Renin-angiotensin System Inhibitors Research Articles

Pilot trial of an electronic decision support to improve care for emergency department patients with acute heart failure.

Emergency department (ED) providers play an important role in the management of patients with acute heart failure (AHF). We present findings from a pilot study of an electronic decision support that includes personalized risk estimates using the STRIDE-HF risk tool and tailored recommendations for initiating guideline directed medical therapy (GDMT) among appropriate patients. Among ED patients treated for AHF who were discharged from the ED or the ED-based observation unit in two EDs from 1 January 2023 to 31 July 2023, we assess prescriptions to the four classes of GDMT at two intervals: (1) ED arrival and (2) ED discharge. Specifically, we report active prescriptions for beta-blockers (BBs), renin-angiotensin receptor system inhibitors (RASis), sodium-glucose transport protein 2 inhibitors (SGLT2is) and mineralocorticoid receptor antagonists (MRA) among patients with reduced ejection fraction (HFrEF) and mildly reduced (HFmrEF). Second, we describe rates of 30-day serious adverse events (SAE) (death, cardiopulmonary resuscitation, balloon-pump insertion, intubation, new dialysis, myocardial infarction or coronary revascularization) among patients predicted to be very low risk by STRIDE-HF and discharged home. Among 234 discharged patients, 55% were female and 76% were non-White. We found 51 (21.8%), 21 (9.0%) and 126 (53.8%) had HFrEF, HFmEF and HFpEF, respectively, while 36 (15.4%) were missing EF, and 51 (22%) were very low risk, 82 (35%) were low risk, 60 (26%) were medium risk and 41 (18%) were high risk. Among HFrEF patients, 68.6%, 66.7%, 25.5% and 19.6% were on a RASi, BB, SGLT2i and MRA, respectively, at ED arrival, while 42.9%, 66.7%, 14.3% and 4.8% of HFmrEF patients were on a RASi, BB, SGLT2i and MRA, respectively. Among patients with HFpEF, only 6 (4.8%) were on an SGLT2i at ED arrival. The most prescribed new medication at ED discharge was an SGLT2i, with a nearly 10% increase in the proportion of patients with an active prescription for SGLT2i at ED discharge among HFrEF and HFmEF patients. We observed no 30-day SAE among the 51 patients predicted to be very low risk and discharged home. Ongoing treatment with GDMT at ED arrival was sub-optimal. Initiation among appropriate patients at discharge may be feasible and safe.

Identification of risk factors associated with oral 5-aminolevulinic acid induced adverse events in photodynamic diagnosis−transurethral resection of bladder tumor

BackgroundOral 5-aminolevulinic acid for transurethral resection of bladder tumor reduces bladder cancer recurrence compared with standard white-light transurethral resection of bladder tumor. However, data regarding risks of adverse events with this drug are unclear. The aim of the present study was to identify risk factors associated with oral 5-aminolevulinic acid induced adverse events in photodynamic diagnosis-transurethral resection of bladder tumor. MethodsWe studied 104 cases of 5-aminolevulinic acid-photodynamic diagnosis-transurethral resection of bladder tumor from October 2021 to April 2023, administering 20 mg/kg 5-aminolevulinic acid orally at least 2 h pre-surgery. Four major adverse events associated with 5-aminolevulinic acid were selected to identify risk factors for their occurrence, including perioperative hypotension, nausea and/or vomiting, photosensitivity, and liver dysfunction. Univariate and multivariate analyses were conducted to identify the risk factors of those adverse events. ResultsPerioperative hypotension (11.5 %), nausea and/or vomiting (37.5 %) photosensitivity (31.7 %), and liver dysfunction (51.9 %) were observed. Multivariate analyses revealed that spinal anesthesia was associated with hypotension (p = 0.02), whereas advanced age (p < 0.01) and higher body mass index (p < 0.01) were associated with nausea and/or vomiting. Also, male sex (p < 0.01) and longer operative time (p = 0.01) were associated with photosensitivity, and renin-angiotensin system inhibitors use was associated with postoperative liver dysfunction (p < 0.01). ConclusionsFor elderly male obese patients taking renin-angiotensin system inhibitors, particular attention is needed during the perioperative period of photodynamic diagnosis-transurethral resection of bladder tumor under spinal anesthesia due to the higher risk of onset of the adverse events involved in oral administration of 5-aminolevulinic acid.

