Renin-angiotensin System Inhibitors Research Articles

Glomerular pressure and tubular oxygen supply: a critical dual target for renal protection.

The primary treatment goal of chronic kidney disease (CKD) is preserving renal function and preventing its progression to end-stage renal disease. Glomerular hypertension and tubular hypoxia are critical risk factors in CKD progression. However, the renal hemodynamics make it difficult to avoid both factors due to the existence of peritubular capillaries that supply oxygen to the renal tubules downstream from the glomerulus through the efferent arteriole. In the treatment strategies for balancing glomerular pressure and tubular oxygen supply, afferent and efferent arterioles of the glomerulus determine glomerular filtration rate and blood flow to the peritubular capillaries. Therefore, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors as well as classical renin-angiotensin system inhibitors, which can change the diameter of afferent and/or efferent arterioles, are promising options for balancing this dual target and achieving renal protection. This review focuses on the clinical importance of glomerular pressure and tubular oxygen supply and proposes an effective treatment modality for this dual target.

Choice Between Free Combination of Antihypertensive Agents and Fixed Dosed Combinations in the Treatment of Arterial Hypertension

Most patients with arterial hypertension require more than one antihypertensive drug for blood pressure target achievement. Some patients are recommended for a multi-pill antihypertensive regimen, others — treatment with fixed dosed combinations in one tablet. Analysis of elibrary and PubMed publications in the period mostly from 2014 to 2024 concerning the choice of two-component combined antihypertensive agents containing renin-angiotensin system inhibitor and diuretic or calcium channel blocker, revealed that fixed-dose combinations (FDC) use and taking one tablet once a day improves adherence to treatment and facilitates blood pressure control. Although the cost of FDC containing the renin-angiotensin-aldosterone system inhibitor and a thiazide/thiazide-like diuretic or calcium channel blocker is in most cases higher than the same drugs taken separately, the use of fixed combinations, increasing patient adherence to therapy, has clinical advantage in terms of the effectiveness of lowering blood pressure, which confirms their economic feasibility. On the other hand, the use of free combination therapy in two different tablets, when taken separately during the day, can sometimes provide a more sustained antihypertensive effect over 24 hours. Evidence of the effectiveness of blood pressure control for FDCs is often extrapolated from data on free combinations. In addition, FDCs are characterized by less detection of possible ineffectiveness of one of the components. The range of FDCs and the dosage ratios of the components presented in them is gradually expanding, but the choice among free combinations is still wider. In addition, the list of vital and essential drugs (VED) for 2024 does not contain FDCs for antihypertensive drugs, which excludes the possibility of free receiving them on a preferential basis and gives the opportunity for the manufacturer to set prices for them. Despite the fact that recently the scientific community has recommended the use of FDC antihypertensive drugs as initial therapy due to better compliance with the regimen, and therefore clinical effectiveness and economic feasibility, it cannot be said that there is no space left for free combinations of antihypertensive drugs in the treatment of arterial hypertension. The choice of doctor, frequency of prescription, share of purchases of the FDCs in the Russian Federation, review of their consumption requires further analysis.

Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors.

Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i). Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium>5.0 mmol/L), mild hyperkalemia (potassium>5-≤5.5mmol/L) and moderate to severe hyperkalemia (potassium>5.5mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs). 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.

Heterogeneous afferent arteriolopathy: a key concept for understanding blood pressure-dependent renal damage.

