Renin-angiotensin System Inhibitors Research Articles

Efficacy and Safety of Sacubitril/Valsartan Versus Amlodipine in Japanese Patients With Essential Hypertension: A Randomized, Multicenter, Open-Label, Noninferiority Study (PARASOL Study).

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has demonstrated a superior blood pressure-lowering effect compared with renin-angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well-established class of antihypertensive drugs. In this open-label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥150 to <180mmHg), aged 18-79, were randomly assigned to receive either once-daily sacubitril/valsartan 200mg or once-daily amlodipine 5mg in a 1:1 allocation ratio. The primary endpoint was the noninferiority of sacubitril/valsartan compared with amlodipine in mean change in 24-h SBP from baseline to Week 8, followed by a significance test as a secondary endpoint analysis. The mean change in 24-h SBP in sacubitril/valsartan was noninferior to that in amlodipine (between-treatment difference -0.62mmHg [95% confidential interval: -3.23 to 1.98; p = 0.003 for noninferiority; independent t-test with noninferiority margin 3.0mmHg]), with no significant difference observed (p=0.637). There was no significant difference in the incidence of adverse events (AEs). These results suggested that the blood pressure-lowering effect of sacubitril/valsartan is comparable to that of amlodipine, with no marked differences in tolerability between the two groups. Sacubitril/valsartan, a potent antihypertensive drug comparable to amlodipine, is expected to improve blood pressure control in clinical practice.

Genotype-First Analysis in an Unselected Health System-Based Population and Phenotypic Severity of COL4A5 Variants.

Our knowledge of X-linked Alport Syndrome comes mostly from selected cohorts with more severe disease. We examined the phenotypic spectrum of X-linked Alport Syndrome in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic or likely pathogenic in ClinVar, or protein-truncating variants, were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. Phenotypes examined included dipstick hematuria, bilateral sensorineural hearing loss, proteinuria, decreased estimated glomerular filtration rate, and kidney failure. Out of 170,856 patients, there were 29 hemizygous males (mean age 52 y [SD 20]) and 55 heterozygous females (mean age 59 y [SD 19]) with a pathogenic/likely pathogenic COL4A5 variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any Alport Syndrome phenotypic feature) was highest for non-p.Gly624Asp variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with kidney failure was highest for males with non-p.Gly624Asp variants (44%), intermediate for males with p.Gly624Asp (15%) and females with non-p.Gly624Asp variants (10%), compared to controls (males: 3%, females 2%). Only 47% of individuals with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport Syndrome or thin basement membrane disease. Using a genotype-first approach, we show that men and women with X-linked Alport Syndrome are at higher risk of related phenotypic features with a wider spectrum of severity than has been described previously and variability by genotype.

Optimal duration of medical therapy for patients with acute myocardial infarction.

Optimal medical therapy, including Beta-blockers (BB), inhibitors of the renin-angiotensin system (RAS), and statins, is recommended for patients with acute myocardial infarction (AMI) in the absence of contraindications. However, the optimal duration of these medications has not been clearly established in clinical studies. This observational study aimed to investigate the period during which these medications are associated with improved clinical outcomes. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), in-hospital survivors were selected. In a Cox-proportional hazard analysis of 12,200 patients, BB (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.57-0.95; P = .019), RAS inhibitors (HR 0.70; 95% CI = 0.55-0.89; P = .004), and statins at discharge (HR = 0.65; 95% CI = 0.48-0.87; P = .004) were all associated with lower 1-year cardiac mortality. At 1-year, 10,613 patients without all-cause death, myocardial infarction, revascularization, or re-hospitalization due to heart failure were selected for further analysis. RAS inhibitors (HR = 0.53; 95% CI = 0.37-0.76; P = .001) and statins (HR = 0.30; 95% CI = 0.14-0.61; P = .001) prescribed at 1-year were associated with lower 2-year cardiac mortality, whereas BB were not (HR = 0.79; 95% CI = 0.51-1.23; P = .23). However, none of these medications prescribed at 2-years were associated with reduced 3-year cardiac mortality among the 9232 patients who remained event-free until then. RAS inhibitors and statins were associated with reduced cardiac mortality for up to 2-years, and BB for up to 1-year after the initial attack. The effectiveness of these medications beyond these periods remains questionable.