Use of heart failure medical therapy before and after a cancer diagnosis: A longitudinal study.

We aim to evaluate change in the use of prognostic guideline-directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non-cancer controls, including renin-angiotensin-system inhibitors (RASIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non-cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR=1.51, 95% CI=1.35-1.68; beta-blockers: OR=1.22, 95% CI=1.08-1.37; MRAs: OR=1.31, 95% CI=1.08-1.59) and poor persistence (RASIs: OR=2.04, 95% CI=1.75-2.37; beta-blockers: OR=1.35, 95% CI=1.12-1.63; MRAs: OR=1.49, 95% CI=1.16-1.93), and higher risks for dose down-titration for RASIs (OR=1.69, 95% CI=1.40-2.04) and beta-blockers (OR=1.31, 95% CI=1.05-1.62). Cancer diagnosis was not associated with treatment initiation or dose up-titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.

Impaired Gastrointestinal Motility and Worsening Heart Failure in Patients Receiving Trans-Catheter Aortic Valve Replacement.

Background: Impaired gastric motility in the form of constipation may often occur in elderly patients with chronic heart failure. Candidates for trans-catheter aortic replacement (TAVR) are of old age and have multiple comorbidities, probably including constipation. However, the clinical implication of a history of constipation in patients receiving TAVR remains unknown. Methods: Patients who underwent TAVR at our large academic center between 2015 and 2022 were eligible. The prognostic impact of the prescribed laxative type and number, which was assumed as the severity of constipation, on the incidence of death or heart failure readmission two years after index discharge was investigated. Results: A total of 344 patients were included. Median age was 85 years, and 99 patients were men. Patients with any laxatives (N = 166) had higher systolic blood pressure, higher plasma B-type natriuretic peptide levels, and a lower prescription rate of renin-angiotensin system inhibitors at the time of index discharge after TAVR (p < 0.05 for all). The number of laxative types was independently associated with the composite primary outcome with an adjusted hazard ratio of 1.83 (95% confidence interval 1.27-2.63, p = 0.001) with a cutoff of one type of laxative used, which significantly stratified the 2-year cumulative incidence of the primary outcome (18% versus 7%, p = 0.001). Conclusions: The presence of constipation was associated with worse clinical outcomes following TAVR. The prognostic impact of an aggressive intervention for constipation remains a future concern in this cohort.

Impact of Renin-Angiotensin System Blockade on Mortality and Allograft Loss among Renal Transplant Recipients: A Systematic Review and Meta-Analysis.

The blockade of the renin-angiotensin system (RAS) has a beneficial effect on reducing the levels of proteinuria and blood pressure in patients with chronic kidney disease (CKD) and reduces the risk of developing end-stage kidney disease in CKD patients. Nonetheless, a debate persists regarding the impact of RAS inhibitors on outcomes such as mortality and graft survival in renal transplant patients. To assess the effect of RAS inhibitors on graft recipients in the past decade, we conducted a systematic review and meta-analysis. We searched Embase, PubMed, and the Cochrane Central Register of Clinical Trials from January 1, 2012, to August 1, 2022. We included 14 articles, comprising 5 randomized controlled trials (RCTs) and 9 cohort studies, including 45,377 patients. These studies compared patient or graft survival between an RAS inhibitor treatment arm and a control arm. The meta-analysis revealed that RAS blockade was significantly associated with lower mortality in cohort studies (risk ratio [RR] = 0.66, 95% confidence interval [CI]: 0.55-0.79), reduced allograft loss in cohort studies (RR = 0.62, 95% CI: 0.54-0.71), and significant changes in systolic blood pressure in RCTs. Subgroup analysis of the groups of interest (interventions involving RAS blockade, follow-up period of ≥5 years) showed consistently reduced mortality (RR = 0.67, 95% CI: 0.56-0.81) and reduced allograft loss (RR = 0.61, 95% CI: 0.54-0.70). Our results demonstrated that the application of RAS blockade among renal transplant recipients was associated with lower mortality and allograft loss in cohort studies but not in RCTs. More powered clinical trials are needed to evaluate the effects of RAS blockade in renal transplant recipients.