Hypertension, aging, and other factors are associated with arteriosclerosis and arteriolosclerosis, primary morphological features of nephrosclerosis. Although such pathological changes are not invariably linked with renal decline but are prevalent across chronic kidney disease (CKD), understanding kidney damage progression is more pragmatic than precisely diagnosing nephrosclerosis itself. Hyalinosis and medial thickening of the afferent arteriole, along with intimal thickening of small arteries, can disrupt the autoregulatory system, jeopardizing glomerular perfusion pressure given systemic blood pressure (BP) fluctuations. Consequently, such vascular lesions cause glomerular damage by inducing glomerular hypertension and ischemia at the single nephron level. Thus, the interaction between systemic BP and afferent arteriolopathy markedly influences BP-dependent renal damage progression in nephrosclerosis. Both dilated and narrowed types of afferent arteriolopathy coexist throughout the kidney, with varying proportions among patients. Therefore, optimizing antihypertensive therapy to target either glomerular hypertension or ischemia is imperative. In recent years, clinical trials have indicated that combining renin-angiotensin system inhibitors (RASis) and sodium-glucose transporter 2 inhibitors (SGLT2is) is superior to using RASis alone in slowing renal function decline, despite comparable reductions in albuminuria. The superior efficacy of SGLT2is may arise from their beneficial effects on both glomerular hypertension and renal ischemia. A comprehensive understanding of the interaction between systemic BP and heterogeneous afferent arteriolopathy is pivotal for optimizing therapy and mitigating renal decline in patients with CKD of any etiology. Therefore, in this comprehensive review, we explore the role of afferent arteriolopathy in BP-dependent renal damage.

The safety of corticosteroid therapy in IGA nephropathy: analysis of a real-life Italian cohort.

Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). A total of 119 (9.8%) adverse events were reported, of which 67 (5.5%) were considered treatment-emergent, and 36 (2.9%) were SAEs (n = 23, 63.8% were infections). One patient died due to sepsis. A significant association was observed between AEs and immunosuppression [8 (2.8%) in RASI, 60 (9.4%) in steroids + immunosuppressants, 14 in oral steroids (14.1%) and 37 pts (19.2%) in steroids + immunosuppressants (p < 0.01)], age and estimated glomerular filtration rate (eGFR), but not with proteinuria and sex. On multivariate analysis, only older age was associated with the occurrence of SAEs. According to our findings, the incidence of SAEs during therapy with steroids alone or associated with immunosuppressors is lower in everyday clinical practice than in randomised clinical trials.

Therapeutic opportunities in targeting the protective arm of the renin-angiotensin system to improve insulin sensitivity: a mechanistic review.

In recent years, the knowledge of the physiological and pathophysiological roles of the renin-angiotensin system (RAS) in glucose metabolism has advanced significantly. It is now well-established that blockade of the angiotensin AT1 receptor (AT1R) improves insulin sensitivity. Activation of the AT2 receptor (AT2R) and the MAS receptor are significant contributors to this beneficial effect. Elevated availability of angiotensin (Ang) II) for interaction with the AT2R and increased Ang-(1-7) formation during AT1R blockade mediate these effects. The ongoing development of selective AT2R agonists, such as compound 21 and the novel Ang III peptidomimetics, has significantly advanced the exploration of the role of AT2R in metabolism and its potential as a therapeutic target. These agents show promise, particularly when RAS inhibition is contraindicated. Additionally, other RAS peptides, including Ang IV, des-Asp-Ang I, Ang-(1-9), and alamandine, hold therapeutic capability for addressing metabolic disturbances linked to type 2 diabetes. The possibility of AT2R heteromerization with either AT1R or MAS receptor offers an exciting area for future research, particularly concerning therapeutic strategies to improve glycemic control. This review focuses on therapeutic opportunities to improve insulin sensitivity, taking advantage of the protective arm of the RAS.

Sacubitril/valsartan reduces proteinuria depending on blood pressure in patients with stage 4-5 chronic kidney disease.

Blood pressure (BP) control is an important factor in the management of chronic kidney disease (CKD). Several studies have shown that BP in many patients with CKD remained uncontrolled even with multiple medications. Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has been newly approved for treating hypertension in Japan. However, the renoprotective effects remain unclear, particularly in patients with advanced CKD. Here, we investigated the effects on proteinuria of this ARNI in patients with stage 4-5 CKD. We retrospectively collected data from outpatients with stage 4-5 CKD who started ARNI from January until December 2023. The primary outcome was the change in urine protein creatinine ratio (UPCR) at 6months after ARNI initiation. Secondary outcomes were systolic and diastolic BP, estimated glomerular filtration rate (eGFR), serum potassium, and serum uric acid (UA). We analyzed factors associated with 50% UPCR reduction by multivariate analysis. In total, 47 patients were analyzed. ARNI reduced UPCR from 2.14g/gCr (interquartile range; 1.09-2.91) to 1.05g/gCr (0.42-1.95; p < 0.001). Systolic BP fell from 150.0mmHg (139.5-160.0) to 134.0mmHg (124.5-140.0; p < 0.001). No significant changes in eGFR, serum potassium, and serum uric acid were observed, except for a slight decrease in eGFR among patients with conversion from a renin-angiotensin system inhibitor to ARNI. In multivariate regression analysis, higher systolic BP (per 10-mmHg increase) was significantly associated with reduced proteinuria (odds ratio 2.51, 95% confidence interval 1.35-4.66; p = 0.004). ARNI reduced proteinuria in patients with stage 4-5 CKD, particularly for those with uncontrolled hypertension.

Management of acute kidney disease in type 2 diabetes: the potential role of GLP-1 RAs and SGLT2-Is.

Acute kidney disease (AKD) is defined as subacute damage and/or loss of kidney function occurring 7 to 90days after acute kidney injury (AKI), and bearing a high risk of progression to chronic kidney disease. Current management of AKD is non-specific and includes prevention of repeated AKI, early and regular follow-up by a nephrologist, resumption and dose adjustment of statins and renin-angiotensin system inhibitors, optimization of blood pressure control, nutrition management, and nephrotoxin avoidance. Recently, SGLT2i and GLP1- RAs have emerged as potential therapeutic tools preventing the transition from acute to chronic kidney disease due to their efficacy in preserving renal function.

Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD.

In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications. Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up. A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80-1.11]) or mortality (aHR, 1.06 [95% CI, 0.88-1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63-0.97]) and mortality (aHR, 0.64 [95% CI, 0.48-0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14-0.86]). Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.

The Combination of Valsartan and Spironolactone Mitigated Mitral Regurgitation-Induced Cardiac Dysfunction in a Novel Rat Model.

Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.

Digoxin Discontinuation in Patients with HFrEF on Beta-Blockers: Implication for Future “Knock-Out Trials” in Heart Failure

Background: National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers. Methods: In OPTIMIZE-HF, of 2,477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for one-year outcomes were estimated. Results: Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85–1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85–1.25) or death (HR, 0.91; 95% CI, 0.72–1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25–2.04), 1.62 (1.18–2.22) and 1.43 (1.08–1.89). Conclusions: Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.

Kidney and Mortality Outcomes on Renin-Angiotensin System Inhibitors in Nonproteinuric CKD: Findings from the CRIC Study

Kidney and Mortality Outcomes on Renin-Angiotensin System Inhibitors in Nonproteinuric CKD: Findings from the CRIC Study

Effects of a Low-Protein Diet in Patients with CKD Taking Renin-Angiotensin System Inhibitors: A Post Hoc Subanalysis of the RICE Study

Effects of a Low-Protein Diet in Patients with CKD Taking Renin-Angiotensin System Inhibitors: A Post Hoc Subanalysis of the RICE Study

Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy

IntroductionEndothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss. MethodsEligibility criteria for the ALIGN main stratum included patients with biopsy-proven IgAN, total protein excretion ≥1g/d, eGFR ≥30 mL/min/1.73m2, receiving a maximally-tolerated stable dose of a renin-angiotensin system inhibitor (RASi). An exploratory stratum enrolled participants also receiving a stable dose of sodium glucose cotransporter-2 inhibitors (SGLT2i). Participants were randomized to 0.75 mg atrasentan or placebo orally daily for 132 weeks followed by a 4-week wash-out period. The primary outcome is proteinuria change from baseline (24h urine protein–creatinine ratio UPCR) to Week 36 in the main stratum. Key secondary endpoints include eGFR change from baseline to Week 136, safety and tolerability. ResultsEnrolment occurred across 20 countries; 404 patients are randomized: 340 in the main stratum and 64 in the SGLT2i stratum. At baseline in the main stratum, mean age was 44.7 years, 42.4% were female, mean eGFR and median UPCR were 58.9 mL/min/1.73 m2 and 1.4 g/g, respectively. ConclusionThe ongoing ALIGN trial evaluates the efficacy and safety of atrasentan in a representative global IgAN population at risk for disease progression despite optimized RASi therapy and includes an exploratory stratum evaluating atrasentan use in combination with an SGLT2i.

Impact of Age on Prescribing Patterns of Cardiovascular Medications in Older Japanese Patients with Non-Dialysis-Dependent Chronic Kidney Disease: A Cross-Sectional Study.

Older patients with chronic kidney disease (CKD) are more likely to be excluded from clinical trials. This exclusion affects the quality of cardiovascular disease (CVD) prevention in this population. Baseline data from the Fukuoka Kidney Disease Registry (FKR) cohort, which included 4476 adult patients with CKD stages G1-G5, were cross-sectionally analyzed to compare the use of recommended drugs for preventing CVD in each age group. Different prescribing patterns were observed according to age for the cardiovascular drug classes. Older patients with CKD were less likely to receive renin-angiotensin system (RAS) inhibitors and were more likely to receive calcium channel blockers. The proportion of anticoagulation prescriptions for patients with CKD and atrial fibrillation decreased in the older age group (≥ 75 years). However, the proportion of antiplatelet therapy in patients with ischemic CVD increased linearly with age, even in the very old group aged ≥ 85 years. These findings suggest a severe cardiovascular burden in patients with CKD. Notably, RAS inhibitor use was avoided in the older group despite a severe cardiovascular burden, such as a high prevalence of CVD history and massive albuminuria ＞300 mg/g creatinine. This finding indicates that an older age independently contributed to the non-use of RAS inhibitors, even after adjusting for other covariates. This study suggests that age is a potential barrier to the treatment of patients with CKD and highlights the need to establish individualized treatment strategies for cardiovascular protection in this population.

Effect of Cessation of Renin-Angiotensin System Inhibitors on Clinical Outcomes in AKI

Effect of Cessation of Renin-Angiotensin System Inhibitors on Clinical Outcomes in AKI

Hypertension and Left Ventricular Strain in Pediatric Chronic Kidney Disease.

Left ventricular global longitudinal strain (LV GLS) on echocardiography is a sensitive yet clinically significant marker of myocardial dysfunction. Reduced LV GLS is prevalent in adults with chronic kidney disease and hypertension and is associated with adverse cardiovascular outcomes. It may be a biomarker of chronic kidney disease-associated myocardial dysfunction in children, but data are limited. Our objective was to describe LV GLS in the CKiD study (Chronic Kidney Disease in Children) and to examine the association between blood pressure (BP) and reduced LV GLS. A single apical 4-chamber view was used to estimate LV GLS. Our main analyses examined the association of clinic BP with the absolute value of LV GLS and LV GLS dichotomized at 16. Sensitivity analyses using 24-hour ambulatory BP monitoring data were also performed. Generalized estimating equations were used to account for within-person correlation and to estimate robust SEs for 95% CIs. Covariates in adjusted models included: age, sex, race, estimated glomerular filtration rate, urine protein, hemoglobin, left ventricular hypertrophy, and the use of renin-angiotensin system inhibitors. LV GLS was measured in 962 person-visits. A total of 77 assessments had an LV GLS <16. In adjusted models, both clinic systolic BP (odds ratio, 1.02 [95% CI, 1.01-1.03]) and diastolic BP (odds ratio, 1.02 [95% CI, 1.00-1.03]) percentiles were associated with LV GLS <16. Having awake or nighttime diastolic BP hypertension on ambulatory BP monitoring was significantly associated with a lower absolute value of LV GLS. Office systolic and diastolic hypertension was associated with diminished LV GLS. Only diastolic hypertension detected on ambulatory BP monitoring was associated with lower LV GLS.

An Integrated Approach for Representing Knowledge on the Potential of Drugs to Cause Acute Kidney Injury.

