевтична еквівалентність Комбісарту і Комбісарту Н референтним — Ексфоржу й Ексфоржу Н. Продемонстрована ефективність досліджуваних препаратів щодо зниження артеріального тиску, покращення його контролю протягом доби при комбінації БРА і БКК із тіазидним діуретиком, добра переносимість Комбісарту і Комбісарту Н, що підвищує комплайєнтність пацієнтів до лікування артеріальної гіпертензії.

Nephroprotective effect of vitamin E added to angiotensin receptor blocker in patients with diabetic nephropathy

Background: Diabetes mellitus is a condition associated with increased oxidative stress as a consequence of hyperglycemia. Therefore, the use of antioxidants in people with diabetes has been advocated. Vitamin E is the most prevalent naturally occurring anti-oxidant. Aim: To evaluate the effect of the combination of angiotensin receptor blocker (ARB) and vitamin E on urine protein in patients with diabetic nephropathy. Methods: One hundred and six patients with diabetic nephropathy, who visited the Alsader medical city in Najaf governorate and Al-Furat Al-Awsat general hospital in Kufa, were investigated, 39 of them are type 1diabetics, and 67 of them are type 2 diabetics. Each patient was followed up for 3 months with valsartan (160mg/day), then for 3 months with addition of tocopherol (400mg). At the screening visits, proteinuria was determined in two 24 h urine sample, arterial blood pressure was measured twice at ten minutes rest with 2 minutes interval and serum level of potassium, sodium &amp; creatinine were determined. Results: Proteinuria was significantly lowered when tocopherol 400mg was added to valsartan, as compared with valsartan without tocopherol. Valsartan alone caused a mean reduction of 24 h urine protein of 27% from the baseline, while the addition of tocopherol caused a mean reduction of 24 hour proteinuria of 30% from result of valsartan. That is mean the combination therapy of valsartan and tocopherol caused a reduction in proteinuria of 44% from baseline. Conclusion: The current study suggests that combination therapy of ARB and vitamin E offers an additional antiproteinuric and nephroprotective effect. Recommendation: Antioxidants, in particular vitamin E have promising nephroprotective effects. However, studies on other antioxidants like vitamin C are needed in the efforts of prevention of diabetic nephropathy

Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations.

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: -0.03%[-0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[-1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment.

Abstract P136: Reference Ranges And Cut-Off Values For Simultaneous Monitoring Of RAS-Blocker Efficacy And Screening For Secondary Hypertension Using RAAS Triple-A Profiling

Uncontrolled hypertension is caused by various factors including compliance issues, patient specific drug uptake and elimination profiles or secondary forms of hypertension, resulting in blood pressure control rates of less that 50%. RAAS Triple-A profiling is a high-throughput mass-spectrometry based assay for Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone in serum samples. Hormone levels are used to calculate markers for plasma-renin-activity (PRA-S), plasma angiotensin-converting-enzyme activity (ACE-S) and adrenal aldosterone secretion (AA2-Ratio). The integrated analysis of these molecular markers together with drug prescription information allows to identify the underlying cause of uncontrolled hypertension, including primary aldosteronism and insufficiency in drug adherence or dosing for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs). 500 participants with prescribed antihypertensive drugs were selected from the “Cooperative Health Research in South Tyrol” (CHRIS) study, a population-based study from an Alpine rural environment. Five age- and sex-matched groups (N=100 each) selected were individuals on single therapy with ARBs, ACEi or beta blockers, and on single pill dual therapy of ACEi or ARBs in combination with diuretics. Three age and sex-matched control groups of 100 participants each were included, being normotensive, hypertensive (treated with non-antihypertensive drugs) and hypertensive participants without any prescribed medication. RAAS Triple-A analysis was performed in all individuals and reference values for Ang I, Ang II, Aldosterone, PRA-S, ACE-S and AA2-Ratio were established in appropriate sub-populations. Drug monitoring by LC-MS/MS based quantification of anti-hypertensive drugs in serum was used as a gold standard to determine cut-off values for compliance with ARB and ACEi therapy and ROC analysis was performed using angiotensin-based biomarkers.

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias.

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.

Efficacy of ARB/HCTZ Combination Therapy in Uncontrolled Hypertensive Patients Compared with ARB Monotherapy: A Meta-Analysis.

Objective To evaluate the efficacy of combination of angiotensin receptor blocker (ARB) with hydrochlorothiazide (HCTZ) compared to ARB alone in patients with uncontrolled hypertension via a systematic review and meta-analysis. Methods We searched databases till July 2019 using relevant search terms. We included articles that were randomised controlled trials (RCTs) comparing ARB/HCTZ with ARB for a duration of at least 4 weeks and reported on the efficacy or safety. Meta-analyses for efficacy outcomes were performed. In addition, groups given different concentrations of HCTZ (12.5 and 25 mg) were analysed separately. Results Sixteen RCTs (12,055 participants) were included. Overall, ARB/HCTZ combination therapy (both 12.5 and 25 mg HCTZ combination) resulted in better sitting systolic and diastolic blood pressure control than ARB alone (mean difference (95% confidence interval (CI): −5.69 [−6.66, −4.73] for 12.5 mg and −9.10 [−11.78, −6.42] for 25 mg and mean difference (95% CI): −2.91 [−3.31, −2.51] for 12.5 mg and −4.16 [−4.75, −3.58] for 25 mg). ARB/HCTZ combination therapy resulted in a higher rate of target blood pressure achievement compared to ARB alone (risk ratio (95% CI): 1.50 [1.42, 1.59]). ARB/HCTZ combination therapy had similar rates of total adverse events (AEs) and severe AEs compared to ARB alone. Conclusion ARB/HCTZ combination therapy is more efficacious for controlling blood pressure, and combination with a low concentration of HCTZ has similar AEs compared to ARB alone. Clinicians should consider adding HCTZ in the medication regime of patients with uncontrolled hypertension using ARB, if their clinical profile allows.