Reductions in renin-angiotensin system inhibitors following hospitalization for heart failure.

Limited data are available that evaluate the efficacy of renin-angiotensin system inhibitor (RASI) dose-reduction in older adults with heart failure with reduced ejection fraction following a heart failure hospitalization. We examined a 5% random sample of Medicare beneficiaries with prescription coverage who were discharged to home following a hospitalization for heart failure with reduced ejection fraction between 1 January 2007 and 30 June 2018 and were treated with RASI prior to hospitalization. We classified patients into three mutually exclusive groups based on RASI dosage before (prescription fills up to 90days prior to) and after a hospitalization (prescription fills up to 365days that were most proximate to the discharge date as possible)-same/increased dose, dose-reduction, and discontinuation. We examined associations between RASI prescribing patterns and outcomes (mortality and all-cause readmission at 30days and 1year) using Cox proportional hazards models. Among 12794 unique older adults, 36.8% experienced a RASI reduction following their hospitalization for HFrEF-15.7% had a dose-reduction and 21.1% had a discontinuation. Neither dose-reduction nor discontinuation was associated with 30-day mortality. Discontinuation was associated 1-year mortality, 30-day all-cause readmission, and 1-year all-cause readmission, whereas dose-reduction was not. RASI dose-reduction occurs in 1 out of 7 HF hospitalizations. In contrast to RASI discontinuation, RASI dose-reduction was not associated with adverse short or long-term outcomes. These findings indicate that RASI dose-reduction is preferred over RASI discontinuation in selected situations where RASI reduction is needed.

Evolving the Role of Black Race in Hypertension Therapeutics.

Black race has been used to guide antihypertensive drug selection for Black patients based on predominant between race (same drug) and intra-race (different drugs) blood pressure (BP) response patterns. Accordingly, thiazide diuretics and calcium antagonists have been recommended over renin-angiotensin system (RAS) inhibitors (angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors) and beta blockers for Black patients. Current antihypertensive drug prescribing reflects historical guidance as calcium antagonists and thiazide diuretics are prescribed more and RAS blockers less in Black than White patients. Hypertension control rates in Blacks, lag those for Whites despite their greater use of combination drug therapy and lesser use of monotherapy. This is also true across drug regimens containing any of the 4 recommended classes for initial therapy as well as for evidence-based combination drug therapy (calcium antagonist or thiazide diuretic + RAS blocker) regimens for which there is no known racial disparity in BP response. Current recommendations acknowledge the need for combination drug therapy in most, especially in Black patients. One exemplary comprehensive hypertension control program achieved >80% control rates in Black and White patients with minimal racial disparity while utilizing a race-agnostic therapeutic algorithm. Black patients manifest robust, if not outsized, BP responses to diet/lifestyle modifications. Importantly, race neither appears to be a necessary nor sufficient consideration for the selection of effective drug therapy. Accordingly, we urge the initiation of adequately intense race-agnostic drug therapy coupled with greater emphasis on diet/lifestyle modifications for Black patients as the cornerstone of a race-informed approach to hypertension therapeutics.

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.

Kidney outcomes with SGLT2 inhibitor vs. DPP4 inhibitor use in older adults with diabetes.

