Gut microbiome and inflammation in cardiovascular drug response: trends in therapeutic success and commercial focus.

The intricate Gut microbiome is evolving as an important system and is hypothesized to be a "metabolic organ" within the host. Alterations in Gut microbiota and inflammation associated with several diseases play a crucial role in drug transformation through microbiota-host co-metabolism, modified pharmacokinetic and pharmacodynamics profiles, and may result in the formation of toxic metabolites with interference in drug response. In recent studies, a large number of drugs are reported that are co-metabolized by the host and the Gut microbial enzymes. we summarize the direct and indirect involvement of Gut microbiome promotion or inhibition of cardiovascular diseases, mechanisms on bioavailability, and therapeutic outcomes of cardiovascular drugs, particularly pharmacokinetics and pharmacodynamics profiles in light of AUC, Tmax, Cmax, and bioavailability and drug transportation via immune cells, inter-individual variations in intestinal microbial taxonomy, influence of drugs on diversity and richness of microflora, high lightening limitations and significance of in personalized medicine. Recent advances in target-drug delivery by nanoparticles with limitations and challenges in application are discussed. The cross-talk between Gut microbiota and cardiovascular drugs signifies a better understanding and rationale for targeting the Gut microbiota to improve the therapeutic outcome for cardiovascular diseases, with present-day limitations.

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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Overstimulation of the renin­angiotensin­aldosterone system­a key regulator of blood pressure, and fluid and electrolyte balance­is known to cause an increase in blood pressure (also known as "hypertension") and other diseases of the heart and blood vessels (the cardiovascular system). As such, treatments to block (or inhibit) this overstimulation are an essential part of medical strategies designed for the prevention of cardiovascular disease, especially in patients with hypertension (in whom the risk of death due to cardiovascular causes is high). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are two types of medication that block overstimulation of the renin­angiotensin­aldosterone system, but they work in different ways. Angiotensin-converting enzyme inhibitors are superior to angiotensin receptor blockers after heart attacks (acute myocardial infarction), in patients with heart failure, for the prevention of stroke in individuals who have already had a stroke, and in patients with diabetes. Both types of medication have beneficial effects on the kidneys and associated outcomes, but only angiotensin-converting enzyme inhibitors have been shown to significantly reduce death due to cardiovascular causes, as well as death due to any cause. Overall, the protective effects of angiotensin-converting enzyme inhibitors on the heart are substantially greater than those of angiotensin receptor blockers, meaning that treatment with an angiotensin-converting enzyme inhibitor is preferred in all patients, except those who cannot tolerate the side effects of this drug class.

Renin-angiotensin system inhibition and mortality in patients undergoing dialysis with coronary artery disease: insights from a multi-center observational study.

BACKGROUND: While the survival benefits of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are firmly established in the general population, their efficacy within patient undergoing dialysis with coronary artery disease (CAD) remains controversial. METHODS: Between January 2015 and June 2021, 1168 patients undergoing dialysis with CAD were assessed from 30 tertiary medical centers. The primary outcome was all-cause death, and the secondary outcome was cardiovascular death. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for between-group differences. RESULTS: Overall, ACEI or ARB were prescribed to 518 patients (44.3%) upon discharge. After a median follow-up of 22.2 months, 361 (30.9%) patients died, including 243 cardiovascular deaths. The use of ACEI or ARB was associated with a significantly lower risk of all-cause (25.3% vs 35.4%, hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52-0.82, p < 0.001) and cardiovascular death (17.0% vs 23.8%; HR 0.64, 95% CI 0.48-0.83, p = 0.001). These findings remained consistent across IPTW and PSM analyses. Sensitivity analyses for ACEI and ARB use separately yielded similar results. CONCLUSIONS: Our findings suggested that among patients undergoing dialysis with CAD, ACEI or ARB use was associated with a lower risk of all-cause and cardiovascular death.

Comparative Analysis of First-Line Antihypertensive Treatment Classes.

