Renin-angiotensin System Blockade Group Research Articles

Angiotensin receptor-neprilysin inhibitor adherence and outcomes in heart failure with reduced ejection fraction.

Whether medication adherence to angiotensin receptor-neprilysin inhibitor (ARNI) in real-world practice is associated with the reduced risk of all-cause mortality or hospitalization relative to that with traditional renin-angiotensin system (RAS) blockade remains unclear. This study investigated the influence of medication adherence of ARNI and traditional RAS blockade in heart failure with reduced ejection fraction (HFrEF). We conducted a nationwide longitudinal cohort study with patients with HFrEF using data from the Korean National Health Insurance Service data (2017-2021) covering the entire population. A total of 13483 patients with HFrEF who received ARNI were matched 1:1 with 13483 patients who received traditional RAS blockade using propensity score matching. The primary outcome was a composite of all-cause mortality or any hospitalization within one year. Medication adherence was assessed by calculating the proportion of days covered (PDC) relative to total medication prescribed. ARNI and traditional RAS blockade adherence rates were directly compared to analyse their respective associations with the primary outcome. Patients in the ARNI group had a lower rate of the primary outcome than those in the traditional RAS blockade group [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.75-0.81; P<0.001]. Mean PDC values spanning 1year were 92.6±14.5% and 90.9±17.7% in the ARNI and RAS blockade groups, respectively (P<0.001). Among patients with PDC≥80%, the risk of primary outcome was significantly lower in the ARNI group than in the RAS blockade group (HR 0.75; 95% CI 0.72-0.78; P<0.001) while a risk reduction with ARNI was not observed among patients with PDC<80% (HR 0.95; 95% CI 0.85-1.05; P=0.313). The beneficial effect was more pronounced among patients with PDC≥80% than that among patients with PDC<80% (P for interaction <0.001). In a real-world cohort with HFrEF, ARNI was superior to traditional RAS blockade in reducing the risk of all-cause mortality and hospitalization. The benefit of ARNI was pronounced among patients with high medication adherence but not among those with low medication adherence, highlighting the importance of adherence to ARNI treatment for HFrEF. PARADE-HF ClinicalTrials.gov number, NCT05329727.

Efficacy and safety of dual renin-angiotensin system (RAS) blockade for non-elderly diabetic kidney disease patients with preserved eGFR.

Although sodium glucose cotransporter2 inhibitor (SGLT-2I) is widely used in clinical practice, sufficient renin-angiotensin system (RAS) inhibition remains the cornerstone of diabetic kidney disease (DKD) treatment. The aim of this single-center study was to evaluate the efficacy and safety of dual RAS blockade compared with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) monotherapy in non-elderly DKD patients with preserved eGFR (WHO Standard, < 60y). This single-center study was registered in Chinese Clinical Trial Registry (ChiCTR1900024752), and approved by the ethical committee (KY201994). In this study, we recruited non-elderly type 2 diabetes volunteers with initial diagnosis of DKD to receive dual RAS blockade or monotherapy. 150 non-elderly DKD patients with preserved eGFR were recruited. The patients were randomly divided into dual RAS blockade group and monotherapy group. The dual RAS blockade group treatment regimen was an 80mg valsartan plus a 4mg perindopril tert-butylamine per day. At the same time, monotherapy group patients who received the 8mg perindopril tert-butylamine or 160mg valsartan monotherapy. The clinical data of the three groups were compared at baseline and collected during the follow-up period of 12months. The baseline of patients who received dual RAS blockade was similar to that of monotherapy group. After 12months of treatment, the median level of proteinuria in the dual RAS blockade group was significantly lower than that in the monotherapy group. There was no significant difference in the estimated glomerular filtration rate (eGFR) level, potassium, blood pressure and no serious adverse reactions. In non-elderly DKD patients with preserved eGFR, dual RAS blockade is superior to control proteinuria, and does not increase the probability of adverse reactions such as hyperkalemia, hypotension and acute kidney injury in 12months.

Renin-Angiotensin System Blockade in Aortic Stenosis: Implications Before and After Aortic Valve Replacement.