While the kidney protective effects of sodium glucose co-transporter-2 (SGLT2) inhibitors have attracted much attention, there are limited real-world clinical data examining the effects of SGLT2 inhibitors on kidney function in older individuals. We aimed to compare the kidney outcomes between SGLT2 inhibitor and dipeptidyl peptidase 4 (DPP4) inhibitor use in older adults with diabetes. Using a nationwide claims database, we studied 6354 older adults (≥ 60 years of age) who had diabetes and newly initiated on SGLT2 inhibitors or DPP4 inhibitors. A 1:4 propensity score matching algorithm was used to compare changes in eGFR between SGLT2 inhibitor and DPP4 inhibitor users. The primary outcome was a decline in the rate of estimated glomerular filtration rate (eGFR), which was obtained using a linear mixed-effects model with an unstructured covariance. Following propensity score matching, 6354 individuals including 1271 SGLT2 inhibitor users and 5083 DPP4 inhibitor users (median age: 68 [65-70] years); men, 60.4%; median eGFR:69.0 [59.1-79.0] ml/min/1.73 m2, median hemoglobin A1c [HbA1c]:6.9 [6.5-7.4]%) were analyzed. SGLT2 inhibitor users had a slower eGFR decline than did DPP4 inhibitor users (-0.97 [95% CI, -1.24 to -0.70] ml/min/1.73m2 vs. -1.83 [95% CI, -1.97 to -1.69] ml/min/1.73m2 per year; p for interaction<0.001). This finding remained consistent across subgroups based on age, sex, body mass index, HbA1c level, renin-angiotensin system inhibitor use, and baseline eGFR. Additionally, the risk of a≥20%, ≥ 30%, and≥40% decrease in eGFR from baseline was significantly lower in SGLT2 inhibitor users than that in DPP4 inhibitor users. Our analysis, utilizing a nationwide epidemiological dataset, demonstrated that the decline in eGFR was slower in individuals aged≥60 years with diabetes who were prescribed SGLT2 inhibitors compared to those prescribed DPP4 inhibitors, suggesting a potential advantage of SGLT2 inhibitors for kidney outcomes even in older individuals with diabetes.

Finerenone: Who should prescribe it for CKD? The physician associate's perspective.

Diabetic kidney disease (DKD) affects 30-40% of all patients with diabetes and contributes significantly to the cardiovascular burden of chronic kidney disease (CKD). Despite the availability of evidence-based medications like finerenone and simple screening tests such as Urinary Albumin-to-Creatinine Ratio (UACR), more resources are still needed to care for DKD patients. Physician Associates (PAs) play a crucial role in the multidisciplinary team responsible for DKD diagnosis, monitoring, and management. A nonsteroidal mineralocorticoid receptor antagonist, namely finerenone, was approved by the FDA in adults with CKD associated with type 2 diabetes to reduce the risk of renal and cardiovascular outcomes. Finerenone is considered among the pillars of care for DKD, furthermore, the addition of finerenone in combination with renin-angiotensin system inhibitors and/or other renal protective medications may offer additional benefits. Primary care providers prescribe finerenone less frequently than specialized care providers, indicating a need to empower physician associates in medication prescription and other renal protection strategies. As part of a multidisciplinary team, physician associates can play an important role in evaluating risk factors that contribute to heart disease and metabolic health. They can also monitor not only kidney function by ordering tests, such as serum creatinine and urinary albumin-to-creatinine ratio every 3-12months, but also serum potassium levels. Additionally, physician associates can encourage patients to take responsibility for their health by regularly monitoring their blood pressure, blood glucose levels, and body weight. With early detection and management, kidney failure and cardiovascular events may be preventable. Specialized physician associates also play a significant role in the comprehensive care of DKD patients, especially in the later stages. DKD care can be hindered by numerous factors such as lack of patient engagement during counseling, cost disparities, and a complex referral system that requires multidisciplinary guidelines to improve professional communication. It is necessary to re-envision the physician associates' role in primary care and empower them in goal-directed therapies.

Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology.

To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT308AKT1/total AKT1, but not with pS307IRS-1/total IRS-1 or the density of cells stained positive for pS616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.