BACKGROUND: The best first-line monotherapy for hypertension remains uncertain, as current guidelines suggest that thiazides, angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB) are appropriate in the absence of specific comorbidities. We aimed to compare the outcomes of first-line antihypertensive classes in a real-life setting with a long follow-up period. METHODS: This nationwide retrospective new-user cohort study included patients insured by the largest health maintenance organization in Israel. We included patients with a new diagnosis of hypertension between 2008 and 2021 who initiated treatment with a single first-line drug for hypertension. Outcomes were assessed with and without propensity score matching for confounding factors. The primary composite outcome was the first occurrence of myocardial infarction (MI), acute coronary syndrome (ACS), stroke, or heart failure (HF). RESULTS: A total of 97,639 patients initiated antihypertensive treatment with a single drug as first-line therapy. The most commonly prescribed class was ACEi/ARB (66,717, 68.3%), followed by CCBs (15,922, 16.3%), beta-blockers (BBs, 12,869, 13.2%), and thiazides (2,131, 2.2%). For the primary outcome, the hazard ratios (HRs) for BBs, CCBs, and ACEi/ARBs were 1.44 (95% CI 1.25 - 1.66), 1.10 (95% CI 0.96 - 1.27), and 1.13 (95% CI 0.99 - 1.29), respectively, when compared to thiazides. CONCLUSION: When initiating pharmacotherapy for hypertension with a single drug, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers were associated with similar risk of MI, ACS, stroke, or HF when compared to thiazides, while beta-blockers were associated with increased risk.

Angiotensin-Converting Enzyme Inhibitor-Induced Psoriasis: A Case Report on Plaque Exacerbation.

Psoriasis is a chronic inflammatory skin condition characterized by well-demarcated, erythematous plaques. Certain medications, including Angiotensin-Converting Enzyme (ACE) inhibitors, have been implicated as potential triggers for psoriasis flare-ups. We report the case of a 48-year-old Indian male with a history of well-controlled plaque psoriasis who experienced severe flare-ups after initiating ACE inhibitor therapy for hypertension. Within two weeks, the patient developed widespread psoriatic plaques accompanied by intense pruritus and discomfort, strongly suggesting a drug-induced reaction. Discontinuation of the ACE inhibitor led to a gradual improvement in symptoms, managed with topical corticosteroids and emollients, and switching to an alternative antihypertensive medication resulted in no further exacerbation of psoriasis. This case underscores the potential for ACE inhibitors to trigger psoriasis flare-ups in susceptible individuals, highlighting the need for clinicians to be vigilant when prescribing these medications to patients with a history of psoriasis. Further studies are needed to elucidate the underlying mechanisms and identify patients at risk.

Integrative approach to assessing bioactivity from hempseed protein isolate extracted and dehydrated by different methods: Synergising in silico prediction and in vitro validation.

This study demonstrated a comprehensive workflow combining in silico screening and prediction with in vitro validation to investigate the bioactivity of hempseed protein isolate (HPI) extracted and dehydrated using different methods. By adopting an in silico approach, 13 major proteins of HPI were hydrolysed by 20 selected enzymes, leading to the prediction of 20 potential bioactivities. With papain hydrolysis, dipeptidyl peptidase-IV (DPP4) and angiotensin-converting enzyme (ACE) inhibitory activities emerged as having the highest potential. In vitro experiments confirmed these predictions, with DPP4 and ACE inhibitory activities displaying IC50 values of 0.32-0.42 mg/mL and 6.8-9.17 µg/mL, respectively. A strong correlation (r2 = 0.96) was observed between in vitro protein inhibitory results and in silico predicted data. This study demonstrated an effective integrative approach for predicting bioactive peptides in food protein, providing valuable guidance on its processing to create value-added products.

Impact of chronic renin-angiotensin-aldosterone inhibitors on short-term outcomes in patients with acute heart failure presenting to the emergency department. A propensity-matched analysis EAHFE cohort.