Pharmacotherapy from Pre-COVID to Post-COVID: Longitudinal Trends and Predictive Indicators for Long COVID Symptoms

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long COVID, a personalized medicine approach is essential for effective disease management. This study aimed to describe trends in pharmacotherapy from pre-COVID to post-COVID phases to gain insights into COVID-19 treatment strategies and assess whether pre-COVID pharmacotherapy can predict long COVID symptoms as a health status indicator. Methods: In the Precision Medicine for more Oxygen (P4O2) COVID-19 study, 95 long COVID patients were comprehensively evaluated through post-COVID outpatient clinics and study visits. This study focused on descriptive analysis of the pharmacotherapy patterns across different phases: pre-COVID-19, acute COVID, and post-COVID. Furthermore, associations between pre-COVID medication and long COVID outcomes were analyzed with regression analyses. Results: We observed peaks in the use of certain medications during the acute infection phase, including corticosteroids and antithrombotic agents, with a decrease in the use of renin–angiotensin system inhibitors. Consistently high use of alimentary tract medications was found across all phases. Pre-COVID respiratory medications were associated with fatigue symptoms, while antiinfectives and cardiovascular drugs were linked to fewer persisting long COVID symptom categories. Conclusion: Our findings provide longitudinal, descriptive pharmacotherapy insights and suggest that medication history can be a valuable health status indicator in characterizing patients for personalized disease management strategies, considering the heterogeneous nature of long COVID.

Exposure to renin-angiotensin system inhibitors before kidney transplantation is associated with a decreased risk of delayed graft function

Exposure to renin-angiotensin system inhibitors before kidney transplantation is associated with a decreased risk of delayed graft function

Treat or not treat COVID-19 with combined renin-angiotensin system and neprilysin inhibition: Have we found a solution?

Treat or not treat COVID-19 with combined renin-angiotensin system and neprilysin inhibition: Have we found a solution?

Quantifying the potential contribution of drugs to the occurrence of acute kidney injury in patients with chronic kidney disease

Abstract Background We sought to comprehensively describe drug-related components associated with AKI in patients with CKD, describing the incidence of drug-related AKI, the proportion of preventable AKI, identified the various drugs potentially associated with it, explored the risk factors, and assessed the one-year incidences of the recurrence of drug-related AKI, kidney failure, and death. Methods CKD-REIN is a French national prospective cohort of 3,033 nephrology outpatients with a confirmed diagnosis of CKD (eGFR &amp;lt;60 mL/min/1.73 m²). AKIs and adverse drug reactions (ADRs) were prospectively identified from hospital reports, medical records, and patient interviews. Expert nephrologists used the KDIGO criteria to adjudicate all stages of AKI, and expert pharmacologists used validated tools to adjudicate ADRs (including drug-related AKIs). Results Over a median [interquartile range] period of 4.9 [3.4-5.1] years, 832 cases of AKI were reported in 639 (21%) of the 3,033 study participants. The drug-related component associated with AKI accounted for 236 cases, and 28% were judged to be preventable or potentially preventable. The three most frequently implicated drug classes were diuretics, renin-angiotensin system inhibitors, and contrast agents. A history of cardiovascular events, diabetes, lower levels of hemoglobin and eGFR, poor medication adherence, and ≥ 5 drug taken daily were associated with a greater risk of drug-related AKI. Full recovery was not attained in 64 (27%) of the 236 cases of drug-related AKI. The one-year cumulative incidences of recurrence of drug-related AKI, kidney replacement therapy, and death were 7%, 15%, and 11%, respectively, after the first drug-related AKI. Conclusions Drug-related AKI is prevalent among patients with CKD. Even though a substantial proportion of these events were classified as stage 1, our findings point to a poor prognosis.