Renin-Angiotensin System Inhibition and Cardiac Damage in Patients Undergoing Transcatheter Aortic Valve Replacement

BackgroundThe optimal medical treatment strategy after transcatheter aortic valve replacement (TAVR) has not been established, and might be affected by the extent of extravalvular cardiac damage. We aimed to investigate the prognostic association of renin-angiotensin system (RAS) inhibitors in TAVR patients stratified according to the extent of extravalvular cardiac damage. MethodsIn a prospective TAVR registry, patients were retrospectively evaluated for baseline cardiac damage and classified into 5 stages of cardiac damage (0-4) according to established criteria. Clinical outcomes at 1 year were compared according to RAS inhibitor prescription at discharge. ResultsAmong 2247 eligible patients who underwent TAVR between August 2007 and June 2021, 1634 (72.7%) were prescribed RAS inhibitors at discharge. Eighty-three patients (3.7%) were classified as stage 0, 276 (12.3%) as stage 1, 889 (39.6%) as stage 2, 489 (21.8%) as stage 3, and 510 (22.7%) as stage 4. RAS inhibitor prescription after TAVR was associated with a reduced risk of 1-year mortality (adjusted hazard ratio [HRadjusted], 0.59; 95% confidence interval [CI], 0.45-0.77). The protective association was accentuated among patients with cardiac stages 3 and 4 (HRadjusted, 0.54 [95% CI, 0.32-0.92]; and HRadjusted, 0.58 [95% CI, 0.36-0.92], respectively), but not statistically significant in for those with stage 2 (HRadjusted, 0.70; 95% CI, 0.43-1.14). ConclusionsIn patients who underwent TAVR, we found a strong association of RAS inhibitor prescription and improved clinical outcome in the overall population, and there were no signs of heterogeneity across stages of cardiac damage. Clinical Trial RegistrationNCT01368250.

Role of renin angiotensin system inhibitors and metformin in Glioblastoma Therapy: a review.

Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.

The co-occurrence of sarcoidosis and anti-PLA2R-associated membranous nephropathy in a patient with underlying genetic susceptibility

BackgroundSarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with sarcoidosis is rare and membranous nephropathy (MN) is cited as the most common. The association between the two diseases remained unclear. This article reported a case of co-occurrence of sarcoidosis and anti-PLA2R-associated MN, to provide a possible relationship between these two entities.Case presentationA 61-year-old Chinese Han woman with a history of sarcoidosis was admitted to our hospital for nephrotic syndrome. Her sarcoidosis was diagnosed according to the adenopathy observed on the computed tomography scan and the biopsy of lymph nodes. The MN presented with nephrotic syndrome with a PLA2R antibody titer of 357RU/ml, and the final diagnosis was based on a renal biopsy. The patient’s sarcoidosis was remitted after treatment with prednisone. One year later MN was diagnosed, and she was treated with prednisone combined with calcineurin inhibitors, based on a full dose of renin-angiotensin system (RAS) inhibitor. The patient’s sarcoidosis had been in remission while the MN was recurrent, and her renal function deteriorated to end-stage renal disease 6 years later due to discontinuation of immunosuppression. A genetic test led to the identification of the HLA-DRB1*0301 and HLA-DRB1*150 genes associated with both sarcoidosis and MN, which provides a new possible explanation of the co-occurrence of these two diseases.ConclusionThis case suggested for the first time a potential genetic connection between idiopathic MN and sarcoidosis which needs further studies in the future.

The potential impact of renin-angiotensin system inhibitors on cancer survival and recurrence: A systemic review and meta-analysis.