OBJECTIVES: The aim of the present study was to evaluate the impact of chronic treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) on short-term clinical outcomes after an episode of AHF. METHODS: A secondary analysis of patients included in the EAHFE (Epidemiology of Acute Heart Failure in Emergency Departments) cohort, which includes patients diagnosed with AHF in 45 Spanish Emergency Departments (EDs). The primary outcome was all-cause in-hospital mortality. The secondary outcomes were all-cause death within 7 days, need for hospital admission and prolonged hospitalisation defined as a stay longer than or equal to 7 days. Multiple regression and propensity-matching was used for multivariate adjustment. RESULTS: Of the 17,920 patients, 10,041 (56 %) were receiving chronic treatment with ACEI/ARB. The mean age was 80.4 years and 55.7 % were women. Adjusted odds ratios (aOR) were 0.76 (95 % CI 0.71-0.82) for in-hospital mortality witch multiple regression and 0.74 (95 %CI 0.63-0.88) with propensity-matching. aOR were 0.72; (95 %CI 0.65-0.79) and 0.70 (95 %CI 0.57-0.87) for mortality at the 7-day follow-up, respectively. The sensitivity analysis ACEI/ARB were associated with few all-cause deaths in patients with elevated natriuretic peptides in the EDs (aOR 0.74; 95 % CI 0.68-0.80), patients requiring hospital admission (aOR 0.78; 95 % CI 0.73-0.84) and patients with a history of HF (aOR 0.72; 95 % CI 0.66-0.78). CONCLUSIONS: Chronic use of ACEI/ARB was associated with better short-term outcomes in terms of all-cause in-hospital mortality in patients with AHF who attend an EDs.

Use of renin-angiotensin system blockers and posttraumatic stress disorder risk in the UK Biobank: a retrospective cohort study.

BACKGROUND: Previous research has shown that the use of renin-angiotensin system (RAS) blockers is linked to a lower prevalence of posttraumatic stress disorder (PTSD), but longitudinal studies are scarce. We aimed to estimate the association between the use of RAS blockers and the risk of PTSD among individuals taking antihypertensive medications. METHODS: This longitudinal study included participants aged 40-69 from the UK Biobank. Exposure data were obtained from the initial assessment (2006-10), while outcome data were obtained from the online mental health questionnaire administered 6-11 years later (2016-17). We included participants who were under antihypertensive treatment and did not have a prior diagnosis of PTSD before the initial assessment. Use of RAS blockers was defined as self-reported regular use, at the initial assessment, of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Among participants who experienced adverse life experiences, cases of probable PTSD were defined with the six-item PTSD Checklist-Civilian version score ≥ 14. Logistic regression with inverse probability of treatment weighting was used to estimate the odds ratios (ORs) and 95% confidence interval (CI) for the association between RAS blocker use and the risk of probable PTSD. RESULTS: Of the 15,954 participants (mean age = 59.9 years; 42.6% women) under antihypertensive treatment with no prior history of PTSD at the initial assessment, 64.5% were taking RAS blockers. After a mean follow-up of 7.5 years, 1,249 (7.8%) were newly identified with probable PTSD. RAS blocker users had a lower risk of probable PTSD than RAS blocker non-users (OR = 0.84 [95% CI: 0.75-0.94]), whereas the use of other antihypertensive medications showed no such association (users vs. non-users; calcium channel blockers, OR = 0.99 [95% CI: 0.88-1.11]; beta-blockers, 1.20 [1.08-1.34]; and thiazide-related diuretics, 1.15 [1.03-1.29]). The association between probable PTSD risk and the use of ACEi vs. ARB showed no significant difference (p = 0.96). CONCLUSIONS: Among individuals under antihypertensive treatment, the use of RAS blockers was associated with a decreased risk of probable PTSD. This added benefit of RAS blockers should be considered in the selection of antihypertensive medications.

The Pattern of Practice in the Management of Early Diabetic Kidney Disease.