Nephroprotective effect of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus and hypertension: a real-world population-based cohort study

ABSTRACT Objectives This study aimed to investigate the nephroprotective effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes mellitus (T2DM) and hypertension based on real-world clinical data. The study aimed to provide a theoretical basis for evidence-based pharmacological treatment of chronic kidney disease in this population. Methods The ‘Health Cloud’ platform of the Shanghai Municipal Health Commission was employed to identify and screen elderly patients with T2DM and hypertension. The propensity score matching cohort was further constructed to estimate the effect of SGLT2i on the risk of rapid decline in renal function (∆eGFR≤-5 mL/min/1.73 m2 or ∆eGFR%≤-5%). Multiple sensitivity analyses were conducted to assess the robustness of the results. Results After propensity score matching, no significant differences of covariates were identified between the SGLT2i and non-SGLT2i groups. The results of multivariate logistic models demonstrated a consistent and inverse correlation between SGLT2i use and the risk of rapid eGFR decline, whether defined as ∆eGFR≤-5 mL/min/1.73 m2 (OR = 0.60, 95% CI:0.38-0.96) or ∆eGFR%≤-5% (OR = 0.57, 95% CI:0.37-0.89). In the stratification of renin-angiotensin system inhibitor (RASi) treatment, SGLT2i was associated with a lower risk of rapid eGFR decline in the RASi group (all ORs < 1, p < 0.05), with no interaction between SGLT2i and RASi (all P for interaction > 0.05) detected. Conclusions SGLT2i significantly reduced the risk of rapid eGFR decline in elderly patients with T2DM and hypertension, but the synergistic effect with RASi remains unclear.

The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial.

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Social Determinants of Health and Disparities in Guideline-Directed Medical Therapy Optimization for Heart Failure.

Fewer than 20% of eligible patients with heart failure with reduced ejection fraction receive all 4 pillars of guideline-directed medical therapy. Understanding disparities by race, ethnicity, sex, and adverse social determinants of health is necessary to equitably optimize quadruple therapy. Utilizing the American Heart Association's Get With The Guidelines-Heart Failure registry, we examined associations between race and ethnicity, sex, and adverse social determinants of health (insurance type and documented social need [any barrier to accessing health care]) with quadruple therapy optimization (QTO) in patients with heart failure with reduced ejection fraction hospitalized between July 1, 2021, and September 30, 2023, with complete medication data at discharge. We calculated adjusted mean differences (AMDs) in the discharge QTO score (range, 0%-100%) reflecting the proportion of eligible use of renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors and compared across demographic and adverse social determinants of health groups. Among 82 637 patients (median age, 66 years; 32.5% female; 57.0% non-Hispanic White; 76.4% prior heart failure with reduced ejection fraction), the overall mean QTO score was 56.2% (SD, 25.5). After adjustment, compared with non-Hispanic White individuals, Black (AMD, 2.56 percentage points [95% CI, 2.16-2.96]) and Hispanic individuals (AMD, 0.71 percentage points [95% CI, 0.11-1.31]) had higher QTO scores. Females had higher QTO scores than males (AMD, 1.94 percentage points [95% CI, 1.58-2.31]). Patients with no insurance (AMD, -4.90 percentage points [-5.62 to -4.17]), Medicaid (AMD, -0.45 percentage points [-0.89 to -0.01]), and Medicare (AMD, -1.64 percentage points [-2.10 to -1.18]) had lower QTO scores versus private insurance. Those with an identified social need (n=24 651) had lower QTO scores than those without (AMD, -3.40 percentage points [95% CI, -4.10 to -2.71]). Disparities in QTO were most evident for patients with no insurance, Medicaid, Medicare, or potentially an identified social need. Future efforts should focus on reducing gaps to improve equitable guideline-directed medical therapy use.

Differences in Pharmacological Treatment of Heart Failure Among Persons with or without Major Cognitive Disorder: A Cross-Sectional Study Based on National Registries in Sweden.

Comorbidities are common among older people, and during the last decade, a strong association between heart failure (HF) and cognitive impairment has been found. As much as 40-50% of individuals with HF will also have some degree of cognitive impairment. Previous studies report an undertreatment for some cardiovascular diseases in patients with major neurocognitive disorder (NCD). The aim of this present study was to explore differences in pharmacological treatment of HF in individuals diagnosed with HF with or without comorbidity of major NCD. This study combined data from three different Swedish national registers: the Swedish National Patient Register, the Swedish registry for cognitive/dementia disorders (SveDem), and the Swedish Prescribed Drug Register. A logistic regression model including variables for age, sex, major NCD, and nursing home residency was used to analyze associations between drug use and major NCD. We found a lower prevalence of filled prescriptions of renin-angiotensin system (RAS) inhibitors, β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) among patients with major NCD. Living in a nursing home was associated with lower prevalence of RAS inhibitors, BBs, digitalis glycosides, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Females were found to have higher odds of using BBs, loop diuretics and digitalis glycosides, and lower odds of using RAS inhibitors and SGLT2 inhibitors than males. Our findings indicate that there is possible undertreatment among individuals with HF identified in specialized care with co-occurring major NCD. Major NCD was associated with less filled prescriptions of basal pharmacological treatments such as RAS inhibitors, BBs, and MRAs. Future research needs to not only investigate this relationship further but also focus on reasons for the undertreatment of HF and other comorbidities within this group.

Calcium Channel Blocker Versus Renin-Angiotensin System Inhibitor in Risk of Kidney Cancer Among Patients With Hypertension: A Propensity Score-Matched Cohort Study.

Use of antihypertensive medications could be associated with an increased risk of kidney cancer. Despite their various mechanisms of action, whether this association differs between different classes of medications remains unclear. The objective of this study is to compare the risk of kidney cancer between first-line treatment options of antihypertensive medications in a hypertensive population. In this retrospective cohort study, we used the MarketScan Databases (2007-2021). We included individuals older than 30 years of age with a diagnosis of hypertension who received first-line medications for hypertension, which included three classes: angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and dihydropyridine calcium channel blockers (dCCB). We applied a propensity score matching method and created three separate cohorts: (1) ARB versus ACEI, (2) dCCB versus ACEI, and (3) dCCB versus ACEI. For non-dCCB, we repeated the analyses. The primary outcome was kidney cancer incidence. To assess kidney cancer risk, we applied multivariable conditional Cox proportional hazards models. In the first cohort, ARB use was associated with an increased risk of kidney cancer compared to ACEI use (hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.02-1.18). In the second cohort, dCCB use was associated with an increased risk of kidney cancer compared to ACEI use (HR 1.29, 95% CI 1.18-1.40). In the third cohort, dCCB use was associated with a higher risk of kidney cancer compared to ARB use (HR 1.17, 95% CI 1.08-1.28). Null association was shown when comparing non-dCCB with ACEI or ARB use. Use of dCCB showed a higher risk of kidney cancer compared to ACEI or ARB use in patients with hypertension.

Impact of Renin-angiotensin system inhibitors on response to PD1/L1 inhibitors in patients with Metastatic Renal Cell Carcinoma

BackgroundThe renin-angiotensin-aldosterone system (RAAS), traditionally associated with blood pressure and fluid regulation, also plays a role in tumorigenesis. Renin-angiotensin-aldosterone system inhibitors (RAASI), including angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown to improve outcomes in various malignant neoplasms. In metastatic urothelial cancer, the use of RAASI have been associated with higher rates of tumor regression in patients receiving immunotherapy (IO) with PD1/L1 inhibitors. This is thought to be due to RAASI-induced downregulation of TGF-beta, for which increased expression is a known mechanism of PD1/L1 inhibitor resistance. We hypothesized that concurrent RAASI in patients with mRCC receiving IO is associated with increased tumor regression. MethodsWe conducted a retrospective analysis of patients with mRCC receiving IO as a first- or second-line therapy from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RAASI on tumor regression. The primary endpoint was any regression of tumor on imaging. ResultsData were available for 128 patients with mRCC who received IO as a first- (n=91, 71.0%) or second- (n=37, 28.9%) line treatment. Patients who received RAASI during IO were more likely to have tumor regression compared to patients who were not on concurrent RAASI (OR 3.84 [95% CI 1.81-8.47, p=<0.001). This held true regardless if patients received IO as a first-line (OR 2.83 [95% CI 1.2-6.94], p=0.0173) or second-line (OR 9.5 [95% CI 1.89-73.1], p=0.005) treatment. ConclusionsOur hypothesis generating study suggests that in our mRCC population, concurrent use of RAASI in patients receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RAASI in combination with IO for mRCC patients. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population. MicroAbstractRenin-angiotensin-aldosterone system inhibitors (RAASI) have been shown to improve outcomes in various malignancies. In this retrospective, single-center study, we found that concurrent use of RAASI in patients with mRCC receiving IO is associated with a significantly increased likelihood of tumor regression. Our findings suggest the potential therapeutic advantage of RAASI in combination with IO for mRCC patients.

Risk of developing hyperkalemia in patients with hypertension treated with combination antihypertensive therapy - a retrospective register-based study.

The risk of hyperkalemia in relation to different combinations of antihypertensive therapy remains to be elucidated. In this Danish register-based study, we aimed to investigate the risk of developing hyperkalemia in relation to different combinations of antihypertensive therapy. Using incidence density matching, we matched a hyperkalemic patient to five normokalemic patients on eGFR groups, age, sex, and time between study entry and date of potassium measurement. Combination therapies were subdivided into eight groups: beta blockers (BB) + calcium channel blockers (CCB), BB + renin angiotensin system inhibitors (RASi), BB + RASi + mineralocorticoid receptor antagonists (MRA), CCB + RASi, CCB + RASi + thiazides, CCB + thiazides, RASi + thiazides, and other combinations. Multivariable conditional logistic regression was used to estimate the odds of hyperkalemia within 90 days for each of the eight antihypertensive combination therapies. A total of 793 patients with hyperkalemia were matched to 3598 normokalemic patients. In multivariable analysis, odds of developing hyperkalemia when being treated with BB + RASi + MRA was 1.95 (95% CI, 1.39-2.72) compared to RASi + thiazides (reference). CCB + thiazides (OR, 0.76 [95% CI, 0.45-1.28]) and CCB + RASi + Thiazid (OR 0.81 [95% CI, 0.51-1.28]) were among the others not significantly associated with hyperkalemia. Combinations of BB + RASi + MRA were significantly associated with an increased risk of developing hyperkalemia within 90 days of initiating treatment. Patients treated with BB + RASi + MRA within 90 days of treatment initiation, were associated with an increased hyperkalemia risk. When treating hypertensive patients with combination antihypertensive therapy, identifying and monitoring patients with a high risk of dyskalemias is a crucial goal to avoid serious adverse effects and detrimental outcomes related to dyskalemia.

Relationship between clinical congestion and worsening renal function after intravenous initiation of furosemide in patients with acute heart failure.

To investigate if worsening renal function (WRF) appearing in some patients with acute heart failure (AHF) after intravenous furosemide initiation is influenced by severity of congestion. We conducted a retrospective secondary analysis of consecutive patients diagnosed with AHF and prospectively included in 10 Spanish emergency departments (EDs) for whom serum creatinine at ED arrival and after 2-7days of intravenous furosemide initiation were available. Congestion was clinically evaluated by identification of 7 signs/symptoms and by chest X-ray. The outcome was WRF, defined as a delta-creatinine ≥ 0.3mg/dL. Risk of WRF according to congestion was estimated in models adjusted by patient baseline characteristics and vitals at ED arrival, and interaction was also investigated. We included 3027 patients (median age 82years, 56% women), and 657 (21.7%) presented WRF after intravenous furosemide initiation. When signs/symptoms were individually considered, only lower limbs edema was associated with decreased risk of WRF (20.1% vs. 24.8%; OR = 0.76, 95%CI = 0.64-0.91). After adjustment, lower limbs edema persisted inversely associated with WRF (aOR = 0.78, 95%CI = 0.65-0.94), with significant lower risk for patients ≤ 80years and without chronic kidney disease, functional limitation, and hypoxemia (p for interaction 0.01, 0.04, 0.02 and 0.03, respectively). Neither degree of clinical congestion (number of signs/symptoms of congestion) nor radiological congestion in chest X-ray were related to WRF. Worsening renal function was associated with a higher 1-year all-cause mortality (40.1% vs 34.6%; HR = 1.27, 1.10-1.46; aHR = 1.331, 1.151-1.540). In patients with WRF, liver cirrhosis, chronic treatment with loop diuretics and renin-angiotensin system inhibitors, age (> 80years), dementia, heart valve disease and NYHA class III-IV were associated with higher mortality. Intravenous furosemide initiation in patients with AHF without lower limbs edema must be cautious, as they are at increasing risk of developing WRF during the next following days, which in turn is associated with a higher 1-year mortality.