The recent rise in acute kidney injury (AKI) incidence, with approximately 30% attributed to potentially preventable adverse drug events (ADEs), poses challenges in evaluating drug-induced AKI due to polypharmacy and other risk factors. This study seeks to consolidate knowledge on the drugs with AKI potential from four distinct sources: (i) bio(medical) peer-reviewed journals; (ii) spontaneous reporting systems (SRS); (iii) drug information databases (DIDs); and (iv) NephroTox website. By harnessing the potential of these underutilised sources, our objective is to bridge gaps and enhance the understanding of drug-induced AKI. By searching Medline, studies with lists of drugs with AKI potential established through consensus amongst medical experts were selected. A final list of 63 drugs was generated aggregating the original studies. For these 63 drugs, the AKI reporting odds ratios (RORs) using three SRS databases, the average frequency of ADEs from four different DIDs and the number of published studies identified via NephroTox was reported. Drugs belonging to the antivirals, antibacterials, and non-steroidal anti-inflammatory pharmacological classes exhibit substantial consensus on AKI potential, which was also reflected in strong ROR signals, frequent to very frequent AKI-related ADEs and a high number of published studies reporting adverse kidney events as identified via NephroTox. Renin-angiotensin aldosterone system inhibitors and diuretics also display comparable signal strengths, but this can be attributed to expected haemodynamic changes. More variability is noted for proton-pump inhibitors. By integrating four disjointed sources of knowledge, we have created a novel, comprehensive resource on drugs with AKI potential, contributing to kidney safety improvement efforts.

Ramipril After Transcatheter Aortic Valve Implantation in Patients Without Reduced Ejection Fraction: The RASTAVI Randomized Clinical Trial.

Patients with aortic stenosis may continue to have an increased risk of heart failure, arrhythmias, and death after successful transcatheter aortic valve implantation. Renin-angiotensin system inhibitors may be beneficial in this setting. We aimed to explore whether ramipril improves the outcomes of patients with aortic stenosis after transcatheter aortic valve implantation. PROBE (Prospective Randomized Open, Blinded Endpoint) was a multicenter trial comparing ramipril with standard care (control) following successful transcatheter aortic valve implantation in patients with left ventricular ejection fraction >40%. The primary end point was the composite of cardiac mortality, heart failure readmission, and stroke at 1-year follow-up. Secondary end points included left ventricular remodeling and fibrosis. A total of 186 patients with median age 83 years (range 79-86), 58.1% women, and EuroSCORE-II 3.75% (range 3.08-4.97) were randomized to receive either ramipril (n=94) or standard treatment (n=92). There were no significant baseline, procedural, or in-hospital differences. The primary end point occurred in 10.6% in the ramipril group versus 12% in the control group (P=0.776), with no differences in cardiac mortality (ramipril 1.1% versus control group 2.2%, P=0.619) but lower rate of heart failure readmissions in the ramipril group (3.2% versus 10.9%, P=0.040). Cardiac magnetic resonance analysis demonstrated better remodeling in the ramipril compared with the control group, with greater reduction in end-systolic and end-diastolic left ventricular volumes, but nonsignificant differences were found in the percentage of myocardial fibrosis. Ramipril administration after transcatheter aortic valve implantation in patients with preserved left ventricular function did not meet the primary end point but was associated with a reduction in heart failure re-admissions at 1-year follow-up. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03201185.

Management of follicular thyroid carcinoma.

Follicular thyroid carcinoma (FTC) is the second most common histological type of thyroid carcinoma. This review aims to summarize the available evidence and guidelines and provide an updated consensus regarding the management of FTC. The cytoarchitectural features of FTC are similar to those of follicular adenoma (FA), and it is difficult to preoperatively distinguish between FA and FTC. For nodules with Bethesda class III-V cytology, molecular test results (if available) should be considered before the operation. However, it should be noted that molecular tests are not available in all countries. The goals of initial surgical therapy for patients with FTC are to improve overall and disease-specific survival, reduce the risk of persistent/recurrent disease and associated morbidity, and permit accurate disease staging and risk stratification while minimizing treatment-related morbidity and unnecessary therapy. Previous studies have reported some prognostic factors such as distant metastasis, age, tumor size, vascular invasion, TERT promoter mutation, and histological subtype. In particular, the degree of vascular invasion is becoming increasingly important. Evaluating these prognostic factors is essential for prognostic prediction and precise management of patients with FTC. Recurrence and distant metastasis of FTC are treated with radioactive iodine (RAI). However, some FTCs become refractory to RAI. Multi-tyrosine kinase inhibitors such as sorafenib and lenvatinib are utilized for treating RAI-refractory FTCs. In addition, given that renin-angiotensin system (RAS) is the most common driver gene for FTC, it is also important to develop RAS inhibitors.