Background and objectives Diabetes is a leading cause of kidney failure in various regions worldwide. To detect renal disease in individuals with diabetes, screening typically involves evaluating the glomerular filtration rate and measuring albuminuria. Although there are established guidelines for these screenings, adherence to them varies. This study aims to examine the prevalence of albuminuria screening among adults with diabetes mellitus (DM) and to assess the different practices in managing these patients across primary and tertiary care settings. Methods This cross-sectional observational study involved adult patients with DM attending outpatient clinics in both primary and tertiary care settings. Patient data were gathered using a standardized form, excluding those with established chronic kidney disease (CKD) who were under nephrology care. Results The study included 1,010 patients, with 303 (30%) from primary care clinics and 707 (70%) from tertiary care clinics. The cohort comprised 582 (58%) females, with a median age of 62 years (IQR: 55-70), and approximately 990 (98%) had type 2 DM (T2DM). Annual albumin-to-creatinine ratio (ACR) screening was conducted for 498 out of 1,010 patients (49%) (95% confidence interval {CI}: 46%-52%). Screening compliance was notably higher in primary care settings compared to tertiary care clinics. Older patients (over 60 years) and those with hypertension or cardiac conditions were less likely to undergo screening. Among those screened, 185 of 498 patients (37%) (95% CI: 33%-41%) had abnormal albuminuria (ACR > 3). Conclusion Albuminuria is a significant indicator of progressing renal disease and cardiovascular risk. The annual screening rate for albuminuria in diabetic patients is inadequate. Primary care physicians show better adherence to screening guidelines compared to their tertiary care counterparts. Increasing physician awareness about the importance of screening could improve guideline compliance and mitigate the adverse effects of albuminuria.

[Antihypertensive therapy in patients with arterial hypertension and concomitant diseases in real clinical practice (according to the National Registry of Arterial Hypertension, 2019-2022)].

BACKGROUND: Arterial hypertension (AH) remains the leading risk factor associated with cardiovascular diseases (CVDs), cerebrovascular disease and chronic kidney disease. About 70% of patients with AH who are on monotherapy cannot achieve blood pressure (BP) targets, and therefore all quidelines for the management of AH have recently recommended prescribing combination therapy (PCT). In real clinical practice (RCP), there remains significant uncertainty in the effectiveness and rationality of therapy, despite the wide availability of antihypertensive drugs (AHD) and the presence of recommendations for a stepwise approach to prescribing combinations of specific groups of AHD in different clinical situations. AIM: Analyze the real ongoing antihypertensive therapy, including the PCT; international nonproprietary names of drugs and their dosages in RCP; compliance of therapy with clinical recommendations; changing trends in the PCT. MATERIALS AND METHODS: An analysis was carried out of the data from the register of AH, the compliance of treatment in different clinical groups of patients and the achievement of BP and low-density lipoprotein cholesterol targets in the sample of 2019-2022 (n=5012). The prescription of AHD and achievement of targets values were assessed in accordance with current clinical guidelines for the management of AH and hypercholesterolemia. Data from 2010 (n=7782) and 2020 (n=3061) were analyzed to assess the dynamics of prescription of monotherapy and PCT. RESULTS: The greatest increase in the number of AHD was observed in patients with hypertension in combination with coronary heart disease, heart failure, and atrial fibrillation. In a small group of patients with hypertension without other CVDs, the recommended combinations of AHD were not prescribed; preference was given to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and ß-adrenoblocker (ß-AB). PCT mainly differed from the recommended combinations by the wider use of drugs from the ß-AB group. The PCT of recommended drugs was highest in patients with hypertension and coronary artery disease - more than 90%, hypertension and heart failure in 56.2%, hypertension and atrial fibrillation - 33.3%, hypertension and chronic kidney desease - 19.6%. Achievement of BP and low-density lipoprotein cholesterol targets was insufficient in all analyzed groups. Among the international nonproprietary names of drugs, the most frequently prescribed are the following: bisoprolol, metoprolol, lisinopril, perindopril, losartan, spironolactone, amlodipine, torasemide, indapamide, hypochlorothiazide, moxonidine. The prescribed daily dosages were closer to the initial recommended ones. By 2020, the prescription of PCT with ß-AB and a more uniform prescription of various combinations will come to the fore, while PCT in 2010 is characterized by the presence of one or two leaders combinations. CONCLUSION: The described features of prescribing AHD partially reproduce clinical recommendations for the management of AH. Differences in therapy provided in RCP may be associated with an attempt to intensify the treatment of hypertension in patients with other concomitant CVDs. At the same time, analysis of combinations and dosages of prescribed drugs suggests the presence of wide opportunities for further escalation of therapy. The presented data can provide insight into current patterns of antihypertensive therapy prescription in patients in RCP and lay the foundation for optimizing therapy in different categories hypertensive patients.