Effect of renin-angiotensin system inhibitors in elderly patients with heart failure and reduced ejection fraction

Abstract Background More than half of the patients admitted for acute decompensated heart failure (ADHF) in Japan are over 80 years of age. Both Japanese and European heart failure guidelines recommend the use of renin-angiotensin system inhibitors (RASIs) in patients with heart failure with reduced ejection fraction (HFrEF). However, there is a paucity of data on the effect of RASIs in elderly patients with HFrEF, because elderly patients have been excluded from large clinical trials. Purpose The purpose of the current study was to clarify the effect of RASIs in elderly patients with HFrEF. Methods This was a post-hoc analysis of a prospective, observational, multicentre cohort study that enrolled consecutive patients admitted with ADHF to 19 secondary and tertiary hospitals in Japan between October 2014 and March 2016. Patients who were ≥ 80 years old, with left ventricular ejection fraction (LVEF) &amp;lt; 40% and discharged alive were included in the present study. RASIs were defined as either ACE inhibitors or angiotensin II receptor blockers. The primary endpoint was a composite of all-cause death and heart failure (HF) hospitalisation. Results Among 518 patients enrolled, 288 patients received RASIs at discharge and 230 patients did not. The median follow-up period was 335 days (interquartile range; 124 – 499 days). Patients receiving RASIs were younger (85.7 ± 4.4 vs. 86.5 ± 4.4 years of age, p=0.03), had a higher body mass index (BMI; 21.4 ± 3.3 vs. 20.6 ± 3.7 kg/m², p=0.01) and better renal function (eGFR; 45.4 ± 21.5 vs. 38.2 ± 19.2 ml/min/1.73m², p&amp;lt;0.001). Patients receiving RASIs had a higher LVEF (30.9 ± 6.3 vs. 28.5 ± 7.1%, p&amp;lt;0.001). The use of beta-blockers at discharge was more prevalent in patients receiving RASIs (77.8% vs. 60.4%, p&amp;lt;0.001), but the use of mineralocorticoid receptor antagonists was not (50.0% vs. 42.2%, p=0.08). The cumulative incidence of all-cause death or HF hospitalisation one year after discharge was significantly lower in patients receiving RASIs (40.1% vs. 59.5%, p&amp;lt;0.001). Even after adjusting for confounders, the risk of a composite of all-cause death and HF hospitalisation was significantly lower in patients receiving RASIs (adjusted hazard ratio 0.59, 95% confidence interval 0.45-0.77, p&amp;lt;0.001). There was no interaction between the effect of RASIs and subgroup factors such as age, BMI, dementia, malignancy, frailty, and renal function. Conclusion Use of RASIs at discharge was associated with lower incidence of all-cause death or HF hospitalisation in elderly patients with HFrEF.

Prognostic implications of guideline-directed medical therapy in functional mitral regurgitation: a meta-analysis

Abstract Background Randomized evidence of the role of heart failure medical therapy for patients with functional mitral regurgitation (FMR) is lacking. Purpose The present meta-analysis sought to investigate the independent long-term prognostic impact of the different medical categories recommended in heart failure, for subjects with FMR. Methods A systematic literature review was conducted in electronic databases to identify studies reporting the association of renin angiotensin system inhibitors (RASi), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) with outcomes in FMR. A random-effects meta-analysis was conducted to quantify the unadjusted and adjusted hazard ratios [(a)HRs] for all-cause death and the composite outcome in each medical category. Results The final sample comprised 12 studies with 6,715 FMR patients (Picture 1). The use of RASi and BBs was associated with a significantly lower risk for all-cause mortality (HR 0.52 [0.39-0.68]; p &amp;lt;0.00001, I2 =62 % and HR 0.62 [0.49-0.77]; p &amp;lt;0.0001, I2 =44 % respectively) and for the composite outcome (HR 0.54 [0.44-0.67]; p &amp;lt;0.00001, I2 =33 % and HR 0.62 [0.52-0.75], p &amp;lt;0.00001, I2 =35% respectively) in unadjusted models (Picture 2). Both RASi (aHR 0.73 [0.56-0.95], p =0.02, I2 =52%) and BBs (aHR 0.60 [0.41-0.88], p = 0.009, I2 =55%) retained their association with the composite outcome in pooled adjusted models (Picture 2). The prognostic benefit of using RASi or BBs was retained in subgroup analysis including only patients with moderate of severe FMR. MRAs did not demonstrate a significant association with improved outcomes in FMR. Conclusions RASi and BBs appear to have a favorable prognostic impact in patients with FMR, regardless of regurgitation severity.Study flow chart for study selectionPharmacotherapy and prognosis in FMR

Prevalent and incident anemia in PARAGON-HF

Abstract Background Anemia is a common comorbidity in patients with heart failure (HF) and is associated with adverse prognosis. Renin-angiotensin system inhibitors (RASi) have been shown to lower hemoglobin levels, potentially related to direct reductions in erythropoetin levels and hematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anemia in patients with HF with mildly reduced or preserved ejection fraction. Methods PARAGON-HF was a global, multicenter randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction≥45%. Anemia was defined as hemoglobin &amp;lt;120 g/L in women and &amp;lt;130 g/L in men. We evaluated changes in hemoglobin, risks of incident anemia and new oral iron initiation during follow-up. We also assessed treatment effects on the primary composite endpoint of total HF hospitalizations (HFH) and cardiovascular (CV) death according to anemia status. Results Among 4,795 participants with a hemoglobin measurement available, 1,111 (23.2%) had anemia at randomization of which 3.5%, 77.7%, and 18.8% were characterized as micro-, normo-, and macrocytic anemia. 5.6% were treated with oral iron at baseline. Over a 2.7-year median follow-up period, patients with anemia were at nearly twice the risk of the primary outcome (21.6 vs. 11.5 per 100py; rate ratio 1.90; 95% CI: 1.62-2.21; P&amp;lt;0.001). Compared with valsartan, sacubitril/valsartan significantly slowed the decline in hemoglobin levels by 1.4 g/L (95% CI: 0.4-2.4 g/L; P = 0.005; Figure 1 Panel A). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anemia (30.3% vs. 37.6%; HR 0.76; 95% CI: 0.68-0.85; P&amp;lt;0.001; Figure 1 Panel B) and starting oral iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI: 0.67-0.97; P = 0.026; Figure 2). Treatment effects of sacubitril/valsartan vs. valsartan on the primary endpoint were consistent among patients with and without anemia (Pinteraction=1.00). Conclusions Among patients with HF with mildly reduced or preserved ejection fraction, treatment with sacubitril/valsartan resulted in slower declines in hemoglobin, lower rates of incident anemia, and fewer new initiations of iron therapy compared with RASi.

Effects of Sacubitril/Valsartan on all-cause hospitalizations in heart failure: participant-level pooled analysis of PARADIGM-HF and PARAGON-HF