Aortic stenosis (AS) is a common valvular heart disease in the aging population that is characterized by a variable period of asymptomatic phase before development of symptoms and severe AS. Mortality and morbidity is substantial even after aortic valve replacement, in part related to persistent left ventricular hypertrophy, diastolic dysfunction, and heart failure. Renin‐angiotensin system (RAS) blockade therapy is associated with modulation of adverse left ventricular remodeling, reduction in myocardial hypertrophy, and fibrosis, resulting in clinical improvements in patients with congestive heart failure There are emerging data to suggest benefit of RAS blockade in patients with AS before and after AVR with regard to potentially slower progression of aortic valve calcification, left ventricular mass and survival benefit in favor of RAS blockade group before AVR, and also survival benefit in patients after AVR. We review the available data to understand the role of RAS blockade before AVR and in patients undergoing surgical AVR and transcatheter AVR. There are significant survival advantages of RAS inhibition in patients with AS undergoing surgical AVR or transcatheter AVR. On the basis of existing literature, adequately powered randomized trials are needed to evaluate the role of RAS inhibition in patients with AS.

Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy

BackgroundInhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial.MethodsSTOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models.ResultsAmong the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies.ConclusionIn the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.

Sequential nephron blockade with combined diuretics improves diastolic function in patients with resistant hypertension.

AimsHypertension is a major contributor to cardiac diastolic dysfunction. Different therapeutics strategies have been proposed to control blood pressure (BP), but their independent impact on cardiac function remains undetermined. In patients with resistant hypertension, we compared the changes in cardiac parameters between two strategies based on sequential nephron blockade (NBD) with a combination of diuretics or sequential renin‐angiotensin system blockade (RASB).Methods and resultsAfter a 4‐week period where all patients received Irbesartan 300 mg/day + hydrochlorothiazide 12.5 mg/day + amlodipine 5 mg/day, 140 resistant hypertension patients (54.8 ± 11.1 years, 76% men, mean duration with hypertension: 13.1 ± 10.5 years, no previous history of heart failure or current symptoms of congestive heart failure) were randomized 1:1 to the NBD regimen or to the RASB regimen at week 0 (W0, baseline). Treatment intensity was increased at week 4, 8, or 10 if home BP was ≥135/85 mmHg, by sequentially adding 25 mg spironolactone, 20–40 mg furosemide, and 5 mg amiloride (NBD group) or 5–10 mg ramipril and 5–10 mg bisoprolol (RASB group). No other antihypertensive drug was allowed during the study. BP, BNP levels, and echocardiographic parameters were assessed at weeks 0 and 12.The baseline characteristics, laboratory parameters, and plasma hormones (BNP, renin, and aldosterone) and cardiac echocardiographic parameters did not significantly differ between the NBD and the RASB groups. Over 12 weeks, BNP levels significantly decreased in NBD but increased in RASB (mean [CI 95%] change in log‐transformed BNP levels: −43% [−67%; −23%] vs. +55% [46%; 62%] in NBD vs. RASB, respectively, P < 0.0001). Similarly, the proportion of patients presenting ≥2 echocardiographic criteria of diastolic dysfunction decreased between baseline and W12 from 31% to 3% in NBD but increased from 19% to 32% in RASB (P = 0.0048). As compared with RASB, NBD induced greater decrease in ambulatory systolic BP (P < 0.0001), pulse pressure (P < 0.0001), and systemic vascular resistance (P < 0.005). In multivariable linear regression analyses, NBD treatment was significantly associated with decreased BNP levels (adjusted ß: −46.41 ± 6.99, P < 0.0001) independent of age, gender, renal function, and changes in BPs or heart rate.ConclusionsIn patients with resistant hypertension, nephron blockade with a combination of diuretics significantly improves cardiac markers of diastolic dysfunction independently of BP lowering.

Effect of Renin-Angiotensin System Blockade on Mortality in Korean Hypertensive Patients with Proteinuria.

BackgroundAlthough renin-angiotensin system (RAS) blockade is recommended for hypertensive patients with proteinuria, the effect of RAS blockade on Korean hypertensive patients has not been investigated.MethodsAmong individuals who underwent a National Health Examination between 2002 and 2003 in Korea, hypertensive patients with proteinuria (defined as a dipstick test result ≥2+) were enrolled in this study. We investigated the outcomes of two groups stratified by RAS blockade prescription (with RAS blockade vs. without RAS blockade). Moreover, Cox proportional hazard regression and Kaplan-Meier analyses were performed to examine the effects of RAS blockade on mortality and end-stage renal disease (ESRD).ResultsA total of 8,460 patients were enrolled in this study, of whom 6,236 (73.7%) were prescribed with RAS blockade. The mean follow-up period was 129 months. A total of 1,003 (11.9%) patients died, of whom 273 (3.2%) died of cardiovascular (CV) events. The Kaplan-Meier curves for all-cause or CV mortality showed that the survival probability was significantly higher in the RAS blockade group than in the non-RAS blockade group. Multivariate Cox analysis also revealed RAS blockade significantly reduced the all-cause and CV mortality rates by 39.1% and 33.7%, respectively, compared with non-RAS blockade, even after adjusting for age, sex, and comorbid diseases; however, ESRD was not affected.ConclusionIn this study, we found that RAS blockade was significantly associated with a reduction in mortality but not in the incidence of ESRD. However, 26.3% of the enrolled patients did not use RAS blockade. Physicians need to consider the usefulness of RAS blockade in hypertensive patients with proteinuria.

Renin-angiotensin system blockade therapy after surgical aortic valve replacement for severe aortic stenosis: a cohort study.

Data are lacking on the effect of renin-angiotensin system (RAS) blockade therapy with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers after surgical aortic valve replacement (SAVR) for severe aortic stenosis (AS). To investigate the association between RAS blockade therapy and outcomes after SAVR for severe AS. Retrospective study. Single tertiary referral care center. Patients who were prescribed angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers after SAVR for severe AS between 1991 and 2010 who had at least 2 refills 90 days apart and at least a 6-month follow-up constituted the RAS blockade group (n=741). Patients who did not receive these prescriptions were in the untreated group (n=1011). Unadjusted and propensity-matched analyses (594 matched pairs of treated and untreated patients) were performed. The primary outcome was survival rates after SAVR. Secondary end points were changes in left ventricular mass index, left ventricular ejection fraction, and left atrial size. Overall unadjusted estimated survival rates at 1, 5, and 10 years were significantly greater in the RAS blockade group than in the non-RAS blockade group (99%, 90%, and 60% vs. 99%, 81%, and 53%, respectively; P<0.001). Among propensity-matched patients, estimated survival rates at 1, 5, and 10 years remained significantly greater in the RAS blockade group than in the non-RAS blockade group (99%, 90%, and 71% vs. 96%, 78%, and 49%, respectively; P<0.001). For the matched cohorts, the groups did not significantly differ in the change in left ventricular mass index (P=0.37), left ventricular ejection fraction (P=0.67), or left atrial size (P=0.43) after SAVR on echocardiographic analysis. Retrospective, single-center analysis. Renin-angiotensin system blockade therapy is associated with increased survival rates in patients after SAVR for severe AS. A randomized trial of RAS blockade therapy after SAVR should be considered. None.

Greater efficacy of aldosterone blockade and diuretic reinforcement vs. dual renin-angiotensin blockade for left ventricular mass regression in patients with resistant hypertension.

We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies - mineralocorticoid receptor blockade (MRB) and dual renin-angiotensin system blockade (RASB) - in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension. After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20-40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5-10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12. Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m in the MRB group, whereas it increased by 1.8 ± 19.1 g/m in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e' ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP. In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

Long-term hemodynamic and molecular effects persist after discontinued renin–angiotensin system blockade in patients with type 1 diabetes mellitus

Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.

Retarding the progression of chronic kidney disease with renin angiotensin system blockade.

We assessed the effect of renin angiotensin system blockade (RASB) in chronic kidney disease (CKD) of diverse etiology. Two hundred and sixty-five consecutive CKD patients attending our renal clinic, with estimated glomerular filtration rate (eGFR) of 20-70 ml/min/1.73m2 at baseline and a minimal follow-up of 1 year, were studied retrospectively. We devised a scoring system to quantify RASB, wherein the maximum dose of an agent recommended for control of hypertension was scored as 1. The renal endpoints studied were the rate of change in eGFR (ΔeGFR) and decline of eGFR>50%. The mean age was 48 ± 11.2 years and 69% were male. The mean duration of follow-up was 4 ± 2.7 years. The rate of ΔeGFR was –1.5 ± 5.0 ml/min/1.73 m2 per year in patients who received RASB (N=168) and –6.0 ± 5.4 in those who did not (N=97) (P<0.001). The incidence of decline of eGFR >50% was 11.3% with RASB and 24.7% without (P=0.003). In a subgroup of patients who received RASB, the incidence of decline of eGFR >50% was 17.8% in the low-dose RASB group (N=84, RASB score 0.63 ± 0.38) and 4.8% in the high-dose group (N=84, RASB score 2.5 ± 0.7) (P=0.001). RASB was associated with significantly better renoprotection in CKD of diverse etiology, even in nonproteinuric diseases. This effect appeared to be dose-dependent, with higher supramaximal doses exhibiting better renoprotection than the lower conventional doses. Our results make a strong case for use of aggressive RASB in all CKD patients to postpone end-stage renal disease.

Clinical and Hemodynamic Effects of Renin–Angiotensin System Blockade in Cardiac Transplant Recipients

Chronic kidney disease continues to be a major limiting factor for long-term survival of heart transplant recipients. Little is known about the early use of renin-angiotensin system (RAS) blocking agents and their impact on renal function and hemodynamics in heart transplant recipients. In this cohort study all eligible recipients of orthotopic heart transplants at the UTAH cardiac transplantation program from 2001 through 2007 were divided into 2 groups-patients who were started on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers within the first 4 weeks of transplantation and continued on these for ≥4 weeks during the first 3 months (RAS blockade group, n = 75) and those who were not (non-RAS blockade group, n = 52). All patients were followed for 1 year after transplantation. There were no significant differences at baseline between the 2 groups. Estimated glomerular filtration rate at 12 months was significantly higher in the RAS blockade group compared to the non-RAS blockade group (mean ± SD, 56.3 ± 22.4 vs 47.3 ± 18.1 ml/min/1.73 m(2), p = 0.036). At 12 months pulmonary artery systolic pressure was significantly lower in the RAS blockade group compared to the non-RAS blockade group (30.2 ± 7.4 vs 32.9 ± 9.3 mm Hg, p = 0.023). Left ventricular ejection fraction and pulmonary capillary wedge pressure were similar between the 2 groups. In conclusion, early RAS blockade after heart transplantation is safe, well tolerated, and associated with better renal function and hemodynamic profile at 1 year after transplantation.

Renin-Angiotensin System Blockade Is Associated with the Long-Term Protection Against Cardiac Remodeling after Cardioversion in Hypertensive Patients with Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia, and renin-angiotensin system blockade (RAS-B) may be favorable for AF because of its effect on cardiac remodeling. However, effects of RAS-B on AF in hypertensive patients are controversial. Thus, in this study, we investigated the long-term effects of RAS-B on cardiac remodeling and rhythm control after electrical cardioversion for hypertensive patients with persistent AF. We studied 27 consecutive hypertensive patients with persistent AF (duration > one week) who received electrical cardioversion and once recovered to sinus rhythm. Blood pressure of the patients was controlled by medication including RAS-B. The patients were divided into those who were pre-treated with RAS-B (n = 10) for at least two months before electrical cardioversion and those without RAS-B (n = 17). We performed echocardiography before electrical cardioversion and 3 years after electrical cardioversion in all patients and compared the differences in echocardiographic cardiac remodeling parameters, including left atrial dimension, left ventricular end-diastolic dimension and left ventricular ejection fraction. The AF recurrence-free ratio during the follow-up period was significantly higher in the RAS-B group than in the non-RAS-B group, judged by Kaplan-Meier analysis (60 vs. 24%, P = 0.01). All cardiac remodeling parameters in the RAS-B group showed better values than those in non-RAS-B group (each parameter, P < 0.05), supporting the beneficial effects of RAS-B on AF in hypertensive patients. In hypertensive patients with AF, pre-treatment with RAS-B before electrical cardioversion can prevent cardiac remodeling for 3 years and maintain sinus rhythm.