Reevaluate the effect of ACEI/ARB therapy at discharge on patients with STEMI in the contemporary reperfusion era.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) had beneficial effects on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) in the pre-reperfusion or thrombolytic era. It is unknown if the benefits persist in the contemporary reperfusion era. OBJECTIVES: We sought to determine if ACEI/ARB improves clinical outcomes of patients with STEMI in the contemporary reperfusion era according to the reperfusion strategy. METHODS: 12596 patients were analyzed from the prospective, nationwide, multicenter China Acute Myocardial Infarction (CAMI) Registry. These patients were classified into the no reperfusion group (n=6004) and the primary percutaneous coronary intervention (PCI) group (n=6592). Two-year all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE) were compared. RESULTS: In the no reperfusion group, ACEI/ARB therapy at discharge may reduce the incidences of 30-day MACCE (4.7% vs 7.4%; adjusted hazard ratio [HR]: 0.67; 95% confidence interval [CI]: 0.53-0.85; P<0.001), stroke (0.5% vs 1.1%; adjusted HR: 0.41; 95% CI: 0.21-0.83; P=0.01), and revascularization (2.1% vs 3.1%; adjusted HR: 0.66; 95% CI: 0.46-0.94; P=0.02) compared to patients not treated with ACEI/ARB. Patients treated with ACEI/ARB also showed a lower rate of two-year MACCE (17.0% versus 19.1%; adjusted HR: 0.87; 95% CI: 0.76-0.99; P=0.04). No differences were observed in the remaining outcomes. In the primary PCI group, no differences were observed for all examined outcomes before and after multivariate adjustments. CONCLUSIONS: Treatment with ACEI/ARB at discharge may reduce cardiovascular events in STEMI patients not receiving reperfusion, while no significant benefits were observed in those receiving primary PCI.

Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review.

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

The Relationship between Using Renin-Angiotensin System Inhibitors with Mortality of Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AFib) is a highly prevalent cardiac arrhythmia associated with increased mortality in affected persons. Renin-angiotensin system inhibitors (RASIs) have been suggested as potential therapeutic agents for cardiovascular and renal diseases. OBJECTIVES: However, the relationship between RASIs and mortality in AFib patients remains uncertain. Therefore, the present study was designed and implemented for this purpose. METHODS: We searched PubMed/MEDLINE, Embase, Web of Science (WOS), Cochrane Library, and Scopus databases for studies published until 12 February 2024 with relevant keywords. We included studies that reported mortality outcomes in AFib patients treated with RASIs and non-users. The data extraction and quality assessment processes were conducted, and subgroup analyses and sensitivity analyses were done. The data were analyzed by Stata 15 using statistical tests, such as Chi-square and I2 tests. RESULTS: A total of 15 studies (2007-2024; n=2,178,565 patients) examined the association between RASI drugs and mortality of patients with AFib. The results indicated that compared to the control group, the odds of AFib mortality in the group receiving RASIs were equal to 0.81(95% CI: 0.71-0.92; P-value ≤0.001). The study results did not indicate publication bias (Pvalue= 0.733). During the meta-regression analysis, none of the study variables demonstrated a significant relationship with the observed heterogeneity (P-value > 0.20). Cumulative OR results showed that from 2022 onwards, there was enough evidence to confirm the relationship using RASIs with mortality of patients with AFib. CONCLUSION: Therefore, this meta-analysis suggests that the use of RASI drugs is associated with reduced AFib mortality. However, the authors emphasize the need for further high-quality studies and large-scale randomized clinical trials to validate these findings.

Association of ACEI/ARB therapy with total and cardiovascular death in coronary artery disease patients with advanced chronic kidney disease: a large multi-center longitudinal study.