Abstract Background Sacubitril/valsartan is indicated to reduce the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalizations other than HF, yet the effects of sacubitril/valsartan on hospitalizations of any cause have not been well described. Methods PARADIGM-HF and PARAGON-HF were phase-3, global multicenter randomized clinical trials that evaluated sacubitril/valsartan versus enalapril (in PARADIGM-HF) or valsartan (in PARAGON-HF) across the spectrum of left ventricular ejection fraction (LVEF; ≤40% in PARADIGM-HF and ≥45% in PARAGON-HF). We pooled individual participant-level data from these 2 trials to examine the effects of sacubitril/valsartan on time-to-first investigator-reported all-cause and cause-specific hospitalization using Cox proportional hazards models, stratified by geographic region and trial. We additionally examined heterogeneity in treatment response by LVEF. Results Over 2.8 years median follow-up, among 13,194 participants in the pooled PARADIGM-HF/PARAGON-HF, sacubitril/valsartan significantly reduced the risk of all-cause hospitalizations compared with renin-angiotensin system inhibitor (HR 0.92; 95% CI 0.88-0.97; P=0.002); Figure 1 Panel A. The absolute risk reduction (ARR) was 2.1 per 100 patient-years corresponding to a number-needed-to-treat (NNT) of 48 patient-years of treatment exposure to prevent 1 all-cause hospitalization. Reductions in overall hospitalizations among patients with identifiable causes (N=5,783) seemed to be primarily driven by lower rates of cardiac and pulmonary hospitalizations associated with sacubitril/valsartan. Patients treated with sacubitril/valsartan did not have a higher rate of composite non-cardiac hospitalizations (Figure 1 Panel B). Similarly, sacubitril/valsartan reduced the risk of the composite of all-cause hospitalization or all-cause mortality (HR 0.92; 95% CI 0.87-0.96; P&amp;lt;0.001), with an ARR of 2.5 per 100 patients-years and an NNT of 40 patient-years. For all-cause hospitalization, we observed significant heterogeneity by LVEF as a continuous measure (Pinteraction=0.027); treatment effects were most apparent in those with an LVEF below 60% (HR 0.91 95% CI 0.86-0.96; Figure 2). Conclusions In a pooled analysis of &amp;gt;13,000 patients with chronic HF, sacubitril/valsartan reduced hospitalization for any reason with benefits most apparent among those with an LVEF below normal.

Race in heart failure: a pooled participant-level analysis of the global PARADIGM-HF and PARAGON-HF trials

Abstract Background Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). Early experiences with neprilysin inhibition suggested possible increased risks of angioedema, especially among Black individuals. We aimed to examine the safety and efficacy profile of sacubitril/valsartan in a pooled participant-level dataset of 2 large cohorts of patients with HF by self-reported race. Methods PARADIGM-HF and PARAGON-HF were multicenter, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi, enalapril or valsartan, respectively) in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF). We included all patients with available data on self-reported race and categorized patients as White, Asian, or Black. We assessed adjudicated outcomes including the composite of first HF hospitalization (HFH) or cardiovascular (CV) death, its components, and angioedema by racial group. Results Among 12,097 included participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Asian participants were from 19 countries, with highest enrollment from India, China, and the Philippines. Black participants were from 18 countries, with highest enrollment from the US, South Africa, and Brazil. Black patients had the worst baseline health status (adjusted KCCQ-OSS mean 70.3), while White (71.4) and Asian patients (76.4) had better health status; P&amp;lt;0.001. Over 2.4-years of median follow-up, Black (adjusted HR 1.67; 95% CI 1.37-1.89; P&amp;lt;0.001) and Asian patients (adjusted HR 1.32; 95% CI 1.16-1.50; P&amp;lt;0.001) experienced higher risks of the primary outcome compared with White patients (Figure 1). The treatment effects of sacubitril/valsartan vs. RASi on the primary endpoint were consistent among White (HR 0.84; 95% CI: 0.77-0.91), Asian (HR 0.92; 95% CI: 0.78-1.10), and Black patients (HR 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.39). In light of higher baseline risks, Black patients accrued the greatest absolute risk reduction with sacubitril/valsartan (Figure 2). Consistent treatment benefits by race were also observed for the individual components (CV death alone and first HFH alone). Rates of any adjudicated angioedema were numerically higher with sacubitril/valsartan vs. RASi across race groups (White 0.4% vs. 0.2%; Asian 0.6% vs. 0.2%; Black 2.3% vs. 0.8%), however no patient in either trial experienced airway compromise or required mechanical airway protection. Conclusions In a pooled experience of over 12,000 participants enrolled in 2 trials conducted across 56 countries, Black and Asian patients exhibited a higher risk of CV events than White patients. Rates of non-serious angioedema were numerically higher with sacubitril/valsartan across race groups. The relative CV benefits of sacubitril/valsartan were consistent across races, with greatest absolute benefits observed in Black patients.