Renin-angiotensin-system inhibitors (RASi), specifically angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), are widely used anti-hypertensives. Their impact on the prognostic outcomes among cancer patients has been subject to scrutiny and debate. The aim of this study is to evaluate the effect of RASi on survival in cancer patients. We systematically searched PubMed, Web of Science, Embase and Cochrane Library for relevant studies published until April 1st, 2022. All the studies, interventional or observational, which examined effects of ARBs and ACEi on cancer prognosis compared to a control group and reported the survival outcomes and Hazards Ratios were included in the analysis. From each study, pooled hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) were identified and collected. Subgroup analysis was conducted to investigate heterogeneity. Sixty-one studies were included in this meta-analysis. Data of 343,283 participants were used in the study. It was found that RASi improved overall survival (OS) (HR=0.88; 95% CI: 0.82-0.93; P<0.0001), progression free survival (PFS) (HR=0.72; 95% CI: 0.65-0.79; P<0.00001), disease specific survival (DSS) (HR=0.86; 95% CI: 0.71-1.04; P=0.03), and recurrence free survival (RFS) (HR=0.74; 95% CI: 0.58-0.93; P=0.01) in cancer patients. The effect of RASi on OS varied depending on the type of cancer or type of RASi (ACEi or ARBs), according to subgroup analysis. The usage of RAS inhibitors has a positive impact on survival outcomes and recurrence among cancer patients.

Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer

IntroductionThe renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)—namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)—with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). Patients and MethodsWe retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. ResultsOverall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. ConclusionACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.

The Association of Withdrawing Maintenance Renin-Angiotensin System Inhibitor on All-Cause Mortality and Intensive Care Unit Admission Among Hypertensive Patients Admitted for Mild to Moderate COVID-19 infection:A Meta-analysis of Observational Studies

INTRODUCTION: The pandemic caused by coronavirus disease 2019 (COVID-19) posed a serious challenge to all health care systems in the world. It has been found to be harmful in people with underlying cardiovascular diseases, particularly in patients with systemic hypertension, which may be due to upregulation of angiotensin-converting enzyme 2 (ACE2) expression, which may lead to increased severe acute respiratory syndrome coronavirus 2 virulence. Renin-angiotensin system inhibitor (RASI) acts by blocking the angiotensin-converting enzyme and angiotensin II type 1 receptors, which in turn affects the production of the ACE2 protein. Hence, there have been arguments on whether to continue or discontinue this medication. Given the widespread use of RASIs globally and the fact that they are generally cardioprotective, research into the safety of continuing these maintenance medications in patients hospitalized with mild to moderate COVID-19 is immensely needed. METHODS: This meta-analysis involved review of observational studies among hypertensive patients on maintenance ACE inhibitor or angiotensin-receptor blocker with confirmed mild to moderate COVID-19 infection. Analyses were performed to determine the adjusted hazard ratio of each event using the raw data obtained from each study. Random-effects model and Cochran-Mantel-Haenszel method were utilized at 95% confidence interval. To check for heterogeneity, χ2 test and I2 statistic were calculated. Cochrane ReviewManager (RevMan version 5.3) was used for data analysis, and forest plots were generated. RESULTS: At 95% confidence interval, the adjusted hazard ratios for all-cause mortality and intensive care unit (ICU) admission at 95% confidence interval were 1.64 (1.22, 2.21) and 1.93 (1.34, 2.79), respectively. The tests of overall estimate effect for both outcomes were P &lt; 0.0001 for all-cause mortality and P = 0.0003 for ICU admission. CONCLUSION: Discontinuation of maintenance RASI during hospitalization is associated with increased all-cause mortality and ICU admission among hypertensive patients with mild to moderate COVID-19 infection. KEYWORDS: angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, coronavirus, COVID-19, renin-angiotensin system inhibitor

Association between Acute Declines in eGFR during Renin-Angiotensin System Inhibition and Risk of Adverse Outcomes.

Declines in glomerular filtration rate (GFR) occur commonly when renin-angiotensin system (RAS) inhibitors are started. Our objective was to determine the relation between declines in estimated GFR during trials of RAS inhibition and kidney outcomes. We included participants with CKD (estimated GFR<60 mL/min/1.73m2) from 16 trials of RAS inhibition. The exposure was subacute declines in estimated GFR expressed as % change between randomization and month 3, and in the subset of trials with data available, we also examined % change in eGFR between randomization and month 1. The primary outcome was kidney failure with replacement therapy. Cox proportional hazards models were used to examine the association between subacute declines in eGFR and risk of kidney failure. We used spline models to identify the threshold of change in eGFR below which RAS inhibition was favorable (conservatively comparing a given decline in eGFR with RAS inhibition to no decline in the comparator). 11,800 individuals with mean eGFR 43 (SD 11) mL/min/1.73m2 and median urine albumin/creatinine ratio of 362 mg/g (IQR 50, 1367) were included, and 1,162 (10%) developed kidney failure. The threshold of decline in eGFR that favored use of RAS inhibitors for kidney failure was estimated to be up to 13% (95%CI 8%, 17%) over a 3-month interval and up to 21% (95%CI 15%, 27%) over a 1-month interval after starting RAS inhibitors. In people treated with RAS inhibitors, ≤ 13% decline in eGFR over a 3-month period or ≤21% decline over a 1-month period was associated with lower risk of kidney failure compared with no decline with the use of placebo or other agents.

Estimated Effect of Restarting Renin-Angiotensin System Inhibitors after Discontinuation on Kidney Outcomes and Mortality.

While renin-angiotensin system inhibitors (RASi) have been the mainstream treatment for patients with CKD, they are often discontinued due to adverse effects such as hyperkalemia and acute kidney injury. It is unknown whether restarting RASi after discontinuation improves clinical outcomes. Using the OCKR (Osaka Consortium for Kidney disease Research) database, we performed a target trial emulation study including 6,065 patients with an eGFR of 10-60 mL/min/1.73m2 who were followed up by nephrologists and discontinued RASi between 2005 and 2021. With a clone-censor-weight approach, we compared a treatment strategy for restarting RASi within a year after discontinuation with that for not restarting RASi. Patients were followed up for five years at maximum after RASi discontinuation. The primary outcome was a composite kidney outcome (initiation of kidney replacement therapy, a ≥50% decline in eGFR, or kidney failure [eGFR <5 mL/min/1.73m2]). Secondary outcomes were all-cause death and incidence of hyperkalemia (serum potassium levels ≥5.5 mEq/L). Among those who discontinued RASi (mean [standard deviation (SD)] age 66 [15] years, 62% male, mean [SD] eGFR 40 [26] ml/min/1.73m2), 2,262 (37%) restarted RASi within a year. Restarting RASi was associated with a lower hazard of the composite kidney outcome (hazard ratio 0.85 [95% confidence intervals (CIs) 0.78 to 0.93]) and all-cause death (hazard ratio 0.70 [95% CI 0.61 to 0.80]) compared with not restarting RASi. The incidence of hyperkalemia did not differ significantly between the two strategies (hazard ratio 1.11 [95% CI 0.96 to 1.27]). Restarting RASi after discontinuation was associated with a lower risk of kidney outcomes and mortality but not related to the incidence of hyperkalemia.

Dapagliflozin treatment in patients with chronic kidney disease associated with autosomal dominant polycystic kidney disease.

The DAPA-CKD study showed a protective effect of dapagliflozin on kidney function in chronic kidney disease (CKD) patients with and without diabetes mellitus. Although dapagliflozin is expected to be effective also in CKD patients with autosomal dominant polycystic kidney disease (ADPKD), its efficacy and safety in this population remain unknown because ADPKD was an exclusion criterion in the DAPA-CKD study. Therefore, we evaluated the effects of dapagliflozin in CKD patients with ADPKD. We performed a retrospective observational study of seven patients with ADPKD treated with dapagliflozin at Toranomon Hospital, Tokyo, Japan. We analyzed changes in estimated glomerular filtration rate (eGFR) slope and annual height-corrected total kidney volume before and after starting dapagliflozin treatment. The median observation period after starting dapagliflozin was 20 months. Four patients received concomitant tolvaptan. The eGFR slope before and after initiation of dapagliflozin could be calculated in six patients and improved in all of them except the one who did not receive a renin-angiotensin system (RAS) inhibitor. Annual height-corrected total kidney volume increased in all patients. Concurrent tolvaptan treatment had no effect. In CKD patients with ADPKD, dapagliflozin may increase kidney volume but may have a protective effect on kidney function when used concomitantly with RAS inhibitors.