INTRODUCTION: Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensin­converting enzyme inhibitors (ACEI) or angiotensin­receptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD. METHODS: CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)<30 ml/min per 1.73 m2. Cox regression models and competing risk Fine and Gray models were used to examine the relationship between ACEI/ARB therapy and all-cause and cardiovascular death, respectively. RESULTS: Of 2527 patients, 47.6% population of our cohort was discharged on ACEI/ARB. The overall all-cause and cardiovascular mortality were 38.6% and 24.7%, respectively. Multivariate Cox regression analyses indicated that ACEI/ARB therapy was found to be associated with lower rates of both all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738-0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699-0.956, p = 0.011). In the propensity-matched cohort, the survival benefit was consistent, and significantly better survival was observed for all-cause mortality (HR = 0.856, 95%CI: 0.752-0.974, p = 0.019) and cardiovascular mortality (HR = 0.830, 95%CI: 0.707-0.974, p = 0.023) among patients treated with ACEI/ARB. CONCLUSION: ACEI/ARB therapy showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, which manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk populations.

What is the current knowledge on the topic? Advanced CKD is highly prevalent and strongly associated with higher mortality risk and worse outcomes among CAD patients, and patients with advanced CKD have often been excluded from randomized controlled trials, creating an evidence gap for these high-risk CAD patients. ACEI/ARB are beneficial for greater survival among CAD patients, but the effect of ACEI/ARB therapy on long-term prognosis is unclear among CAD patients with advanced CKD.What does this study add to our knowledge? ACEI/ARB treatment showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up.How might this change clinical pharmacology or translational science? CAD patients with advanced CKD are not only have worse outcomes but also limited in their choice of therapy strategies. Our study may prompt an important reference for the subsequent improvement of long-term prognosis among these high-risk populations.

Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial.

BACKGROUND: We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). PATIENTS AND METHODS: SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. RESULTS: We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15-0.28) versus without concomitant statins (aHR: 0.31 [0.24-0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. CONCLUSIONS: In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are associated with improved amputation-free survival in chronic limb-threatening ischemia.

BACKGROUND: In the Heart Outcomes Prevention Evaluation study, investigators found that ramipril was associated with improved survival as well as decreased MI and stroke rates in patients with peripheral arterial disease. Nonetheless, their effect on chronic limb-threatening ischemia (CLTI)-specific outcomes is unclear. We aim to assess the effect of ACEIs/ARBs on amputation-free survival in patients with CLTI undergoing peripheral vascular intervention (PVI) in a Medicare-linked database. METHODS: Patients undergoing PVI in the Vascular Quality Initiative Vascular Implant Surveillance and Interventional Outcomes Network database were included. Primary outcomes included amputation-free survival. Kaplan-Meier survival and multivariable Cox regression analyses were used to assess 1-year outcomes. RESULTS: A total of 34,284 patients were included, 46.3% of whom were discharged on ACEIs/ARBs. Patients discharged on ACEIs/ARBs were more likely to be smokers, have diabetes, and have hypertension. They were also more likely to present with rest pain. The overall 1-year survival rate for patients on ACEIs/ARBs vs those who are not was (79.1% vs 69.4%; P < .001). Freedom from amputation was 87.8% for patients on ACEIs/ARBs vs 84.2% for those who were not (P < .001). Amputation-free survival was 70.5% vs 59.5% for ACEIs/ARBs vs no ACEIs/ARBs (P < .001). After adjusting for potential confounders, ACEIs/ARBs use was associated with lower 1-year mortality (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.7-0.8; P < .001), amputation (HR, 0.89; 95% CI, 0.8-0.9; P < .001), and amputation or death (HR, 0.79; 95% CI, 0.76-0.8; P < .001). CONCLUSIONS: ACEIs/ARBs were associated independently with lower amputation, improved survival, and amputation-free rates survival at 1 year in patients with CLTI undergoing PVI. The fact that more than one-half the patients were not discharged on these medications presents an area for potential quality improvement.

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

BACKGROUND: Sarcoidosis is a multisystem inflammatory disease in which management and outcomes can vary widely. The renin-angiotensin-aldosterone system (RAAS) has been implicated in its pathogenesis, yet the impact of RAAS modulators on health outcomes in sarcoidosis remains poorly understood. RESEARCH QUESTION: How do pharmacologic modulators of RAAS affect health outcomes in patients with a diagnosis of sarcoidosis?. STUDY DESIGN AND METHODS: We conducted a large multicenter investigation using the TriNetX Research Network database. Patients included in this study were individuals with a diagnosis of sarcoidosis who were prescribed either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). All cohorts were matched for important covariates, and outcomes measured included mortality, cardiac and respiratory outcomes, and sepsis rates after sarcoidosis diagnosis. RESULTS: We observed an increased mortality risk among patients with sarcoidosis prescribed ACEIs compared with patients prescribed ARB therapies. Furthermore, patients with sarcoidosis prescribed ACEIs showed worse cardiac and respiratory outcomes and increased sepsis rates compared with the ARB cohort. INTERPRETATION: Our findings suggest that ACEIs and ARBs have divergent effects on outcomes in patients with sarcoidosis. These findings highlight the potential pathogenic role of RAAS signaling in this disease and underscore the importance of carefully selecting RAAS modulators for individuals with sarcoidosis.

Effect of different single and combined antihypertensive drug regimens on the mortality of critical care patients.

Objective: To investigate the effect of different single and combined pre-admission antihypertensive drug regimens on the prognosis of critically ill patients. Methods: We performed a retrospective cohort study using data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. All initial ICU admission records of patients with hypertension and previous antihypertensive exposure before ICU admission were included. Our primary outcome was 90-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance the distribution of baseline characteristics. Logistic regression analysis and subgroup analysis were performed to determine the independent effect of different single and combined antihypertensive drug regimens on 90-day mortality. Results: A total of 13,142 patients were included in the final analysis. The 90-day mortality rate in the combined groups is lower than that in the single therapy group (10.94% vs 11.12%), but no statistical significance was found in the original cohort (p = 0.742). After adjustment for potential confounders, the significantly decreased 90-day mortality rate was found in the combined groups (10.78% vs 12.65%, p = 0.004 in PSM; 10.34% vs 11.90%, p = 0.007). Patients who were exposed to either ACEIs or ARBs had a better prognosis than those not exposed (7.19% vs 17.08%, p < 0.001 in single antihypertensive groups; 8.14% vs18.91%, p < 0.001 in combined antihypertensive groups). The results keep robustness in the PSM and IPTW cohorts. In the logistic regression model analysis, combined therapy was associated with a 12%-20% reduced risk of 90-day death after adjusting potential confounders (OR 0.80-0.88, all p < 0.05), while exposure to ACEIs or ARBs was associated with the decreased risk of 90-day death by 52%-62% (OR 0.38-0.48, all p < 0.001) and 40%-62% (OR 0.38-0.60, all p < 0.001) in the single and combined therapy groups, respectively. The results were still robust to subgroup analysis. Conclusions: Pre-admission combined antihypertensive therapy is associated with a significantly lower risk of death than exposure to single antihypertensives in critically ill patients. Meanwhile, either ACEIs or ARBs seem to be the optimal candidates for both single and combined therapy. Further high-quality trials are needed to confirm our findings.

Pharmacogenetics of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in cardiovascular diseases.

Cardiovascular diseases (CVDs) have a high mortality rate, and despite the several available therapeutic targets, non-response to antihypertensives remains a common problem. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are important classes of drugs recommended as first-line therapy for several CVDs. However, response to ACEIs and ARBs varies among treated patients. Pharmacogenomics assesses how an individual's genetic characteristics affect their likely response to drug therapy. Currently, numerous studies suggest that genetic polymorphisms may contribute to variability in drug response. Moreover, further studies evaluating gene-gene interactions within signaling pathways in response to antihypertensives might help to unravel potential genetic predictors for antihypertensive response. This review summarizes the pharmacogenetic data for ACEIs and ARBs in patients with CVD, and discusses the potential pharmacogenetics of these classes of antihypertensives in clinical practice. However, replication studies in different populations are needed. In addition, studies that evaluate gene-gene interactions that share signaling pathways in the response to antihypertensive drugs might facilitate the discovery of genetic predictors for antihypertensive response.