BACKGROUND: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations.
METHODS: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors.
RESULTS: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]).
CONCLUSIONS: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.

BACKGROUND: The therapeutic efficacy of renin-angiotensin system inhibitors (RASi) in elderly patients with hypertension and at risk of fractures has been in the limelight because of accumulating evidence that localized RAS activation in bone tissue leads to osteoclastic bone resorption, resulting in osteoporosis. This study set out to investigate the association between RASi use and fracture incidence in a large cohort.
METHODS: We employed a nested case-control design to investigate the association between RASi use and newly developed fractures. A case was defined as a patient newly diagnosed with a fracture between January 2004 and December 2015. We selected 1,049 cases and controls using 1:1 propensity score matching. Conditional logistic regression analysis was conducted to estimate the association between RASi exposure and fracture incidence.
RESULTS: Overall, RASi usage was significantly associated with lower odds for fracture incidence (ever-users vs never-users: OR, 0.73; 95% CI, 0.59-0.91). We found that ARB-only users experienced fewer fractures than RASi-never users (OR, 0.65; 95% CI, 0.49-0.86), whereas ACEi-only users or ARB/ACEi-ever users did not. In subgroup analysis, RASi-ever users without cerebrovascular disease, those with a BMI exceeding 23, and statin exposure had significantly lower ORs.
CONCLUSIONS: The present study established a significant association between RASi use and reduced fracture incidence, thus highlighting the potential clinical utility of RASi use as a preventive strategy in elderly patients at risk for osteoporotic fractures.

It is unknown whether initiating diuretics on top of renin-angiotensin system inhibitors (RASi) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs) in patients with chronic kidney disease (CKD). For this purpose, we emulated a target trial in the Swedish Renal Registry 2007-2022 that included nephrologist-referred patients with moderate-advanced CKD and treated with RASi, who initiated diuretics or CCB. Using propensity score-weighted cause-specific Cox regression, we compared risks of major adverse kidney events (MAKE; composite of kidney replacement therapy [KRT], experiencing over a 40% eGFR decline from baseline, or an eGFR under 15 ml/min per 1.73m2), major cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction or stroke), and all-cause mortality. We identified 5875 patients (median age 71 years, 64% men, median eGFR 26 ml/min per 1.73m2), of whom 3165 started a diuretic and 2710 a CCB. After a median follow-up of 6.3 years, 2558 MAKE, 1178 MACE and 2299 deaths occurred. Compared to CCB, diuretic use was associated with a lower risk of MAKE (weighted hazard ratio 0.87 [95% confidence interval: 0.77-0.97]), consistent across single components (KRT: 0.77 [0.66-0.88], over 40% eGFR decline: 0.80 [0.71-0.91] and eGFR under 15ml/min/1.73m2: 0.84 [0.74-0.96]). The risks of MACE (1.14 [0.96-1.36]) and all-cause mortality (1.07 [0.94-1.23]) did not differ between therapies. Results were consistent when modeling the total time drug exposure, across sub-groups and a broad range of sensitivity analyses. Thus, our observational study suggests that in patients with advanced CKD, using a diuretic rather than a CCB on top of RASi may improve kidney outcomes without compromising cardioprotection.

UNASSIGNED: To investigate the correlation between preoperative use of ACEIs/ARBs and postoperative delirium (POD) in surgical patients with pulmonary arterial hypertension (PAH).
UNASSIGNED: The present study is a secondary analysis of a retrospective cohort study conducted at the University of Washington Medical Center from April 2007 to September 2013. Patients with PAH who underwent non-cardiac, non-obstetric surgery were enrolled in the original research. We further excluded stroke, sepsis, and craniotomy patients from interfering with POD evaluation. The univariate regression analysis and multivariate-adjusted model were used to explore the influence of preoperative ACEIs/ARBs use on the occurrence of POD.
UNASSIGNED: A total of 539 patients were included in this study. The incidence of POD in these patients was 3.0%. Following the adjustment of potential confounders (age, BMI, smoking status, pulmonary arterial systolic pressure, length of surgery, vascular surgery, asthma, obstructive sleep apnea, renal failure, atrial fibrillation, coronary artery disease, hydrochlorothiazide, alpha-blocker, calcium channel blocker, antiplatelet, steroids, statin, isoflurane), a negative relationship was found between preoperative use of ACEIs/ARBs and occurrence of POD (OR = 0.15, 95%CI: 0.03 to 0.80, P = 0.0266).
UNASSIGNED: Preoperative use of ACEIs/ARBs in patients with PAH reduces the risk of POD. ACEIs/ARBs may be more recommended for patients with PAH in the future.

Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma.

In the first wave of the COVID-19 pandemic, the hypothesis that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) increased the risk and/or severity of the disease was widely spread. Consequently, in many hospitals, these drugs were discontinued as a \"precautionary measure\". We aimed to assess whether the in-hospital discontinuation of ARBs or ACEIs, in real-life conditions, was associated with a reduced risk of death as compared to their continuation and also to compare head-to-head the continuation of ARBs with the continuation of ACEIs.
Adult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs), and their 95%CIs were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators.
Out of 625 ACEI/ARB users, 340 (54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI 0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%, N=125) as compared to those who continued with ACEIs (33.1%, N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI 0.29-0.93), being especially notorious among males (HR=0.34; 95%CI 0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI 0.25-0.85), and patients with obesity (HR=0.22; 95%CI 0.05-0.94), diabetes (HR=0.36; 95%CI 0.13-0.97), and heart failure (HR=0.12; 95%CI 0.03-0.97).
The discontinuation of ACEIs/ARBs at admission did not improve the in-hospital survival. On the contrary, the continuation with ARBs was associated with a trend to a reduced mortality as compared to their discontinuation and to a significantly lower mortality risk as compared to the continuation with ACEIs, particularly in high-risk patients.

BACKGROUND: To date, there has been a renewed interest in renin-angiotensin system inhibitors (RASi) for HCC prevention because they may reduce potent angiogenic factors.
OBJECTIVE: This study set out to investigate associations between RASi use and HCC development.
METHODS: We conducted a nested case-control study. A case was defined as a patient who was newly diagnosed with HCC. We selected 567 cases and controls using 1:1 propensity score matching. RASi exposure was classified into ever-user and never-user, then categorized according to cumulative dose and prescription period. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for HCC incidence according to RASi use were analyzed.
RESULTS: Overall, no significant association was found between exposure to RASi and HCC incidence (ever-user vs. never-user: aOR, 0.77; 95% CI, 0.56-1.07). In subgroup analysis, women receiving RASi ≥30 cumulative defined daily doses (cDDDs) showed significantly lower aORs (0.49; 95% CI, 0.24-0.95. Angiotensin II receptor blockers only-use ≥30 cDDD was significantly associated with reduced risk of HCC (aOR, 0.65; 95% CI, 0.43-0.97). In cases where subjects did not have diabetes mellitus and where the cDDD of RASi was 1800 or more, the risk of HCC development was significantly reduced compared to that in subjects with no RASi exposure (aOR, 0.26; 95% CI, 0.08-0.72).
CONCLUSIONS: The present study did not verify a significant overall association between RASi use and HCC but indicated lower HCC incidence in some subgroups. The possibility of a beneficial effect at a higher cumulative RASi dose was also presented.

OBJECTIVE: There is currently no consensus on the effect of treatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), on the prognosis of patients with heart failure and preserved ejection fraction (HFpEF). Therefore, we have analysed the relationship of commencing treatment with ACEIs or ARBs and the prognosis of patients with incident HFpEF.
METHODS: Retrospective study over 15 years on 3864 patients with HFpEF (GAMIC cohort). Main outcomes were mortality (all-cause and cardiovascular) and hospitalisations for HF. The independent relationship between CT-RASIs and the prognosis, stratifying patients for cardiovascular comorbidity after propensity score-matching was analysed.
RESULTS: During a median follow-up of 7.94 years, 2960 died (76.6%) and 3138 were hospitalised (81.2%). Therapy with RASIs was associated with a lower mortality, all-cause (RR [95% CI] for ACEIs: 0.76 [0.66-0.86], and RR for ARBs: 0.88 [0.80-0.96]; P < 0.001 in both cases), and cardiovascular (RR for ACEIs: 0.72 [0.66-0.78], and RR for ARBs: 0.87 [0.80-0.94]; P < 0.001), a lower hospitalisation rate (RR for ACEIs: 0.82 [0.74-0.90], and RR for ARBs: 0.90 [0.82-0.98]; P < 0.001), and a lower 30-day readmission rate (RR for ACEIs: 0.66 [0.60-0.73], and RR for ARBs: 0.86 [0.75-0.97]; P < 0.001), after adjustment for the propensity to take RASIs or other medications, comorbidities and other potential confounders. Results on the effect of ARBs are compromised by the small number of patients. Analyses of recurrent hospitalisations gave larger treatment benefits than time-to-first-event analyses.
CONCLUSIONS: In this propensity-matched study, commencing treatment with ACEIs is associated with an improved prognosis of patients newly diagnosed with incident HFpEF.

Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy.
This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors.
A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non-RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18-0.99]; P = 0.048).
The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy.